Control of axonal sprouting and dendrite branching by the Nrg-Ank complex at the neuron-glia interface.

PubMed

Yamamoto, Misato; Ueda, Ryu; Takahashi, Kuniaki; Saigo, Kaoru; Uemura, Tadashi

2006-08-22

Neurons are highly polarized cells with distinct subcellular compartments, including dendritic arbors and an axon. The proper function of the nervous system relies not only on correct targeting of axons, but also on development of neuronal-class-specific geometry of dendritic arbors [1-4]. To study the intercellular control of the shaping of dendritic trees in vivo, we searched for cell-surface proteins expressed by Drosophila dendritic arborization (da) neurons [5-7]. One of them was Neuroglian (Nrg), a member of the Ig superfamily ; Nrg and vertebrate L1-family molecules have been implicated in various aspects of neuronal wiring, such as axon guidance, axonal myelination, and synapse formation [9-12]. A subset of the da neurons in nrg mutant embryos exhibited deformed dendritic arbors and abnormal axonal sprouting. Our functional analysis in a cell-type-selective manner strongly suggested that those da neurons employed Nrg to interact with the peripheral glia for suppressing axonal sprouting and for forming second-order dendritic branches. At least for the former role, Nrg functioned in concert with the intracellular adaptor protein Ankyrin (Ank) [13]. Thus, the neuron-glia interaction that is mediated by Nrg, together with Ank under some situations, contributes to axonal and dendritic morphogenesis.

Presynaptic Type III Neuregulin1-ErbB signaling targets α7 nicotinic acetylcholine receptors to axons

PubMed Central

Hancock, Melissa L.; Canetta, Sarah E.; Role, Lorna W.; Talmage, David A.

2008-01-01

Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of α7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface α7 nAChRs, which results from a redistribution of preexisting intracellular pools of α7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting α7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function. PMID:18458158

Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons.

PubMed

Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

2008-05-05

Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

Presynaptic type III neuregulin1-ErbB signaling targets alpha7 nicotinic acetylcholine receptors to axons.

PubMed

Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

2008-06-01

Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

Stimulation of cardiomyocyte regeneration in neonatal mice and in human myocardium with neuregulin reveals a therapeutic window

PubMed Central

Polizzotti, Brian D.; Ganapathy, Balakrishnan; Walsh, Stuart; Choudhury, Sangita; Ammanamanchi, Niyatie; Bennett, David G.; dos Remedios, Cristobal G.; Haubner, Bernhard J.; Penninger, Josef M.; Kuhn, Bernhard

2015-01-01

Background Pediatric patients with heart failure are treated with medical therapies that were developed for adult patients. These therapies have been shown to be ineffective in pediatric trials, leading to the recognition that new pediatric-specific therapies must be developed. We have previously shown that administration of the recombinant growth factor neuregulin-1 (rNRG1) stimulates heart muscle cell (cardiomyocyte) regeneration in adult mice. We hypothesized that rNRG1 administration may be more effective in the neonatal period, which could provide a new therapeutic paradigm for treating heart failure in pediatric patients. Methods We used a cryoinjury model to induce myocardial dysfunction and scar formation for evaluating the effectiveness of rNRG1-administration in neonatal mice. We evaluated the ability of rNRG1 to stimulate cardiomyocyte proliferation in intact cultured myocardium from pediatric patients. Results After cryoinjury in neonatal mice, early administration of rNRG1 from birth for 34 days improved myocardial function and reduced the prevalence of transmural scars. In contrast, late administration of rNRG1 from 4 to 34 days after cryoinjury transiently improved myocardial function. The mechanisms of early administration involved cardiomyocyte protection (38%) and proliferation (62%). rNRG1 induced cardiomyocyte proliferation in myocardium from infants with heart disease less than 6 months of age. Conclusion Our results identify a more effective time period within which to execute future clinical trials of rNRG1 for stimulating cardiomyocyte regeneration. PMID:25834111

Amygdala NRG1–ErbB4 Is Critical for the Modulation of Anxiety-Like Behaviors

PubMed Central

Bi, Lin-Lin; Sun, Xiang-Dong; Zhang, Jie; Lu, Yi-Sheng; Chen, Yi-Hua; Wang, Jue; Geng, Fei; Liu, Fang; Zhang, Meng; Liu, Ji-Hong; Li, Xiao-Wen; Mei, Lin; Gao, Tian-Ming

2015-01-01

Anxiety disorder is related to the pathophysiology of psychiatric diseases, including major depression, substance abuse, and schizophrenia. The amygdala is important for manifestation and modulation of anxiety. However, relatively little is known regarding the mechanisms that control the amygdala inhibitory activity that is involved in anxiety. We found that almost all ErbB4, which is the only autonomous receptor of neuregulin 1 (NRG1) in the basolateral amygdala (BLA), was expressed in GABAergic neurons. Endogenous NRG1–ErbB4 signaling pathway in the BLA could modulate anxiety-like behaviors and GABA release, whereas it had no effect on glutamatergic transmission. The administration of NRG1 into the BLA of high-anxiety mice alleviated their anxiety and enhanced GABAergic neurotransmission. Moreover, exogenous NRG1 also produced an anxiolytic effect in the stressed mice. Together, these observations indicated that NRG1–ErbB4 signaling is critical to maintaining GABAergic activity in the amygdala and thus to modulating anxiety-like behaviors. Because NRG1 and ErbB4 are susceptibility genes of schizophrenia, our findings might also help to explain the potential mechanism of emotional abnormality in schizophrenia. PMID:25308353

Neuregulin 1 Deficiency Modulates Adolescent Stress-Induced Dendritic Spine Loss in a Brain Region-Specific Manner and Increases Complement 4 Expression in the Hippocampus.

PubMed

Clarke, David J; Chohan, Tariq W; Kassem, Mustafa S; Smith, Kristie L; Chesworth, Rose; Karl, Tim; Kuligowski, Michael P; Fok, Sandra Y; Bennett, Maxwell R; Arnold, Jonathon C

2018-03-16

One neuropathological feature of schizophrenia is a diminished number of dendritic spines in the prefrontal cortex and hippocampus. The neuregulin 1 (Nrg1) system is involved in the plasticity of dendritic spines, and chronic stress decreases dendritic spine densities in the prefrontal cortex and hippocampus. Here, we aimed to assess whether Nrg1 deficiency confers vulnerability to the effects of adolescent stress on dendritic spine plasticity. We also assessed other schizophrenia-relevant neurobiological changes such as microglial cell activation, loss of parvalbumin (PV) interneurons, and induction of complement factor 4 (C4). Adolescent male wild-type (WT) and Nrg1 heterozygous mice were subjected to chronic restraint stress before their brains underwent Golgi impregnation or immunofluorescent staining of PV interneurons, microglial cells, and C4. Stress in WT mice promoted dendritic spine loss and microglial cell activation in the prefrontal cortex and the hippocampus. However, Nrg1 deficiency rendered mice resilient to stress-induced dendritic spine loss in the infralimbic cortex and the CA3 region of the hippocampus without affecting stress-induced microglial cell activation in these brain regions. Nrg1 deficiency and adolescent stress combined to trigger increased dendritic spine densities in the prelimbic cortex. In the hippocampal CA1 region, Nrg1 deficiency accentuated stress-induced dendritic spine loss. Nrg1 deficiency increased C4 protein and decreased C4 mRNA expression in the hippocampus, and the number of PV interneurons in the basolateral amygdala. This study demonstrates that Nrg1 modulates the impact of stress on the adolescent brain in a region-specific manner. It also provides first evidence of a link between Nrg1 and C4 systems in the hippocampus.

Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation.

PubMed

Canetta, Sarah E; Luca, Edlira; Pertot, Elyse; Role, Lorna W; Talmage, David A

2011-01-01

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Type III Neuregulin-1 is required for normal sensorimotor gating, memory related behaviors and cortico-striatal circuit components

PubMed Central

Chen, Ying-Jiun J.; Johnson, Madeleine A.; Lieberman, Michael D.; Goodchild, Rose E.; Schobel, Scott; Lewandowski, Nicole; Rosoklija, Gorazd; Liu, Ruei-Che; Gingrich, Jay A.; Small, Scott; Moore, Holly; Dwork, Andrew J.; Talmage, David A.; Role, Lorna W.

2008-01-01

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we have studied the regulation of Type III Nrg1 expression and evaluated the effect of decreased expression of the Type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus and ventral subiculum, regions involved in the regulation of sensorimotor gating and short term memory. Adult heterozygous mutant mice with a targeted disruption for Type III Nrg1 (Nrg1tm1.1Lwr+/-) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. MRI imaging of Type III Nrg1 heterozygous mice revealed hypo-function in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between Type III Nrg1 heterozygous mice and their wild type littermates. Our findings demonstrate a role of Type III Nrg1-signaling in the maintenance of cortico-striatal components, and in the neural circuits involved in sensorimotor gating and short term memory. PMID:18596162

Type I neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice

PubMed Central

Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin-ichi; Semba, Kentaro; Goda, Nobuhito

2017-01-01

Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade. PMID:28218289

Recreational use of 1-(2-naphthyl)-2-(1-pyrrolidinyl)-1-pentanone hydrochloride (NRG-1), 6-(2-aminopropyl) benzofuran (benzofury/ 6-APB) and NRG-2 with review of available evidence-based literature.

PubMed

Jebadurai, Jeshoor; Schifano, Fabrizio; Deluca, Paolo

2013-07-01

This study aimed to review the available evidence-based literature on novel psychoactive substances and to inform health care professionals. Internet searches were carried out using Google and Yahoo by using specific key words. For each set of key words, the first 100 websites identified by Google and Yahoo were fully assessed, together with a further 5% of random samples selected by research randomizer of the remaining websites. Thus, a list of unique web forums was identified, and qualitative information was extracted. Available evidence-based literature were reviewed along with a user's experimentation with mephedrone, NRG-1, NRG-2 and Benzofury. It showed that when a substance (mephedrone) became controlled, the vendors aggressively promote the sale of other new compounds (NRG-1, NRG-2, Benzofury) to attract vulnerable adults. The characteristics, toxicity and suggested management of these new compounds (NRG-1, NRG-2, Benzofury) are discussed. The arrival of hundreds of novel psychoactive substances for sale online has raised a number of public health and legal issues. Although evidence-based literature remains limited, few studies identified that most products do not contain the ingredients as advertised. Better levels of international cooperation and rapid share of available information may be needed to tackle this emerging problem. Copyright © 2013 John Wiley & Sons, Ltd.

Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model

PubMed Central

Papaleo, Francesco; Yang, Feng; Paterson, Clare; Palumbo, Sara; Carr, Gregory V.; Wang, Yanhong; Floyd, Kirsten; Huang, Wenwei; Thomas, Craig J.; Chen, Jingshan; Weinberger, Daniel R.

2016-01-01

Schizophrenia is a chronic, disabling neuropsychiatric disorder with complex genetic origins. The development of strategies for genome manipulation in rodents provides a platform for understanding the pathogenic role of genes and for testing novel therapeutic agents. Neuregulin 1 (NRG1), a critical developmental neurotrophin, is associated with schizophrenia. The NRG1 gene undergoes extensive alternative splicing and, to date, little is known about the neurobiology of a novel NRG1 isoform, NRG1-IV, which is increased in the brains of individuals with schizophrenia and associated with genetic risk variation. Here, we developed a transgenic mouse model (NRG1-IV/NSE-tTA) in which human NRG1-IV is selectively overexpressed in a neuronal specific manner. Using a combination of molecular, biochemical, electrophysiological, and behavioral analyses, we demonstrate that NRG1-IV/NSE-tTA mice exhibit abnormal behaviors relevant to schizophrenia, including impaired sensorimotor gating, discrimination memory, and social behaviors. These neurobehavioral phenotypes are accompanied by increases in cortical expression of the NRG1 receptor, ErbB4 and the downstream signaling target, PIK3-p110δ, along with disrupted dendritic development, synaptic pathology, and altered prefrontal cortical excitatory–inhibitory balance. Pharmacological inhibition of p110δ reversed sensorimotor gating and cognitive deficits. These data demonstrate a novel role for NRG1-IV in learning, memory, and neural circuit formation and a potential neurobiological mechanism for schizophrenia risk; show that deficits are pharmacologically reversible in adulthood; and further highlight p110δ as a target for antipsychotic drug development. SIGNIFICANCE STATEMENT Schizophrenia is a disabling psychiatric disorder with neurodevelopmental origins. Genes that increase risk for schizophrenia have been identified. Understanding how these genes affect brain development and function is necessary. This work is the first report of a newly generated humanized transgenic mouse model engineered to express human NRG1-IV, an isoform of the NRG1 (Neuregulin 1) gene that is increased in the brains of patients with schizophrenia in association with genetic risk. Using behavioral neuroscience, molecular biology, electrophysiology, and pharmacology, we identify a role for NRG1-IV in learning, memory, and cognition and determine that this relates to brain excitatory–inhibitory balance and changes in ErbB4/PI3K/AKT signaling. Moreover, the study further highlights the potential of targeting the PI3K pathway for the treatment of schizophrenia. PMID:27122041

Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders.

PubMed

Paterson, Clare; Wang, Yanhong; Hyde, Thomas M; Weinberger, Daniel R; Kleinman, Joel E; Law, Amanda J

2017-03-01

Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I-IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. NRG3 isoform classes I-IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development.

Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

PubMed Central

Paterson, Clare; Wang, Yanhong; Hyde, Thomas M.; Weinberger, Daniel R.; Kleinman, Joel E.; Law, Amanda J.

2018-01-01

Objective Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I–IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. Method NRG3 isoform classes I–IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. Results NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Conclusions Mapping the temporal expression of genes during human brain development provides vital insight into gene function and identifies critical sensitive periods whereby genetic factors may influence risk for psychiatric disease. Here the authors provide comprehensive insight into the transcriptional landscape of the psychiatric risk gene, NRG3, in human neocortical development and expand on previous findings in schizophrenia to identify increased expression of developmentally and genetically regulated isoforms in the brain of patients with mood disorders. Principally, the finding that NRG3 classes II and III are brain-specific isoforms predicted by rs10748842 risk genotype and are increased in mood disorders further implicates a molecular mechanism of psychiatric risk at the NRG3 locus and identifies a potential developmental role for NRG3 in bipolar disorder and major depression. These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development. PMID:27771971

Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons

PubMed Central

Chen, Yachi; Hancock, Melissa L.; Role, Lorna W.; Talmage, David A.

2010-01-01

Neuregulin 1 (NRG1) signaling is critical to various aspects of neuronal development and function. Among different NRG1 isoforms, the Type III isoforms of NRG1 are unique in their ability to signal via the intracellular domain following γ-secretase-dependent intramembranous processing. However, the functional consequences of Type III NRG1 signaling via its intracellular domain are largely unknown. In this study, we have identified mutations within Type III NRG1 that disrupt intramembranous proteolytic processing and abolish intracellular domain signaling. In particular, substitutions at valine 321, previously linked to schizophrenia risks, result in NRG1 proteins that fail to undergo γ-secretase-mediated nuclear localization and transcriptional activation. Using processing-defective mutants of Type III NRG1, we demonstrate that the intracellular domain signaling is specifically required for NRG1 regulation of the growth and branching of cortical dendrites but not axons. Consistent with the role of Type III NRG1 signaling via the intracellular domain in the initial patterning of cortical dendrites, our findings from pharmacological and genetic studies indicate that Type III NRG1 functions in dendritic development independent of ERBB kinase activity. Taken together, these results support the proposal that aberrant intracellular processing and defective signaling via the intracellular domain of Type III NRG1 impair a subset of NRG1 functions in cortical development and contribute to abnormal neuroconnectivity implicated in schizophrenia. PMID:20610754

Endocannabinoid dysregulation in cognitive and stress-related brain regions in the Nrg1 mouse model of schizophrenia.

PubMed

Clarke, David J; Stuart, Jordyn; McGregor, Iain S; Arnold, Jonathon C

2017-01-04

The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 (Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations. Nrg1 application to hippocampal slices decreased 2-arachidonoylglycerol (2-AG) signalling and disrupted long-term depression, a form of synaptic plasticity critical to spatial learning. Therefore we specifically aimed to examine whether Nrg1 HET mice exhibit increased 2-AG concentrations and disruption of spatial learning. As chronic stress influences brain endocannabinoids, we also sought to examine whether Nrg1 deficiency moderates adolescent stress-induced alterations in brain endocannabinoids. Adolescent Nrg1 HET and wild-type (WT) mice were submitted to chronic restraint stress and brain endocannabinoid concentrations were analysed. A separate cohort of WT and Nrg1 HET mice was also assessed for spatial learning performance in the Morris Water Maze. Partial genetic deletion of Nrg1 increased anandamide concentrations in the amygdala and decreased 2-AG concentrations in the hypothalamus. Further, Nrg1 HET mice exhibited increased 2-AG concentrations in the hippocampus and impaired spatial learning performance. Chronic adolescent stress increased anandamide concentrations in the amygdala, however, Nrg1 disruption did not influence this stress-induced change. These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain. Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippocampus to impair cognition, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry. Copyright © 2016 Elsevier Inc. All rights reserved.

Glutamate-dependent ectodomain shedding of neuregulin-1 type II precursors in rat forebrain neurons.

PubMed

Iwakura, Yuriko; Wang, Ran; Inamura, Naoko; Araki, Kazuaki; Higashiyama, Shigeki; Takei, Nobuyuki; Nawa, Hiroyuki

2017-01-01

The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells. However, the molecular mechanisms that govern this process in the nervous system are not defined in detail. Here we prepared neuron-enriched and glia-enriched cultures from embryonic rat neocortex to investigate the role of neurotransmitters that regulate the liberation/release of NRG1 from the membrane of neurons or glial cells. Using a two-site enzyme immunoassay to detect soluble NRG1, we show that, of various neurotransmitters, glutamate was the most potent inducer of NRG1 release in neuron-enriched cultures. NRG1 release in glia-enriched cultures was relatively limited. Furthermore, among glutamate receptor agonists, N-Methyl-D-Aspartate (NMDA) and kainate (KA), but not AMPA or tACPD, mimicked the effects of glutamate. Similar findings were acquired from analysis of the hippocampus of rats with KA-induced seizures. To evaluate the contribution of members of a disintegrin and metalloproteinase (ADAM) families to NRG1 release, we transfected primary cultures of neurons with cDNA vectors encoding NRG1 types I, II, or III precursors, each tagged with the alkaline phosphatase reporter. Analysis of alkaline phosphatase activity revealed that the NRG1 type II precursor was subjected to tumor necrosis factor-α-converting enzyme (TACE) / a Disintegrin And Metalloproteinase 17 (ADAM17) -dependent ectodomain shedding in a protein kinase C-dependent manner. These results suggest that glutamatergic neurotransmission positively regulates the ectodomain shedding of NRG1 type II precursors and liberates the active NRG1 domain in an activity-dependent manner.

Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei

2012-07-15

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylflurophosphate (DFP). Adult male Sprague–Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatmentmore » with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. -- Highlights: ► NRG-1 blocked DFP induced neuronal injury. ► NRG-1 did not protect against seizures in rats exposed to DFP. ► NRG-1 blocked apoptosis and oxidative stress in the brains of DFP-intoxicated rats. ► Administration of NRG-1 at 1 h after DFP injection prevented delayed neuronal injury.« less

AB053. NRG1 rare variant effects in Hirschsprung disease patients

PubMed Central

Gunadi; Budi, Nova; Iskandar, Kristy; Adrianto, Indra

2017-01-01

Background Hirschsprung disease (HSCR) is a heterogeneous genetic disorder characterized by absence of ganglion cells along intestines resulting in functional bowel obstruction. NRG1 gene has been implicated in the intestinal ganglionosis. This study aimed to investigate the contribution of NRG1 gene into the HSCR development in Indonesian population. Methods We performed Sanger sequencing to find NRG1 variants in 54 HSCR patients. Results All patients were sporadic non-syndromic HSCR with 53/54 (98%) and 1/54 (2%) were short-segment and long-segment patients, respectively. NRG1 analysis showed one rare variant, c.397G > C (p.V133L), and three common variants, rs7834206, rs3735774, and rs75155858. The p.V133L was predicted to reside within in a region of high mammalian conservation, overlap with the promoter and enhancer histone marks of relevant tissues such as digestive and smooth muscle tissues and alter AP-4_2, BDP1_disc3, Egr-1_known1, Egr-1_known4, HEN1_2 transcription factor binding motifs. Furthermore, this variant was absent in 92 controls. Conclusions This study is the first report of NRG1 rare variant associated with HSCR patients in South-East Asian ancestry and adds insights into the NRG1 effect in the molecular pathogenesis of HSCR.

Interleukin-6 and neuregulin-1 as regulators of utrophin expression via the activation of NRG-1/ErbB signaling pathway in mdx cells.

PubMed

Juretić, Nevenka; Díaz, Josefina; Romero, Felipe; González, Gustavo; Jaimovich, Enrique; Riveros, Nora

2017-03-01

Duchenne muscular dystrophy (DMD) is a neuromuscular disease originated by mutations in the dystrophin gene. A promising therapeutic approach deals with functional substitution of dystrophin by utrophin, a structural homolog that might be able to compensate dystrophin absence in DMD muscle fibers. It has been described that both interleukin-6 (IL-6) and neuregulin-1 (NRG-1; Heregulin-HRG) induce utrophin expression in skeletal muscle. We investigated a possible functional link among IL-6, NRG-1 and utrophin, in normal (C57) and dystrophic (mdx) skeletal muscle cells. Western Blot analysis allowed us to demonstrate that IL-6 (100ng/mL) induces NRG-1 receptor phosphorylation (ErbB2/ErbB3) in both cell types, in a process that depends on intracellular Ca 2+ and metalloproteinase activity; it also induces a transient increase of ERK1 and GABPα phosphorylation only in dystrophic myotubes. Semiquantitative PCR showed that IL-6 treatment increases utrophin mRNA levels just in mdx myotubes. We observed that utrophin mRNA induction was abolished by BAPTA-AM (an intracellular Ca 2+ chelator), GM6001 (a general metalloproteinase inhibitor), genistein (a general protein tyrosine kinase inhibitor), PD-158780 (an ErbB receptor tyrosine kinase inhibitor) and PD-98059 (a MEK inhibitor), whereas Ly-294002 and wortmannin (PI3K inhibitors) did not affect utrophin induction evoked by IL-6 in dystrophic myotubes. Our results suggest that IL-6 induces utrophin expression in mdx myotubes through activation of a NRG-1/ErbBs signaling cascade. Soluble NRG-1 elicited by proteolytic processing of transmembrane NRG-1 might induce ErbBs phosphorylation and ERK1/2 pathway activation, leading to utrophin up-regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

PubMed

Agarwal, Amit; Zhang, Mingyue; Trembak-Duff, Irina; Unterbarnscheidt, Tilmann; Radyushkin, Konstantin; Dibaj, Payam; Martins de Souza, Daniel; Boretius, Susann; Brzózka, Magdalena M; Steffens, Heinz; Berning, Sebastian; Teng, Zenghui; Gummert, Maike N; Tantra, Martesa; Guest, Peter C; Willig, Katrin I; Frahm, Jens; Hell, Stefan W; Bahn, Sabine; Rossner, Moritz J; Nave, Klaus-Armin; Ehrenreich, Hannelore; Zhang, Weiqi; Schwab, Markus H

2014-08-21

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Partial Genetic Deletion of Neuregulin 1 Modulates the Effects of Stress on Sensorimotor Gating, Dendritic Morphology, and HPA Axis Activity in Adolescent Mice

PubMed Central

Chohan, Tariq W.; Boucher, Aurelie A.; Spencer, Jarrah R.; Kassem, Mustafa S.; Hamdi, Areeg A.; Karl, Tim; Fok, Sandra Y.; Bennett, Maxwell R.; Arnold, Jonathon C.

2014-01-01

Stress has been linked to the pathogenesis of schizophrenia. Genetic variation in neuregulin 1 (NRG1) increases the risk of developing schizophrenia and may help predict which high-risk individuals will transition to psychosis. NRG1 also modulates sensorimotor gating, a schizophrenia endophenotype. We used an animal model to demonstrate that partial genetic deletion of Nrg1 interacts with stress to promote neurobehavioral deficits of relevance to schizophrenia. Nrg1 heterozygous (HET) mice displayed greater acute stress-induced anxiety-related behavior than wild-type (WT) mice. Repeated stress in adolescence disrupted the normal development of higher prepulse inhibition of startle selectively in Nrg1 HET mice but not in WT mice. Further, repeated stress increased dendritic spine density in pyramidal neurons of the medial prefrontal cortex (mPFC) selectively in Nrg1 HET mice. Partial genetic deletion of Nrg1 also modulated the adaptive response of the hypothalamic-pituitary-adrenal axis to repeated stress, with Nrg1 HET displaying a reduced repeated stress-induced level of plasma corticosterone than WT mice. Our results demonstrate that Nrg1 confers vulnerability to repeated stress-induced sensorimotor gating deficits, dendritic spine growth in the mPFC, and an abberant endocrine response in adolescence. PMID:24442851

Rapid transient isoform-specific neuregulin1 transcription in motor neurons is regulated by neurotrophic factors and axon-target interactions.

PubMed

Wang, Jiajing; Hmadcha, Abdelkrim; Zakarian, Vaagn; Song, Fei; Loeb, Jeffrey A

2015-09-01

The neuregulins (NRGs) are a family of alternatively spliced factors that play important roles in nervous system development and disease. In motor neurons, NRG1 expression is regulated by activity and neurotrophic factors, however, little is known about what controls isoform-specific transcription. Here we show that NRG1 expression in the chick embryo increases in motor neurons that have extended their axons and that limb bud ablation before motor axon outgrowth prevents this induction, suggesting a trophic role from the developing limb. Consistently, NRG1 induction after limb bud ablation can be rescued by adding back the neurotrophic factors BDNF and GDNF. Mechanistically, BDNF induces a rapid and transient increase in type I and type III NRG1 mRNAs that peak at 4h in rat embryonic ventral spinal cord cultures. Blocking MAPK or PI3K signaling or blocking transcription with Actinomycin D blocks BDNF induced NRG1 gene induction. BDNF had no effect on mRNA degradation, suggesting that transcriptional activation rather than message stability is important. Furthermore, BDNF activates a reporter construct that includes 700bp upstream of the type I NRG1 start site. Protein synthesis is also required for type I NRG1 mRNA transcription as cycloheximide produced a super-induction of type I, but not type III NRG1 mRNA, possibly through a mechanism involving sustained activation of MAPK and PI3K. These results reveal the existence of highly responsive, transient transcriptional regulatory mechanisms that differentially modulate NRG1 isoform expression as a function of extracellular and intracellular signaling cascades and mediated by neurotrophic factors and axon-target interactions. Copyright © 2015 Elsevier Inc. All rights reserved.

The interaction of disrupted Type II Neuregulin 1 and chronic adolescent stress on adult anxiety and fear related behaviors

PubMed Central

Taylor, Sara B; Taylor, Adam R; Koenig, James I

2012-01-01

The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. Previously, we established that Type II NRG1 is expressed in the hypothalamic-pituitary-adrenal (HPA) axis neurocircuitry. We also found, using a line of Nrg1 hypomorphic rats (Nrg1Tn), that genetic disruption of Type II NRG1 results in altered HPA axis function and environmental reactivity. The present studies used the Nrg1Tn rats to test whether Type II NRG1 gene disruption and chronic stress exposure during adolescence interact to alter adult anxiety- and fear-related behaviors. Male and female Nrg1Tn and wild type rats were exposed to chronic variable stress (CVS) during mid-adolescence and then tested for anxiety-like behavior, cued fear conditioning and basal corticosterone secretion in adulthood. The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated Nrg1Tn females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function. PMID:23022220

Decreased plasma neuregulin 4 concentration is associated with increased high-sensitivity C-reactive protein in newly diagnosed type 2 diabetes mellitus patients: a cross-sectional study.

PubMed

Yan, Pi-Jun; Xu, Yong; Wan, Qin; Feng, Jian; Li, Hua; Gao, Chen-Lin; Yang, Jun; Zhong, Hai-Hua; Zhang, Zhi-Hong

2017-12-01

Inflammation has been reported to be involved in the pathogenesis of atherosclerosis. This principal objective of this study was to investigate if the secretion of neuregulin 4 (Nrg4), a soluble protein associated with metabolic syndrome and subclinical cardiovascular disease, is correlated with the inflammation marker high-sensitivity C-reactive protein (hs-CRP) in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). A study group of 311 nT2DM patients was divided into three subgroups based on hs-CRP tertiles. Multiple linear regression was conducted to explore the association between plasma Nrg4 and hs-CRP levels. The nT2DM patients with the highest hs-CRP levels (>2.46 mg/L) exhibited higher atherogenic coefficients and atherogenic index of plasma (AIP) levels, but lower levels of plasma Nrg4, as compared to those with the lowest hs-CRP levels (<0.63 mg/L). Plasma Nrg4 levels were inversely associated with white blood cell count, hs-CRP, and AIP and positively associated with high-density lipoprotein cholesterol (HDL-C), before and after adjustment for age, gender, body mass index (BMI), and body fat percentage (P < 0.01 or P < 0.05). hs-CRP was the factor most strongly associated with plasma Nrg4 levels. These results indicate that lower plasma Nrg4 levels may be associated with elevated hs-CRP in nT2DM patients. It generates the hypothesis that decreased levels of Nrg4 may trigger the development of atherosclerosis through its proinflammatory effects. These findings need to be confirmed by further prospective studies.

Vibrational spectra of halide-water dimers: Insights on ion hydration from full-dimensional quantum calculations on many-body potential energy surfaces

NASA Astrophysics Data System (ADS)

Bajaj, Pushp; Wang, Xiao-Gang; Carrington, Tucker; Paesani, Francesco

2018-03-01

Full-dimensional vibrational spectra are calculated for both X-(H2O) and X-(D2O) dimers (X = F, Cl, Br, I) at the quantum-mechanical level. The calculations are carried out on two sets of recently developed potential energy functions (PEFs), namely, Thole-type model energy (TTM-nrg) and many-body energy (MB-nrg), using the symmetry-adapted Lanczos algorithm with a product basis set including all six vibrational coordinates. Although both TTM-nrg and MB-nrg PEFs are derived from coupled-cluster single double triple-F12 data obtained in the complete basis set limit, they differ in how many-body effects are represented at short range. Specifically, while both models describe long-range interactions through the combination of two-body dispersion and many-body classical electrostatics, the relatively simple Born-Mayer functions employed in the TTM-nrg PEFs to represent short-range interactions are replaced in the MB-nrg PEFs by permutationally invariant polynomials to achieve chemical accuracy. For all dimers, the MB-nrg vibrational spectra are in close agreement with the available experimental data, correctly reproducing anharmonic and nuclear quantum effects. In contrast, the vibrational frequencies calculated with the TTM-nrg PEFs exhibit significant deviations from the experimental values. The comparison between the TTM-nrg and MB-nrg results thus reinforces the notion that an accurate representation of both short-range interactions associated with electron density overlap and long-range many-body electrostatic interactions is necessary for a correct description of hydration phenomena at the molecular level.

RhNRG-1β Protects the Myocardium against Irradiation-Induced Damage via the ErbB2-ERK-SIRT1 Signaling Pathway

PubMed Central

Gu, Anxin; Jie, Yamin; Sun, Liang; Zhao, Shuping; E, Mingyan; You, Qingshan

2015-01-01

Radiation-induced heart disease (RIHD), which is a serious side effect of the radiotherapy applied for various tumors due to the inevitable irradiation of the heart, cannot be treated effectively using current clinical therapies. Here, we demonstrated that rhNRG-1β, an epidermal growth factor (EGF)-like protein, protects myocardium tissue against irradiation-induced damage and preserves cardiac function. rhNRG-1β effectively ameliorated irradiation-induced myocardial nuclear damage in both cultured adult rat-derived cardiomyocytes and rat myocardium tissue via NRG/ErbB2 signaling. By activating ErbB2, rhNRG-1β maintained mitochondrial integrity, ATP production, respiratory chain function and the Krebs cycle status in irradiated cardiomyocytes. Moreover, the protection of irradiated cardiomyocytes and myocardium tissue by rhNRG-1β was at least partly mediated by the activation of the ErbB2-ERK-SIRT1 signaling pathway. Long-term observations further showed that rhNRG-1β administered in the peri-irradiation period exerts continuous protective effects on cardiac pump function, the myocardial energy metabolism, cardiomyocyte volume and interstitial fibrosis in the rats receiving radiation via NRG/ErbB2 signaling. Our findings indicate that rhNRG-1β can protect the myocardium against irradiation-induced damage and preserve cardiac function via the ErbB2-ERK-SIRT1 signaling pathway. PMID:26332771

Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts.

PubMed

Kirabo, Annet; Ryzhov, Sergey; Gupte, Manisha; Sengsayadeth, Seng; Gumina, Richard J; Sawyer, Douglas B; Galindo, Cristi L

2017-04-01

Neuregulin-1β (NRG-1β) is critical for cardiac development and repair, and recombinant forms are currently being assessed as possible therapeutics for systolic heart failure. We previously demonstrated that recombinant NRG-1β reduces cardiac fibrosis in an animal model of cardiac remodeling and heart failure, suggesting that there may be direct effects on cardiac fibroblasts. Here we show that NRG-1β receptors (ErbB2, ErbB3, and ErbB4) are expressed in normal human cardiac ventricular (NHCV) fibroblast cell lines. Treatment of NHCV fibroblasts with recombinant NRG-1β induced activation of the AKT pathway, which was phosphoinositide 3-kinase (PI3K)-dependent. Moreover, the NRG-1β-induced PI3K/AKT signaling in these cells required phosphorylation of both ErbB2 and ErbB3 receptors at tyrosine (Tyr)1248 and Tyr1289 respectively. RNASeq analysis of NRG-1β-treated cardiac fibroblasts obtained from three different individuals revealed a global gene expression signature consistent with cell growth and survival. We confirmed enhanced cellular proliferation and viability in NHCV fibroblasts in response to NRG-1β, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. NRG-1β also induced production and secretion of cytokines (interleukin-1α and interferon-γ) and pro-reparative factors (angiopoietin-2, brain-derived neurotrophic factor, and crypto-1), suggesting a role in cardiac repair through the activation of paracrine signaling. Copyright © 2017 Elsevier Ltd. All rights reserved.

Specialized Information Processing Deficits and Distinct Metabolomic Profiles Following TM-Domain Disruption of Nrg1.

PubMed

O'Tuathaigh, Colm M P; Mathur, Naina; O'Callaghan, Matthew J; MacIntyre, Lynsey; Harvey, Richard; Lai, Donna; Waddington, John L; Pickard, Benjamin S; Watson, David G; Moran, Paula M

2017-09-01

Although there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signaling in schizophrenia. The present study focused on hitherto uncharacterized information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across 2 different sites and protocols, Nrg1 mutants demonstrated deficits in prepulse inhibition, a measure of sensorimotor gating, that is, disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in a "what-where-when" object recognition memory task, Nrg1 mutants displayed sex-specific (males only) disruption of "what-when" performance, indicative of impaired temporal aspects of episodic memory. Differential metabolomic profiling revealed that these behavioral phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioral changes in adulthood. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

The interaction of disrupted type II neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors.

PubMed

Taylor, S B; Taylor, A R; Koenig, J I

2013-09-26

The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. Previously, we established that Type II NRG1 is expressed in the hypothalamic-pituitary-adrenal (HPA) axis neurocircuitry. We also found, using a line of Nrg1 hypomorphic rats (Nrg1(Tn)), that genetic disruption of Type II NRG1 results in altered HPA axis function and environmental reactivity. The present studies used the Nrg1(Tn) rats to test whether Type II NRG1 gene disruption and chronic stress exposure during adolescence interact to alter adult anxiety- and fear-related behaviors. Male and female Nrg1(Tn) and wild-type rats were exposed to chronic variable stress (CVS) during mid-adolescence and then tested for anxiety-like behavior, cued fear conditioning and basal corticosterone secretion in adulthood. The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild-type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated Nrg1(Tn) females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Neuregulin in Cardiovascular Development and Disease

PubMed Central

Odiete, Oghenerukevwe; Hill, Michael F.; Sawyer, Douglas B.

2013-01-01

Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease. PMID:23104879

Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers.

PubMed

Drilon, Alexander; Somwar, Romel; Mangatt, Biju P; Edgren, Henrik; Desmeules, Patrice; Ruusulehto, Anja; Smith, Roger S; Delasos, Lukas; Vojnic, Morana; Plodkowski, Andrew J; Sabari, Joshua; Ng, Kenneth; Montecalvo, Joseph; Chang, Jason; Tai, Huichun; Lockwood, William W; Martinez, Victor; Riely, Gregory J; Rudin, Charles M; Kris, Mark G; Arcila, Maria E; Matheny, Christopher; Benayed, Ryma; Rekhtman, Natasha; Ladanyi, Marc; Ganji, Gopinath

2018-06-01

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1 -rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1 -rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1 -rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1 -rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686-95. ©2018 AACR. See related commentary by Wilson and Politi, p. 676 This article is highlighted in the In This Issue feature, p. 663 . ©2018 American Association for Cancer Research.

Neuregulin 1 Reduces Motoneuron Cell Death and Promotes Neurite Growth in an in Vitro Model of Motoneuron Degeneration

PubMed Central

Mòdol-Caballero, Guillem; Santos, Daniel; Navarro, Xavier; Herrando-Grabulosa, Mireia

2018-01-01

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with no effective treatment currently available. Although the mechanisms of motoneuron (MN) death are still unclear, glutamate excitotoxicity and neuroinflammatory reaction are two main features in the neurodegenerative process of ALS. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Several recent evidences suggest that NRG1 and their ErbB receptors are involved in ALS. However, further knowledge is still needed to clarify the role of the NRG1-ErbB pathway on MN survival. In this study we used an in vitro model of spinal cord organotypic cultures (SCOCs) subject to chronic excitotoxicity caused by DL-threo-β-hydroxyaspartic acid (THA) to characterize the effect of NRG1 on MN survival. Our results show that addition of recombinant human NRG1 (rhNRG1) to the medium significantly increased MN survival through the activation of ErbB receptors which was ablated with lapatinib (LP), an ErbB inhibitor, and reduced microglial reactivity overcoming the excitotoxicity effects. rhNRG1 activated the pro-survival PI3K/AKT pathway and restored the autophagic flux in the spinal cord culture. Moreover, addition of rhNRG1 to the medium promoted motor and sensory neurite outgrowth. These findings indicate that increasing NRG1 at the spinal cord is an interesting approach for promoting MN protection and regeneration. PMID:29375317

Partial genetic deletion of neuregulin 1 modulates the effects of stress on sensorimotor gating, dendritic morphology, and HPA axis activity in adolescent mice.

PubMed

Chohan, Tariq W; Boucher, Aurelie A; Spencer, Jarrah R; Kassem, Mustafa S; Hamdi, Areeg A; Karl, Tim; Fok, Sandra Y; Bennett, Maxwell R; Arnold, Jonathon C

2014-11-01

Stress has been linked to the pathogenesis of schizophrenia. Genetic variation in neuregulin 1 (NRG1) increases the risk of developing schizophrenia and may help predict which high-risk individuals will transition to psychosis. NRG1 also modulates sensorimotor gating, a schizophrenia endophenotype. We used an animal model to demonstrate that partial genetic deletion of Nrg1 interacts with stress to promote neurobehavioral deficits of relevance to schizophrenia. Nrg1 heterozygous (HET) mice displayed greater acute stress-induced anxiety-related behavior than wild-type (WT) mice. Repeated stress in adolescence disrupted the normal development of higher prepulse inhibition of startle selectively in Nrg1 HET mice but not in WT mice. Further, repeated stress increased dendritic spine density in pyramidal neurons of the medial prefrontal cortex (mPFC) selectively in Nrg1 HET mice. Partial genetic deletion of Nrg1 also modulated the adaptive response of the hypothalamic-pituitary-adrenal axis to repeated stress, with Nrg1 HET displaying a reduced repeated stress-induced level of plasma corticosterone than WT mice. Our results demonstrate that Nrg1 confers vulnerability to repeated stress-induced sensorimotor gating deficits, dendritic spine growth in the mPFC, and an abberant endocrine response in adolescence. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Type III Neuregulin 1 Is Required for Multiple Forms of Excitatory Synaptic Plasticity of Mouse Cortico-Amygdala Circuits

PubMed Central

Emmetsberger, Jaime; Talmage, David A.; Role, Lorna W.

2013-01-01

The amygdala plays an important role in the formation and storage of memories associated with emotional events. The cortical glutamatergic inputs onto pyramidal neurons in the basolateral nucleus of the amygdala (BLA) contribute to this process. As the interaction between neuregulin 1 (Nrg1) and its ErbB receptors has been implicated in the pathological mechanisms of schizophrenia, loss of Nrg1 may disrupt cortical–amygdala neural circuits, resulting in altered processing of salient memories. Here we show that Nrg1 is critical in multiple forms of plasticity of cortical projections to pyramidal neurons of the BLA. The miniature EPSCs in Nrg1 heterozygous animals have a faster time constant of decay and evoked synaptic currents have a smaller NMDA/AMPA ratio than those recorded in wild-type (WT) littermates. Both high-frequency electrical stimulation of cortical inputs and θ burst stimulation combined with nicotine exposure results in long-lasting potentiation in WT animals. However, the same manipulations have little to no effect on glutamatergic synaptic plasticity in the BLA from Nrg1 heterozygous mice. Comparison of WT, Nrg1 heterozygous animals and α7 nicotinic receptor heterozygous mice reveals that the sustained phase of potentiation of glutamatergic transmission after θ burst stimulation with or without nicotine only occurs in the WT mice. Together, these findings support the idea that type III Nrg1 is essential to multiple aspects of the modulation of excitatory plasticity at cortical–BLA synapses. PMID:23739962

TNF-α blocker effect of naringenin-loaded sericin microparticles that are potentially useful in the treatment of psoriasis.

PubMed

Chlapanidas, Theodora; Perteghella, Sara; Leoni, Flavio; Faragò, Silvio; Marazzi, Mario; Rossi, Daniela; Martino, Emanuela; Gaggeri, Raffaella; Collina, Simona

2014-08-06

This study aims to evaluate the effect of combined use of the racemic flavanone Naringenin (NRG) and the protein sericin as TNF-α blockers. Sericin (SMs) and (R/S) NRG-loaded Sericin (SNRGMs) microparticles were prepared by spray-drying, characterized in terms of morphology and particle size distribution, and encapsulation efficiency was determined. Concerning morphology and particle size distribution of microparticles, results indicated that they were not affected by the presence of NRG. The encapsulation efficiency was almost quantitative (93%), thus proving that sericin can be advantageously loaded with (R/S) NRG. Biological evaluation of (R/S) NRG, SMs and SNRGMs was then performed in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (hPBMC). SNRGMs resulted cytotoxic at the higher dose used (200 μg/mL) and the effect was greater than (R/S) NRG alone. Moreover, even if sericin alone was not effective in suppressing LPS-induced serum TNF-α levels, SNRGMs loaded with 9.3% of (R/S) NRG were significantly more potent than (R/S) NRG alone. In summary, this study provides the proof of concept that sericin-based microspheres loaded with TNF-α-blockers could contribute to the down regulation of the cytokine and represents the starting point for the development of new topical formulations for the treatment of middle-stage psoriasis.

TNF-α Blocker Effect of Naringenin-Loaded Sericin Microparticles that Are Potentially Useful in the Treatment of Psoriasis

PubMed Central

Chlapanidas, Theodora; Perteghella, Sara; Leoni, Flavio; Faragò, Silvio; Marazzi, Mario; Rossi, Daniela; Martino, Emanuela; Gaggeri, Raffaella; Collina, Simona

2014-01-01

This study aims to evaluate the effect of combined use of the racemic flavanone Naringenin (NRG) and the protein sericin as TNF-α blockers. Sericin (SMs) and (R/S) NRG-loaded Sericin (SNRGMs) microparticles were prepared by spray-drying, characterized in terms of morphology and particle size distribution, and encapsulation efficiency was determined. Concerning morphology and particle size distribution of microparticles, results indicated that they were not affected by the presence of NRG. The encapsulation efficiency was almost quantitative (93%), thus proving that sericin can be advantageously loaded with (R/S) NRG. Biological evaluation of (R/S) NRG, SMs and SNRGMs was then performed in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (hPBMC). SNRGMs resulted cytotoxic at the higher dose used (200 μg/mL) and the effect was greater than (R/S) NRG alone. Moreover, even if sericin alone was not effective in suppressing LPS-induced serum TNF-α levels, SNRGMs loaded with 9.3% of (R/S) NRG were significantly more potent than (R/S) NRG alone. In summary, this study provides the proof of concept that sericin-based microspheres loaded with TNF-α-blockers could contribute to the down regulation of the cytokine and represents the starting point for the development of new topical formulations for the treatment of middle-stage psoriasis. PMID:25101847

Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice

PubMed Central

Long, Leonora E.; Chesworth, Rose; Huang, Xu-Feng; Wong, Alexander; Spiro, Adena; McGregor, Iain S.; Arnold, Jonathon C.; Karl, Tim

2012-01-01

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABAA receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes. PMID:22509273

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice.

PubMed

Long, Leonora E; Chesworth, Rose; Huang, Xu-Feng; Wong, Alexander; Spiro, Adena; McGregor, Iain S; Arnold, Jonathon C; Karl, Tim

2012-01-01

The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

Neuregulin-1 is Neuroprotective in a Rat Model of Organophosphate-Induced Delayed Neuronal Injury

PubMed Central

Li, Yonggang; Lein, Pamela J.; Liu, Cuimei; Bruun, Donald A.; Giulivi, Cecilia; Ford, Gregory; Tewolde, Teclemichael; Ross-Inta, Catherine; Ford, Byron D.

2012-01-01

Current medical countermeasures against organophosphate (OP) nerve agents are effective in reducing mortality, but do not sufficiently protect the CNS from delayed brain damage and persistent neurological symptoms. In this study, we examined the efficacy of neuregulin-1 (NRG-1) in protecting against delayed neuronal cell death following acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats were pretreated with pyridostigmine (0.1 mg/kg BW, i.m.) and atropine methylnitrate (20 mg/kg BW, i.m.) prior to DFP (9 mg/kg BW, i.p.) intoxication to increase survival and reduce peripheral signs of cholinergic toxicity but not prevent DFP-induced seizures or delayed neuronal injury. Pretreatment with NRG-1 did not protect against seizures in rats exposed to DFP. However, neuronal injury was significantly reduced in most brain regions by pretreatment with NRG-1 isoforms NRG-EGF (3.2 μg/kg BW, i.a) or NRG-GGF2 (48 μg/kg BW, i.a.) as determined by FluroJade-B labeling in multiple brain regions at 24 h post-DFP injection. NRG-1 also blocked apoptosis and oxidative stress-mediated protein damage in the brains of DFP-intoxicated rats. Administration of NRG-1 at 1 h after DFP injection similarly provided significant neuroprotection against delayed neuronal injury. These findings identify NRG-1 as a promising adjuvant therapy to current medical countermeasures for enhancing neuroprotection against acute OP intoxication. PMID:22583949

Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy.

PubMed

Liu, Xifu; Gu, Xinhua; Li, Zhaoming; Li, Xinyan; Li, Hui; Chang, Jianjie; Chen, Ping; Jin, Jing; Xi, Bing; Chen, Denghong; Lai, Donna; Graham, Robert M; Zhou, Mingdong

2006-10-03

We evaluated the therapeutic potential of a recombinant 61-residue neuregulin-1 (beta2a isoform) receptor-active peptide (rhNRG-1) in multiple animal models of heart disease. Activation of the erbB family of receptor tyrosine kinases by rhNRG-1 could provide a treatment option for heart failure, because neuregulin-stimulated erbB2/erbB4 heterodimerization is not only critical for myocardium formation in early heart development but prevents severe dysfunction of the adult heart and premature death. Disabled erbB-signaling is also implicated in the transition from compensatory hypertrophy to failure, whereas erbB receptor-activation promotes myocardial cell growth and survival and protects against anthracycline-induced cardiomyopathy. rhNRG-1 was administered IV to animal models of ischemic, dilated, and viral cardiomyopathy, and cardiac function and survival were evaluated. Short-term intravenous administration of rhNRG-1 to normal dogs and rats did not alter hemodynamics or cardiac contractility. In contrast, rhNRG-1 improved cardiac performance, attenuated pathological changes, and prolonged survival in rodent models of ischemic, dilated, and viral cardiomyopathy, with the survival benefits in the ischemic model being additive to those of angiotensin-converting enzyme inhibitor therapy. In addition, despite continued pacing, rhNRG-1 produced global improvements in cardiac function in a canine model of pacing-induced heart failure. These beneficial effects make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.

Lissencephaly-1 dependent axonal retrograde transport of L1-type CAM Neuroglian in the adult drosophila central nervous system

PubMed Central

Börner, Jana; Slipchuk, Olesya; Kakad, Priyanka; Lee, LaTasha H.; Qureshi, Aater; Pielage, Jan

2017-01-01

Here, we established the Drosophila Giant Fiber neurons (GF) as a novel model to study axonal trafficking of L1-type Cell Adhesion Molecules (CAM) Neuroglian (Nrg) in the adult CNS using live imaging. L1-type CAMs are well known for their importance in nervous system development and we previously demonstrated a role for Nrg in GF synapse formation. However, in the adult they have also been implicated in synaptic plasticity and regeneration. In addition, to its canonical role in organizing cytoskeletal elements at the plasma membrane, vertebrate L1CAM has also been shown to regulate transcription indirectly as well as directly via its import to the nucleus. Here, we intend to determine if the sole L1CAM homolog Nrg is retrogradley transported and thus has the potential to relay signals from the synapse to the soma. Live imaging of c-terminally tagged Nrg in the GF revealed that there are at least two populations of retrograde vesicles that differ in speed, and either move with consistent or varying velocity. To determine if endogenous Nrg is retrogradely transported, we inhibited two key regulators, Lissencephaly-1 (Lis1) and Dynactin, of the retrograde motor protein Dynein. Similar to previously described phenotypes for expression of poisonous subunits of Dynactin, we found that developmental knock down of Lis1 disrupted GF synaptic terminal growth and that Nrg vesicles accumulated inside the stunted terminals in both mutant backgrounds. Moreover, post mitotic Lis1 knock down in mature GFs by either RNAi or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) induced mutations, resulted in normal length terminals with fully functional GF synapses which also exhibited severe accumulation of endogenous Nrg vesicles. Thus, our data suggests that accumulation of Nrg vesicles is due to failure of retrograde transport rather than a failure of terminal development. Together with the finding that post mitotic knock down of Lis1 also disrupted retrograde transport of tagged Nrg vesicles in GF axons, it demonstrates that endogenous Nrg protein is transported from the synapse to the soma in the adult central nervous system in a Lis1-dependent manner. PMID:28837701

Lissencephaly-1 dependent axonal retrograde transport of L1-type CAM Neuroglian in the adult drosophila central nervous system.

PubMed

Kudumala, Sirisha R; Penserga, Tyrone; Börner, Jana; Slipchuk, Olesya; Kakad, Priyanka; Lee, LaTasha H; Qureshi, Aater; Pielage, Jan; Godenschwege, Tanja A

2017-01-01

Here, we established the Drosophila Giant Fiber neurons (GF) as a novel model to study axonal trafficking of L1-type Cell Adhesion Molecules (CAM) Neuroglian (Nrg) in the adult CNS using live imaging. L1-type CAMs are well known for their importance in nervous system development and we previously demonstrated a role for Nrg in GF synapse formation. However, in the adult they have also been implicated in synaptic plasticity and regeneration. In addition, to its canonical role in organizing cytoskeletal elements at the plasma membrane, vertebrate L1CAM has also been shown to regulate transcription indirectly as well as directly via its import to the nucleus. Here, we intend to determine if the sole L1CAM homolog Nrg is retrogradley transported and thus has the potential to relay signals from the synapse to the soma. Live imaging of c-terminally tagged Nrg in the GF revealed that there are at least two populations of retrograde vesicles that differ in speed, and either move with consistent or varying velocity. To determine if endogenous Nrg is retrogradely transported, we inhibited two key regulators, Lissencephaly-1 (Lis1) and Dynactin, of the retrograde motor protein Dynein. Similar to previously described phenotypes for expression of poisonous subunits of Dynactin, we found that developmental knock down of Lis1 disrupted GF synaptic terminal growth and that Nrg vesicles accumulated inside the stunted terminals in both mutant backgrounds. Moreover, post mitotic Lis1 knock down in mature GFs by either RNAi or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) induced mutations, resulted in normal length terminals with fully functional GF synapses which also exhibited severe accumulation of endogenous Nrg vesicles. Thus, our data suggests that accumulation of Nrg vesicles is due to failure of retrograde transport rather than a failure of terminal development. Together with the finding that post mitotic knock down of Lis1 also disrupted retrograde transport of tagged Nrg vesicles in GF axons, it demonstrates that endogenous Nrg protein is transported from the synapse to the soma in the adult central nervous system in a Lis1-dependent manner.

77 FR 48148 - NRG Solar Borrego I LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-13

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER12-2398-000] NRG Solar Borrego I LLC; Supplemental Notice That Initial Market- Based Rate Filing Includes Request for Blanket Section 204 Authorization This is a supplemental notice in the above-referenced proceeding, of NRG Solar...

77 FR 37666 - NRG Solar Avra Valley LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-22

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. ER12-2019-000] NRG Solar Avra Valley LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes Request for Blanket Section 204 Authorization This is a supplemental notice in the above-referenced proceeding of NRG Solar...

Excessive exercise habits of runners as new signs of hypertension and arrhythmia.

PubMed

Kim, Young-Joo; Kim, Chul-Hyun; Park, Kyoung-Min

2016-08-15

Excessive exercise may induce arrhythmia, and this risk is higher in middle-aged people. The study aim was to compare the exercise characteristics of middle-aged runners participating in excessive endurance exercise. The subjects of this study were 552 runners (mean age; 49.0±7.4years) without structural heart disease who performed exercise at least twice per week, had consistently exercised for at least three years, and had finished at least five marathons. The arrhythmia runner group (ARG, n=14) and normal runner group (NRG, n=538) were compared with regard to hemodynamic response, cardiorespiratory fitness level, training history, number of finished races, finishing times, and exercise habits. The mean resting systolic (134.0±15.8mmHg) and diastolic (85.8±10.9mmHg) blood pressure values indicated pre-hypertension, while the mean maximal SBP (213.7±27.4mmHg) values indicated exercise-induced hypertension. The VO2max was significantly higher and the maximal DBP was significantly lower in the ARG than in the NRG (p<0.05). Training history was significantly longer in the ARG than in the NRG (p<0.05), while the number of finished marathons, the finishing times in marathons and the exercise frequency per week didn't differ significantly between the two groups. Exercise intensity was significantly higher in the ARG than in the NRG (p<0.01). Middle-aged long-distance runners showed pre-hypertension and exercise-induced hypertension, and the ARG had higher VO2max values, greater exercise intensities, and longer training histories than the NRG. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Electrical stimulation of rhesus monkey nucleus reticularis gigantocellularis. I. Characteristics of evoked head movements.

PubMed

Quessy, Stephan; Freedman, Edward G

2004-06-01

The nucleus reticularis gigantocellularis (NRG) receives monosynaptic input from the superior colliculus (SC) and projects directly to neck motor neuron pools. Neurons in NRG are well situated to play a critical role in transforming SC signals into head movement commands. A previous study of movements evoked by NRG stimulation in the primate reported a variety of ipsilateral and contralateral head movements with horizontal, vertical and torsional components. In addition to head movements, it was reported that NRG stimulation could evoke movements of the pinnae, face, upper torso, and co-contraction of neck muscles. In this report, the role of the rhesus monkey NRG in head movement control was investigated using electrical stimulation of the rostral portion of the NRG. The goal was to characterize head movements evoked by NRG stimulation, describe the effects of altering stimulation parameters, and assess the relative movements of the eyes and head. Results indicate that electrical stimulation in the rostral portion of the NRG of the primate can consistently evoke ipsilateral head rotations in the horizontal plane. Head movement amplitude and peak velocity depend upon stimulation parameters (primarily frequency and duration of stimulation trains). During stimulation-induced head movements the eyes counter-rotate (presumably a result of the vestibulo-ocular reflex: VOR). At 46 stimulation sites from two subjects the average gain of this counter-rotation was -0.38 (+/-0.18). After the end of the stimulation train the head generally continued to move. During this epoch, after electrical stimulation ceased, VOR gain remained at this reduced level. In addition, VOR gain was similarly low when electrical stimulation was carried out during active fixation of a visual target. These data extend existing descriptions of head movements evoked by electrical stimulation of the NRG, and add to the understanding of the role of this structure in producing head movements.

Olanzapine Prevents the PCP-induced Reduction in the Neurite Outgrowth of Prefrontal Cortical Neurons via NRG1

PubMed Central

Zhang, Qingsheng; Yu, Yinghua; Huang, Xu-Feng

2016-01-01

Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length (28.5%) and the number of neurite branches (35.6%) in primary prefrontal cortical neuron cultures. PCP reduced protein and mRNA expressions of synaptophysin (24.9% and 23.2%, respectively) and PSD95 (31.5% and 21.4%, respectively), and the protein expression of p-Akt (26.7%) and p-GSK3β (35.2%). Olanzapine co-treatment prevented these PCP-induced effects in normal neurons but not in neurons from NRG1-knockout mice. These results indicate that NRG1 mediates the preventive effects of olanzapine on the PCP-induced impairment of neurite outgrowth and synaptic protein expression. This study provides potential targets for interventions on improving the efficacy of olanzapine on preventing cognitive deficits in schizophrenia. PMID:26781398

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia

PubMed Central

Huang, Ching-Hsun; Pei, Ju-Chun; Luo, Da-Zhong; Chen, Ching; Chen, Yi-Wen; Lai, Wen-Sung

2015-01-01

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1+/−, Nrg1+/−, and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1+/− and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1+/− mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition. PMID:25688191

Investigation of gene effects and epistatic interactions between Akt1 and neuregulin 1 in the regulation of behavioral phenotypes and social functions in genetic mouse models of schizophrenia.

PubMed

Huang, Ching-Hsun; Pei, Ju-Chun; Luo, Da-Zhong; Chen, Ching; Chen, Yi-Wen; Lai, Wen-Sung

2014-01-01

Accumulating evidence from human genetic studies has suggested several functional candidate genes that might contribute to susceptibility to schizophrenia, including AKT1 and neuregulin 1 (NRG1). Recent findings also revealed that NRG1 stimulates the PI3-kinase/AKT signaling pathway, which might be involved in the functional outcomes of some schizophrenic patients. The aim of this study was to evaluate the effect of Akt1-deficiency and Nrg1-deficiency alone or in combination in the regulation of behavioral phenotypes, cognition, and social functions using genetically modified mice as a model. Male Akt1 (+/-), Nrg1 (+/-), and double mutant mice were bred and compared with their wild-type (WT) littermate controls. In Experiment 1, general physical examination revealed that all mutant mice displayed a normal profile of body weight during development and a normal brain activity with microPET scan. In Experiment 2, no significant genotypic differences were found in our basic behavioral phenotyping, including locomotion, anxiety-like behavior, and sensorimotor gating function. However, both Nrg1 (+/-) and double mutant mice exhibited impaired episodic-like memory. Double mutant mice also had impaired sociability. In Experiment 3, a synergistic epistasis between Akt1 and Nrg1 was further confirmed in double mutant mice in that they had impaired social interaction compared to the other 3 groups, especially encountering with a novel male or an ovariectomized female. Double mutant and Nrg1 (+/-) mice also emitted fewer female urine-induced ultrasonic vocalization calls. Collectively, our results indicate that double deficiency of Akt1 and Nrg1 can result in the impairment of social cognitive functions, which might be pertinent to the pathogenesis of schizophrenia-related social cognition.

Neuroglian activates Echinoid to antagonize the Drosophila EGF receptor signaling pathway.

PubMed

Islam, Rafique; Wei, Shu-Yi; Chiu, Wei-Hsin; Hortsch, Michael; Hsu, Jui-Chou

2003-05-01

echinoid (ed) encodes an cell-adhesion molecule (CAM) that contains immunoglobulin domains and regulates the EGFR signaling pathway during Drosophila eye development. Based on our previous genetic mosaic and epistatic analysis, we proposed that Ed, via homotypic interactions, activates a novel, as yet unknown pathway that antagonizes EGFR signaling. In this report, we demonstrate that Ed functions as a homophilic adhesion molecule and also engages in a heterophilic trans-interaction with Drosophila Neuroglian (Nrg), an L1-type CAM. Co-expression of ed and nrg in the eye exhibits a strong genetic synergy in inhibiting EGFR signaling. This synergistic effect requires the intracellular domain of Ed, but not that of Nrg. In addition, Ed and Nrg colocalize in the Drosophila eye and are efficiently co-immunoprecipitated. Together, our results suggest a model in which Nrg acts as a heterophilic ligand and activator of Ed, which in turn antagonizes EGFR signaling.

A Novel Regulatory Mechanism of Smooth Muscle α-Actin Expression by NRG-1/circACTA2/miR-548f-5p Axis.

PubMed

Sun, Yan; Yang, Zhan; Zheng, Bin; Zhang, Xin-Hua; Zhang, Man-Li; Zhao, Xue-Shan; Zhao, Hong-Ye; Suzuki, Toru; Wen, Jin-Kun

2017-09-01

Neuregulin-1 (NRG-1) includes an extracellular epidermal growth factor-like domain and an intracellular domain (NRG-1-ICD). In response to transforming growth factor-β1, its cleavage by proteolytic enzymes releases a bioactive fragment, which suppresses the vascular smooth muscle cell (VSMC) proliferation by activating ErbB (erythroblastic leukemia viral oncogene homolog) receptor. However, NRG-1-ICD function in VSMCs remains unknown. Here, we characterize the function of NRG-1-ICD and underlying mechanisms in VSMCs. Immunofluorescence staining, Western blotting, and quantitative real-time polymerase chain reaction showed that NRG-1 was expressed in rat, mouse, and human VSMCs and was upregulated and cleaved in response to transforming growth factor-β1. In the cytoplasm of HASMCs (human aortic smooth muscle cells), the NRG-1-ICD participated in filamentous actin formation by interacting with α-SMA (smooth muscle α-actin). In the nucleus, the Nrg-1-ICD induced circular ACTA2 (alpha-actin-2; circACTA2) formation by recruitment of the zinc-finger transcription factor IKZF1 (IKAROS family zinc finger 1) to the first intron of α-SMA gene. We further confirmed that circACTA2, acting as a sponge binding microRNA (miR)-548f-5p, interacted with miR-548f-5p targeting 3' untranslated region of α-SMA mRNA, which in turn relieves miR-548f-5p repression of the α-SMA expression and thus upregulates α-SMA expression, thereby facilitating stress fiber formation and cell contraction in HASMCs. Accordingly, in vivo studies demonstrated that the localization of the interaction of circACTA2 with miR-548f-5p is significantly decreased in human intimal hyperplastic arteries compared with normal arteries, implicating that dysregulation of circACTA2 and miR-548f-5p expression is involved in intimal hyperplasia. These results suggest that circACTA2 mediates NRG-1-ICD regulation of α-SMA expression in HASMCs via the NRG-1-ICD/circACTA2/miR-548f-5p axis. Our data provide a molecular basis for fine-tuning α-SMA expression and VSMC contraction by transcription factor, circular RNA, and microRNA. © 2017 American Heart Association, Inc.

Toward chemical accuracy in the description of ion-water interactions through many-body representations. Alkali-water dimer potential energy surfaces

NASA Astrophysics Data System (ADS)

Riera, Marc; Mardirossian, Narbe; Bajaj, Pushp; Götz, Andreas W.; Paesani, Francesco

2017-10-01

This study presents the extension of the MB-nrg (Many-Body energy) theoretical/computational framework of transferable potential energy functions (PEFs) for molecular simulations of alkali metal ion-water systems. The MB-nrg PEFs are built upon the many-body expansion of the total energy and include the explicit treatment of one-body, two-body, and three-body interactions, with all higher-order contributions described by classical induction. This study focuses on the MB-nrg two-body terms describing the full-dimensional potential energy surfaces of the M+(H2O) dimers, where M+ = Li+, Na+, K+, Rb+, and Cs+. The MB-nrg PEFs are derived entirely from "first principles" calculations carried out at the explicitly correlated coupled-cluster level including single, double, and perturbative triple excitations [CCSD(T)-F12b] for Li+ and Na+ and at the CCSD(T) level for K+, Rb+, and Cs+. The accuracy of the MB-nrg PEFs is systematically assessed through an extensive analysis of interaction energies, structures, and harmonic frequencies for all five M+(H2O) dimers. In all cases, the MB-nrg PEFs are shown to be superior to both polarizable force fields and ab initio models based on density functional theory. As previously demonstrated for halide-water dimers, the MB-nrg PEFs achieve higher accuracy by correctly describing short-range quantum-mechanical effects associated with electron density overlap as well as long-range electrostatic many-body interactions.

Neuroglian stabilizes epithelial structure during Drosophila oogenesis.

PubMed

Wei, Jun; Hortsch, Michael; Goode, Scott

2004-08-01

The vertebrate L1 family of cell adhesion molecules (CAMs) and their fly homolog, Neuroglian, are members of the immunoglobulin (Ig) superfamily of CAMs. In general, Ig CAMs have been found to play critical roles in mediating axon guidance. One Ig CAM, NCAM, has also been implicated in maintaining epithelial integrity and suppressing metastatic dissemination of tumor cells. Other Ig CAMs, such as Nrg, are also expressed in epithelia. We thus tested the hypothesis that, like NCAM, Nrg might also be required for maintaining epithelial integrity and for inhibiting tumor invasion. We used the Drosophila follicular epithelium to determine the function of Nrg in vivo in maintaining epithelial structure, and in regulating the motility of migrating border cells and invasive tumorous follicle cells. Nrg(167) is expressed on the lateral membrane of follicle cells. Loss of Nrg(167) causes border cells to delay delamination and causes other follicle cells to delaminate inappropriately. The delaminated cells have aberrant epithelial polarity manifested as severe mislocalization of apical and basal membrane proteins, and uniform localization of lateral membrane proteins. Furthermore, loss of Nrg(167) dramatically enhances the invasive phenotype associated with loss of Discs Large, a neoplastic tumor suppressor. These results indicate that Nrg(167) stabilizes epithelial polarity by regulating junctional adhesion and function in normal and tumorous epithelia. Our data also suggest that Ig superfamily members have significant functional redundancy in maintaining epithelial polarity, with individual members playing subtle, unique roles during epithelial morphogenesis. Copyright 2004 Wiley-Liss, Inc.

Uniformly Dispersed ZnFe2O4 Nanoparticles on Nitrogen-Modified Graphene for High-Performance Supercapacitor as Electrode.

PubMed

Li, Lei; Bi, Huiting; Gai, Shili; He, Fei; Gao, Peng; Dai, Yunlu; Zhang, Xitian; Yang, Dan; Zhang, Milin; Yang, Piaoping

2017-02-21

A facile strategy has been adopted for the preparation of ZnFe 2 O 4 /NRG composite by anchoring ultrasmall ZnFe 2 O 4 nanoparticles on nitrogen-doped reduced graphene (denoted as NRG) for high-performance supercapacitor electrode. Remarkably, the growth of ZnFe 2 O 4 nanocrystals, the reduction of graphitic oxide and the doping of nitrogen to graphene have been simultaneously achieved in one process. It is found that the NRG employed as substrate can not only control the formation of nano-sized ZnFe 2 O 4 , but also guarantee the high dispersion without any agglomeration. Benefiting from this novel combination and construction, the hybrid material has large surface area which can provide high exposure of active sites for easy access of electrolyte and fast electron transport. When served as supercapacitor electrode, the ZnFe 2 O 4 /NRG composite exhibits a favorable specific capacitance of 244 F/g at 0.5 A/g within the potential range from -1 to 0 V, desirable rate stability (retain 131.5 F/g at 10 A/g) and an admirable cycling durability of 83.8% at a scan rate of 100 mV/s after 5000 cycles. When employed as symmetric supercapacitor, the device demonstrates favorable performance. These satisfactory properties of the ZnFe 2 O 4 /NRG composite can make it be of great promise in the supercapacitor application.

Direct connection of the nucleus reticularis gigantocellularis neurons with neck motoneurons in cats.

PubMed

Sasaki, S

1999-10-01

Functional connections of single reticulospinal neurons (RSNs) in the nucleus reticularis gigantocellularis (NRG) with ipsilateral dorsal neck motoneurons were examined with the spike-triggered averaging technique. Extracellular spikes of single NRG-RSNs activated antidromically from the C6, but not from the L1 segment (C-RSNs) were used as the trigger. These neurons were monosynaptically activated from the superior colliculus and the cerebral peduncle. Single-RSN PSPs were recorded in 43 dorsal neck motoneurons [biventer cervicis and complexus (BCC) and splenius (SPL)] for 21 NRG-RSNs and 135 motoneurons tested. All synaptic potentials were EPSPs, and most of their latencies, measured from the triggering spikes, were 0.8-1.5 ms, which is in a monosynaptic range. The amplitudes of single-RSN EPSPs were 10-360 microV. Spike-triggered averaging revealed single-RSN EPSPs in multiple motoneurons of the same species (SPL or BCC), their locations extending up to nearly 1 mm rostrocaudally. Synaptic connections of single RSNs with both SPL and BCC motoneurons were also found with some predominance for one of them. The results provide direct evidence that NRG-RSNs make monosynaptic excitatory connections with SPL and BCC motoneurons. It appears that some NRG-RSNs connect predominantly with SPL motoneurons and others with BCC motoneurons.

Identification of Neuregulin-2 as a novel stress granule component.

PubMed

Kim, Jin Ah; Jayabalan, Aravinth Kumar; Kothandan, Vinoth Kumar; Mariappan, Ramesh; Kee, Younghoon; Ohn, Takbum

2016-08-01

Stress Granules (SGs) are microscopically visible, phase dense aggregates of translationally stalled messenger ribonucleoprotein (mRNP) complexes formed in response to distinct stress conditions. It is generally considered that SG formation is induced to protect cells from conditions of stress. The precise constituents of SGs and the mechanism through which SGs are dynamically regulated in response to stress are not completely understood. Hence, it is important to identify proteins which regulate SG assembly and disassembly. In the present study, we report Neuregulin-2 (NRG2) as a novel component of SGs; furthermore, depletion of NRG2 potently inhibits SG formation. We also demonstrate that NRG2 specifically localizes to SGs under various stress conditions. Knockdown of NRG2 has no effect on stress-induced polysome disassembly, suggesting that the component does not influence early step of SG formation. It was also observed that reduced expression of NRG2 led to marginal increase in cell survival under arsenite-induced stress. [BMB Reports 2016; 49(8): 449-454].

Identification of Neuregulin-2 as a novel stress granule component

PubMed Central

Kim, Jin Ah; Jayabalan, Aravinth Kumar; Kothandan, Vinoth Kumar; Mariappan, Ramesh; Kee, Younghoon; Ohn, Takbum

2016-01-01

Stress Granules (SGs) are microscopically visible, phase dense aggregates of translationally stalled messenger ribonucleoprotein (mRNP) complexes formed in response to distinct stress conditions. It is generally considered that SG formation is induced to protect cells from conditions of stress. The precise constituents of SGs and the mechanism through which SGs are dynamically regulated in response to stress are not completely understood. Hence, it is important to identify proteins which regulate SG assembly and disassembly. In the present study, we report Neuregulin-2 (NRG2) as a novel component of SGs; furthermore, depletion of NRG2 potently inhibits SG formation. We also demonstrate that NRG2 specifically localizes to SGs under various stress conditions. Knockdown of NRG2 has no effect on stress-induced polysome disassembly, suggesting that the component does not influence early step of SG formation. It was also observed that reduced expression of NRG2 led to marginal increase in cell survival under arsenite-induced stress. [BMB Reports 2016; 49(8): 449-454] PMID:27345716

Filament condition-specific response elements control the expression of NRG1 and UME6, key transcriptional regulators of morphology and virulence in Candida albicans.

PubMed

Childers, Delma S; Kadosh, David

2015-01-01

Candida albicans is the most frequently isolated human fungal pathogen and can cause a range of mucosal and systemic infections in immunocompromised individuals. Morphogenesis, the ability to undergo a reversible transition from budding yeast to elongated filaments, is an essential virulence trait. The yeast-to-filament transition is associated with expression of genes specifically important for filamentation as well as other virulence-related processes, and is controlled, in part, by the key transcriptional regulators Nrg1 and Ume6. Both of these regulators are themselves controlled at the transcriptional level by filament-inducing environmental cues, although little is known about how this process occurs. In order to address this question and determine whether environmental signals regulate transcription of UME6 and NRG1 via distinct and/or common promoter elements, we performed promoter deletion analyses. Strains bearing promoter deletion constructs were induced to form filaments in YEPD plus 10% serum at 37°C, Spider medium (nitrogen and carbon starvation) and/or Lee's medium pH 6.8 (neutral pH) and reporter gene expression was measured. In the NRG1 promoter we identified several distinct condition-specific response elements for YEPD plus 10% serum at 37°C and Spider medium. In the UME6 promoter we also identified response elements for YEPD plus 10% serum at 37°C. While a few of these elements are distinct, others overlap with those which respond to Lee's pH 6.8 medium. Consistent with UME6 possessing a very long 5' UTR, many response elements in the UME6 promoter are located significantly upstream from the coding sequence. Our data indicate that certain distinct condition-specific elements can control expression of C. albicans UME6 and NRG1 in response to key filament-inducing environmental cues. Because C. albicans encounters a variety of host microenvironments during infection, our results suggest that UME6 and NRG1 expression can be differentially modulated by multiple signaling pathways to control filamentation and virulence in vivo.

Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

PubMed Central

Law, Amanda J.; Lipska, Barbara K.; Weickert, Cynthia Shannon; Hyde, Thomas M.; Straub, Richard E.; Hashimoto, Ryota; Harrison, Paul J.; Kleinman, Joel E.; Weinberger, Daniel R.

2006-01-01

Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5′ upstream region of the gene for their effects on mRNA abundance of NRG1 types I–IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia. PMID:16618933

Female receptivity phenotype of icebox mutants caused by a mutation in the L1-type cell adhesion molecule neuroglian.

PubMed

Carhan, A; Allen, F; Armstrong, J D; Hortsch, M; Goodwin, S F; O'Dell, K M C

2005-11-01

Relatively little is known about the genes and brain structures that enable virgin female Drosophila to make the decision to mate or not. Classical genetic approaches have identified several mutant females that have a reluctance-to-mate phenotype, but most of these have additional behavioral defects. However, the icebox (ibx) mutation was previously reported to lower the sexual receptivity of females, without apparently affecting any other aspect of female behavior. We have shown that the ibx mutation maps to the 7F region of the Drosophila X chromosome to form a complex complementation group with both lethal and viable alleles of neuroglian (nrg). The L1-type cell adhesion molecule encoded by nrg consists of six immunoglobulin-like domains, five fibronectin-like domains, one transmembrane domain and one alternatively spliced intracellular domain. The ibx strain has a missense mutation causing a glycine-to-arginine change at amino acid 92 in the first immunoglobulin domain of nrg. Defects in the central brain of ibx mutants are similar to those observed in another nrg mutant, central brain deranged(1) (ceb(1)). However, both ceb(1) homozygous and ceb(1)/ibx heterozygous females are receptive. The expression of a transgene containing the non-neural isoform of nrg rescues both the receptivity and the brain structure phenotypes of ibx females.

No association between NRG1 and ErbB4 genes and psychopathological symptoms of schizophrenia.

PubMed

Tosato, Sarah; Zanoni, Martina; Bonetto, Chiara; Tozzi, Federica; Francks, Clyde; Ira, Elisa; Tomassi, Simona; Bertani, Mariaelena; Rujescu, Dan; Giegling, Ina; St Clair, David; Tansella, Michele; Ruggeri, Mirella; Muglia, Pierandrea

2014-12-01

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5' end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration.

PubMed

Formiga, Fabio R; Pelacho, Beatriz; Garbayo, Elisa; Imbuluzqueta, Izaskun; Díaz-Herráez, Paula; Abizanda, Gloria; Gavira, Juan J; Simón-Yarza, Teresa; Albiasu, Edurne; Tamayo, Esther; Prósper, Felipe; Blanco-Prieto, Maria J

2014-01-10

Acidic fibroblast growth factor (FGF1) and neuregulin-1 (NRG1) are growth factors involved in cardiac development and regeneration. Microparticles (MPs) mediate cytokine sustained release, and can be utilized to overcome issues related to the limited therapeutic protein stability during systemic administration. We sought to examine whether the administration of microparticles (MPs) containing FGF1 and NRG1 could promote cardiac regeneration in a myocardial infarction (MI) rat model. We investigated the possible underlying mechanisms contributing to the beneficial effects of this therapy, especially those linked to endogenous regeneration. FGF1- and NRG1-loaded MPs were prepared using a multiple emulsion solvent evaporation technique. Seventy-three female Sprague-Dawley rats underwent permanent left anterior descending coronary artery occlusion, and MPs were intramyocardially injected in the peri-infarcted zone four days later. Cardiac function, heart tissue remodeling, revascularization, apoptosis, cardiomyocyte proliferation, and stem cell homing were evaluated one week and three months after treatment. MPs were shown to efficiently encapsulate FGF1 and NRG1, releasing the bioactive proteins in a sustained manner. Three months after treatment, a statistically significant improvement in cardiac function was detected in rats treated with growth factor-loaded MPs (FGF1, NRG1, or FGF1/NRG1). The therapy led to inhibition of cardiac remodeling with smaller infarct size, a lower fibrosis degree and induction of tissue revascularization. Cardiomyocyte proliferation and progenitor cell recruitment were detected. Our data support the therapeutic benefit of NRG1 and FGF1 when combined with protein delivery systems for cardiac regeneration. This approach could be scaled up for use in pre-clinical and clinical studies. © 2013.

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia.

PubMed

Yamamori, Hidenaga; Hashimoto, Ryota; Verrall, Louise; Yasuda, Yuka; Ohi, Kazutaka; Fukumoto, Motoyuki; Umeda-Yano, Satomi; Ito, Akira; Takeda, Masatoshi

2011-07-01

The dysbindin-1 and neuregulin-1 (NRG-1) genes are related to schizophrenia. Expression studies in postmortem brains have revealed lower expression of dysbindin-1 and higher expression of NRG-1 in brain tissue from subjects with schizophrenia. In addition to the difficulty of sampling, the use of postmortem brain tissues is not ideal because these tissues are heterogeneous with respect to biochemical parameters, lifetime history of medications and physiological status at the time of death. In contrast, medication and environmental influences that could mask the genetic basis of differences in RNA expression are removed in immortalized lymphocytes by culturing. Only a few microarray analysis studies using immortalized lymphocytes in schizophrenia have been reported, and whether immortalized lymphocytes are an appropriate alternative to neuronal tissue remains controversial. In this study, we measured the mRNA expression levels of dysbindin-1, NRG-1 and two other genes (NPY1R and GNAO1) in immortalized lymphocytes from 45 patients with schizophrenia and 45 controls using real-time quantitative reverse transcriptase-PCR. No difference was observed between patients and controls with respect to the expression of dysbindin-1, NRG-1, NPY1R or GNAO1 gene. Our findings suggest that the gene expression profile of immortalized lymphocyte from schizophrenic patients is different from that in postmortem brain tissue at least with respect to the dysbindin-1 and NRG-1 genes.

Endocytic pathways downregulate the L1-type cell adhesion molecule neuroglian to promote dendrite pruning in Drosophila.

PubMed

Zhang, Heng; Wang, Yan; Wong, Jack Jing Lin; Lim, Kah-Leong; Liou, Yih-Cherng; Wang, Hongyan; Yu, Fengwei

2014-08-25

Pruning of unnecessary axons and/or dendrites is crucial for maturation of the nervous system. However, little is known about cell adhesion molecules (CAMs) that control neuronal pruning. In Drosophila, dendritic arborization neurons, ddaCs, selectively prune their larval dendrites. Here, we report that Rab5/ESCRT-mediated endocytic pathways are critical for dendrite pruning. Loss of Rab5 or ESCRT function leads to robust accumulation of the L1-type CAM Neuroglian (Nrg) on enlarged endosomes in ddaC neurons. Nrg is localized on endosomes in wild-type ddaC neurons and downregulated prior to dendrite pruning. Overexpression of Nrg alone is sufficient to inhibit dendrite pruning, whereas removal of Nrg causes precocious dendrite pruning. Epistasis experiments indicate that Rab5 and ESCRT restrain the inhibitory role of Nrg during dendrite pruning. Thus, this study demonstrates the cell-surface molecule that controls dendrite pruning and defines an important mechanism whereby sensory neurons, via endolysosomal pathway, downregulate the cell-surface molecule to trigger dendrite pruning. Copyright © 2014 Elsevier Inc. All rights reserved.

The Drosophila L1CAM homolog Neuroglian signals through distinct pathways to control different aspects of mushroom body axon development

PubMed Central

Goossens, Tim; Kang, Yuan Y.; Wuytens, Gunther; Zimmermann, Pascale; Callaerts-Végh, Zsuzsanna; Pollarolo, Giulia; Islam, Rafique; Hortsch, Michael; Callaerts, Patrick

2011-01-01

The spatiotemporal integration of adhesion and signaling during neuritogenesis is an important prerequisite for the establishment of neuronal networks in the developing brain. In this study, we describe the role of the L1-type CAM Neuroglian protein (NRG) in different steps of Drosophila mushroom body (MB) neuron axonogenesis. Selective axon bundling in the peduncle requires both the extracellular and the intracellular domain of NRG. We uncover a novel role for the ZO-1 homolog Polychaetoid (PYD) in axon branching and in sister branch outgrowth and guidance downstream of the neuron-specific isoform NRG-180. Furthermore, genetic analyses show that the role of NRG in different aspects of MB axonal development not only involves PYD, but also TRIO, SEMA-1A and RAC1. PMID:21389050

The Drosophila L1CAM homolog Neuroglian signals through distinct pathways to control different aspects of mushroom body axon development.

PubMed

Goossens, Tim; Kang, Yuan Y; Wuytens, Gunther; Zimmermann, Pascale; Callaerts-Végh, Zsuzsanna; Pollarolo, Giulia; Islam, Rafique; Hortsch, Michael; Callaerts, Patrick

2011-04-01

The spatiotemporal integration of adhesion and signaling during neuritogenesis is an important prerequisite for the establishment of neuronal networks in the developing brain. In this study, we describe the role of the L1-type CAM Neuroglian protein (NRG) in different steps of Drosophila mushroom body (MB) neuron axonogenesis. Selective axon bundling in the peduncle requires both the extracellular and the intracellular domain of NRG. We uncover a novel role for the ZO-1 homolog Polychaetoid (PYD) in axon branching and in sister branch outgrowth and guidance downstream of the neuron-specific isoform NRG-180. Furthermore, genetic analyses show that the role of NRG in different aspects of MB axonal development not only involves PYD, but also TRIO, SEMA-1A and RAC1.

Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration.

PubMed

Farkas, Johanna E; Freitas, Polina D; Bryant, Donald M; Whited, Jessica L; Monaghan, James R

2016-08-01

The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration. © 2016. Published by The Company of Biologists Ltd.

Transcriptional profiling of the early stages of germination in Candida albicans by real-time RT-PCR.

PubMed

Toyoda, Mika; Cho, Tamaki; Kaminishi, Hidenori; Sudoh, Masayuki; Chibana, Hiroji

2004-12-01

By using real-time RT-PCR, we profiled the expression of CGR1, CaMSI3, EFG1, NRG1, and TUP1 in Candida albicans strains JCM9061 and CAI4 under several conditions, including induction of morphological transition, heat shock, and treatment with calcium inhibitors. Expression of CaMSI3 changed under these growth conditions except during heat shock. CGR1 expression increased during the early stages of hyphal growth in JCM9061, while expression was strain-dependent during heat shock. Both EFG1 and NRG1 were similarly expressed under hypha-inducing conditions and heat shock. Expression of TUP1 was slightly different from the expression of EFG1 or NRG1.

ErbB4 signaling stimulates pro-inflammatory macrophage apoptosis and limits colonic inflammation

PubMed Central

Schumacher, Michael A; Hedl, Matija; Abraham, Clara; Bernard, Jessica K; Lozano, Patricia R; Hsieh, Jonathan J; Almohazey, Dana; Bucar, Edie B; Punit, Shivesh; Dempsey, Peter J; Frey, Mark R

2017-01-01

Efficient clearance of pro-inflammatory macrophages from tissues after resolution of a challenge is critical to prevent prolonged inflammation. Defects in clearance can contribute to conditions such as inflammatory bowel disease, and thus may be therapeutically targetable. However, the signaling pathways that induce termination of pro-inflammatory macrophages are incompletely defined. We tested whether the ErbB4 receptor tyrosine kinase, previously not known to have role in macrophage biology, is involved in this process. In vitro, pro-inflammatory activation of cultured murine and human macrophages induced ErbB4 expression; in contrast, other ErbB family members were not induced in pro-inflammatory cells, and other innate immune lineages (dendritic cells, neutrophils) did not express detectable ErbB4 levels. Treatment of activated pro-inflammatory macrophages with the ErbB4 ligand neuregulin-4 (NRG4) induced apoptosis. ErbB4 localized to the mitochondria in these cells. Apoptosis was accompanied by loss of mitochondrial membrane potential, and was dependent upon the proteases that generate the cleaved ErbB4 intracellular domain fragment, suggesting a requirement for this fragment and mitochondrial pathway apoptosis. In vivo, ErbB4 was highly expressed on pro-inflammatory macrophages but not neutrophils during experimental DSS colitis in C57Bl/6 mice. Active inflammation in this model suppressed NRG4 expression, which may allow for macrophage persistence and ongoing inflammation. Consistent with this notion, NRG4 levels rebounded during the recovery phase, and administration of exogenous NRG4 during colitis reduced colonic macrophage numbers and ameliorated inflammation. These data define a novel role for ErbB4 in macrophage apoptosis, and outline a mechanism of feedback inhibition that may promote resolution of colitis. PMID:28230865

NPDES Permit for NRG Energy (Formerly GenOn Potomac River Generating Station)

EPA Pesticide Factsheets

Under National Pollutant Discharge Elimination System permit number DC0022004, NRG Energy (Formerly GenOn Potomac River Generating Station) is authorized to discharge from a facility into receiving waters named Potomac River.

76 FR 26282 - NRG Solar Roadrunner LLC; Supplemental Notice That Initial Market-Based Rate Filing Includes...

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Development of an ErbB4 monoclonal antibody that blocks neuregulin-1-induced ErbB4 activation in cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Okazaki, Shogo; Nakatani, Fumi; Masuko, Kazue

2016-01-29

The use of monoclonal antibodies (mAbs) for cancer therapy is one of the most important strategies for current cancer treatment. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, which regulates cancer cell proliferation, survival, and migration, is a major molecular target for antibody-based therapy. ErbB4/HER4, which contains a ligand-binding extracellular region, is activated by several ligands, including neuregulins (NRGs), heparin-binding EGF-like growth factor, betacellulin and epiregulin. Although there are clinically approved antibodies for ErbB1 and ErbB2, there are no available therapeutic mAbs for ErbB4, and it is not known whether ErbB4 is a useful target for antibody-basedmore » cancer therapy. In this study, we developed an anti-ErbB4 mAb (clone P6-1) that suppresses NRG-dependent activation of ErbB4 and examined its effect on breast cancer cell proliferation in the extracellular matrix. - Highlights: • We newly generated four clones of human ErbB4 specific mAb. • ErbB4 mAb clone P6-1 blocks ErbB4 phosphorylation induced by NRG-1. • ErbB4 mAb clone P6-1 suppresses NRG-1-promoted breast cancer cells proliferation on three dimensional culture condition.« less

Transsynaptic coordination of synaptic growth, function, and stability by the L1-type CAM Neuroglian.

PubMed

Enneking, Eva-Maria; Kudumala, Sirisha R; Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg-Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture.

75 FR 62374 - Combined Notice of Filings #1

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Cell autonomous regulation of hippocampal circuitry via Aph1b-γ-secretase/neuregulin 1 signalling

PubMed Central

Fazzari, Pietro; Snellinx, An; Sabanov, Victor; Ahmed, Tariq; Serneels, Lutgarde; Gartner, Annette; Shariati, S Ali M; Balschun, Detlef; De Strooper, Bart

2014-01-01

Neuregulin 1 (NRG1) and the γ-secretase subunit APH1B have been previously implicated as genetic risk factors for schizophrenia and schizophrenia relevant deficits have been observed in rodent models with loss of function mutations in either gene. Here we show that the Aph1b-γ-secretase is selectively involved in Nrg1 intracellular signalling. We found that Aph1b-deficient mice display a decrease in excitatory synaptic markers. Electrophysiological recordings show that Aph1b is required for excitatory synaptic transmission and plasticity. Furthermore, gain and loss of function and genetic rescue experiments indicate that Nrg1 intracellular signalling promotes dendritic spine formation downstream of Aph1b-γ-secretase in vitro and in vivo. In conclusion, our study sheds light on the physiological role of Aph1b-γ-secretase in brain and provides a new mechanistic perspective on the relevance of NRG1 processing in schizophrenia. DOI: http://dx.doi.org/10.7554/eLife.02196.001 PMID:24891237

YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression

PubMed Central

He, Chunbo; Lv, Xiangmin; Hua, Guohua; Lele, Subodh M; Remmenga, Steven; Dong, Jixin; Davis, John S; Wang, Cheng

2014-01-01

Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces expression of EGF receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, while knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF&NRGs/ERBBs/YAP/HBEGF&NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression. PMID:25798835

Perinatal phencyclidine administration decreases the density of cortical interneurons and increases the expression of neuregulin-1.

PubMed

Radonjić, Nevena V; Jakovcevski, Igor; Bumbaširević, Vladimir; Petronijević, Nataša D

2013-06-01

Perinatal phencyclidine (PCP) administration in rat blocks the N-methyl D-aspartate receptor (NMDAR) and causes symptoms reminiscent of schizophrenia in human. A growing body of evidence suggests that alterations in γ-aminobutyric acid (GABA) interneuron neurotransmission may be associated with schizophrenia. Neuregulin-1 (NRG-1) is a trophic factor important for neurodevelopment, synaptic plasticity, and wiring of GABA circuits. The aim of this study was to determine the long-term effects of perinatal PCP administration on the projection and local circuit neurons and NRG-1 expression in the cortex and hippocampus. Rats were treated on postnatal day 2 (P2), P6, P9, and P12 with either PCP (10 mg/kg) or saline. Morphological studies and determination of NRG-1 expression were performed at P70. We demonstrate reduced densities of principal neurons in the CA3 and dentate gyrus (DG) subregions of the hippocampus and a reduction of major interneuronal populations in all cortical and hippocampal regions studied in PCP-treated rats compared with controls. For the first time, we show the reduced density of reelin- and somatostatin-positive cells in the cortex and hippocampus of animals perinatally treated with PCP. Furthermore, an increase in the numbers of perisomatic inhibitory terminals around the principal cells was observed in the motor cortex and DG. We also show that perinatal PCP administration leads to an increased NRG-1 expression in the cortex and hippocampus. Taken together, our findings demonstrate that perinatal PCP administration increases NRG-1 expression and reduces the number of projecting and local circuit neurons, revealing complex consequences of NMDAR blockade.

Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

PubMed Central

Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

2016-01-01

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials. PMID:27184924

The neuron-specific RNA-binding protein ELAV regulates neuroglian alternative splicing in neurons and binds directly to its pre-mRNA

PubMed Central

Lisbin, Michael J.; Qiu, Jan; White, Kalpana

2001-01-01

Drosophila melanogaster neural-specific protein, ELAV, has been shown to regulate the neural-specific splicing of three genes: neuroglian (nrg), erect wing, and armadillo. Alternative splicing of the nrg transcript involves alternative inclusion of a 3′-terminal exon. Here, using a minigene reporter, we show that the nrg alternatively spliced intron (nASI) has all the determinants required to recreate proper neural-specific RNA processing seen with the endogenous nrg transcript, including regulation by ELAV. An in vitro UV cross-linking assay revealed that ELAV from nuclear extracts cross-links to four distinct sites along the 3200 nucleotide long nASI; one EXS is positioned at the polypyrimidine tract of the default 3′ splice site. ELAV cross-linking sites (EXSs) have in common long tracts of (U)-rich sequence rather than a precise consensus; moreover, each tract has at least two 8/10U elements; their importance is validated by mutant transgene reporter analysis. Further, we propose criteria for ELAV target sequence recognition based on the four EXSs, sites within the nASI that are (U) rich but do not cross-link with ELAV, and predicted EXSs from a phylogenetic comparison with Drosophila virilis nASI. These results suggest that ELAV regulates nrg alternative splicing by direct interaction with the nASI. PMID:11581160

The neuron-specific RNA-binding protein ELAV regulates neuroglian alternative splicing in neurons and binds directly to its pre-mRNA.

PubMed

Lisbin, M J; Qiu, J; White, K

2001-10-01

Drosophila melanogaster neural-specific protein, ELAV, has been shown to regulate the neural-specific splicing of three genes: neuroglian (nrg), erect wing, and armadillo. Alternative splicing of the nrg transcript involves alternative inclusion of a 3'-terminal exon. Here, using a minigene reporter, we show that the nrg alternatively spliced intron (nASI) has all the determinants required to recreate proper neural-specific RNA processing seen with the endogenous nrg transcript, including regulation by ELAV. An in vitro UV cross-linking assay revealed that ELAV from nuclear extracts cross-links to four distinct sites along the 3200 nucleotide long nASI; one EXS is positioned at the polypyrimidine tract of the default 3' splice site. ELAV cross-linking sites (EXSs) have in common long tracts of (U)-rich sequence rather than a precise consensus; moreover, each tract has at least two 8/10U elements; their importance is validated by mutant transgene reporter analysis. Further, we propose criteria for ELAV target sequence recognition based on the four EXSs, sites within the nASI that are (U) rich but do not cross-link with ELAV, and predicted EXSs from a phylogenetic comparison with Drosophila virilis nASI. These results suggest that ELAV regulates nrg alternative splicing by direct interaction with the nASI.

Analysis of temperature profile and electric field in natural rubber glove due to microwave heating: effects of waveguide position

NASA Astrophysics Data System (ADS)

Keangin, P.; Narumitbowonkul, U.; Rattanadecho, P.

2018-01-01

Natural rubber (NR) is the key raw material used in the manufacture of other products such as rubber band, tire and shoes. Recently, the NR is used in natural rubber glove ( NRG) manufacturing in the industrial and medical fields. This research aims to investigate the electromagnetic wave propagation and heat transfer in NRG due to heating with microwave energy within the microwave oven at a microwave frequency of 2.45 GHz. Three-dimensional model of NRG and microwave oven are considered in this work. The comparative effects of waveguide position on the electric field and temperature profile in NRG when subjected to microwave energy are discussed. The finite element method (FEM) is used to solve the transient Maxwell’s equation coupled with the transient heat transfer equation. The simulation results with computer programs are validated with experimental results. The placement of waveguides in three cases are left hand side of microwave oven, right hand side of microwave oven and left and right hand sides of microwave oven are investigated. The findings revealed that the placing the waveguide on the right side of the microwave oven gives the highest electric field and temperature profile. The values obtained provide an indication toward understanding the study of heat transfer in NRG during microwave heating in the industry.

Catheter-based Intramyocardial Injection of FGF1 or NRG1-loaded MPs Improves Cardiac Function in a Preclinical Model of Ischemia-Reperfusion

NASA Astrophysics Data System (ADS)

Garbayo, Elisa; Gavira, Juan José; de Yebenes, Manuel Garcia; Pelacho, Beatriz; Abizanda, Gloria; Lana, Hugo; Blanco-Prieto, María José; Prosper, Felipe

2016-05-01

Cardiovascular protein therapeutics such as neuregulin (NRG1) and acidic-fibroblast growth factor (FGF1) requires new formulation strategies that allow for sustained bioavailability of the drug in the infarcted myocardium. However, there is no FDA-approved injectable protein delivery platform due to translational concerns about biomaterial administration through cardiac catheters. We therefore sought to evaluate the efficacy of percutaneous intramyocardial injection of poly(lactic-co-glycolic acid) microparticles (MPs) loaded with NRG1 and FGF1 using the NOGA MYOSTAR injection catheter in a porcine model of ischemia-reperfusion. NRG1- and FGF1-loaded MPs were prepared using a multiple emulsion solvent-evaporation technique. Infarcted pigs were treated one week after ischemia-reperfusion with MPs containing NRG1, FGF1 or non-loaded MPs delivered via clinically-translatable percutaneous transendocardial-injection. Three months post-treatment, echocardiography indicated a significant improvement in systolic and diastolic cardiac function. Moreover, improvement in bipolar voltage and decrease in transmural infarct progression was demonstrated by electromechanical NOGA-mapping. Functional benefit was associated with an increase in myocardial vascularization and remodeling. These findings in a large animal model of ischemia-reperfusion demonstrate the feasibility and efficacy of using MPs as a delivery system for growth factors and provide strong evidence to move forward with clinical studies using therapeutic proteins combined with catheter-compatible biomaterials.

Myocardial ischemia/reperfusion upregulates the transcription of the Neuregulin1 receptor ErbB3, but only postconditioning preserves protein translation: Role in oxidative stress.

PubMed

Morano, Michela; Angotti, Carmelina; Tullio, Francesca; Gambarotta, Giovanna; Penna, Claudia; Pagliaro, Pasquale; Geuna, Stefano

2017-04-15

Neuregulin1 (Nrg1) and its receptors ErbB are crucial for heart development and for adult heart structural maintenance and function and Nrg1 has been proposed for heart failure treatment. Infarct size is the major determinant of heart failure and the mechanism of action and the role of each ErbB receptor remain obscure, especially in the post-ischemic myocardium. We hypothesized that Nrg1 and ErbB are affected at transcriptional level early after ischemia/reperfusion (I/R) injury, and that the protective postconditioning procedure (PostC, brief cycles of ischemia/reperfusion carried out after a sustained ischemia) can influence this pathway. The Langendorff's heart was used as an ex-vivo model to mimic an I/R injury in the whole rat heart; after 30min of ischemia and 2h of reperfusion, with or without PostC, Nrg1 and ErbB expression were analysed by quantitative real-time PCR and Western blot. While no changes occur for ErbB2, ErbB4 and Nrg1, an increase of ErbB3 expression occurs after I/R injury, with and without PostC. However, I/R reduces ErbB3 protein, whereas PostC preserves it. An in vitro analysis with H9c2 cells exposed to redox-stress indicated that the transient over-expression of ErbB3 alone is able to increase cell survival (MTT assay), limiting mitochondrial dysfunction (JC-1 probe) and apoptotic signals (Bax/Bcl-2 ratio). This study suggests ErbB3 as a protective factor against death pathways activated by redox stress and supports an involvement of this receptor in the pro-survival responses. Copyright © 2017 Elsevier B.V. All rights reserved.

75 FR 75994 - Application To Export Electric Energy; NRG Power Marketing LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-07

... Marketing LLC AGENCY: Office of Electricity Delivery and Energy Reliability, DOE. ACTION: Notice of application. SUMMARY: NRG Power Marketing LLC (NRGPML) has applied to renew its authority to transmit electric... to Canada would be surplus energy purchased from electric utilities, Federal power marketing agencies...

Molecular Characterization of Striated Muscle-Specific Gab1 Isoform as a Critical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes

PubMed Central

Yasui, Taku; Masaki, Takeshi; Arita, Yoh; Ishibashi, Tomohiko; Inagaki, Tadakatsu; Okazawa, Makoto; Oka, Toru; Shioyama, Wataru; Yamauchi-Takihara, Keiko; Komuro, Issei; Sakata, Yasushi; Nakaoka, Yoshikazu

2016-01-01

Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice. In that study, we also found that there is an unknown high-molecular weight (high-MW) Gab1 isoform (120 kDa) expressed exclusively in the heart, in addition to the ubiquitously expressed low-MW (100 kDa) Gab1. However, the high-MW Gab1 has been molecularly ill-defined to date. Here, we identified the high-MW Gab1 as a striated muscle-specific isoform. The high-MW Gab1 has an extra exon encoding 27 amino acid residues between the already-known 3rd and 4th exons of the ubiquitously expressed low-MW Gab1. Expression analysis by RT-PCR and immunostaining with the antibody specific for the high-MW Gab1 demonstrate that the high-MW Gab1 isoform is exclusively expressed in striated muscle including heart and skeletal muscle. The ratio of high-MW Gab1/ total Gab1 mRNAs increased along with heart development. The high-MW Gab1 isoform in heart underwent tyrosine-phosphorylation exclusively after intravenous administration of NRG-1, among several growth factors. Adenovirus-mediated overexpression of the high-MW Gab1 induces more sustained activation of AKT after stimulation with NRG-1 in cardiomyocytes compared with that of β-galactosidase. On the contrary, siRNA-mediated knockdown of the high-MW Gab1 significantly attenuated AKT activation after stimulation with NRG-1 in cardiomyocytes. Taken together, these findings suggest that the striated muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling in cardiomyocytes. PMID:27861634

Molecular Characterization of Striated Muscle-Specific Gab1 Isoform as a Critical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes.

PubMed

Yasui, Taku; Masaki, Takeshi; Arita, Yoh; Ishibashi, Tomohiko; Inagaki, Tadakatsu; Okazawa, Makoto; Oka, Toru; Shioyama, Wataru; Yamauchi-Takihara, Keiko; Komuro, Issei; Sakata, Yasushi; Nakaoka, Yoshikazu

2016-01-01

Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice. In that study, we also found that there is an unknown high-molecular weight (high-MW) Gab1 isoform (120 kDa) expressed exclusively in the heart, in addition to the ubiquitously expressed low-MW (100 kDa) Gab1. However, the high-MW Gab1 has been molecularly ill-defined to date. Here, we identified the high-MW Gab1 as a striated muscle-specific isoform. The high-MW Gab1 has an extra exon encoding 27 amino acid residues between the already-known 3rd and 4th exons of the ubiquitously expressed low-MW Gab1. Expression analysis by RT-PCR and immunostaining with the antibody specific for the high-MW Gab1 demonstrate that the high-MW Gab1 isoform is exclusively expressed in striated muscle including heart and skeletal muscle. The ratio of high-MW Gab1/ total Gab1 mRNAs increased along with heart development. The high-MW Gab1 isoform in heart underwent tyrosine-phosphorylation exclusively after intravenous administration of NRG-1, among several growth factors. Adenovirus-mediated overexpression of the high-MW Gab1 induces more sustained activation of AKT after stimulation with NRG-1 in cardiomyocytes compared with that of β-galactosidase. On the contrary, siRNA-mediated knockdown of the high-MW Gab1 significantly attenuated AKT activation after stimulation with NRG-1 in cardiomyocytes. Taken together, these findings suggest that the striated muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling in cardiomyocytes.

Perinatal asphyxia alters neuregulin-1 and COMT gene expression in the medial prefrontal cortex in rats.

PubMed

Wakuda, Tomoyasu; Iwata, Keiko; Iwata, Yasuhide; Anitha, Ayyappan; Takahashi, Taro; Yamada, Kohei; Vasu, Mahesh Mundalil; Matsuzaki, Hideo; Suzuki, Katsuaki; Mori, Norio

2015-01-02

Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15 min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12 weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12 weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12 weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia. Copyright © 2014 Elsevier Inc. All rights reserved.

An efficient Volumetric Arc Therapy treatment planning approach for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT).

PubMed

Shen, Jin; Bender, Edward; Yaparpalvi, Ravindra; Kuo, Hsiang-Chi; Basavatia, Amar; Hong, Linda; Bodner, William; Garg, Madhur K; Kalnicki, Shalom; Tomé, Wolfgang A

2015-01-01

An efficient and simple class solution is proposed for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) planning using the Volumetric Arc Therapy (VMAT) delivery technique following the NRG Oncology protocol NRG-CC001 treatment planning guidelines. The whole-brain planning target volume (PTV) was subdivided into subplanning volumes that lie in plane and out of plane with the hippocampal-avoidance volume. To further improve VMAT treatment plans, a partial-field dual-arc technique was developed. Both the arcs were allowed to overlap on the in-plane subtarget volume, and in addition, one arc covered the superior out-of-plane sub-PTV, while the other covered the inferior out-of-plane subtarget volume. For all plans (n = 20), the NRG-CC001 protocol dose-volume criteria were met. Mean values of volumes for the hippocampus and the hippocampal-avoidance volume were 4.1 cm(3) ± 1.0 cm(3) and 28.52 cm(3) ± 3.22 cm(3), respectively. For the PTV, the average values of D(2%) and D(98%) were 36.1 Gy ± 0.8 Gy and 26.2 Gy ± 0.6 Gy, respectively. The hippocampus D(100%) mean value was 8.5 Gy ± 0.2 Gy and the maximum dose was 15.7 Gy ± 0.3 Gy. The corresponding plan quality indices were 0.30 ± 0.01 (homogeneity index), 0.94 ± 0.01 (target conformality), and 0.75 ± 0.02 (confirmation number). The median total monitor unit (MU) per fraction was 806 MU (interquartile range [IQR]: 792 to 818 MU) and the average beam total delivery time was 121.2 seconds (IQR: 120.6 to 121.35 seconds). All plans passed the gamma evaluation using the 5-mm, 4% criteria, with γ > 1 of not more than 9.1% data points for all fields. An efficient and simple planning class solution for HA-WBRT using VMAT has been developed that allows all protocol constraints of NRG-CC001 to be met. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, Jin; Bender, Edward; Yaparpalvi, Ravindra

An efficient and simple class solution is proposed for hippocampal-avoidance whole-brain radiation therapy (HA-WBRT) planning using the Volumetric Arc Therapy (VMAT) delivery technique following the NRG Oncology protocol NRG-CC001 treatment planning guidelines. The whole-brain planning target volume (PTV) was subdivided into subplanning volumes that lie in plane and out of plane with the hippocampal-avoidance volume. To further improve VMAT treatment plans, a partial-field dual-arc technique was developed. Both the arcs were allowed to overlap on the in-plane subtarget volume, and in addition, one arc covered the superior out-of-plane sub-PTV, while the other covered the inferior out-of-plane subtarget volume. For allmore » plans (n = 20), the NRG-CC001 protocol dose-volume criteria were met. Mean values of volumes for the hippocampus and the hippocampal-avoidance volume were 4.1 cm{sup 3} ± 1.0 cm{sup 3} and 28.52 cm{sup 3} ± 3.22 cm{sup 3}, respectively. For the PTV, the average values of D{sub 2%} and D{sub 98%} were 36.1 Gy ± 0.8 Gy and 26.2 Gy ± 0.6 Gy, respectively. The hippocampus D{sub 100%} mean value was 8.5 Gy ± 0.2 Gy and the maximum dose was 15.7 Gy ± 0.3 Gy. The corresponding plan quality indices were 0.30 ± 0.01 (homogeneity index), 0.94 ± 0.01 (target conformality), and 0.75 ± 0.02 (confirmation number). The median total monitor unit (MU) per fraction was 806 MU (interquartile range [IQR]: 792 to 818 MU) and the average beam total delivery time was 121.2 seconds (IQR: 120.6 to 121.35 seconds). All plans passed the gamma evaluation using the 5-mm, 4% criteria, with γ > 1 of not more than 9.1% data points for all fields. An efficient and simple planning class solution for HA-WBRT using VMAT has been developed that allows all protocol constraints of NRG-CC001 to be met.« less

75 FR 59247 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-27

... Segundo Power II LLC, Long Beach Generation LLC, Long Beach Peakers LLC, NRG Power Marketing Inc., Cabrillo Power I LLC, Cabrillo Power II LLC, El Segundo Power LLC, NRG Solar Blythe LLC, Saguaro Power... LLC, Dunkirk Power LLC, GenConn Energy LLC, GenCon Devon LLC, GenConn Middletown LLC, Huntley Power...

77 FR 11515 - Application to Export Electric Energy; NRG Power Marketing LLC

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-27

... DEPARTMENT OF ENERGY [OE Docket No. EA-384] Application to Export Electric Energy; NRG Power... electric energy from the United States to Mexico pursuant to section 202(e) of the Federal Power Act (FPA... requested. The electric energy that NRGPML proposes to export to Mexico would be surplus energy purchased...

The L1-CAM, Neuroglian, functions in glial cells for Drosophila antennal lobe development.

PubMed

Chen, Weitao; Hing, Huey

2008-07-01

Although considerable progress has been made in understanding the roles of olfactory receptor neurons (ORNs) and projection neurons (PNs) in Drosophila antennal lobe (AL) development, the roles of glia have remained largely mysterious. Here, we show that during Drosophila metamorphosis, a population of midline glial cells in the brain undergoes extensive cellular remodeling and is closely associated with the collateral branches of ORN axons. These glial cells are required for ORN axons to project across the midline and establish the contralateral wiring in the ALs. We find that Neuroglian (Nrg), the Drosophila homolog of the vertebrate cell adhesion molecule, L1, is expressed and functions in the midline glial cells to regulate their proper development. Loss of Nrg causes the disruption in glial morphology and the agenesis of the antennal commissural tract. Our genetic analysis further demonstrates that the functions of Nrg in the midline glia require its ankyrin-binding motif. We propose that Nrg is an important regulator of glial morphogenesis and axon guidance in AL development. (Copyright) 2008 Wiley Periodicals, Inc.

YAP forms autocrine loops with the ERBB pathway to regulate ovarian cancer initiation and progression.

PubMed

He, C; Lv, X; Hua, G; Lele, S M; Remmenga, S; Dong, J; Davis, J S; Wang, C

2015-12-10

Mechanisms underlying ovarian cancer initiation and progression are unclear. Herein, we report that the Yes-associated protein (YAP), a major effector of the Hippo tumor suppressor pathway, interacts with ERBB signaling pathways to regulate the initiation and progression of ovarian cancer. Immunohistochemistry studies indicate that YAP expression is associated with poor clinical outcomes in patients. Overexpression or constitutive activation of YAP leads to transformation and tumorigenesis in human ovarian surface epithelial cells, and promotes growth of cancer cells in vivo and in vitro. YAP induces the expression of epidermal growth factor (EGF) receptors (EGFR, ERBB3) and production of EGF-like ligands (HBEGF, NRG1 and NRG2). HBEGF or NRG1, in turn, activates YAP and stimulates cancer cell growth. Knockdown of ERBB3 or HBEGF eliminates YAP effects on cell growth and transformation, whereas knockdown of YAP abrogates NRG1- and HBEGF-stimulated cell proliferation. Collectively, our study demonstrates the existence of HBEGF & NRGs/ERBBs/YAP/HBEGF & NRGs autocrine loop that controls ovarian cell tumorigenesis and cancer progression.

SU-F-P-13: NRG Oncology Medical Physics Manpower Survey Quantifying Support Demands for Multi Institutional Clinical Trials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Monroe, J; Case Western Reserve University; Boparai, K

Purpose: A survey was taken by NRG Oncology to assess Full Time Equivalent (FTE) contributions to multi institutional clinical trials by medical physicists.No current quantification of physicists’ efforts in FTE units associated with clinical trials is available. The complexity of multi-institutional trials increases with new technologies and techniques. Proper staffing may directly impact the quality of trial data and outcomes. The demands on physics time supporting clinical trials needs to be assessed. Methods: The NRG Oncology Medical Physicist Subcommittee created a sixteen question survey to obtain this FTE data. IROC Houston distributed the survey to their list of 1802 contactmore » physicists. Results: After three weeks, 363 responded (20.1% response). 187 (51.5%) institutions reporting external beam participation were processed. There was a wide range in number of protocols active and supported at each institution. Of the 187 clinics, 134 (71.7%) participate in 0 to 10 trials, 28 (15%) in 11 to 20 trials, 10 (5.3%) in 21 to 30 trials, 9 (4.8%) had 40 to 75 trials. On average, physicist spent 2.7 hours (SD: 6.0) per week supervising or interacting with clinical trial staff. 1.25 hours (SD: 3.37), 1.83 hours (SD: 4.13), and 0.64 hours(SD: 1.13) per week were spent on patient simulation, reviewing treatment plans, and maintaining a DICOM server, respectively. For all protocol credentialing activities, physicist spent an average of 37.05 hours (SD: 96.94) yearly. To support dosimetrists, clinicians, and therapists, physicist spend on average 2.07 hours (SD: 3.52) per week just reading protocols. Physicist attended clinical trial meetings for on average 1.13 hours (SD: 1.85) per month. Conclusion: Responding physicists spend a nontrivial amount of time: 8.8 hours per week (0.22 FTE) supporting, on average, 9 active multi-institutional clinical trials.« less

Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1.

PubMed

O'Tuathaigh, Colm M P; Fumagalli, Fabio; Desbonnet, Lieve; Perez-Branguli, Francesc; Moloney, Gerard; Loftus, Samim; O'Leary, Claire; Petit, Emilie; Cox, Rachel; Tighe, Orna; Clarke, Gerard; Lai, Donna; Harvey, Richard P; Cryan, John F; Mitchell, Kevin J; Dinan, Timothy G; Riva, Marco A; Waddington, John L

2017-01-01

Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Predictors of Radiation Therapy–Related Gastrointestinal Toxicity From Anal Cancer Dose-Painted Intensity Modulated Radiation Therapy: Secondary Analysis of NRG Oncology RTOG 0529

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olsen, Jeffrey R., E-mail: Jeffrey.R.Olsen@ucdenver.edu; Moughan, Jennifer; Myerson, Robert

Purpose: NRG Oncology RTOG 0529 assessed the feasibility of dose-painted intensity modulated radiation therapy (DP-IMRT) to reduce the acute morbidity of chemoradiation with 5-fluorouracil (5FU) and mitomycin-C (MMC) for T2-4N0-3M0 anal cancer. This secondary analysis was performed to identify patient and treatment factors associated with acute and late gastrointestinal (GI) adverse events (AEs). Methods and Materials: NRG Oncology RTOG 0529 treatment plans were reviewed to extract dose-volume data for tightly contoured small bowel, loosely contoured anterior pelvic contents (APC), and uninvolved colon outside the target volume (UC). Univariate logistic regression was performed to evaluate association between volumes of each structuremore » receiving doses ≥5 to 60 Gy (V5-V60) in 5-Gy increments between patients with and without grade ≥2 acute and late GI AEs, and grade ≥3 acute GI AEs. Additional patient and treatment factors were evaluated in multivariate logistic regression (acute AEs) or Cox proportional hazards models (late AEs). Results: Among 52 evaluable patients, grade ≥2 acute, grade ≥2 late, and grade ≥3 acute GI AEs were observed in 35, 17, and 10 patients, respectively. Trends (P<.05) toward statistically significant associations were observed between grade ≥2 acute GI AEs and small bowel dose (V20-V40), grade ≥2 late GI AEs and APC dose (V60), grade ≥3 acute GI AEs and APC dose (V5-V25), increasing age, tumor size >4 cm, and worse Zubrod performance status. Small bowel volumes of 186.0 cc, 155.0 cc, 41.0 cc, and 30.4 cc receiving doses greater than 25, 30, 35, and 40 Gy, respectively, correlated with increased risk of acute grade ≥2 GI AEs. Conclusions: Acute and late GI AEs from 5FU/MMC chemoradiation using DP-IMRT correlate with radiation dose to the small bowel and APC. Such associations will be incorporated in the dose-volume normal tissue constraint design for future NRG oncology anal cancer studies.« less

76 FR 36914 - Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-23

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL11-42-000] Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas Turbine Power LLC, Dunkirk Power LLC, Huntley Power LLC, Oswego Harbor Power LLC, TC Ravenswood, LLC, v. New York Independent System Operator, Inc. Notice of Revised...

76 FR 34692 - Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-14

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL11-42-000] Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas Turbine Power LLC, Dunkirk Power LLC, Huntley Power LLC, Oswego Harbor Power LLC, TC Ravenswood, LLC; v. New York Independent System Operator, Inc.; Notice of Complaint...

76 FR 36910 - Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-23

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. EL11-42-000] Astoria Generating Company, L.P., NRG Power Marketing LLC, Arthur Kill Power LLC, Astoria Gas Turbine Power LLC, Dunkirk Power LLC, Huntley Power LLC, Oswego Harbor Power LLC, TC Ravenswood, LLC. v. New York Independent System Operator, Inc.; Notice of Amendment t...

Neuregulin 1 Type II-ErbB Signaling Promotes Cell Divisions Generating Neurons from Neural Progenitor Cells in the Developing Zebrafish Brain.

PubMed

Sato, Tomomi; Sato, Fuminori; Kamezaki, Aosa; Sakaguchi, Kazuya; Tanigome, Ryoma; Kawakami, Koichi; Sehara-Fujisawa, Atsuko

2015-01-01

Post-mitotic neurons are generated from neural progenitor cells (NPCs) at the expense of their proliferation. Molecular and cellular mechanisms that regulate neuron production temporally and spatially should impact on the size and shape of the brain. While transcription factors such as neurogenin1 (neurog1) and neurod govern progression of neurogenesis as cell-intrinsic mechanisms, recent studies show regulatory roles of several cell-extrinsic or intercellular signaling molecules including Notch, FGF and Wnt in production of neurons/neural progenitor cells from neural stem cells/radial glial cells (NSCs/RGCs) in the ventricular zone (VZ). However, it remains elusive how production of post-mitotic neurons from neural progenitor cells is regulated in the sub-ventricular zone (SVZ). Here we show that newborn neurons accumulate in the basal-to-apical direction in the optic tectum (OT) of zebrafish embryos. While neural progenitor cells are amplified by mitoses in the apical ventricular zone, neurons are exclusively produced through mitoses of neural progenitor cells in the sub-basal zone, later in the sub-ventricular zone, and accumulate apically onto older neurons. This neurogenesis depends on Neuregulin 1 type II (NRG1-II)-ErbB signaling. Treatment with an ErbB inhibitor, AG1478 impairs mitoses in the sub-ventricular zone of the optic tectum. Removal of AG1478 resumes sub-ventricular mitoses without precedent mitoses in the apical ventricular zone prior to basal-to-apical accumulation of neurons, suggesting critical roles of ErbB signaling in mitoses for post-mitotic neuron production. Knockdown of NRG1-II impairs both mitoses in the sub-basal/sub-ventricular zone and the ventricular zone. Injection of soluble human NRG1 into the developing brain ameliorates neurogenesis of NRG1-II-knockdown embryos, suggesting a conserved role of NRG1 as a cell-extrinsic signal. From these results, we propose that NRG1-ErbB signaling stimulates cell divisions generating neurons from neural progenitor cells in the developing vertebrate brain.

Structural Analysis of Succinoglycan Oligosaccharides from Sinorhizobium meliloti Strains with Different Host Compatibility Phenotypes

PubMed Central

Wood, Karl; Reuhs, Bradley L.

2013-01-01

Sinorhizobium meliloti NRG247 has a Fix+ phenotype on Medicago truncatula A20 and is Fix− on M. truncatula A17, and the phenotype is reversed with S. meliloti NRG185. As the succinoglycan was shown to impact host specificity, an analysis of the succinoglycan oligosaccharides produced by each strain was conducted. The symbiotically active succinoglycan trimeric oligosaccharides (STOs) from the two S. meliloti strains were compared by chromatography and mass spectrometry, and the analysis of the S. meliloti NRG247 oligosaccharides showed that this strain produces an abundance of STO trimer 1 (T1), containing no succinate (i.e., three nonsuccinylated repeats), yet the low-molecular-weight pool contained no nonsuccinylated monomers (potential repeats). This showed that STO T1 is likely to be the active signal on M. truncatula A20 and that the biosynthesis of the STOs is not a random polymerization of the monomer population. The results also suggest that the fully succinylated STO T7 is required for the infection of M. truncatula A17. PMID:23457246

Genome-wide association study for the interaction between BMR and BMI in obese Korean women including overweight.

PubMed

Lee, Myoungsook; Kwon, Dae Young; Kim, Myung-Sunny; Choi, Chong Ran; Park, Mi-Young; Kim, Ae-Jung

2016-02-01

This is the first study to identify common genetic factors associated with the basal metabolic rate (BMR) and body mass index (BMI) in obese Korean women including overweight. This will be a basic study for future research of obese gene-BMR interaction. The experimental design was 2 by 2 with variables of BMR and BMI. A genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) was conducted in the overweight and obesity (BMI > 23 kg/m(2)) compared to the normality, and in women with low BMR (< 1426.3 kcal/day) compared to high BMR. A total of 140 SNPs reached formal genome-wide statistical significance in this study (P < 1 × 10(-4)). Surveys to estimate energy intake using 24-h recall method for three days and questionnaires for family history, a medical examination, and physical activities were conducted. We found that two NRG3 gene SNPs in the 10q23.1 chromosomal region were highly associated with BMR (rs10786764; P = 8.0 × 10(-7), rs1040675; 2.3 × 10(-6)) and BMI (rs10786764; P = 2.5 × 10(-5), rs10786764; 6.57 × 10(-5)). The other genes related to BMI (HSD52, TMA16, MARCH1, NRG1, NRXN3, and STK4) yielded P <10 × 10(-4). Five new loci associated with BMR and BMI, including NRG3, OR8U8, BCL2L2-PABPN1, PABPN1, and SLC22A17 were identified in obese Korean women (P < 1 × 10(-4)). In the questionnaire investigation, significant differences were found in the number of starvation periods per week, family history of stomach cancer, coffee intake, and trial of weight control in each group. We discovered several common BMR- and BMI-related genes using GWAS. Although most of these newly established loci were not previously associated with obesity, they may provide new insights into body weight regulation. Our findings of five common genes associated with BMR and BMI in Koreans will serve as a reference for replication and validation of future studies on the metabolic rate.

Identification and functional analysis of an ammonium transporter in Streptococcus mutans.

PubMed

Ardin, Arifah Chieko; Fujita, Kazuyo; Nagayama, Kayoko; Takashima, Yukiko; Nomura, Ryota; Nakano, Kazuhiko; Ooshima, Takashi; Matsumoto-Nakano, Michiyo

2014-01-01

Streptococcus mutans, a Gram-positive bacterium, is considered to be a major etiologic agent of human dental caries and reported to form biofilms known as dental plaque on tooth surfaces. This organism is also known to possess a large number of transport proteins in the cell membrane for export and import of molecules. Nitrogen is an essential nutrient for Gram-positive bacteria, though alternative sources such as ammonium can also be utilized. In order to obtain nitrogen for macromolecular synthesis, nitrogen-containing compounds must be transported into the cell. However, the ammonium transporter in S. mutans remains to be characterized. The present study focused on characterizing the ammonium transporter gene of S. mutans and its operon, while related regulatory genes were also analyzed. The SMU.1658 gene corresponding to nrgA in S. mutans is homologous to the ammonium transporter gene in Bacillus subtilis and SMU.1657, located upstream of the nrgA gene and predicted to be glnB, is a member of the PII protein family. Using a nrgA-deficient mutant strain (NRGD), we examined bacterial growth in the presence of ammonium, calcium chloride, and manganese sulfate. Fluorescent efflux assays were also performed to reveal export molecules associated with the ammonium transporter. The growth rate of NRGD was lower, while its fluorescent intensity was much higher as compared to the parental strain. In addition, confocal laser scanning microscopy revealed that the structure of biofilms formed by NRGD was drastically different than that of the parental strain. Furthermore, transcriptional analysis showed that the nrgA gene was co-transcribed with the glnB gene. These results suggest that the nrgA gene in S. mutans is essential for export of molecules and biofilm formation.

Identification and Functional Analysis of an Ammonium Transporter in Streptococcus mutans

PubMed Central

Ardin, Arifah Chieko; Fujita, Kazuyo; Nagayama, Kayoko; Takashima, Yukiko; Nomura, Ryota; Nakano, Kazuhiko; Ooshima, Takashi; Matsumoto-Nakano, Michiyo

2014-01-01

Streptococcus mutans, a Gram-positive bacterium, is considered to be a major etiologic agent of human dental caries and reported to form biofilms known as dental plaque on tooth surfaces. This organism is also known to possess a large number of transport proteins in the cell membrane for export and import of molecules. Nitrogen is an essential nutrient for Gram-positive bacteria, though alternative sources such as ammonium can also be utilized. In order to obtain nitrogen for macromolecular synthesis, nitrogen-containing compounds must be transported into the cell. However, the ammonium transporter in S. mutans remains to be characterized. The present study focused on characterizing the ammonium transporter gene of S. mutans and its operon, while related regulatory genes were also analyzed. The SMU.1658 gene corresponding to nrgA in S. mutans is homologous to the ammonium transporter gene in Bacillus subtilis and SMU.1657, located upstream of the nrgA gene and predicted to be glnB, is a member of the PII protein family. Using a nrgA-deficient mutant strain (NRGD), we examined bacterial growth in the presence of ammonium, calcium chloride, and manganese sulfate. Fluorescent efflux assays were also performed to reveal export molecules associated with the ammonium transporter. The growth rate of NRGD was lower, while its fluorescent intensity was much higher as compared to the parental strain. In addition, confocal laser scanning microscopy revealed that the structure of biofilms formed by NRGD was drastically different than that of the parental strain. Furthermore, transcriptional analysis showed that the nrgA gene was co-transcribed with the glnB gene. These results suggest that the nrgA gene in S. mutans is essential for export of molecules and biofilm formation. PMID:25229891

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC.

PubMed

Alvarado, Diego; Ligon, Gwenda F; Lillquist, Jay S; Seibel, Scott B; Wallweber, Gerald; Neumeister, Veronique M; Rimm, David L; McMahon, Gerald; LaVallee, Theresa M

2017-01-01

Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.

MNL1 Regulates Weak Acid–induced Stress Responses of the Fungal Pathogen Candida albicans

PubMed Central

Selway, Laura; Stead, David; Walker, Jan; Yin, Zhikang; Nicholls, Susan M.; Crowe, Jonathan; Sheils, Emma M.; Brown, Alistair J.P.

2008-01-01

MNL1, the Candida albicans homologue of an orphan Msn2-like gene (YER130c in Saccharomyces cerevisiae) has no known function. Here we report that MNL1 regulates weak acid stress responses. Deletion of MNL1 prevents the long-term adaptation of C. albicans cells to weak acid stresses and compromises their global transcriptional response under these conditions. The promoters of Mnl1-dependent genes contain a novel STRE-like element (SLE) that imposes Mnl1-dependent, weak acid stress–induced transcription upon a lacZ reporter in C. albicans. The SLE (HHYYCCCCTTYTY) is related to the Nrg1 response element (NRE) element recognized by the transcriptional repressor Nrg1. Deletion of NRG1 partially restores the ability of C. albicans mnl1 cells to adapt to weak acid stress, indicating that Mnl1 and Nrg1 act antagonistically to regulate this response. Molecular, microarray, and proteomic analyses revealed that Mnl1-dependent adaptation does not occur in cells exposed to proapoptotic or pronecrotic doses of weak acid, suggesting that Ras-pathway activation might suppress the Mnl1-dependent weak acid response in dying cells. Our work defines a role for this YER130c orthologue in stress adaptation and cell death. PMID:18653474

Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian

PubMed Central

Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A.; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg–Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture. PMID:23610557

[Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats].

PubMed

Ji, Y Q; Zhang, R; Teng, L; Li, H Y; Guo, Y L

2017-07-18

Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P <0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats ( P <0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giaddui, T; Li, N; Moore, K

Purpose: To establish a workflow for NRG-GY006 IMRT pre-treatment reviews, incorporating advanced radiotherapy technologies being evaluated as part of the clinical trial. Methods: Pre-Treatment reviews are required for every IMRT case as part of NRG-GY006 (a randomized phase II trial of radiation therapy and cisplatin alone or in combination with intravenous triapine in women with newly diagnosed bulky stage I B2, stage II, IIIB, or IVA cancer of the uterine cervix or stage II-IVA vaginal cancer. The pretreatment review process includes structures review and generating an active bone marrow(ABM)- to be used as an avoidance structure during IMRT optimization- andmore » evaluating initial IMRT plan quality using knowledgeengineering based planning (KBP). Institutions will initially submit their simulation CT scan, structures file and PET/CT to IROC QA center for generating ABM. The ABM will be returned to the institution for use in planning. Institutions will then submit an initial IMRT plan for review and will receive information back following implementation of a KBP algorithm, for use in re-optimization, before submitting the final IMRT used for treatment. Results: ABM structure is generated using MIM vista software (Version 6.5, MIM corporation, Inc.). Here, the planning CT and the diagnostic PET/CT are fused and a sub threshold structure is auto segmented above the mean value of the SUV of the bone marrow. The generated ABM were compared with those generated with other software system (e.g. Velocity, Varian) and Dice coefficient (reflects the overlap of structures) ranged between 80 – 90% was achieved. A KBP model was built in Varian Eclipse TPS using the RapidPlan KBP software to perform plan quality assurance. Conclusion: The workflow for IMRT pretreatment reviews has been established. It represents a major improvement of NRG Oncology clinical trial quality assurance and incorporates the latest radiotherapy technologies as part of NCI clinical trials. This project was supported by grants U24CA180803 (IROC), UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI) and PA CURE grant.« less

Quantitative evaluation of refolding conditions for a disulfide-bond-containing protein using a concise 18O-labeling technique

PubMed Central

Uchimura, Hiromasa; Kim, Yusam; Mizuguchi, Takaaki; Kiso, Yoshiaki; Saito, Kazuki

2011-01-01

A concise method was developed for quantifying native disulfide-bond formation in proteins using isotopically labeled internal standards, which were easily prepared with proteolytic 18O-labeling. As the method has much higher throughput to estimate the amounts of fragments possessing native disulfide arrangements by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) than the conventional high performance liquid chromatography (HPLC) analyses, it allows many different experimental conditions to be assessed in a short time. The method was applied to refolding experiments of a recombinant neuregulin 1-β1 EGF-like motif (NRG1-β1), and the optimum conditions for preparing native NRG1-β1 were obtained by quantitative comparisons. Protein disulfide isomerase (PDI) was most effective at the reduced/oxidized glutathione ratio of 2:1 for refolding the denatured sample NRG1-β1 with the native disulfide bonds. PMID:21500299

Long-term human immune system reconstitution in non-obese diabetic (NOD)-Rag (-)-γ chain (-) (NRG) mice is similar but not identical to the original stem cell donor.

PubMed

Harris, D T; Badowski, M; Balamurugan, A; Yang, O O

2013-12-01

The murine immune system is not necessarily identical to it human counterpart, which has led to the construction of humanized mice. The current study analysed whether or not a human immune system contained within the non-obese diabetic (NOD)-Rag1(null) -γ chain(null) (NRG) mouse model was an accurate representation of the original stem cell donor and if multiple mice constructed from the same donor were similar to one another. To that end, lightly irradiated NRG mice were injected intrahepatically on day 1 of life with purified cord blood-derived CD34(+) stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analysed quarterly for changes in the immune system, and followed for periods up to 12 months post-transplant. Mice from the same donor were compared directly with each other as well as with the original donor. Analyses were performed for immune reconstitution, including flow cytometry, T cell receptor (TCR) and B cell receptor (BCR) spectratyping. It was observed that NRG mice could be 'humanized' long-term using cord blood stem cells, and that animals constructed from the same cord blood donor were nearly identical to one another, but quite different from the original stem cell donor immune system. © 2013 British Society for Immunology.

Additive Manufacturing of Molds for Fabrication of Insulated Concrete Block

DOE Office of Scientific and Technical Information (OSTI.GOV)

Love, Lonnie J.; Lloyd, Peter D.

ORNL worked with concrete block manufacturer, NRG Insulated Block, to demonstrate additive manufacturing of a multi-component block mold for its line of insulated blocks. Solid models of the mold parts were constructed from existing two-dimensional drawings and the parts were fabricated on a Stratasys Fortus 900 using ULTEM 9085. Block mold parts were delivered to NRG and installed on one of their fabrication lines. While form and fit were acceptable, the molds failed to function during NRG’s testing.

Rationale of technical requirements for NRG-BR001: The first NCI-sponsored trial of SBRT for the treatment of multiple metastases.

PubMed

Al-Hallaq, Hania A; Chmura, Steven; Salama, Joseph K; Winter, Kathryn A; Robinson, Clifford G; Pisansky, Thomas M; Borges, Virginia; Lowenstein, Jessica R; McNulty, Susan; Galvin, James M; Followill, David S; Timmerman, Robert D; White, Julia R; Xiao, Ying; Matuszak, Martha M

In 2014, the NRG Oncology Group initiated the first National Cancer Institute-sponsored, phase 1 clinical trial of stereotactic body radiation therapy (SBRT) for the treatment of multiple metastases in multiple organ sites (BR001; NCT02206334). The primary endpoint is to test the safety of SBRT for the treatment of 2 to 4 multiple lesions in several anatomic sites in a multi-institutional setting. Because of the technical challenges inherent to treating multiple lesions as their spatial separation decreases, we present the technical requirements for NRG-BR001 and the rationale for their selection. Patients with controlled primary tumors of breast, non-small cell lung, or prostate are eligible if they have 2 to 4 metastases distributed among 7 extracranial anatomic locations throughout the body. Prescription and organ-at-risk doses were determined by expert consensus. Credentialing requirements include (1) irradiation of the Imaging and Radiation Oncology Core phantom with SBRT, (2) submitting image guided radiation therapy case studies, and (3) planning the benchmark. Guidelines for navigating challenging planning cases including assessing composite dose are discussed. Dosimetric planning to multiple lesions receiving differing doses (45-50 Gy) and fractionation (3-5) while irradiating the same organs at risk is discussed, particularly for metastases in close proximity (≤5 cm). The benchmark case was selected to demonstrate the planning tradeoffs required to satisfy protocol requirements for 2 nearby lesions. Examples of passing benchmark plans exhibited a large variability in plan conformity. NRG-BR001 was developed using expert consensus on multiple issues from the dose fractionation regimen to the minimum image guided radiation therapy guidelines. Credentialing was tied to the task rather than the anatomic site to reduce its burden. Every effort was made to include a variety of delivery methods to reflect current SBRT technology. Although some simplifications were adopted, the successful completion of this trial will inform future designs of both national and institutional trials and would allow immediate clinical adoption of SBRT trials for oligometastases. Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.

Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation.

PubMed

Swisher, Stephen G; Moughan, Jennifer; Komaki, Ritsuko U; Ajani, Jaffer A; Wu, Tsung T; Hofstetter, Wayne L; Konski, Andre A; Willett, Christopher G

2017-02-01

The impact of selective surgical resection for patients with esophageal cancer treated with definitive chemoradiation has not been clearly evaluated long-term. NRG (National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, Gynecologic Oncology Group) Oncology Radiation Therapy Oncology Group 0246 was a multi-institutional, single-arm, open-label, nonrandomized phase II study that enrolled 43 patients from September 2003 to March 2008 with clinical stage T1-4N0-1M0 squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction from 19 sites. Patients received induction chemotherapy with fluorouracil (650 mg/m 2 /d), cisplatin (15 mg/m 2 /d), and paclitaxel (200 mg/m 2 /d) for two cycles followed by concurrent chemoradiation consisting of 50.4 Gy of radiation (1.8 Gy per fraction) and daily fluorouracil (300 mg/m 2 /d) with cisplatin (15 mg/m 2 /d) over the first 5 days. After definitive chemoradiation, patients were evaluated for residual disease. Selective esophagectomy was considered only for patients with residual disease after chemoradiation (clinical incomplete response) or recurrent disease on surveillance. This report looks at the long-term outcome of this selective surgical strategy. With a median follow-up of 8.1 years (minimum to maximum for 12 alive patients 7.2-9.8 years), the estimated 5- and 7-year survival rates are 36.6% (95% confidence interval [CI]: 22.3-51.0) and 31.7% (95% CI: 18.3-46.0). Clinical complete response was achieved in 15 patients (37%), with 5- and 7-yearr survival rates of 53.3% (95% CI: 26.3-74.4) and 46.7% (95% CI: 21.2-68.7). Esophageal resection was not required in 20 of 41 patients (49%) on this trial. The long-term results of NRG Oncology Radiation Therapy Oncology Group 0246 demonstrate promising efficacy of a selective surgical resection strategy and suggest the need for larger randomized studies to further evaluate this organ-preserving approach. Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Transcriptome Meta-Analysis of Lung Cancer Reveals Recurrent Aberrations in NRG1 and Hippo Pathway Genes

PubMed Central

Dhanasekaran, Saravana M.; Balbin, O. Alejandro; Chen, Guoan; Nadal, Ernest; Kalyana-Sundaram, Shanker; Pan, Jincheng; Veeneman, Brendan; Cao, Xuhong; Malik, Rohit; Vats, Pankaj; Wang, Rui; Huang, Stephanie; Zhong, Jinjie; Jing, Xiaojun; Iyer, Matthew; Wu, Yi-Mi; Harms, Paul W.; Lin, Jules; Reddy, Rishindra; Brennan, Christine; Palanisamy, Nallasivam; Chang, Andrew C.; Truini, Anna; Truini, Mauro; Robinson, Dan R.; Beer, David G.; Chinnaiyan, Arul M.

2014-01-01

Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here, we perform transcriptome analysis of 153 samples representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyze 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumors without known driver mutations. In addition, we observe exon skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations. PMID:25531467

Geotechnical characterization of the North Ramp of the Exploratory Studies Facility: Yucca Mountain Site Characterization Project. Volume 2, NRG corehole data appendices

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brechtel, C.E.; Lin, Ming; Martin, E.

1995-05-01

This report presents the results of the geological and geotechnical characterization of the Miocene volcanic tuff rocks of the Timber Mountain and Paintbrush groups that the tunnel boring machine will encounter during excavations of the Exploratory Studies Facility (ESF) North Ramp. The information in this report was developed to support the design of the ESF North Ramp. The ESF is being constructed by the DOE as part of the Yucca Mountain Project site characterization activities. The purpose of these activities is to evaluate the potential to locate the national high-level nuclear waste repository on land within and adjacent to themore » Nevada Test Site (NTS), Nye County, Nevada. This report was prepared as part of the Soil and Rock Properties Studies in accordance with the 8.3.1.14.2 Study Plan to Provide Soil and Rock Properties. This is volume 2 which contains NRG Corehole Data for each of the NRG Holes.« less

TACE (ADAM17) inhibits Schwann cell myelination

PubMed Central

Marca, Rosa La; Cerri, Federica; Horiuchi, Keisuke; Bachi, Angela; Feltri, M Laura; Wrabetz, Lawrence; Blobel, Carl P; Quattrini, Angelo; Salzer, James L; Taveggia, Carla

2012-01-01

Tumor necrosis factor-α–converting enzyme (TACE; also known as ADAM17) is a proteolytic sheddase that is responsible for the cleavage of several membrane-bound molecules. We report that TACE cleaves neuregulin-1 (NRG1) type III in the epidermal growth factor domain, probably inactivating it (as assessed by deficient activation of the phosphatidylinositol-3-OH kinase pathway), and thereby negatively regulating peripheral nervous system (PNS) myelination. Lentivirus-mediated knockdown of TACE in vitro in dorsal root ganglia neurons accelerates the onset of myelination and results in hypermyelination. In agreement, motor neurons of conditional knockout mice lacking TACE specifically in these cells are significantly hypermyelinated, and small-caliber fibers are aberrantly myelinated. Further, reduced TACE activity rescues hypomyelination in NRG1 type III haploinsufficient mice in vivo. We also show that the inhibitory effect of TACE is neuron-autonomous, as Schwann cells lacking TACE elaborate myelin of normal thickness. Thus, TACE is a modulator of NRG1 type III activity and is a negative regulator of myelination in the PNS. PMID:21666671

Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population.

PubMed

Wen, Zujia; Chen, Jianhua; Khan, Raja Amjad Waheed; Song, Zhijian; Wang, Meng; Li, Zhiqiang; Shen, Jiawei; Li, Wenjin; Shi, Yongyong

2016-04-01

Schizophrenia, major depressive disorder, and bipolar disorder are three major psychiatric disorders affecting around 0.66%, 3.3%, and 1.5% of the Han Chinese population respectively. Several genetic linkage analyses and genome wide association studies identified NRG1 as a susceptibility gene of schizophrenia, which was validated by its role in neurodevelopment, glutamate, and other neurotransmitter receptor expression regulation. To further investigate whether NRG1 is a shared risk gene for major depressive disorder, bipolar disorder as well as schizophrenia, we performed an association study among 1,248 schizophrenia cases, 1,056 major depression cases, 1,344 bipolar disorder cases, and 1,248 controls. Totally 15 tag SNPs were genotyped and analyzed, and no population stratification was found in our sample set. Among the sites, rs4236710 (corrected Pgenotye  = 0.015) and rs4512342 (Pallele  = 0.03, Pgenotye  = 0.045 after correction) were associated with schizophrenia, and rs2919375 (corrected Pgenotye  = 0.004) was associated with major depressive disorder. The haplotype rs4512342-rs6982890 showed association with schizophrenia (P = 0.03 for haplotype "TC" after correction), and haplotype rs4531002-rs11989919 proved to be a shared risk factor for both major depressive disorder ("CC": corrected P = 0.009) and bipolar disorder ("CT": corrected P = 0.003). Our results confirmed that NRG1 was a shared common susceptibility gene for major mental disorders in Han Chinese population. © 2016 Wiley Periodicals, Inc.

Neuregulin-1 genotype is associated with structural differences in the normal human brain.

PubMed

Barnes, Anna; Isohanni, Matti; Barnett, Jennifer H; Pietiläinen, Olli; Veijola, Juha; Miettunen, Jouko; Paunio, Tiina; Tanskanen, Päivikki; Ridler, Khanum; Suckling, John; Bullmore, Edward T; Jones, Peter B; Murray, Graham K

2012-02-01

The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions. Copyright © 2011 Elsevier Inc. All rights reserved.

Attrition in NRG Oncology's Radiation-Based Clinical Trials.

PubMed

Ulrich, Connie M; Deshmukh, Snehal; Pugh, Stephanie L; Hanlon, Alexandra; Grady, Christine; Watkins Bruner, Deborah; Curran, Walter

2018-05-10

To determine individual, organizational, and protocol-specific factors associated with attrition in NRG Oncology's radiation-based clinical trials. This retrospective analysis included 27,443 patients representing 134 NRG Oncology's radiation-based clinical trials .trials with primary efficacy results published from 1985-2011. Trials were separated on the basis of the primary endpoint (fixed time vs event driven). The cumulative incidence approach was used to estimate time to attrition, and cause-specific Cox proportional hazards models were used to assess factors associated with attrition. Most patients (69%) were enrolled in an event-driven trial (n = 18,809), while 31% were enrolled in a fixed-time trial (n = 8634). Median follow-up time for patients enrolled in fixed-time trials was 4.1 months and 37.2 months for patients enrolled in event-driven trials. Fixed time trials with a duration < 6 months had a 5 month attrition rate of 4.3% (95% confidence interval [CI]: 3.4%, 5.5%) and those with a duration ≥ 6 months had a 1 year attrition rate of 1.6% (95% CI: 1.2, 2.1). Event-driven trials had 1- and 5-year attrition rates of 0.5% (95% CI: 0.4%, 0.6%) and 13.6% (95% CI: 13.1%, 14.1%), respectively. Younger age, female gender, and Zubrod performance status >0 were associated with greater attrition as were enrollment by institutions in the West and South regions and participation in fixed-time trials. Attrition in clinical trials can have a negative effect on trial outcomes. Data on factors associated with attrition can help guide the development of strategies to enhance retention. These strategies should focus on patient characteristics associated with attrition in both fixed-time and event-driven trials as well as in differing geographic regions of the country. Copyright © 2018. Published by Elsevier Inc.

The Significance of Co-Expression of Epidermal Growth Factor Receptor (EGFR) and Ki67 on Clinical Outcome in Patients with Anal Cancer Treated with Chemoradiotherapy: An Analysis of NRG Oncology RTOG 9811

PubMed Central

Doll, Corinne M.; Moughan, Jennifer; Klimowicz, Alexander; Ho, Clement K.; Kornaga, Elizabeth N.; Lees-Miller, Susan P.; Ajani, Jaffer A.; Crane, Christopher H.; Kachnic, Lisa A.; Okawara, Gordon S.; Berk, Lawrence B.; Roof, Kevin S.; Becker, Mark J.; Grisell, David L.; Ellis, Robert J; Sperduto, Paul; Marsa, Gerald; Guha, Chandan; Magliocco, Anthony

2017-01-01

Purpose To measure co-expression of EGFR and Ki67 proteins in pre-treatment tumor biopsies of anal cancer patients enrolled on NRG Oncology RTOG 9811, a phase III trial comparing 5FU/MMC/RT (Arm A) vs. 5FU/cisplatin/RT (Arm B), and to correlate expression with clinical outcome. Materials/Methods EGFR and Ki67 co-expression was measured after constructing a tissue microarray using fluorescence immunohistochemistry and automated quantitative image analysis (AQUA). Ki67 score within EGFR high vs. low areas (Ki67ratio in EGFRhigh:low) in each tumor core was analyzed at the median, quartiles and as a continuous variable. Associations between the tumor markers and clinical endpoints [overall and disease-free survival (OS, DFS), locoregional and colostomy failure (LRF, CF), and distant metastases (DM] were explored. Results 282 pre-treatment tumors were analyzed from NRG Oncology RTOG 9811. Of evaluated specimens, 183 (65%, n=89, Arm A; n=94, Arm B) were eligible and analyzable. There were no significant differences in baseline characteristics or outcomes between analyzable and unanalyzable patient cases. Median follow-up was 6.0 years. On multivariate analysis, after adjusting for gender, patients with Ki67ratio in EGFRhigh:low ≥ median had worse OS (HR=2.41, 95% C.I. = [1.38, 4.19], p=0.0019). After adjusting for N stage and largest tumor dimension, patients with Ki67ratio in EGFRhigh:low ≥ median had a higher risk of a disease-free failure (HR=1.85, 95% C.I. = [1.18, 2.92], p=0.0078). Technical validation with an independent anal cancer patient cohort was performed and shows a very similar biomarker score distribution. Conclusions High Ki67ratio in EGFRhigh:low is associated with worse clinical outcome in this subset of patients with anal cancer treated with chemoradiation on NRG Oncology RTOG 9811. Evaluation within a clinical trial will be required to determine whether patients with these tumor characteristics may specifically benefit from an EGFR targeted therapeutic agent. PMID:28126304

The lateral mobility of cell adhesion molecules is highly restricted at septate junctions in Drosophila.

PubMed

Laval, Monique; Bel, Christophe; Faivre-Sarrailh, Catherine

2008-07-18

A complex of three cell adhesion molecules (CAMs) Neurexin IV(Nrx IV), Contactin (Cont) and Neuroglian (Nrg) is implicated in the formation of septate junctions between epithelial cells in Drosophila. These CAMs are interdependent for their localization at septate junctions and e.g. null mutation of nrx IV or cont induces the mislocalization of Nrg to the baso-lateral membrane. These mutations also result in ultrastructural alteration of the strands of septate junctions and breakdown of the paracellular barrier. Varicose (Vari) and Coracle (Cora), that both interact with the cytoplasmic tail of Nrx IV, are scaffolding molecules required for the formation of septate junctions. We conducted photobleaching experiments on whole living Drosophila embryos to analyze the membrane mobility of CAMs at septate junctions between epithelial cells. We show that GFP-tagged Nrg and Nrx IV molecules exhibit very stable association with septate junctions in wild-type embryos. Nrg-GFP is mislocalized to the baso-lateral membrane in nrx IV or cont null mutant embryos, and displays increased mobile fraction. Similarly, Nrx IV-GFP becomes distributed to the baso-lateral membrane in null mutants of vari and cora, and its mobile fraction is strongly increased. The loss of Vari, a MAGUK protein that interacts with the cytoplasmic tail of Nrx IV, has a stronger effect than the null mutation of nrx IV on the lateral mobility of Nrg-GFP. The strands of septate junctions display a stable behavior in vivo that may be correlated with their role of paracellular barrier. The membrane mobility of CAMs is strongly limited when they take part to the multimolecular complex forming septate junctions. This restricted lateral diffusion of CAMs depends on both adhesive interactions and clustering by scaffolding molecules. The lateral mobility of CAMs is strongly increased in embryos presenting alteration of septate junctions. The stronger effect of vari by comparison with nrx IV null mutation supports the hypothesis that this scaffolding molecule may cross-link different types of CAMs and play a crucial role in stabilizing the strands of septate junctions.

Elevated Atmospheric CO2 and Strain of Rhizobium Alter Freezing Tolerance and Cold-induced Molecular Changes in Alfalfa (Medicago sativa)

PubMed Central

Bertrand, Annick; Prévost, Danielle; Bigras, Francine J.; Castonguay, Yves

2007-01-01

Background and Aims The objective of the study was to assess the impact of elevated CO2 in interaction with rhizobial strains on freezing tolerance and cold-induced molecular changes in alfalfa. Methods Alfalfa inoculated with two different strains of rhizobium (A2 and NRG34) was grown and cold acclimated (2 weeks at 2 °C) under either 400 (ambient) or 800 µmol mol−1 (elevated) CO2. Key Results Plants acclimated under 400 µmol mol−1 CO2 were more freezing tolerant than those maintained under 800 µmol mol−1. Cryoprotective sugars typically linked with the acquisition of freezing tolerance such as sucrose, stachyose and raffinose increased in roots in response to low temperature but did not differ between CO2 treatments. Similarly high CO2 did not alter the expression of many cold-regulated (COR) genes although it significantly increased the level of transcripts encoding a COR gene homologous to glyceraldehyde-3-phosphate-dehydrogenase (GAPDH). A significant effect of rhizobial strain was observed on both freezing tolerance and gene expression. Plants of alfalfa inoculated with strain A2 were more freezing tolerant than those inoculated with strain NRG34. Transcripts of COR genes homologous to a pathogenesis-related protein (PR-10) and to a nuclear-targeted protein were markedly enhanced in roots of alfalfa inoculated with strain A2 as compared with strain NRG34. Transcripts encoding the vegetative storage proteins (VSPs) β-amylase and chitinase were more abundant in roots of non-acclimated plants inoculated with strain NRG34 than with strain A2. Conclusions Taken together, the results suggest that elevated CO2 stimulates plant growth and reduces freezing tolerance. The acquisition of cold tolerance is also influenced by the rhizobial strain, as indicated by lower levels of expression of COR genes and sustained accumulation of VSP-encoding transcripts in alfalfa inoculated with strain NRG34 as compared with strain A2. PMID:17218341

Neuron-glia signaling and the protection of axon function by Schwann cells.

PubMed

Quintes, Susanne; Goebbels, Sandra; Saher, Gesine; Schwab, Markus H; Nave, Klaus-Armin

2010-03-01

The interaction between neurons and glial cells is a feature of all higher nervous systems. In the vertebrate peripheral nervous system, Schwann cells ensheath and myelinate axons thereby allowing rapid saltatory conduction and ensuring axonal integrity. Recently, some of the key molecules in neuron-Schwann cell signaling have been identified. Neuregulin-1 (NRG1) type III presented on the axonal surface determines the myelination fate of axons and controls myelin sheath thickness. Recent observations suggest that NRG1 regulates myelination via the control of Schwann cell cholesterol biosynthesis. This concept is supported by the finding that high cholesterol levels in Schwann cells are a rate-limiting factor for myelin protein production and transport of the major myelin protein P0 from the endoplasmic reticulum into the growing myelin sheath. NRG1 type III activates ErbB receptors on the Schwann cell, which leads to an increase in intracellular PIP3 levels via the PI3-kinase pathway. Surprisingly, enforced elevation of PIP3 levels by inactivation of the phosphatase PTEN in developing and mature Schwann cells does not entirely mimic NRG1 type III stimulated myelin growth, but predominantly causes focal hypermyelination starting at Schmidt-Lanterman incisures and nodes of Ranvier. This indicates that the glial transduction of pro-myelinating signals has to be under tight and life-long control to preserve integrity of the myelinated axon. Understanding the cross talk between neurons and Schwann cells will help to further define the role of glia in preserving axonal integrity and to develop therapeutic strategies for peripheral neuropathies such as CMT1A.

Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy.

PubMed

Law, Amanda J; Wang, Yanhong; Sei, Yoshitatsu; O'Donnell, Patricio; Piantadosi, Patrick; Papaleo, Francesco; Straub, Richard E; Huang, Wenwei; Thomas, Craig J; Vakkalanka, Radhakrishna; Besterman, Aaron D; Lipska, Barbara K; Hyde, Thomas M; Harrison, Paul J; Kleinman, Joel E; Weinberger, Daniel R

2012-07-24

Neuregulin 1 (NRG1) and ErbB4, critical neurodevelopmental genes, are implicated in schizophrenia, but the mediating mechanisms are unknown. Here we identify a genetically regulated, pharmacologically targetable, risk pathway associated with schizophrenia and with ErbB4 genetic variation involving increased expression of a PI3K-linked ErbB4 receptor (CYT-1) and the phosphoinositide 3-kinase subunit, p110δ (PIK3CD). In human lymphoblasts, NRG1-mediated phosphatidyl-inositol,3,4,5 triphosphate [PI(3,4,5)P3] signaling is predicted by schizophrenia-associated ErbB4 genotype and PIK3CD levels and is impaired in patients with schizophrenia. In human brain, the same ErbB4 genotype again predicts increased PIK3CD expression. Pharmacological inhibition of p110δ using the small molecule inhibitor, IC87114, blocks the effects of amphetamine in a mouse pharmacological model of psychosis and reverses schizophrenia-related phenotypes in a rat neonatal ventral hippocampal lesion model. Consistent with these antipsychotic-like properties, IC87114 increases AKT phosphorylation in brains of treated mice, implicating a mechanism of action. Finally, in two family-based genetic studies, PIK3CD shows evidence of association with schizophrenia. Our data provide insight into a mechanism of ErbB4 association with schizophrenia; reveal a previously unidentified biological and disease link between NRG1-ErbB4, p110δ, and AKT; and suggest that p110δ is a previously undescribed therapeutic target for the treatment of psychiatric disorders.

Impact of an incremental running test on jumping kinematics in endurance runners: can jumping kinematic explain the post-activation potentiation phenomenon?

PubMed

García-Pinillos, Felipe; Molina-Molina, Alejandro; Latorre-Román, Pedro Á

2016-06-01

This study aimed to determine whether kinematic data during countermovement jump (CMJ) might explain post-activation potentiation (PAP) phenomenon after an exhausting running test. Thirty-three trained endurance runners performed the Léger Test; an incremental test which consists of continuous running between two lines 20 m apart. CMJ performance was determined before (pre-test) and immediately after the protocol (post-test). Sagittal plane, video of CMJs was recorded and kinematic data were obtained throughout 2-Dimensional analysis. In addition to the duration of eccentric and concentric phases of CMJ, hip, knee and ankle angles were measured at four key points during CMJ: the lowest position of the squat, take-off, landing, and at the lowest position after landing. Additionally, heart rate was monitored, and rate of perceived exertion was recorded at post-test. Analysis of variance revealed a significant improvement in CMJ (p = 0.002) at post-test. Cluster analysis grouped according to whether PAP was experienced (responders group: RG, n = 25) or not (non-responders group: NRG, n = 8) relative to CMJ change from rest to post-test. RG significantly improved (p < 0.001) the performance in CMJ, whereas NRG remained unchanged. Kinematic data did not show significant differences between RG and NRG. Thus, the data suggest that jumping kinematic does not provide the necessary information to explain PAP phenomenon after intensive running exercises in endurance athletes.

A conserved role for Drosophila Neuroglian and human L1-CAM in central-synapse formation.

PubMed

Godenschwege, Tanja A; Kristiansen, Lars V; Uthaman, Smitha B; Hortsch, Michael; Murphey, Rodney K

2006-01-10

Drosophila Neuroglian (Nrg) and its vertebrate homolog L1-CAM are cell-adhesion molecules (CAM) that have been well studied in early developmental processes. Mutations in the human gene result in a broad spectrum of phenotypes (the CRASH-syndrome) that include devastating neurological disorders such as spasticity and mental retardation. Although the role of L1-CAMs in neurite extension and axon pathfinding has been extensively studied, much less is known about their role in synapse formation. We found that a single extracellular missense mutation in nrg(849) mutants disrupted the physiological function of a central synapse in Drosophila. The identified giant neuron in nrg(849) mutants made a synaptic terminal on the appropriate target, but ultrastructural analysis revealed in the synaptic terminal a dramatic microtubule reduction, which was likely to be the cause for disrupted active zones. Our results reveal that tyrosine phosphorylation of the intracellular ankyrin binding motif was reduced in mutants, and cell-autonomous rescue experiments demonstrated the indispensability of this tyrosine in giant-synapse formation. We also show that this function in giant-synapse formation was conserved in human L1-CAM but neither in human L1-CAM with a pathological missense mutation nor in two isoforms of the paralogs NrCAM and Neurofascin. We conclude that Nrg has a function in synapse formation by organizing microtubules in the synaptic terminal. This novel synaptic function is conserved in human L1-CAM but is not common to all L1-type proteins. Finally, our findings suggest that some aspects of L1-CAM-related neurological disorders in humans may result from a disruption in synapse formation rather than in axon pathfinding.

Electrical stimulation of rhesus monkey nucleus reticularis gigantocellularis. II. Effects on metrics and kinematics of ongoing gaze shifts to visual targets.

PubMed

Freedman, Edward G; Quessy, Stephan

2004-06-01

Saccade kinematics are altered by ongoing head movements. The hypothesis that a head movement command signal, proportional to head velocity, transiently reduces the gain of the saccadic burst generator (Freedman 2001, Biol Cybern 84:453-462) can account for this observation. Using electrical stimulation of the rhesus monkey nucleus reticularis gigantocellularis (NRG) to alter the head contribution to ongoing gaze shifts, two critical predictions of this gaze control hypothesis were tested. First, this hypothesis predicts that activation of the head command pathway will cause a transient reduction in the gain of the saccadic burst generator. This should alter saccade kinematics by initially reducing velocity without altering saccade amplitude. Second, because this hypothesis does not assume that gaze amplitude is controlled via feedback, the added head contribution (produced by NRG stimulation on the side ipsilateral to the direction of an ongoing gaze shift) should lead to hypermetric gaze shifts. At every stimulation site tested, saccade kinematics were systematically altered in a way that was consistent with transient reduction of the gain of the saccadic burst generator. In addition, gaze shifts produced during NRG stimulation were hypermetric compared with control movements. For example, when targets were briefly flashed 30 degrees from an initial fixation location, gaze shifts during NRG stimulation were on average 140% larger than control movements. These data are consistent with the predictions of the tested hypothesis, and may be problematic for gaze control models that rely on feedback control of gaze amplitude, as well as for models that do not posit an interaction between head commands and the saccade burst generator.

NRG CO 2NCEPT - Confirmation Of Novel Cost-effective Emerging Post-combustion Technology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stevenson, Matthew; Armpriester, Anthony

Under DOE's solicitation DE-FOA-0001190, NRG and Inventys conceptualized a Large-Scale pilot (>10MWe) post-combustion CO 2 capture project using Inventys' VeloxoThermTM carbon capture technology. The technology is comprised of an intensified thermal swing adsorption (TSA) process that uses a patented architecture of structured adsorbent and a novel process design and embodiment to capture CO 2 from industrial flue gas streams. The result of this work concluded that the retrofit of this technology is economically and technically viable, but that the sorbent material selected for the program would need improving to meet the techno-economic performance requirements of the solicitation.

One- and two-channel Kondo model with logarithmic Van Hove singularity: A numerical renormalization group solution

NASA Astrophysics Data System (ADS)

Zhuravlev, A. K.; Anokhin, A. O.; Irkhin, V. Yu.

2018-02-01

Simple scaling consideration and NRG solution of the one- and two-channel Kondo model in the presence of a logarithmic Van Hove singularity at the Fermi level is given. The temperature dependences of local and impurity magnetic susceptibility and impurity entropy are calculated. The low-temperature behavior of the impurity susceptibility and impurity entropy turns out to be non-universal in the Kondo sense and independent of the s-d coupling J. The resonant level model solution in the strong coupling regime confirms the NRG results. In the two-channel case the local susceptibility demonstrates a non-Fermi-liquid power-law behavior.

Quantum quench of Kondo correlations in optical absorption

NASA Astrophysics Data System (ADS)

Weichselbaum, Andreas

2013-03-01

Absorption spectra of individual semiconductor quantum dots tunnel-coupled to a degenerate electron gas in the Kondo regime have recently become accessible to the experiment. The absorption of a single photon leads to an abrupt change in the system Hamiltonian, which can be tailored such that it results in a quantum quench of the Kondo correlations. This is accompanied by a clear signature in the form of an Anderson orthogonality catastrophe, induced by a vanishing overlap between initial and final many-body wave functions and with power-law exponents that can be tuned by an applied magnetic field. We have modeled the experiment in terms of an Anderson impurity model undergoing an optically induced quench, and studied this Kondo exciton in detail using both analytical methods and the Numerical Renormalization Group (NRG). Our NRG results reproduce the measured absorption line shapes very well, showing that NRG is ideally suited for the study of Kondo excitons. In summary, the experiments demonstrate that optical measurements on single artificial atoms offer new perspectives on many-body phenomena previously studied using transport spectroscopy only. Co-authors: Andreas Weichselbaum, Markus Hanl, and Jan von Delft, Ludwig Maximilians University.

No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population.

PubMed

Ito, Yoshihito; Yamada, Shinnosuke; Takahashi, Nagahide; Saito, Shinichi; Yoshimi, Akira; Inada, Toshiya; Noda, Yukihiro; Ozaki, Norio

2008-10-05

NRG1-ERBB signaling influences the risk for schizophrenia pathology. A recent study has reported that MAGI1, MAGI2, and protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1; located on 7q31.3) gene products regulate the NRG1-ERBB4 signaling pathway, and PTPRZ1 is associated with schizophrenia in a Caucasian population. By applying a gene-based association concept, we analyzed any association between PTPRZ1 tagging SNPs and schizophrenia in the Japanese population (576 schizophrenics and 768 controls). After linkage disequilibrium analysis, 29 single nucleotide polymorphisms (SNPs) were genotyped using a 5'-exonuclease allelic discrimination assay. We found a significant association of one tagging SNP in a genotype-wise analysis (P = 0.007); however, this might be resulted from type I error due to multiple testing (P = 0.17 after SNPSpD correction). No association was observed between schizophrenic patients and controls in either allelic, genotypic, or haplotypic analyses. Our results therefore suggest that PTPRZ1 is unlikely to be related to the development of schizophrenia in the Japanese population.

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

PubMed

Caine, Chip; Deshmukh, Snehal; Gondi, Vinai; Mehta, Minesh; Tomé, Wolfgang; Corn, Benjamin W; Kanner, Andrew; Rowley, Howard; Kundapur, Vijayananda; DeNittis, Albert; Greenspoon, Jeffrey Noah; Konski, Andre A; Bauman, Glenn S; Raben, Adam; Shi, Wenyin; Wendland, Merideth; Kachnic, Lisa

2016-01-01

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

BIOMASS REBURNING - MEDELING/ENGINEERING STUDIES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vladimir Zamansky; Michael Booth

This project is designed to develop engineering and modeling tools for a family of NO{sub x} control technologies utilizing biomass as a reburning fuel. During the seventh reporting period (April 1--June 30, 1999), no information was received at EER on scheduled FETC R&D group's project activities. EER activities were on hold due to the pending purchase of the Niagara Mohawk's Dunkirk Station, a target demonstration site in this program, and then by the actual purchase of the Station by NRG. This report includes information about the current project status, recently submitted to NRG for soliciting their interest to proceed withmore » biomass reburn demonstration, and notes on alternative demonstrative partners.« less

Neuroglian, Gliotactin, and the Na+/K+ ATPase are essential for septate junction function in Drosophila

PubMed Central

Genova, Jennifer L.; Fehon, Richard G.

2003-01-01

One essential function of epithelia is to form a barrier between the apical and basolateral surfaces of the epithelium. In vertebrate epithelia, the tight junction is the primary barrier to paracellular flow across epithelia, whereas in invertebrate epithelia, the septate junction (SJ) provides this function. In this study, we identify new proteins that are required for a functional paracellular barrier in Drosophila. In addition to the previously known components Coracle (COR) and Neurexin (NRX), we show that four other proteins, Gliotactin, Neuroglian (NRG), and both the α and β subunits of the Na+/K+ ATPase, are required for formation of the paracellular barrier. In contrast to previous reports, we demonstrate that the Na pump is not localized basolaterally in epithelial cells, but instead is concentrated at the SJ. Data from immunoprecipitation and somatic mosaic studies suggest that COR, NRX, NRG, and the Na+/K+ ATPase form an interdependent complex. Furthermore, the observation that NRG, a Drosophila homologue of vertebrate neurofascin, is an SJ component is consistent with the notion that the invertebrate SJ is homologous to the vertebrate paranodal SJ. These findings have implications not only for invertebrate epithelia and barrier functions, but also for understanding of neuron–glial interactions in the mammalian nervous system. PMID:12782686

Neuroglian, Gliotactin, and the Na+/K+ ATPase are essential for septate junction function in Drosophila.

PubMed

Genova, Jennifer L; Fehon, Richard G

2003-06-09

One essential function of epithelia is to form a barrier between the apical and basolateral surfaces of the epithelium. In vertebrate epithelia, the tight junction is the primary barrier to paracellular flow across epithelia, whereas in invertebrate epithelia, the septate junction (SJ) provides this function. In this study, we identify new proteins that are required for a functional paracellular barrier in Drosophila. In addition to the previously known components Coracle (COR) and Neurexin (NRX), we show that four other proteins, Gliotactin, Neuroglian (NRG), and both the alpha and beta subunits of the Na+/K+ ATPase, are required for formation of the paracellular barrier. In contrast to previous reports, we demonstrate that the Na pump is not localized basolaterally in epithelial cells, but instead is concentrated at the SJ. Data from immunoprecipitation and somatic mosaic studies suggest that COR, NRX, NRG, and the Na+/K+ ATPase form an interdependent complex. Furthermore, the observation that NRG, a Drosophila homologue of vertebrate neurofascin, is an SJ component is consistent with the notion that the invertebrate SJ is homologous to the vertebrate paranodal SJ. These findings have implications not only for invertebrate epithelia and barrier functions, but also for understanding of neuron-glial interactions in the mammalian nervous system.

Nucleus Ruber of Actinopterygians.

PubMed

Nakayama, Tomoya; Miyajima, Satoshi; Nishino, Hirotaka; Narita, Junya; Abe, Hideki; Yamamoto, Naoyuki

2016-01-01

Nucleus ruber is known as an important supraspinal center that controls forelimb movements in tetrapods, and the rubral homologue may serve similar functions in fishes (motor control of pectoral fin). However, two apparently different structures have been identified as 'nucleus ruber' in actinopterygians. One is nucleus ruber of Goldstein (1905) (NRg), and the other nucleus ruber of Nieuwenhuys and Pouwels (1983) (NRnp). It remains unclear whether one of these nuclei (or perhaps both) is homologous to tetrapod nucleus ruber. To resolve this issue from a phylogenetic point of view, we have investigated the distribution of tegmental neurons retrogradely labeled from the spinal cord in eight actinopterygian species. We also investigated the presence/absence of the two nuclei with Nissl- or Bodian-stained brain section series of an additional 28 actinopterygian species by comparing the morphological features of candidate rubral neurons with those of neurons revealed by the tracer studies. Based on these analyses, the NRg was identified in all actinopterygians investigated in the present study, while the NRnp appears to be absent in basal actinopterygians. The phylogenetic distribution pattern indicates that the NRg is the more likely homologue of nucleus ruber, and the NRnp may be a derived nucleus that emerged during the course of actinopterygian evolution. © 2016 S. Karger AG, Basel.

Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123.

PubMed

Small, William; James, Jennifer L; Moore, Timothy D; Fintel, Dan J; Lutz, Stephen T; Movsas, Benjamin; Suntharalingam, Mohan; Garces, Yolanda I; Ivker, Robert; Moulder, John; Pugh, Stephanie; Berk, Lawrence B

2018-04-01

The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Eligible patients included stage II-IIIB non-small cell lung cancer, stage I central non-small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

The Drosophila cell adhesion molecule Neuroglian regulates Lissencephaly-1 localisation in circulating immunosurveillance cells.

PubMed

Williams, Michael J

2009-03-25

When the parasitoid wasp Leptopilina boulardi lays its eggs in Drosophila larvae phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. This requires these circulating immunosurveillance cells (haemocytes) to change from a non-adhesive to an adhesive state enabling them to bind to the invader. Interestingly, attachment of leukocytes, platelets, and insect haemocytes requires the same adhesion complexes as epithelial and neuronal cells. Here evidence is presented showing that the Drosophila L1-type cell adhesion molecule Neuroglian (Nrg) is required for haemocytes to encapsulate L. boulardi wasp eggs. The amino acid sequence FIGQY containing a conserved phosphorylated tyrosine is found in the intracellular domain of all L1-type cell adhesion molecules. This conserved tyrosine is phosphorylated at the cell periphery of plasmatocytes and lamellocytes prior to parasitisation, but dephosphorylated after immune activation. Intriguingly, another pool of Nrg located near the nucleus of plasmatocytes remains phosphorylated after parasitisation. In mammalian neuronal cells phosphorylated neurofascin, another L1-type cell adhesion molecule interacts with a nucleokinesis complex containing the microtubule binding protein lissencephaly-1 (Lis1) 1. Interestingly in plasmatocytes from Nrg mutants the nucleokinesis regulating protein Lissencephaly-1 (Lis1) fails to localise properly around the nucleus and is instead found diffuse throughout the cytoplasm and at unidentified perinuclear structures. After attaching to the wasp egg control plasmatocytes extend filopodia laterally from their cell periphery; as well as extending lateral filopodia plasmatocytes from Nrg mutants also extend many filopodia from their apical surface. The Drosophila cellular adhesion molecule Neuroglian is expressed in haemocytes and its activity is required for the encapsulation of L. boularli eggs. At the cell periphery of haemocytes Neuroglian may be involved in cell-cell interactions, while at the cell centre Neuroglian regulates the localisation of the nucleokinesis complex protein lissencephaly-1.

A RET-ER81-NRG1 Signaling Pathway Drives the Development of Pacinian Corpuscles.

PubMed

Fleming, Michael S; Li, Jian J; Ramos, Daniel; Li, Tong; Talmage, David A; Abe, Shin-Ichi; Arber, Silvia; Luo, Wenqin

2016-10-05

Axon-Schwann cell interactions are crucial for the development, function, and repair of the peripheral nervous system, but mechanisms underlying communication between axons and nonmyelinating Schwann cells are unclear. Here, we show that ER81 is functionally required in a subset of mouse RET + mechanosensory neurons for formation of Pacinian corpuscles, which are composed of a single myelinated axon and multiple layers of nonmyelinating Schwann cells, and Ret is required for the maintenance of Er81 expression. Interestingly, Er81 mutants have normal myelination but exhibit deficient interactions between axons and corpuscle-forming nonmyelinating Schwann cells. Finally, ablating Neuregulin-1 (Nrg1) in mechanosensory neurons results in no Pacinian corpuscles, and an Nrg1 isoform not required for communication with myelinating Schwann cells is specifically decreased in Er81-null somatosensory neurons. Collectively, our results suggest that a RET-ER81-NRG1 signaling pathway promotes axon communication with nonmyelinating Schwann cells, and that neurons use distinct mechanisms to interact with different types of Schwann cells. Communication between neurons and Schwann cells is critical for development, normal function, and regeneration of the peripheral nervous system. Despite many studies about axonal communication with myelinating Schwann cells, mostly via a specific isoform of Neuregulin1, the molecular nature of axonal communication with nonmyelinating Schwann cells is poorly understood. Here, we described a RET-ER81-Neuregulin1 signaling pathway in neurons innervating Pacinian corpuscle somatosensory end organs, which is essential for communication between the innervating axon and the end organ nonmyelinating Schwann cells. We also showed that this signaling pathway uses isoforms of Neuregulin1 that are not involved in myelination, providing evidence that neurons use different isoforms of Neuregulin1 to interact with different types of Schwann cells. Copyright © 2016 the authors 0270-6474/16/3610337-19$15.00/0.

The Drosophila cell adhesion molecule Neuroglian regulates Lissencephaly-1 localisation in circulating immunosurveillance cells

PubMed Central

Williams, Michael J

2009-01-01

Background When the parasitoid wasp Leptopilina boulardi lays its eggs in Drosophila larvae phagocytic cells called plasmatocytes and specialized cells known as lamellocytes encapsulate the egg. This requires these circulating immunosurveillance cells (haemocytes) to change from a non-adhesive to an adhesive state enabling them to bind to the invader. Interestingly, attachment of leukocytes, platelets, and insect haemocytes requires the same adhesion complexes as epithelial and neuronal cells. Results Here evidence is presented showing that the Drosophila L1-type cell adhesion molecule Neuroglian (Nrg) is required for haemocytes to encapsulate L. boulardi wasp eggs. The amino acid sequence FIGQY containing a conserved phosphorylated tyrosine is found in the intracellular domain of all L1-type cell adhesion molecules. This conserved tyrosine is phosphorylated at the cell periphery of plasmatocytes and lamellocytes prior to parasitisation, but dephosphorylated after immune activation. Intriguingly, another pool of Nrg located near the nucleus of plasmatocytes remains phosphorylated after parasitisation. In mammalian neuronal cells phosphorylated neurofascin, another L1-type cell adhesion molecule interacts with a nucleokinesis complex containing the microtubule binding protein lissencephaly-1 (Lis1) [1]. Interestingly in plasmatocytes from Nrg mutants the nucleokinesis regulating protein Lissencephaly-1 (Lis1) fails to localise properly around the nucleus and is instead found diffuse throughout the cytoplasm and at unidentified perinuclear structures. After attaching to the wasp egg control plasmatocytes extend filopodia laterally from their cell periphery; as well as extending lateral filopodia plasmatocytes from Nrg mutants also extend many filopodia from their apical surface. Conclusion The Drosophila cellular adhesion molecule Neuroglian is expressed in haemocytes and its activity is required for the encapsulation of L. boularli eggs. At the cell periphery of haemocytes Neuroglian may be involved in cell-cell interactions, while at the cell centre Neuroglian regulates the localisation of the nucleokinesis complex protein lissencephaly-1. PMID:19320973

MIG1-dependent and MIG1-independent regulation of GAL gene expression in Saccharomyces cerevisiae: role of Imp2p.

PubMed

Alberti, Adriana; Lodi, Tiziana; Ferrero, Iliana; Donnini, Claudia

2003-10-15

Imp2p (Yil154c) is a transcriptional activator involved in glucose derepression of the maltose, galactose and raffinose utilization pathways and in resistance to thermal, oxidative or osmotic stress. We analysed the role of Imp2 in the regulation of GAL genes. Imp2 was shown to have a positive effect on glucose derepression of Leloir pathway genes and their activator gene GAL4. The effect of Imp2 on galactose metabolism was shown to be partially dependent on Mig1p. The Mig1-independent role depends on Nrg1p. However, disruption of both MIG1 and NRG1 only partially relieves the glucose repression of GAL genes in the Deltaimp2 mutant, indicating that Imp2 must also have other function(s). Moreover, the interaction between IMP2 and GAL6/BLH1, a recently isolated gene involved in the regulation of GAL genes that shares with Imp2 the ability to protect cells from the glycopeptide bleomycin, was also analysed. The results suggest a major role of Imp2 in a GAL6-independent pathway. Copyright 2003 John Wiley & Sons, Ltd.

NRG Oncology medical physicists' manpower survey quantifying support demands for multi-institutional clinical trials.

PubMed

Monroe, James I; Boparai, Karan; Xiao, Ying; Followill, David; Galvin, James M; Klein, Eric E; Low, Daniel A; Moran, Jean M; Zhong, Haoyu; Sohn, Jason W

2018-02-04

A survey was created by NRG to assess a medical physicists' percent full time equivalent (FTE) contribution to multi-institutional clinical trials. A 2012 American Society for Radiation Oncology report, "Safety Is No Accident," quantified medical physics staffing contributions in FTE factors for clinical departments. No quantification of FTE effort associated with clinical trials was included. To address this lack of information, the NRG Medical Physics Subcommittee decided to obtain manpower data from the medical physics community to quantify the amount of time medical physicists spent supporting clinical trials. A survey, consisting of 16 questions, was designed to obtain information regarding physicists' time spent supporting clinical trials. The survey was distributed to medical physicists at 1996 radiation therapy institutions included on the membership rosters of the 5 National Clinical Trials Network clinical trial groups. Of the 451 institutions who responded, 50% (226) reported currently participating in radiation therapy trials. On average, the designated physicist at each institution spent 2.4 hours (standard deviation [SD], 5.5) per week supervising or interacting with clinical trial staff. On average, 1.2 hours (SD, 3.1), 1.8 hours (SD, 3.9), and 0.6 hours (SD, 1.1) per week were spent on trial patient simulations, treatment plan reviews, and maintaining a Digital Imaging and Communications in Medicine server, respectively. For all trial credentialing activities, physicists spent an average of 32 hours (SD, 57.2) yearly. Reading protocols and supporting dosimetrists, clinicians, and therapists took an average of 2.1 hours (SD, 3.4) per week. Physicists also attended clinical trial meetings, on average, 1.2 hours (SD, 1.9) per month. On average, physicist spent a nontrivial total of 9 hours per week (0.21 FTE) supporting an average of 10 active clinical trials. This time commitment indicates the complexity of radiation therapy clinical trials and should be taken into account when staffing radiation therapy institutions. Copyright © 2018 Elsevier Inc. All rights reserved.

In vitro evaluation of the accuracy of five different electronic apex locators for determining the working length of endodontically retreated teeth.

PubMed

Ebrahim, Aqeel Khalil; Wadachi, Reiko; Suda, Hideaki

2007-04-01

The aim of this study was to evaluate the accuracy of five electronic apex locators (EALs) in determining the working length (WL) of teeth after removal of the root canal obturation materials. A total of 32 extracted straight, single-rooted teeth were used. The actual canal length (AL) was determined and the WL was established by subtracting 0.5 mm from the AL. The root canals were instrumented and divided into two groups. One group (n = 6) served as control, while the other group (n = 26) was the experimental group. In the experimental group, the root canals were obturated using vertically compacted gutta-percha with AH 26 sealer. In both groups, the access cavities were restored with a provisional restoration and stored for 15 days at 37 degrees C and 100% humidity. The root canal obturation material was removed, and the teeth were then mounted in an experimental apparatus. Five EALs were used: Dentaport ZX, ProPex, Foramatron D10, Apex NRG and Apit 7. For the electronic measurement of canal length, a size 25 K-file was used. During measurement, the canal was irrigated with 2.5% sodium hypochlorite. The difference (D) between the AL and the electronically determined length (EDL), AL-EDL, was calculated and recorded for each measurement. Data were analysed by two-way anova and Fisher's PLSD test. In both groups, statistically significant differences were found among the EALs (P < 0.01). In conclusion, the Dentaport ZX, ProPex and Foramatron D10 were more accurate than the other two EALs in determining the WL in teeth after removal of the root canal obturation materials. However, the Apex NRG and Apit 7 were also reliable for determination of the WL in the majority of the cases.

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation

PubMed Central

Park, So Young; Jang, So Young; Shin, Yoon Kyoung; Jung, Dong Keun; Yoon, Byeol A; Kim, Jong Kook; Jo, Young Rae; Lee, Hye Jeong

2017-01-01

The vertebrate neuromuscular junction (NMJ) is considered as a “tripartite synapse” consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system. PMID:28680299

The Scaffolding Protein, Grb2-associated Binder-1, in Skeletal Muscles and Terminal Schwann Cells Regulates Postnatal Neuromuscular Synapse Maturation.

PubMed

Park, So Young; Jang, So Young; Shin, Yoon Kyoung; Jung, Dong Keun; Yoon, Byeol A; Kim, Jong Kook; Jo, Young Rae; Lee, Hye Jeong; Park, Hwan Tae

2017-06-01

The vertebrate neuromuscular junction (NMJ) is considered as a "tripartite synapse" consisting of a motor axon terminal, a muscle endplate, and terminal Schwann cells that envelope the motor axon terminal. The neuregulin 1 (NRG1)-ErbB2 signaling pathway plays an important role in the development of the NMJ. We previously showed that Grb2-associated binder 1 (Gab1), a scaffolding mediator of receptor tyrosine kinase signaling, is required for NRG1-induced peripheral nerve myelination. Here, we determined the role of Gab1 in the development of the NMJ using muscle-specific conditional Gab1 knockout mice. The mutant mice showed delayed postnatal maturation of the NMJ. Furthermore, the selective loss of the gab1 gene in terminal Schwann cells produced delayed synaptic elimination with abnormal morphology of the motor endplate, suggesting that Gab1 in both muscles and terminal Schwann cells is required for proper NMJ development. Gab1 in terminal Schwann cells appeared to regulate the number and process elongation of terminal Schwann cells during synaptic elimination. However, Gab2 knockout mice did not show any defects in the development of the NMJ. Considering the role of Gab1 in postnatal peripheral nerve myelination, our findings suggest that Gab1 is a pleiotropic and important component of NRG1 signals during postnatal development of the peripheral neuromuscular system.

Icebox, a recessive X-linked mutation in Drosophila causing low sexual receptivity.

PubMed

Kerr, C; Ringo, J; Dowse, H; Johnson, E

1997-11-01

The X-linked recessive mutation icebox (ibx; 1-23, 7F1) of Drosophila melanogaster lowers the sexual receptivity of females. The probability of mating with mature wild-type males is reduced in ibx homozygotes, and the frequency of rejection behavior (rate per minute) towards courting males is increased. ibx fails to complement In(1)RA35, which is a lethal allele of Neuroglian (Nrg, which encodes a transmembrane protein found in embryonic tissues including the nervous system) due to a breakpoint in that gene; however, both l(1)B4 and l(1)VA142, other lethal mutations of Nrg, do complement ibx. 12-h ibx embryos exhibit a normal pattern of staining for the Neuroglian-specific antibody, Mab BP104. Males and females mutant for ibx have normal egg-to-adult survival and appear normal in several "general" behavioral traits including olfaction, phototaxis, locomotor activity, and heartbeat. ibx males court normally, and are successful in mating. These characteristics suggest that ibx does not cause sensory or motor defects. Ovarian growth and sperm storage are wild-type in ibx/ibx females. Treatment with the JH analog methoprene increases the receptivity of ibx/ibx females.

78 FR 5435 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-25

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice... CCI Roseton LLC. Filed Date: 1/16/13. Accession Number: 20130116-5132. Comments Due: 5 p.m. ET 2/6/13... Status of NRG Power Marketing LLC, et al. Filed Date: 1/14/13. Accession Number: 20130114-5241. Comments...

Sulfatase-mediated manipulation of the astrocyte-Schwann cell interface.

PubMed

O'Neill, Paul; Lindsay, Susan L; Pantiru, Andreea; Guimond, Scott E; Fagoe, Nitish; Verhaagen, Joost; Turnbull, Jeremy E; Riddell, John S; Barnett, Susan C

2017-01-01

Schwann cell (SC) transplantation following spinal cord injury (SCI) may have therapeutic potential. Functional recovery is limited however, due to poor SC interactions with host astrocytes and the induction of astrogliosis. Olfactory ensheathing cells (OECs) are closely related to SCs, but intermix more readily with astrocytes in culture and induce less astrogliosis. We previously demonstrated that OECs express higher levels of sulfatases, enzymes that remove 6-O-sulfate groups from heparan sulphate proteoglycans, than SCs and that RNAi knockdown of sulfatase prevented OEC-astrocyte mixing in vitro. As human OECs are difficult to culture in large numbers we have genetically engineered SCs using lentiviral vectors to express sulfatase 1 and 2 (SC-S1S2) and assessed their ability to interact with astrocytes. We demonstrate that SC-S1S2s have increased integrin-dependent motility in the presence of astrocytes via modulation of NRG and FGF receptor-linked PI3K/AKT intracellular signaling and do not form boundaries with astrocytes in culture. SC-astrocyte mixing is dependent on local NRG concentration and we propose that sulfatase enzymes influence the bioavailability of NRG ligand and thus influence SC behavior. We further demonstrate that injection of sulfatase expressing SCs into spinal cord white matter results in less glial reactivity than control SC injections comparable to that of OEC injections. Our data indicate that sulfatase-mediated modification of the extracellular matrix can influence glial interactions with astrocytes, and that SCs engineered to express sulfatase may be more OEC-like in character. This approach may be beneficial for cell transplant-mediated spinal cord repair. GLIA 2016 GLIA 2017;65:19-33. © 2016 The Authors. Glia Published by Wiley Periodicals, Inc.

A randomized trial of diet and physical activity in women treated for stage II—IV ovarian cancer: Rationale and design of the Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES): An NRG Oncology/Gynecologic Oncology Group (GOG-225) Study☆,☆☆

PubMed Central

Thomson, Cynthia A.; Crane, Tracy E.; Miller, Austin; Garcia, David O.; Basen-Engquist, Karen; Alberts, David S.

2016-01-01

Ovarian cancer is the most common cause of gynecological cancer death in United States women. Efforts to improve progression free survival (PFS) and quality of life (QoL) after treatment for ovarian cancer are necessary. Observational studies suggest that lifestyle behaviors, including diet and physical activity, are associated with lower mortality in this population. The Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES) NRG 0225 study is a randomized, controlled trial designed to test the hypothesis that a 24 month lifestyle intervention will significantly increase PFS after oncological therapy for stage II-IV ovarian cancer. Women are randomized 1:1 to a high vegetable and fiber, low-fat diet with daily physical activity goals or an attention control group. Secondary outcomes to be evaluated include QoL and gastrointestinal health. Moreover an a priori lifestyle adherence score will be used to evaluate relationships between adoption of the diet and activity goals and PFS. Blood specimens are collected at baseline, 6, 12 and 24 months for analysis of dietary adherence (carotenoids) in addition to mechanistic biomarkers (lipids, insulin, telomere length). Women are enrolled at NRG clinic sites nationally and the telephone based lifestyle intervention is delivered from The University of Arizona call center by trained health coaches. A study specific multi-modal telephone, email, and SMS behavior change software platform is utilized for information delivery, coaching and data capture. When completed, LIVES will be the largest behavior-based lifestyle intervention trial conducted among ovarian cancer survivors. PMID:27394382

Striatal response to reward anticipation: evidence for a systems-level intermediate phenotype for schizophrenia.

PubMed

Grimm, Oliver; Heinz, Andreas; Walter, Henrik; Kirsch, Peter; Erk, Susanne; Haddad, Leila; Plichta, Michael M; Romanczuk-Seiferth, Nina; Pöhland, Lydia; Mohnke, Sebastian; Mühleisen, Thomas W; Mattheisen, Manuel; Witt, Stephanie H; Schäfer, Axel; Cichon, Sven; Nöthen, Markus; Rietschel, Marcella; Tost, Heike; Meyer-Lindenberg, Andreas

2014-05-01

Attenuated ventral striatal response during reward anticipation is a core feature of schizophrenia that is seen in prodromal, drug-naive, and chronic schizophrenic patients. Schizophrenia is highly heritable, raising the possibility that this phenotype is related to the genetic risk for the disorder. To examine a large sample of healthy first-degree relatives of schizophrenic patients and compare their neural responses to reward anticipation with those of carefully matched controls without a family psychiatric history. To further support the utility of this phenotype, we studied its test-retest reliability, its potential brain structural contributions, and the effects of a protective missense variant in neuregulin 1 (NRG1) linked to schizophrenia by meta-analysis (ie, rs10503929). Examination of a well-established monetary reward anticipation paradigm during functional magnetic resonance imaging at a university hospital; voxel-based morphometry; test-retest reliability analysis of striatal activations in an independent sample of 25 healthy participants scanned twice with the same task; and imaging genetics analysis of the control group. A total of 54 healthy first-degree relatives of schizophrenic patients and 80 controls matched for demographic, psychological, clinical, and task performance characteristics were studied. Blood oxygen level-dependent response during reward anticipation, analysis of intraclass correlations of functional contrasts, and associations between striatal gray matter volume and NRG1 genotype. Compared with controls, healthy first-degree relatives showed a highly significant decrease in ventral striatal activation during reward anticipation (familywise error-corrected P < .03 for multiple comparisons across the whole brain). Supplemental analyses confirmed that the identified systems-level functional phenotype is reliable (with intraclass correlation coefficients of 0.59-0.73), independent of local gray matter volume (with no corresponding group differences and no correlation to function, and with all uncorrected P values >.05), and affected by the NRG1 genotype (higher striatal responses in controls with the protective rs10503929 C allele; familywise error-corrected P < .03 for ventral striatal response). Healthy first-degree relatives of schizophrenic patients show altered striatal activation during reward anticipation in a directionality and localization consistent with prior patient findings. This provides evidence for a functional neural system mechanism related to familial risk. The phenotype can be assessed reliably, is independent of alterations in striatal structure, and is influenced by a schizophrenia candidate gene variant in NRG1. These data encourage us to further investigate the genetic and molecular contributions to this phenotype.

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer

PubMed Central

Cosgrove, Casey M; Tritchler, David L; Cohn, David E; Mutch, David G; Rush, Craig M; Lankes, Heather A; Creasman, William T.; Miller, David S; Ramirez, Nilsa C; Geller, Melissa A; Powell, Matthew A; Backes, Floor J; Landrum, Lisa M; Timmers, Cynthia; Suarez, Adrian A; Zaino, Richard J; Pearl, Michael L; DiSilvestro, Paul A; Lele, Shashikant B; Goodfellow, Paul J

2017-01-01

Objectives The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification. Methods Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods. Results Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53–3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10–7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04–4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status. Conclusions A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system. PMID:29132872

Exploratory Factor Analysis of NRG Oncology's University of Washington Quality of Life Questionnaire – RTOG Modification

PubMed Central

Pugh, Stephanie L.; Wyatt, Gwen; Wong, Raimond K. W.; Sagar, Stephen M.; Yueh, Bevan; Singh, Anurag K.; Yao, Min; Nguyen-Tan, Phuc Felix; Yom, Sue S.; Cardinale, Francis S.; Sultanem, Khalil; Hodson, D. Ian; Krempl, Greg A.; Chavez, Ariel; Yeh, Alexander M.; Bruner, Deborah W.

2016-01-01

Context The 15-item University of Washington Quality of Life questionnaire – Radiation Therapy Oncology Group (RTOG) modification (UW-QOL-RTOG modification) has been used in several trials of head and neck cancer conducted by NRG Oncology such as RTOG 9709, RTOG 9901, RTOG 0244, and RTOG 0537. Objectives This study is an exploratory factor analysis (EFA) to establish validity and reliability of the instrument subscales. Methods EFA on the UW-QOL - RTOG modification was conducted using baseline data from NRG Oncology's RTOG 0537, a trial of acupuncture-like transcutaneous electrical nerve stimulation in treating radiation-induced xerostomia. Cronbach's α coefficient was calculated to measure reliability; correlation with the University of Michigan Xerostomia Related Quality of Life Scale (XeQOLS) was used to evaluate concurrent validity; and correlations between consecutive time points were used to assess test-retest reliability. Results The 15-item EFA of the modified tool resulted in 11 items split into 4 factors: mucus, eating, pain, and activities. Cronbach's α ranged from 0.71 to 0.93 for the factors and total score, consisting of all 11 items. There were strong correlations (ρ≥0.60) between consecutive time points and between total score and the XeQOLS total score (ρ>0.65). Conclusion The UW-QOL-RTOG modification is a valid tool that can be used to assess symptom burden of head and neck cancer patients receiving radiation therapy or those who have recently completed radiation. The modified tool has acceptable reliability, concurrent validity, and test-retest reliability in this patient population, as well as the advantage of having being shortened from 15 to 11 items. PMID:27899312

Radiation Therapy for Gynecologic Cancers

MedlinePlus

... A RE LEARNING ABOUT CLINICAL TRIALS The radiation oncology team is constantly exploring new ways to treat ... Cl inical Trials. gov www.clinicaltrials.gov NRG Oncology (Clinical Trials Using Radiation) www.nrgoncology.org Gynecologic ...

Convergent synaptic inputs from the caudal fastigial nucleus and the superior colliculus onto pontine and pontomedullary reticulospinal neurons.

PubMed

Takahashi, Mayu; Sugiuchi, Yuriko; Shinoda, Yoshikazu

2014-02-01

The caudal fastigial nucleus (FN) is known to be related to the control of eye movements and projects mainly to the contralateral reticular nuclei where excitatory and inhibitory burst neurons for saccades exist [the caudal portion of the nucleus reticularis pontis caudalis (NRPc), and the rostral portion of the nucleus reticularis gigantocellularis (NRG) respectively]. However, the exact reticular neurons targeted by caudal fastigioreticular cells remain unknown. We tried to determine the target reticular neurons of the caudal FN and superior colliculus (SC) by recording intracellular potentials from neurons in the NRPc and NRG of anesthetized cats. Neurons in the rostral NRG received bilateral, monosynaptic excitation from the caudal FNs, with contralateral predominance. They also received strong monosynaptic excitation from the rostral and caudal contralateral SC, and disynaptic excitation from the rostral ipsilateral SC. These reticular neurons with caudal fastigial monosynaptic excitation were not activated antidromically from the contralateral abducens nucleus, but most of them were reticulospinal neurons (RSNs) that were activated antidromically from the cervical cord. RSNs in the caudal NRPc received very weak monosynaptic excitation from only the contralateral caudal FN, and received either monosynaptic excitation only from the contralateral caudal SC, or monosynaptic and disynaptic excitation from the contralateral caudal and ipsilateral rostral SC, respectively. These results suggest that the caudal FN helps to control also head movements via RSNs targeted by the SC, and these RSNs with SC topographic input play different functional roles in head movements.

Serum expression level of squamous cell carcinoma antigen, highly sensitive C-reactive protein, and CA-125 as potential biomarkers for recurrence of cervical cancer.

PubMed

Guo, Suyang; Yang, Bo; Liu, Hongli; Li, Yuzhi; Li, Shengze; Ma, Ling; Liu, Jian; Guo, Wei

2017-01-01

The aim of this study was to evaluate the serum expression levels of squamous cell carcinoma antigen (SCC-Ag), highly sensitive C-reactive protein (hs-CRP), and CA-125 as potential serum biomarkers for recurrence of cervical cancer. Eighty-six cervical cancer patients who received radical treatment were retrospectively included in this study from February 2011 to January 2014. Of the included 86 cases, 23 were recurred within the 36 months (recurrence group [RG]) and other 63 patients did not (non-RG [NRG]). The serum levels of SCC-Ag, hs-CRP, and CA-125 were examined and compared between the two groups. The prediction recurrence sensitivity, specificity area under the receiver operating characteristic curve were calculated by STATA11.0 software (http://www.stata.com). The correlation among SCC-Ag, hs-CRP, and CA-125 were analyzed by Pearson correlation test. The serum levels of SCC-Ag, hs-CRP, and CA-125 were 1.29 (0.21-33.20) mg/mL, 4.78 (0.22-175.20) mg/mL, and 11.56 (2.028-123.66) IU/mL for NRG and 5.64 (0.50-136.80) mg/mL, 22.41 (0.56-588.90) mg/mL, and 25.41 (3.658-3687.00) IU/mL for RG, respectively. The serum levels of SCC-Ag, hs-CRP, and CA-125 in NG group were significant higher than those of NRG group (P < 0.05). The recurrence prediction sensitivity was 0.74, 0.65, and 0.74; specificity was 0.65, 0.63, and 0.58; area under the curve was 0.75, 0.66, and 0.67, respectively, for serum SCC-Ag, hs-CRP, and CA-125. Significant positive correlation between SCC-Ag and hs-CRP (rpearson = 0.20, P = 0.04), SCC-Ag and CA-125 (rpearson = 0.64, P < 0.001), hs-CRP and CA-125 (rpearson= -0.13, P = 0.56) was found in the RG patients. Serum SCC-Ag, hs-CRP, and CA-125 were higher in recurrence cervical patients which could be potential biomarkers for predicting cervical cancer recurrence risk.

Impact of Intensity-Modulated Radiation Therapy Technique for Locally Advanced Non-Small-Cell Lung Cancer: A Secondary Analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.

PubMed

Chun, Stephen G; Hu, Chen; Choy, Hak; Komaki, Ritsuko U; Timmerman, Robert D; Schild, Steven E; Bogart, Jeffrey A; Dobelbower, Michael C; Bosch, Walter; Galvin, James M; Kavadi, Vivek S; Narayan, Samir; Iyengar, Puneeth; Robinson, Clifford G; Wynn, Raymond B; Raben, Adam; Augspurger, Mark E; MacRae, Robert M; Paulus, Rebecca; Bradley, Jeffrey D

2017-01-01

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Examining the protective role of ErbB2 modulation in human-induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Eldridge, Sandy; Guo, Liang; Mussio, Jodie; Furniss, Mike; Hamre, John; Davis, Myrtle

2014-10-01

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are being used as an in vitro model system in cardiac biology and in drug discovery (e.g., cardiotoxicity testing). Qualification of these cells for use in mechanistic investigations will require detailed evaluations of cardiomyocyte signaling pathways and cellular responses. ErbB signaling and the ligand neuregulin play critical roles in survival and functional integrity of cardiac myocytes. As such, we sought to characterize the expression and activity of the ErbB family of receptors. Antibody microarray analysis performed on cell lysates derived from maturing hiPSC-CMs detected expression of ∼570 signaling proteins. EGFR/ErbB1, HER2/ErbB2, and ErbB4, but not ErbB3 receptors, of the epidermal growth factor receptor family were confirmed by Western blot. Activation of ErbB signaling by neuregulin-1β (NRG, a natural ligand for ErbB4) and its modulation by trastuzumab (a monoclonal anti-ErbB2 antibody) and lapatinib (a small molecule ErbB2 tyrosine kinase inhibitor) were evaluated through assessing phosphorylation of AKT and Erk1/2, two major downstream kinases of ErbB signaling, using nanofluidic proteomic immunoassay. Downregulation of ErbB2 expression by siRNA silencing attenuated NRG-induced AKT and Erk1/2 phosphorylation. Activation of ErbB signaling with NRG, or inhibition with trastuzumab, alleviated or aggravated doxorubicin-induced cardiomyocyte damage, respectively, as assessed by a real-time cellular impedance analysis and ATP measurement. Collectively, these results support the expanded use of hiPSC-CMs to examine mechanisms of cardiotoxicity and support the value of using these cells in early assessments of cardiotoxicity or efficacy. Published by Oxford University Press on behalf of Toxicological Sciences 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal.

PubMed

Wood, David M; Davies, Susannah; Cummins, Aaron; Button, Jennifer; Holt, David W; Ramsey, John; Dargan, Paul I

2011-12-01

A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs β-keto-N-methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances.

Energy-1 ('NRG-1'): don't believe what the newspapers say about it being legal.

PubMed

Wood, David M; Davies, Susannah; Cummins, Aaron; Button, Jennifer; Holt, David W; Ramsey, John; Dargan, Paul I

2011-02-02

A 31-year-old man purchased the legal high Energy-1 (NRG-1) over the internet; this was advertised as containing the compound naphthylpyrovalerone (NPV), which at the time was currently legally available in the UK. He ingested 1 g of this substance and developed a prolonged high associated with palpitations, sweating and insomnia. Analysis of both the powder and serum samples from the patient demonstrated that he ingested two classified recreational drugs β-keto-N-methylbenzodioxolylpropylamine (butylone) and methylenedioxypyrovalerone (MDPV) rather than the legal substance NPV. Users of legal highs need to be aware that legal highs purchased over the internet may contain illegal substances and therefore they may be liable for prosecution if found in possession of these substances. Future educational campaigns aimed at recreational drug and legal high users should include reference to the potential legal implications of buying these substances.

Numerical renormalization group method for entanglement negativity at finite temperature

NASA Astrophysics Data System (ADS)

Shim, Jeongmin; Sim, H.-S.; Lee, Seung-Sup B.

2018-04-01

We develop a numerical method to compute the negativity, an entanglement measure for mixed states, between the impurity and the bath in quantum impurity systems at finite temperature. We construct a thermal density matrix by using the numerical renormalization group (NRG), and evaluate the negativity by implementing the NRG approximation that reduces computational cost exponentially. We apply the method to the single-impurity Kondo model and the single-impurity Anderson model. In the Kondo model, the negativity exhibits a power-law scaling at temperature much lower than the Kondo temperature and a sudden death at high temperature. In the Anderson model, the charge fluctuation of the impurity contributes to the negativity even at zero temperature when the on-site Coulomb repulsion of the impurity is finite, while at low temperature the negativity between the impurity spin and the bath exhibits the same power-law scaling behavior as in the Kondo model.

The EGFR signaling pathway controls gut progenitor differentiation during planarian regeneration and homeostasis.

PubMed

Barberán, Sara; Fraguas, Susanna; Cebrià, Francesc

2016-06-15

The planarian Schmidtea mediterranea maintains and regenerates all its adult tissues through the proliferation and differentiation of a single population of pluripotent adult stem cells (ASCs) called neoblasts. Despite recent advances, the mechanisms regulating ASC differentiation into mature cell types are poorly understood. Here, we show that silencing of the planarian EGF receptor egfr-1 by RNA interference (RNAi) impairs gut progenitor differentiation into mature cells, compromising gut regeneration and maintenance. We identify a new putative EGF ligand, nrg-1, the silencing of which phenocopies the defects observed in egfr-1(RNAi) animals. These findings indicate that egfr-1 and nrg-1 promote gut progenitor differentiation, and are thus essential for normal cell turnover and regeneration in the planarian gut. Our study demonstrates that the EGFR signaling pathway is an important regulator of ASC differentiation in planarians. © 2016. Published by The Company of Biologists Ltd.

New Combinational Method for Noninvasive Treatments of Superficial Tissues for Body Aesthetics Applications

NASA Astrophysics Data System (ADS)

Rybyanets, A. N.; Naumenko, A. A.

The paper introduces an innovative combinational treatment method based on ultrasonic standing waves (USW) technology for noninvasive surgical, therapeutic, lypolitic or cosmetic treatment of tissues including subcutaneous adipose tissue, cellulite or skin on arbitrary body part of patient. The method is based on simultaneous or successive applying of constructively interfering physically and biologically sensed influences: USW, ultrasonic shear waves, radio-frequency (RF) heating, and vacuum massage. The paper provides basic physical principles of USW as well as critical comparison of USW and HIFU methods. The results of finite-elements and finite- difference modeling of USW transducer design and nodal pattern structure in tissue are presented. Biological effects of USW-tissue interaction and synergetic aspects of USW and RF combination are explored. Combinational treatment transducer designs and original in-vitro experiments on tissues are described.

A Common Missense Variant in the Neuregulin1 Gene is associated with Both Schizophrenia and Sudden Cardiac Death

PubMed Central

Huertas-Vazquez, Adriana; Teodorescu, Carmen; Reinier, Kyndaron; Uy-Evanado, Audrey; Chugh, Harpriya; Jerger, Katherine; Ayala, Jo; Gunson, Karen; Jui, Jonathan; Newton-Cheh, Christopher; Albert, Christine M.; Chugh, Sumeet S.

2013-01-01

Background Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD. Objective To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy. Methods From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for association between 17 SNPs mapped to 14 loci previously implicated in schizophrenia and epilepsy using logistic regression, assuming additive, dominant and recessive genetic models. Results The minor allele of the non-synonymous SNP rs10503929 within the Neuregulin 1 gene (NRG1) was associated with SCD under all three investigated models, with the strongest association for the recessive genetic model (recessive P=4.01×10−5, OR= 4.04; additive P=2.84×10−7, OR= 1.9 and dominant P=9.01×10−6, OR= 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P=0.0005, OR= 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown. Conclusions The observed association between a schizophrenia-related NRG1 variant and SCD may represent the first evidence of coexisting genetic susceptibility between two conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD. PMID:23524320

W.A. Parish Post Combustion CO 2 Capture and Sequestration Project Final Public Design Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Armpriester, Anthony

The Petra Nova Project is a commercial scale post-combustion carbon dioxide capture project that is being developed by a joint venture between NRG Energy (NRG) and JX Nippon Oil and Gas Exploration (JX). The project is designed to separate and capture carbon dioxide from an existing coal-fired unit's flue gas slipstream at NRG's W.A. Parish Generation Station located southwest of Houston, Texas. The captured carbon dioxide will be transported by pipeline and injected into the West Ranch oil field to boost oil production. The project, which is partially funded by financial assistance from the U.S. Department of Energy will usemore » Mitsubishi Heavy Industries of America, Inc.'s Kansai Mitsubishi Carbon Dioxide Recovery (KM-CDR(R)) advanced amine-based carbon dioxide absorption technology to treat and capture at least 90% of the carbon dioxide from a 240 megawatt equivalent flue gas slipstream off of Unit 8 at W.A. Parish. The project will capture approximately 5,000 tons of carbon dioxide per day or 1.5 million tons per year that Unit 8 would otherwise emit, representing the largest commercial scale deployment of post-combustion carbon dioxide capture at a coal power plant to date. The joint venture issued full notice to proceed in July 2014 and when complete, the project is expected to be the world's largest post-combustion carbon dioxide capture facility on an existing coal plant. The detailed engineering is sufficiently complete to prepare and issue the Final Public Design Report.« less

Association study of neuregulin-1 gene polymorphisms in a North Indian schizophrenia sample.

PubMed

Kukshal, Prachi; Bhatia, Triptish; Bhagwat, A M; Gur, Raquel E; Gur, Ruben C; Deshpande, Smita N; Nimgaonkar, Vishwajit L; Thelma, B K

2013-03-01

Neuregulin-1 (NRG1) gene polymorphisms have been proposed as risk factors for several common disorders. Associations with cognitive variation have also been tested. With regard to schizophrenia (SZ) risk, studies of Caucasian ancestry samples indicate associations more consistently than East Asian samples, suggesting heterogeneity. To exploit the differences in linkage disequilibrium (LD) structure across ethnic groups, we conducted a SZ case-control study (that included cognitive evaluations) in a sample from the north Indian population. NRG1 variants (n=35 SNPs, three microsatellite markers) were initially analyzed among cases (DSM IV criteria, n=1007) and controls (n=1019, drawn from two groups) who were drawn from the same geographical region in North India. Nominally significant associations with SZ were next analyzed in relation to neurocognitive measures estimated with a computerized neurocognitive battery in a subset of the sample (n=116 cases, n=170 controls). Three variants and one microsatellite showed allelic association with SZ (rs35753505, rs4733263, rs6994992, and microsatellite 420M9-1395, p≤0.05 uncorrected for multiple comparisons). A six marker haplotype 221121 (rs35753505-rs6994992-rs1354336-rs10093107-rs3924999-rs11780123) showed (p=0.0004) association after Bonferroni corrections. Regression analyses with the neurocognitive measures showed nominal (uncorrected) associations with emotion processing and attention at rs35753505 and rs6994992, respectively. Suggestive associations with SZ and SZ-related neurocognitive measures were detected with two SNPs from the NRG1 promoter region in a north Indian cohort. The functional role of the alleles merits further investigation. Copyright © 2013 Elsevier B.V. All rights reserved.

SU-F-T-539: Dosimetric Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiation Therapy for Whole Brain Hippocampal Sparing Radiation Therapy Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendall, E; Higby, C; Algan, O

2016-06-15

Purpose: To compare the treatment plan quality and dose gradient near the hippocampus between VMAT (RapidArc) and IMRT delivery techniques for whole brain radiation therapy. Methods: Fifteen patients were evaluated in this retrospective study. All treatments were planned on Varian Eclipse TPS, using 3-Arc VMAT and 9-Field IMRT, following NRG Oncology protocol NRG-CC001 guidelines evaluated by a single radiation oncologist. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 100% of the dose covering 95% of the target volume. Identical contour sets and dose-volume constraints following protocol guidelines were also applied inmore » all plans. A paired t-test analysis was used to compare VMAT and IMRT plans. Results: NRG-CC001 protocol dose-volume constraints were met for all VMAT and IMRT plans. For the planning target volume (PTV), the average values for D2% and D98% were 6% lower and 4% higher in VMAT than in IMRT, respectively. The average mean and maximum hippocampus doses in Gy for VMAT vs IMRT plans were (11.85±0.81 vs. 12.24±0.56, p=0.10) and (16.27±0.78 vs. 16.59±0.71, p=0.24), respectively. In VMAT, the average mean and maximum chiasm doses were 3% and 1% higher than in IMRT plans, respectively. For the left optic nerve, the average mean and maximum doses were 10% and 5% higher in VMAT than in IMRT plans, respectively. These values were 12% and 3% for the right optic nerve. The average percentage of dose gradient around the hippocampus in the 0–5mm and 5–10mm abutted regions for VMAT vs. IMRT were (4.42%±2.22% /mm vs. 3.95%±2.61% /mm, p=0.43) and (4.54%±1.50% /mm vs. 4.39%±1.28% /mm, p=0.73), respectively. Conclusion: VMAT plans can achieve higher hippocampus sparing with a faster dose fall-off than IMRT plans. Though statistically insignificant, VMAT offers better PTV coverage with slightly higher doses to OARs.« less

Multiple clinical presentations of anal ultra slow waves and high anal pressure: megacolon, hemorrhoids and constipation.

PubMed

Yoshino, Hiroaki; Kayaba, Hiroyuki; Hebiguchi, Tatsuzo; Morii, Mayako; Hebiguchi, Taku; Ito, Wataru; Chihara, Junichi; Kato, Tetsuo

2007-02-01

The physiopathology of idiopathic chronic constipation is complex and yet to be investigated. In the manometric studies of the patients with severe chronic constipation, we noticed that some patients with megacolon show very slow periodical (< 2/min) pressure change in the anal canal, namely ultra slow waves (USWs). USWs are considered to represent the hyperactivity of the internal anal sphincter; however, USW-related clinical presentations have yet to be investigated. We retrospectively re-evaluated the patient records and manometric studies of 85 cases, 51 subjects without defecatory problems and 34 patients with constipation, to elucidate USW-related clinical presentations. USWs were seen in 10 patients, including eight patients with chronic constipation and two subjects without defecatory problems. Out of the eight patients with constipation, one had no organic change in the anorectum, three had hemorrhoids and four exhibited megacolon. Manometric and pathological studies proved that none of the four patients with megacolon was suffering from Hirschsprung's disease. Among the 51 subjects without defecatory problems, only two had USWs. Anal pressure in the USW-positive group (106.0 +/- 37.0 cmH2O) was significantly higher than that in the group without defecatory problems (56.0 +/- 27.0 cmH2O) or constipated patients without USWs (55.0 +/- 26.0 cmH2O). Megacolon and high anal pressure, as well as chronic constipation and hemorrhoids, were the clinical presentations related to USWs. This is the first report to show the clinical relevance of USWs to megacolon. USWs should be recognized as an important manometric finding indicating a possible new clinical entity in chronic constipation.

Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities.

PubMed

Li, Ji-Tao; Feng, Yu; Su, Yun-Ai; Wang, Xiao-Dong; Si, Tian-Mei

2013-07-01

The neuregulin 1 (NRG1)-ErbB4 signaling pathway has been implicated in the pathophysiology of schizophrenia. Recent studies suggest that this pathway may interact with the N-methyl-d-aspartate receptor (NMDAR) via the postsynaptic scaffold protein PSD-95. This interaction is of particular interest given the leading role of the NMDAR hypofunction in schizophrenia. The present study investigated the short- and long-term effects of chronic NMDAR blockade on the functional interaction between the two systems in rat prefrontal cortex and hippocampus using immunoprecipitation. Adult male Wistar rats were treated intraperitoneally with MK-801 (0.25 mg/kg) or saline for 28 days. Twenty-four hours after the last injection, the associations of ErbB4 with PSD-95 and NMDAR were enhanced in the prefrontal cortex, whereas only phosphorylated-ErbB4 relative to ErbB4 was increased in the hippocampus. These effects, however, were not detectable 12 days after the last MK-801 treatment, indicating the reversible nature of these changes. We also investigated the effects of chronic MK-801 treatment on locomotion, prepulse inhibition, recognition memory, and spatial working memory. The results showed that this treatment led to decreased locomotor activity, reduced exploration in the center arena, and elevated startle magnitudes, indicating an anxiety-like phenotype. Taken together, our findings suggest that the NRG1-ErbB4 signaling could be modulated by repeated NMDAR blockade, and provide further evidence for the cross-talk between the two signaling pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

Host Defense Peptide Resistance Contributes to Colonization and Maximal Intestinal Pathology by Crohn's Disease-Associated Adherent-Invasive Escherichia coli

PubMed Central

McPhee, Joseph B.; Small, Cherrie L.; Reid-Yu, Sarah A.; Brannon, John R.; Le Moual, Hervé

2014-01-01

Host defense peptides secreted by colonocytes and Paneth cells play a key role in innate host defenses in the gut. In Crohn's disease, the burden of tissue-associated Escherichia coli commonly increases at epithelial surfaces where host defense peptides concentrate, suggesting that this bacterial population might actively resist this mechanism of bacterial killing. Adherent-invasive E. coli (AIEC) is associated with Crohn's disease; however, the colonization determinants of AIEC in the inflamed gut are undefined. Here, we establish that host defense peptide resistance contributes to host colonization by Crohn's-associated AIEC. We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease. Implicit in these findings are new bacterial targets whose inhibition might limit AIEC burden and disease in the gut. PMID:24866805

Biomarkers of Renal Tumor Burden and Progression in TSC

DTIC Science & Technology

2013-09-01

found no significant increase in CKD in those TSC patients with cysts versus those with normal renal anatomy , excluding patients with PKD, 8 and...similarly no significant increase in CKD in patients with “undisturbed” AMLs versus those with cysts or normal renal anatomy . Biopsy of AMLs had no...SMDF (NRG1 Isoform), Soggy-1, Sonic Hedgehog (ShhN-terminal), SPARC, Spinesin, TACI (TNFRSF13B), Tarc, TCCR (WSX-1), TECK (CCL25), TFPI, TGF alpha, TGF

Parent-of-origin effects on schizophrenia-relevant behaviours of type III neuregulin 1 mutant mice.

PubMed

Shang, Kani; Talmage, David A; Karl, Tim

2017-08-14

A robust, disease-relevant phenotype is paramount to the validity of genetic mouse models, which are an important tool in understanding complex diseases. Recent evidence from genome-wide association studies suggests the genetic contribution of parents to offspring is not equivalent. Despite this, few studies to date have examined the potential impact of parent genotype (i.e. origin of mutation) on the offspring of disease-relevant genetic mouse models. To elucidate the potential impact of the sex of the mutant parent on offspring phenotype, we characterized male and female offspring of an established schizophrenia mouse model, which had been generated using two different breeding schemes, in a range of disease-relevant behaviours. We compared heterozygous type III neuregulin 1 mutant (type III Nrg1 +/- ) and wild type-like control (WT) offspring from mutant father x WT mother pairings with offspring from mutant mother x WT father pairings. Offspring were tested in schizophrenia-relevant paradigms including the elevated plus maze (EPM), fear conditioning (FC), prepulse inhibition (PPI), social interaction (SI), and open field (OF). We found type III Nrg1 +/- males from mutant fathers, but not mutant mothers, showed deficits in contextual fear-associated memory and exhibited increased social interaction, compared to their WT littermates. Type III Nrg1 +/- females across breeding colonies only exhibited a subtle change to their acoustic startle response and sensorimotor gating. These results suggest a paternal-dependent transmission of genetically induced behavioural characteristics. Though the mechanisms governing this phenomenon are unclear, our results show that parental origin of mutation can alter the behavioural phenotype of genetic mouse models. Thus, researchers should carefully consider their breeding scheme when dealing with genetic mouse models of diseases such as schizophrenia. Copyright © 2017. Published by Elsevier B.V.

Xerostomia health-related quality of life: NRG oncology RTOG 0537.

PubMed

Wyatt, Gwen; Pugh, Stephanie L; Wong, Raimond K W; Sagar, Stephen; Singh, Anurag K; Koyfman, Shlomo A; Nguyen-Tân, Phuc F; Yom, Sue S; Cardinale, Francis S; Sultanem, Khalil; Hodson, Ian; Krempl, Greg A; Lukaszczyk, Barbara; Yeh, Alexander M; Berk, Lawrence

2016-09-01

The purpose of this secondary analysis was to determine change in overall health-related quality of life (HRQOL) based on patient data obtained from NRG Oncology RTOG 0537 as measured by the RTOG-modified University of Washington Head and Neck Symptom Score (RM-UWHNSS). A multi-site prospective randomized clinical trial design stratified 137 patients with post-radiation therapy xerostomia according to prior pilocarpine (PC) treatment and time after radiation therapy and/or chemotherapy and randomized patients into two groups. Patients were assigned to acupuncture or PC. Twenty-four sessions of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) were administered over 12 weeks, or oral PC (5 mg) three times daily over the same 12 weeks. The RM-UWHNSS was administered at baseline and at 4, 6, 9, and 15 months after the date of randomization. There were no between-arm differences in change scores on the RM-UWHNSS in the individual items, total score, or factor scores. For statistical modeling, race and time were significant for all outcomes (total and factor scores), while treatment arm was not significant. The ALTENS arm showed greater yet nonsignificant improvement in outcomes compared to the PC arm. Although no significant treatment differences were seen in this trial, patients receiving ALTENS consistently had lower scores, indicating better function, as compared to those receiving PC. Radiation-induced xerostomia improved over time for all patients.

78 FR 18371 - Investigations Regarding Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-26

... 02/22/13 82506 Experian (Company) Costa Mesa, CA........ 02/27/13 02/26/13 82507 Clover Industries...). 82514 NRG Energy/GenOn Energy Houston, TX 03/01/13 02/28/13 (State/One-Stop). 82515 DuPont Teijin Films...

78 FR 76609 - Genesis Solar, LLC; NRG Delta LLC; Mountain View Solar, LLC; Pheasant Run Wind, LLC; Pheasant Run...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-18

... Delta LLC; Mountain View Solar, LLC; Pheasant Run Wind, LLC; Pheasant Run Wind II, LLC; Tuscola Wind II, LLC; Mountain Wind Power, LLC; Mountain Wind Power II, LLC; Summerhaven Wind, LP; Notice of...

75 FR 18496 - Notice of Complaint Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-12

... marketing LLC, Connecticut Jet Power LLC, Devon Power LLC, Middletown Power LLC, Montville Power LLC... Resources & Trade, LLC, PSEG Power Connecticut LLC, NRG Power marketing LLC, Connecticut Jet Power LLC... subscribed docket(s). For assistance with any FERC Online service, please e-mail [email protected

Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.

PubMed

Tang, Clara Sze-Man; Gui, Hongsheng; Kapoor, Ashish; Kim, Jeong-Hyun; Luzón-Toro, Berta; Pelet, Anna; Burzynski, Grzegorz; Lantieri, Francesca; So, Man-Ting; Berrios, Courtney; Shin, Hyoung Doo; Fernández, Raquel M; Le, Thuy-Linh; Verheij, Joke B G M; Matera, Ivana; Cherny, Stacey S; Nandakumar, Priyanka; Cheong, Hyun Sub; Antiñolo, Guillermo; Amiel, Jeanne; Seo, Jeong-Meen; Kim, Dae-Yeon; Oh, Jung-Tak; Lyonnet, Stanislas; Borrego, Salud; Ceccherini, Isabella; Hofstra, Robert M W; Chakravarti, Aravinda; Kim, Hyun-Young; Sham, Pak Chung; Tam, Paul K H; Garcia-Barceló, Maria-Mercè

2016-12-01

Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

78 FR 19477 - Combined Notice of Filings #1

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-01

... California Edison Company. Description: Letter Agreement NRG Solar Alpine II Project to be effective 3/11... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Combined Notice of Filings 1 Take notice... System Operator, Inc. Description: 03-20-2013 Module D Clarification to be effective 3/ 26/2013. Filed...

Coregulated Expression of the Na+/Phosphate Pho89 Transporter and Ena1 Na+-ATPase Allows Their Functional Coupling under High-pH Stress

PubMed Central

Serra-Cardona, Albert; Petrezsélyová, Silvia; Canadell, David; Ramos, José

2014-01-01

The yeast Saccharomyces cerevisiae has two main high-affinity inorganic phosphate (Pi) transporters, Pho84 and Pho89, that are functionally relevant at acidic/neutral pH and alkaline pH, respectively. Upon Pi starvation, PHO84 and PHO89 are induced by the activation of the PHO regulon by the binding of the Pho4 transcription factor to specific promoter sequences. We show that PHO89 and PHO84 are induced by alkalinization of the medium with different kinetics and that the network controlling Pho89 expression in response to alkaline pH differs from that of other members of the PHO regulon. In addition to Pho4, the PHO89 promoter is regulated by the transcriptional activator Crz1 through the calcium-activated phosphatase calcineurin, and it is under the control of several repressors (Mig2, Nrg1, and Nrg2) coordinately regulated by the Snf1 protein kinase and the Rim101 transcription factor. This network mimics the one regulating expression of the Na+-ATPase gene ENA1, encoding a major determinant for Na+ detoxification. Our data highlight a scenario in which the activities of Pho89 and Ena1 are functionally coordinated to sustain growth in an alkaline environment. PMID:25266663

Geohydrologic and drill-hole data for test well USW H-4, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whitfield, M.S. Jr.; Thordarson, W.; Eshom, E.P.

This report presents data on drilling operations, lithology, geophysical well logs, sidewall-core samples, water-level monitoring, pumping tests, injection tests, radioactive-tracer borehole flow survey, and water chemistry for test well USW H-4. The well is one of a series of test wells drilled in the southwestern part of the Nevada Test Site, Nye County, Nevada, in cooperation with the US Department of Energy. These test wells are part of the Nevada Nuclear Waste Storage Investigations to identify sites for storage of high-level radioactive wastes. Test well USW H-4 was drilled in ash-flow tuff to a total depth of 1219 meters. Depthmore » to water below land surface was 519 meters, or at an altitude of 730 meters above sea level. After test pumping at a rate of 17.4 liters per second for approximately 9 days, the drawdown was 4.85 meters. A radioactive borehole-flow survey indicated that the Bullfrog Member of the Crater Flat Tuff (Tertiary age) was the most productive geologic unit, producing 36.5 percent of the water in the well. The second most productive geologic unit was the Tram Member of the Crater Flat Tuff, which produced 32 percent of the water. The water in test well USW H-4 is predominantly a soft, sodium bicarbonate type of water typical of water produced in tuffaceous rocks in southern Nevada. 7 references, 26 figures, 9 tables.« less

Use of genetic algorithms to improve the solid waste collection service in an urban area.

PubMed

Buenrostro-Delgado, Otoniel; Ortega-Rodriguez, Juan Manuel; Clemitshaw, Kevin C; González-Razo, Carlos; Hernández-Paniagua, Iván Y

2015-07-01

Increasing generation of Urban Solid Waste (USW) has become a significant issue in developing countries due to unprecedented population growth and high rates of urbanisation. This issue has exceeded current plans and programs of local governments to manage and dispose of USW. In this study, a Genetic Algorithm for Rule-set Production (GARP) integrated into a Geographic Information System (GIS) was used to find areas with socio-economic conditions that are representative of the generation of USW constituents in such areas. Socio-economic data of selected variables categorised by Basic Geostatistical Areas (BGAs) were taken from the 2000 National Population Census (NPC). USW and additional socio-economic data were collected during two survey campaigns in 1998 and 2004. Areas for sampling of USW were stratified into lower, middle and upper economic strata according to income. Data on USW constituents were analysed using descriptive statistics and Multivariate Analysis. ARC View 3.2 was used to convert the USW data and socio-economic variables to spatial data. Desk-top GARP software was run to generate a spatial model to identify areas with similar socio-economic conditions to those sampled. Results showed that socio-economic variables such as monthly income and education are positively correlated with waste constituents generated. The GARP used in this study revealed BGAs with similar socio-economic conditions to those sampled, where a similar composition of waste constituents generated is expected. Our results may be useful to decrease USW management costs by improving the collection services. Copyright © 2015 Elsevier Ltd. All rights reserved.

77 FR 58533 - Notice of Availability of the Draft Environmental Impact Statement for the W.A. Parish Post...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-21

....A. Parish Post-Combustion CO 2 Capture and Sequestration Project, Southeastern TX AGENCY: U.S... availability of the Draft Environmental Impact Statement for the W.A. Parish Post-Combustion Carbon Dioxide.... Parish Post-Combustion CO 2 Capture and Sequestration Project (Parish PCCS Project). NRG's proposed...

77 FR 69618 - Notice of Effectiveness of Exempt Wholesale Generator Status

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-20

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Notice of Effectiveness of Exempt Wholesale Generator Status Docket Nos. NRG Solar Borrego I LLC EG12-96-000 Energy Alternatives Wholesale, LLC..... EG12-97-000 Brookfield Smoky Mountain Hydropower EG12-98-000 LLC. Horse Butte Wind I LLC EG12...

Effects of correlated hybridization in the single-impurity Anderson model

NASA Astrophysics Data System (ADS)

Líbero, Valter; Veiga, Rodrigo

2013-03-01

The development of new materials often dependents on the theoretical foundations which study the microscopic matter, i.e., the way atoms interact and create distinct configurations. Among the interesting materials, those with partially filled d or f orbitals immersed in nonmagnetic metals have been described by the Anderson model, which takes into account Coulomb correlation (U) when a local level (energy Ed) is doubled occupied, and an electronic hybridization between local levels and conduction band states. In addition, here we include a correlated hybridization term, which depends on the local-level occupation number involved. This term breaks particle-hole symmetry (even when U + 2Ed = 0), enhances charge fluctuations on local levels and as a consequence strongly modifies the crossover between the Hamiltonian fixed-points, even suppressing one or other. We exemplify these behaviors showing data obtained from the Numerical Renormalization Group (NRG) computation for the impurity temperature-dependent specific heat, entropy and magnetic susceptibility. The interleaving procedure is used to recover the continuum spectrum after the NRG-logarithmic discretization of the conduction band. Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP.

Reply to "Comment on `Conductance scaling in Kondo-correlated quantum dots: Role of level asymmetry and charging energy'"

NASA Astrophysics Data System (ADS)

Merker, L.; Kirchner, S.; Muñoz, E.; Costi, T. A.

2014-08-01

The Comment of A. A. Aligia claims that the superperturbation theory (SPT) approach [E. Muñoz, C. J. Bolech, and S. Kirchner, Phys. Rev. Lett. 110, 016601 (2013), 10.1103/PhysRevLett.110.016601] formulated using dual fermions [A. N. Rubtsov, M. I. Katsnelson, and A. I. Lichtenstein, Phys. Rev. B 77, 033101 (2008), 10.1103/PhysRevB.77.033101] and used by us to compare with numerical renormalization group (NRG) results for the conductance [L. Merker, S. Kirchner, E. Muñoz, and T. A. Costi, Phys. Rev. B 87, 165132 (2013), 10.1103/PhysRevB.87.165132], fails to correctly extend the results of the symmetric Anderson impurity model (SIAM) for general values of the local level Ed in the Kondo regime. We answer this criticism. We also compare new NRG results for cB, with cB calculated directly from the low-field conductance, with new higher-order SPT calculations for this quantity, finding excellent agreement for all Ed and for U /πΔ extending into the strong coupling regime.

OSO paradigm--A rapid behavioral screening method for acute psychosocial stress reactivity in mice.

PubMed

Brzózka, M M; Unterbarnscheidt, T; Schwab, M H; Rossner, M J

2016-02-09

Chronic psychosocial stress is an important environmental risk factor for the development of psychiatric diseases. However, studying the impact of chronic psychosocial stress in mice is time consuming and thus not optimally suited to 'screen' increasing numbers of genetically manipulated mouse models for psychiatric endophenotypes. Moreover, many studies focus on restraint stress, a strong physical stressor with limited relevance for psychiatric disorders. Here, we describe a simple and a rapid method based on the resident-intruder paradigm to examine acute effects of mild psychosocial stress in mice. The OSO paradigm (open field--social defeat--open field) compares behavioral consequences on locomotor activity, anxiety and curiosity before and after exposure to acute social defeat stress. We first evaluated OSO in male C57Bl/6 wildtype mice where a single episode of social defeat reduced locomotor activity, increased anxiety and diminished exploratory behavior. Subsequently, we applied the OSO paradigm to mouse models of two schizophrenia (SZ) risk genes. Transgenic mice with neuronal overexpression of Neuregulin-1 (Nrg1) type III showed increased risk-taking behavior after acute stress exposure suggesting that NRG1 dysfunction is associated with altered affective behavior. In contrast, Tcf4 transgenic mice displayed a normal stress response which is in line with the postulated predominant contribution of TCF4 to cognitive deficits of SZ. In conclusion, the OSO paradigm allows for rapid screening of selected psychosocial stress-induced behavioral endophenotypes in mouse models of psychiatric diseases. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression.

PubMed

Hu, Xiangyou; Schlanger, Rita; He, Wanxia; Macklin, Wendy B; Yan, Riqiang

2013-05-01

β-Site amyloid precursor protein convertase enzyme 1 (BACE1), a type I transmembrane aspartyl protease required to cleave amyloid precursor protein for releasing a toxic amyloid peptide, also cleaves type I and type III neuregulin-1 (Nrg-1). BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination if injured. In BACE1-null mice, the abolished cleavage of neuregulin-1 by BACE1 is speculated to cause reduced myelin sheath thickness in both the central nervous system and peripheral nervous system because reduced cleavage of Nrg-1 correlates with reduced Akt phosphorylation, a downstream signaling molecule of the Nrg-1/ErbB pathway. Here we tested specifically whether increasing Akt activity alone in oligodendrocytes would be sufficient to reverse the hypomyelination phenotype in BACE1-null mice. BACE1-null mice were bred with transgenic mice expressing constitutively active Akt (Akt-DD; mutations with D(308)T and D(473)S) in oligodendrocytes. Relative to littermate BACE1-null controls, BACE1(-/-)/Akt-DD mice exhibited enhanced expression of myelin basic protein and promoter of proteolipid protein. The elevated expression of myelin proteins correlated with a thicker myelin sheath in optic nerves; comparison of quantified g ratios with statistic significance was used to confirm this reversion. However, it appeared that myelin sheath thickness in the sciatic nerves was not increased in BACE1(-/-)/Akt-DD mice, as the g ratio was not significantly different from the control. Hence, increased Akt activity in BACE1-null myelinating cells only compensates for the loss of BACE1 activity in the central nervous system, which is consistent with the observation that overexpression of Akt-DD in Schwann cells did not induce hypermyelination. Our results suggest that signaling activity other than Akt may also contribute to proper myelination in peripheral nerves.

Long-Term Outcomes Among Patients Who Achieve Complete or Near-Complete Responses After the Induction Phase of Bladder-Preserving Combined-Modality Therapy for Muscle-Invasive Bladder Cancer: A Pooled Analysis of NRG Oncology/RTOG 9906 and 0233

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitin, Timur, E-mail: mitin@ohsu.edu; George, Asha; Zietman, Anthony L.

Purpose: To investigate the differences in outcomes among patients with muscle-invasive bladder cancer on NRG Oncology Radiation Therapy Oncology Group protocols 9906 and 0233 who achieved complete response and near-complete response after induction chemoradiation and then completed bladder-preserving therapy with chemoradiation therapy (chemo-RT) to full dose (60-64 Gy). Patients and Methods: A pooled analysis was performed on 119 eligible patients with muscle-invasive bladder cancer enrolled on NRG Oncology Radiation Therapy Oncology Group trials 9906 and 0233, who were classified as having a complete (T0) or near-complete (Ta or Tis) response after induction chemo-RT and completed consolidation with a total RT dose ofmore » at least 60 Gy. Bladder recurrence, salvage cystectomy rates, and disease-specific survival were estimated by the cumulative incidence method and bladder-intact and overall survivals by the Kaplan-Meier method. Results: Among the 119 eligible patients, 101 (85%) achieved T0, and 18 (15%) achieved Ta or Tis after induction chemo-RT and proceeded to consolidation. After a median follow-up of 5.9 years, 36 of 101 T0 patients (36%) versus 5 of 18 Ta or Tis patients (28%) experienced bladder recurrence (P=.52). Thirteen patients among complete responders eventually required late salvage cystectomy for tumor recurrence, compared with 1 patient among near-complete responders (P=.63). Disease-specific, bladder-intact, and overall survivals were not significantly different between T0 and Ta/Tis cases. Conclusions: The bladder recurrence and salvage cystectomy rates of the complete and the near-complete responders were similar. Therefore it is reasonable to recommend that patients with Ta or Tis after induction chemo-RT continue with bladder-sparing therapy with consolidation chemo-RT to full dose (60-64 Gy).« less

Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation

PubMed Central

Kim, Sang Hu; Clark, Shawn T.; Surendra, Anuradha; Copeland, Julia K.; Wang, Pauline W.; Ammar, Ron; Collins, Cathy; Tullis, D. Elizabeth; Nislow, Corey; Hwang, David M.; Guttman, David S.; Cowen, Leah E.

2015-01-01

The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic colonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation. PMID:26588216

Global Analysis of the Fungal Microbiome in Cystic Fibrosis Patients Reveals Loss of Function of the Transcriptional Repressor Nrg1 as a Mechanism of Pathogen Adaptation.

PubMed

Kim, Sang Hu; Clark, Shawn T; Surendra, Anuradha; Copeland, Julia K; Wang, Pauline W; Ammar, Ron; Collins, Cathy; Tullis, D Elizabeth; Nislow, Corey; Hwang, David M; Guttman, David S; Cowen, Leah E

2015-11-01

The microbiome shapes diverse facets of human biology and disease, with the importance of fungi only beginning to be appreciated. Microbial communities infiltrate diverse anatomical sites as with the respiratory tract of healthy humans and those with diseases such as cystic fibrosis, where chronic colonization and infection lead to clinical decline. Although fungi are frequently recovered from cystic fibrosis patient sputum samples and have been associated with deterioration of lung function, understanding of species and population dynamics remains in its infancy. Here, we coupled high-throughput sequencing of the ribosomal RNA internal transcribed spacer 1 (ITS1) with phenotypic and genotypic analyses of fungi from 89 sputum samples from 28 cystic fibrosis patients. Fungal communities defined by sequencing were concordant with those defined by culture-based analyses of 1,603 isolates from the same samples. Different patients harbored distinct fungal communities. There were detectable trends, however, including colonization with Candida and Aspergillus species, which was not perturbed by clinical exacerbation or treatment. We identified considerable inter- and intra-species phenotypic variation in traits important for host adaptation, including antifungal drug resistance and morphogenesis. While variation in drug resistance was largely between species, striking variation in morphogenesis emerged within Candida species. Filamentation was uncoupled from inducing cues in 28 Candida isolates recovered from six patients. The filamentous isolates were resistant to the filamentation-repressive effects of Pseudomonas aeruginosa, implicating inter-kingdom interactions as the selective force. Genome sequencing revealed that all but one of the filamentous isolates harbored mutations in the transcriptional repressor NRG1; such mutations were necessary and sufficient for the filamentous phenotype. Six independent nrg1 mutations arose in Candida isolates from different patients, providing a poignant example of parallel evolution. Together, this combined clinical-genomic approach provides a high-resolution portrait of the fungal microbiome of cystic fibrosis patient lungs and identifies a genetic basis of pathogen adaptation.

78 FR 6818 - Notice of Issuance of Prevention of Significant Deterioration Modification and Part 71 Operating...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-31

..., EPA issued a Modification to a Prevention of Significant Deterioration (PSD) permit to NRG Backup..., Minnesota. The modified PSD permit changes the required interval of nitrogen oxide performance testing for... comment period, which ended on October 19, 2012, EPA received a comment on the modified draft PSD permit...

Occurrence of Endocrine and Thyroid Cancers Among Alaska Native People, 1969-2013.

PubMed

Nash, Sarah H; Lanier, Anne P; Southworth, Molly B

2018-04-01

Nationwide, the incidence of thyroid cancer is lower among American Indian/Alaska Native (AI/AN) people than among U.S. whites (USW). However, little is known about the incidence of thyroid or other endocrine cancers specifically among Alaska Native (AN) people. Data were examined from the National Cancer Institute's Surveillance, Epidemiology, and End Results Alaska Native Tumor Registry on endocrine cancers diagnosed among AN people from 1969-2013, with a specific focus on thyroid cancers. Frequencies of endocrine cancers by site and also of thyroid cancers by histology, size, and stage at diagnosis were evaluated. Distributions were compared to USW (Surveillance, Epidemiology, and End Results 9 Registries) using the chi-square test. Five-year average annual age-adjusted incidence rates of thyroid cancers were calculated, stratified by histology, age, and five-year period of diagnosis, and compared to those observed among USW. Five-year cause-specific survival was evaluated using cause of death data from the National Death Index Plus from the National Center for Health Statistics. During the 45-year period (1969-2013), 224 endocrine cancers were diagnosed among AN people, of which 210 (94%) were thyroid cancers. Compared to USW, AN people were diagnosed at a slightly younger age, had a higher proportion of thyroid cancers diagnosed with a size of 20-40 mm, and a larger proportion of patients with regional metastases. More than 85% of AN thyroid cancers were of papillary histology. The incidence of thyroid cancers was similar between AN people and USW, and appeared to increase among AN people over the period of surveillance. Finally, five-year cause-specific survival rate was 100% for papillary carcinoma patients and 86.3% [confidence interval 54.7-96.5] for follicular thyroid cancer patients. This study is the first report of endocrine cancers and the first detailed examination of thyroid cancer among AN people. The incidence of thyroid cancer was similar among AN people and USW. However, compared to USW, AN people appear to be at risk for diagnosis at a younger age, larger size, and higher stage. Further research is needed to explore the causes of these differences.

Effects of radiation on the epidermal growth factor receptor pathway in the heart

PubMed Central

Sridharan, Vijayalakshmi; Sharma, Sunil K.; Moros, Eduardo G.; Corry, Peter M.; Tripathi, Preeti; Lieblong, Benjamin J.; Guha, Chandan; Hauer-Jensen, Martin; Boerma, Marjan

2013-01-01

Purpose Radiation-induced heart disease (RIHD) is a serious side effect of thoracic radiotherapy. The epidermal growth factor receptor (EGFR) pathway is essential for the function and survival of cardiomyocytes. Hence, agents that target the EGFR pathway are cardiotoxic. Tocotrienols protect from radiation injury, but may also enhance the therapeutic effects of EGFR pathway inhibitors in cancer treatment. This study investigates the effects of local irradiation on the EGFR pathway in the heart and tests whether tocotrienols may modify radiation-induced changes in this pathway. Methods Male Sprague-Dawley rats received image-guided localized heart irradiation with 21 Gy. Twenty four hours before irradiation, rats received a single dose of tocotrienol-enriched formulation or vehicle by oral gavage. At time points from 2 hours to 9 months after irradiation, left ventricular expression of EGFR pathway mediators was studied. Results Irradiation caused a decrease in the expression of epidermal growth factor (EGF) and neuregulin-1 (Nrg-1) mRNA from 6 hours up to 10 weeks, followed by an upregulation of these ligands and the receptor erythroblastic leukemia viral oncogene homolog (ErbB)4 at 6 months. In addition, the upregulation of Nrg-1 was statistically significant up to 9 months after irradiation. A long-term upregulation of ErbB2 protein did not coincide with changes in transcription or post-translational interaction with the chaperone heat shock protein 90 (HSP90). Pretreatment with tocotrienols prevented radiation-induced changes at 2 weeks. Conclusions Local heart irradiation causes long-term changes in the EGFR pathway. Studies have to address how radiation may interact with cardiotoxic effects of EGFR inhibitors. PMID:23488537

ErbB4 in Laminated Brain Structures: A Neurodevelopmental Approach to Schizophrenia

PubMed Central

Perez-Garcia, Carlos G.

2015-01-01

The susceptibility genes for schizophrenia Neuregulin-1 (NRG1) and ErbB4 have critical functions during brain development and in the adult. Alterations in the ErbB4 signaling pathway cause a variety of neurodevelopmental defects including deficiencies in neuronal migration, synaptic plasticity, and myelination. I have used the ErbB4-/- HER4heart KO mice to study the neurodevelopmental insults associated to deficiencies in the NRG1-ErbB4 signaling pathway and their potential implication with brain disorders such as schizophrenia, a chronic psychiatric disease affecting 1% of the population worldwide. ErbB4 deletion results in an array of neurodevelopmental deficits that are consistent with a schizophrenic model. First, similar defects appear in multiple brain structures, from the cortex to the cerebellum. Second, these defects affect multiple aspects of brain development, from deficits in neuronal migration to impairments in excitatory/inhibitory systems, including reductions in brain volume, cortical and cerebellar heterotopias, alterations in number and distribution of specific subpopulations of interneurons, deficiencies in the astrocytic and oligodendrocytic lineages, and additional insults in major brain structures. This suggests that alterations in specific neurodevelopmental genes that play similar functions in multiple neuroanatomical structures might account for some of the symptomatology observed in schizophrenic patients, such as defects in cognition. ErbB4 mutation uncovers flaws in brain development that are compatible with a neurodevelopmental model of schizophrenia, and it establishes a comprehensive model to study the basis of the disorder before symptoms are detected in the adult. PMID:26733804

77 FR 9225 - Notice of Effectiveness of Exempt Wholesale Generator Status

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-16

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Notice of Effectiveness of Exempt Wholesale Generator Status Docket Nos. Fire Island Wind, LLC EG12-9-000 Kaheawa Wind Power II, LLC EG12-12-000 Broken Bow Wind, LLC EG12-13-000 Crofton Bluffs Wind, LLC EG12-14-000 NRG Texas Power LLC EG12-15...

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

PubMed

Saunus, Jodi M; Quinn, Michael C J; Patch, Ann-Marie; Pearson, John V; Bailey, Peter J; Nones, Katia; McCart Reed, Amy E; Miller, David; Wilson, Peter J; Al-Ejeh, Fares; Mariasegaram, Mythily; Lau, Queenie; Withers, Teresa; Jeffree, Rosalind L; Reid, Lynne E; Da Silva, Leonard; Matsika, Admire; Niland, Colleen M; Cummings, Margaret C; Bruxner, Timothy J C; Christ, Angelika N; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourse, Craig; Nourbakhsh, Ehsan; Wani, Shivangi; Anderson, Matthew J; Fink, J Lynn; Holmes, Oliver; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Taylor, Darrin; Waddell, Nick; Wood, Scott; Xu, Qinying; Kassahn, Karin S; Narayanan, Vairavan; Taib, Nur Aishah; Teo, Soo-Hwang; Chow, Yock Ping; kConFab; Jat, Parmjit S; Brandner, Sebastian; Flanagan, Adrienne M; Khanna, Kum Kum; Chenevix-Trench, Georgia; Grimmond, Sean M; Simpson, Peter T; Waddell, Nicola; Lakhani, Sunil R

2015-11-01

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2)  = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Institutional Enrollment and Survival Among NSCLC Patients Receiving Chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617.

PubMed

Eaton, Bree R; Pugh, Stephanie L; Bradley, Jeffrey D; Masters, Greg; Kavadi, Vivek S; Narayan, Samir; Nedzi, Lucien; Robinson, Cliff; Wynn, Raymond B; Koprowski, Christopher; Johnson, Douglas W; Meng, Joanne; Curran, Walter J

2016-09-01

The purpose of this analysis is to evaluate the effect of institutional accrual volume on clinical outcomes among patients receiving chemoradiation for locally advanced non-small cell lung cancer (LA-NSCLC) on a phase III trial. Patients with LA-NSCLC were randomly assigned to 60 Gy or 74 Gy radiotherapy (RT) with concurrent carboplatin/paclitaxel +/- cetuximab on NRG Oncology RTOG 0617. Participating institutions were categorized as low-volume centers (LVCs) or high-volume centers (HVCs) according to the number of patients accrued (≤3 vs > 3). All statistical tests were two-sided. Range of accrual for LVCs (n = 195) vs HVCs (n = 300) was 1 to 3 vs 4 to 18 patients. Baseline characteristics were similar between the two cohorts. Treatment at a HVC was associated with statistically significantly longer overall survival (OS) and progression-free survival (PFS) compared with treatment at a LVC (median OS = 26.2 vs 19.8 months; HR = 0.70, 95% CI = 0.56 to 0.88, P = .002; median PFS: 11.4 vs 9.7 months, HR = 0.80, 95% CI = 0.65-0.99, P = .04). Patients treated at HVCs were more often treated with intensity-modulated RT (54.0% vs 39.5%, P = .002), had a lower esophageal dose (mean = 26.1 vs 28.0 Gy, P = .03), and had a lower heart dose (median = V5 Gy 38.2% vs 54.1%, P = .006; V50 Gy 3.6% vs 7.3%, P < .001). Grade 5 adverse events (AEs) (5.3% vs 9.2%, P = .09) and RT termination because of AEs (1.3% vs 4.1%, P = .07) were less common among patients treated at HVCs. HVC remained independently associated with longer OS (P = .03) when accounting for other factors. Treatment at institutions with higher clinical trial accrual volume is associated with longer OS among patients with LA-NSCLC participating in a phase III trial. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Geohydrologic and drill-hole data for test well USW H-4, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Whitfield, M.S.; Thordarson, William; Eshom, E.P.

1984-01-01

Data are presented on drilling operations, lithology, geophysical well logs, sidewall-core samples, water-level monitoring, pumping tests, injection tests, radioactive-tracer borehole flow survey, and water chemistry for test well USW H-4. The well is one of a series of test wells drilled in the southwestern part of the Nevada Test Site, Nye County, Nevada, in cooperation with the U.S. Department of Energy. These test wells are part of the Nevada Nuclear Waste Storage Investigations to identify sites for storage of high-level radioactive wastes. Test well USW H-4 was drilled in ash-flow tuff to a total depth of 1,219 meters. Depth to water below land surface was 519 meters or at an altitude of 730 meters above sea level. After test pumping at a rate of 17.4 liters per second for approximately 9 days, the drawdown was 4.85 meters. A radioactive borehole-flow survey indicated that the Bullfrog Member was the most productive geologic unit, producing 36.5 percent of the water in the well. The second most productive geologic unit was the Tram Member, which produced 32 percent of the water. The water in test well USW H-4 is predominantly a soft, sodium bicarbonate type of water typical of water produced in tuffaceous rocks in southern Nevada. (USGS)

ErbB4 deletion predisposes to development of metabolic syndrome in mice.

PubMed

Zeng, Fenghua; Wang, Yinqiu; Kloepfer, Lance A; Wang, Suwan; Harris, Raymond C

2018-06-26

ErbB4, a member of the EGF receptor family, plays a variety of roles in physiologic and pathologic states. Genetic studies have indicated linkage of ErbB4 and type II diabetes and obesity, but its role in metabolic syndrome (MetS) has not been reported. In the current study, we found that compared to wild-type, mice with ErbB4 deletion developed MetS after 24 weeks on a medium-fat diet (MFD) as indicated by development of obesity, dyslipidemia, hepatic steatosis, hyperglycemia, hyperinsulinemia, and insulin resistance. ErbB4 deletion mice also had increased amounts of subcutaneous and visceral fat with increased serum leptin levels, whereas levels of adiponectin were not significantly different. Histologically, severe inflammation, indicated by F4/80 immunostaining and M1 macrophage polarization, was detected in both inguinal white adipose tissue (iWAT) and epididymal WAT (eWAT) in ErbB4 deletion mice. ErbB4 expression decreased during 3T3-L1 preadipocyte differentiation. Administration to 3T3-L1 adipocytes of NRG4, a specific ligand for ErbB4, had no effect on adipogenesis and lipolysis, but significantly inhibited lipogenesis, promoted browning, induced GLUT4 redistribution to cell membrane, and increased glucose uptake. NRG4 treatment also significantly increased glucose uptake in adipocytes isolated from wild-type mice, while those effects were significantly decreased in adipocytes isolated from ErbB4 deletion mice. In conclusion, our results indicate that ErbB4 may play an important role in glucose homeostasis and lipogenesis. ErbB4 deficiency-related obesity and adipose tissue inflammation may contribute to the development of metabolic syndrome.

Commercial geophysical well logs from the USW G-1 drill hole, Nevada Test Site, Nevada

USGS Publications Warehouse

Muller, D.C.; Kibler, J.E.

1983-01-01

Drill hole USW G-1 was drilled at Yucca Mountain, Nevada Test Site, Nevada, as part of the ongoing exploration program for the Nevada Nuclear Waste Storage Investigations. Contract geophysical well logs run at USW G-1 show only limited stratigraphic correlations, but correlate reasonably well with the welding of the ash-flow and ash-fall tuffs. Rocks in the upper part of the section have highly variable physical properties, but are more uniform and predictably lower in the section.

SU-F-T-388: Comparison of Biophysical Indices in Hippocampal-Avoidance Whole Brain VMAT and IMRT Radiation Therapy Treatment Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kendall, E; Ahmad, S; Algan, O

2016-06-15

Purpose: To compare biophysical indices of Volumetric Modulated Arc Therapy (VMAT) and Intensity Modulated Radiation Therapy (IMRT) treatment plans for whole brain radiation therapy following the NRG-CC001 protocol. Methods: In this retrospective study, a total of fifteen patients were planned with Varian Eclipse Treatment Planning System using VMAT (RapidArc) and IMRT techniques. The planning target volume (PTV) was defined as the whole brain volume excluding a uniform three-dimensional 5mm expansion of the hippocampus volume. Prescribed doses in all plans were 30 Gy delivered over 10 fractions normalized to a minimum of 95% of the target volume receiving 100% of themore » prescribed dose. The NRG Oncology protocol guidelines were followed for contouring and dose-volume constraints. A single radiation oncologist evaluated all treatment plans. Calculations of statistical significance were performed using Student’s paired t-test. Results: All VMAT and IMRT plans met the NRG-CC001 protocol dose-volume criteria. The average equivalent uniform dose (EUD) for the PTV for VMAT vs. IMRT was respectively (19.05±0.33 Gy vs. 19.38±0.47 Gy) for α/β of 2 Gy and (19.47±0.30 Gy vs. 19.84±0.42 Gy) for α/β of 10 Gy. For the PTV, the average mean and maximum doses were 2% and 5% lower in VMAT plans than in IMRT plans, respectively. The average EUD and the normal tissue complication probability (NTCP) for the hippocampus in VMAT vs. IMRT plans were (15.28±1.35 Gy vs. 15.65±0.99 Gy, p=0.18) and (0.305±0.012 Gy vs. 0.308±0.008 Gy, p=0.192), respectively. The average EUD and NTCP for the optic chiasm were both 2% higher in VMAT than in IMRT plans. Conclusion: Though statistically insignificant, VMAT plans indicate a lower hippocampus EUD than IMRT plans. Also, a small variation in NTCP was found between plans.« less

Paralogous ALT1 and ALT2 Retention and Diversification Have Generated Catalytically Active and Inactive Aminotransferases in Saccharomyces cerevisiae

PubMed Central

Peñalosa-Ruiz, Georgina; Aranda, Cristina; Ongay-Larios, Laura; Colon, Maritrini; Quezada, Hector; Gonzalez, Alicia

2012-01-01

Background Gene duplication and the subsequent divergence of paralogous pairs play a central role in the evolution of novel gene functions. S. cerevisiae possesses two paralogous genes (ALT1/ALT2) which presumably encode alanine aminotransferases. It has been previously shown that Alt1 encodes an alanine aminotransferase, involved in alanine metabolism; however the physiological role of Alt2 is not known. Here we investigate whether ALT2 encodes an active alanine aminotransferase. Principal Findings Our results show that although ALT1 and ALT2 encode 65% identical proteins, only Alt1 displays alanine aminotransferase activity; in contrast ALT2 encodes a catalytically inert protein. ALT1 and ALT2 expression is modulated by Nrg1 and by the intracellular alanine pool. ALT1 is alanine-induced showing a regulatory profile of a gene encoding an enzyme involved in amino acid catabolism, in agreement with the fact that Alt1 is the sole pathway for alanine catabolism present in S. cerevisiae. Conversely, ALT2 expression is alanine-repressed, indicating a role in alanine biosynthesis, although the encoded-protein has no alanine aminotransferase enzymatic activity. In the ancestral-like yeast L. kluyveri, the alanine aminotransferase activity was higher in the presence of alanine than in the presence of ammonium, suggesting that as for ALT1, LkALT1 expression could be alanine-induced. ALT2 retention poses the questions of whether the encoded protein plays a particular function, and if this function was present in the ancestral gene. It could be hypotesized that ALT2 diverged after duplication, through neo-functionalization or that ALT2 function was present in the ancestral gene, with a yet undiscovered function. Conclusions ALT1 and ALT2 divergence has resulted in delegation of alanine aminotransferase activity to Alt1. These genes display opposed regulatory profiles: ALT1 is alanine-induced, while ALT2 is alanine repressed. Both genes are negatively regulated by the Nrg1 repressor. Presented results indicate that alanine could act as ALT2 Nrg1-co-repressor. PMID:23049841

Effectiveness of supplementary irrigant agitation with the Finisher GF Brush on the debridement of oval root canals instrumented with the Gentlefile or nickel titanium rotary instruments.

PubMed

Neelakantan, P; Khan, K; Li, K Y; Shetty, H; Xi, W

2018-07-01

To examine the efficacy of a novel supplementary irrigant agitating brush (Finisher GF Brush, MedicNRG, Kibbutz Afikim, Israel) on the debridement of root canals prepared with a novel stainless steel rotary instrumentation system (Gentlefile; MedicNRG), or nickel titanium rotary instruments in oval root canals. Mandibular premolars (n = 72) were selected and divided randomly into three experimental groups (n = 24) after microCT scanning: group 1, canal preparation to rotary NiTi size 20, .04 taper (R20); group 2, rotary NiTi to size 25, .04 taper (R25) and group 3, Gentlefile size 23, .04 taper (GF). Specimens were subdivided into two subgroups: subgroup A, syringe-and-needle irrigation (SNI); subgroup B, Finisher GF Brush (GB). Ten untreated canals served as controls. Specimens were processed for histological evaluation, and the remaining pulp tissue (RPT) was measured. Data were analysed using Mann-Whitney and Kruskal-Wallis tests (P = 0.05). All experimental groups had significantly less RPT than the control (P < 0.05). Group 3B (GF-GB) had significantly less RPT than groups 1B (R20-GB) and 2B (R25-GF; P < 0.05). When irrigated with SNI, there was no significant difference in the RPT between the three groups (P > 0.05). When instrumented with R20, there was no significant difference between SNI and GF (P < 0.05) whilst GB had significantly less RPT than SNI for R25 (P < 0.05). Supplementary irrigant agitation with the Finisher GF Brush improved the debridement of canals prepared with Gentlefile and size 25, .04 taper rotary NiTi. Root canal debridement did not significantly differ between the instruments when syringe irrigation was used. © 2018 International Endodontic Journal. Published by John Wiley & Sons Ltd.

Ultrasonic Stir Welding

NASA Technical Reports Server (NTRS)

Nabors, Sammy

2015-01-01

NASA Marshall Space Flight Center (MSFC) developed Ultrasonic Stir Welding (USW) to join large pieces of very high-strength metals such as titanium and Inconel. USW, a solid-state weld process, improves current thermal stir welding processes by adding high-power ultrasonic (HPU) energy at 20 kHz frequency. The addition of ultrasonic energy significantly reduces axial, frictional, and shear forces; increases travel rates; and reduces wear on the stir rod, which results in extended stir rod life. The USW process decouples the heating, stirring, and forging elements found in the friction stir welding process allowing for independent control of each process element and, ultimately, greater process control and repeatability. Because of the independent control of USW process elements, closed-loop temperature control can be integrated into the system so that a constant weld nugget temperature can be maintained during welding.

Cortical Proteins are Chemokinetic to Cells from the Medial Ganglionic Eminence

DTIC Science & Technology

2011-05-28

et al., 2009). Disruption of interneuron migration can lead to improper distribution within the cortex and is associated with schizophrenia, autism ...include the neurotrophins; the growth factors NRG1 and GDNF, the chemokine, SDF-1 and neurotransmitters, glutamate, GABA, and dopamine (Stumm et al...Bhide PG ( Dopamine receptor activation modulates GABA neuron migration from the basal forebrain to the cerebral cortex. J Neurosci 27:3813-3822.2007

Zero bias STS Kondo anomalies of Co impurities on Cu surfaces: do ab initio calculations work?

NASA Astrophysics Data System (ADS)

Baruselli, Pier Paolo; Smogunov, Alexander; Fabrizio, Michele; Requist, Ryan; Tosatti, Erio

2012-02-01

Transition metal atoms such as Co on Cu (111), (100), and (110) surfaces produce STS I-V spectra showing different zero bias Kondo anomalies [1] but these differences have been neither quantitatively predicted nor fully explained theoretically. We apply to this problem the DFT+NRG scheme of Lucignano et al [2], where one solves by NRG an Anderson model built from ab initio phase shifts provided by DFT. For Co/Cu(100) and Co/Cu(110) our calculations describe correctly the experimental trend of Kondo temperatures, and fairly the lineshapes too. By contrast, they fail to describe Co/Cu(111) where in particular the anti-lorentzian lineshape found in experiment remains unexplained. This failure underscores the role of surface states, probably relevant for Co/Cu(111) [3] but not correctly described by our thin slab calculations. Future efforts to quantitatively include Kondo screening by surface states are therefore called for. 1. N. Knorr et al PRL 88, 096804 (2002); M. Ternes et al 2009 J. Phys.: Cond. Matt. 21, 053001 (2009); A. Gumbsch et al PRB81, 165420 (2010). 2. P. Lucignano et al Nature Mat. 8, 563 (2009); P.P. Baruselli et al, Physica E, doi:10.1016/j.physe.2011.05.005. 3. C. Lin et al. PRB 71, 035417 (2005).

Application for the Drosophila ventral nerve cord standard in neuronal circuit reconstruction and in-depth analysis of mutant morphology.

PubMed

Boerner, Jana; Godenschwege, Tanja Angela

2010-09-01

The Drosophila standard brain has been a useful tool that provides information about position and size of different brain structures within a wild-type brain and allows the comparison of imaging data that were collected from individual preparations. Therefore the standard can be used to reveal and visualize differences of brain regions between wild-type and mutant brains and can provide spatial description of single neurons within the nervous system. Recently the standard brain was complemented by the generation of a ventral nerve cord (VNC) standard. Here the authors have registered the major components of a simple neuronal circuit, the Giant Fiber System (GFS), into this standard. The authors show that they can also virtually reconstruct the well-characterized synaptic contact of the Giant Fiber with its motorneuronal target when they register the individual neurons from different preparations into the VNC standard. In addition to the potential application for the standard thorax in neuronal circuit reconstruction, the authors show that it is a useful tool for in-depth analysis of mutant morphology of single neurons. The authors find quantitative and qualitative differences when they compared the Giant Fibers of two different neuroglian alleles, nrg(849) and nrg(G00305), using the averaged wild-type GFS in the standard VNC as a reference.

Dose assessment of aircraft crew in The Netherlands.

PubMed

Van Dijk, J W E

2003-01-01

As the operator of the National Dose Registration and Information System, NRG has implemented a system for radiation exposure monitoring for the Dutch airlines. The system is based on the use of computer generated flight plans together with dose calculations using the CARI-6M program. Before installing the system a study was performed to estimate the uncertainty in the assessment of the annual dose of the crew members. It was concluded that the proposed system complies with international recommendations on the uncertainty in dose assessments in individual monitoring and that the operational costs of the system are low.

Re-Examining first principles of regulation: NRG power marketing, LLC v. Maine public utilities Commission

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haskell, Mark R.

Maine PUC and Morgan Stanley have resolved some of the key issues facing the energy industry. The Supreme Court has plainly and directly in both cases reaffirmed the central role that private contracts play in the energy industry and set terms to balance the need to secure long-term investment with the public interest that lies at the heart of the Federal Power Act. (author)

Glial cell-derived neurotrophic factor alleviates sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nicotinic acetylcholine receptors in an experimental rat model of neuromyopathy.

PubMed

Wang, Xin; Min, Su; Xie, Fei; Yang, Jun; Li, Liang; Chen, Jingyuan

2018-02-05

Sepsis-induced neuromuscular dysfunction results from up-regulation of the expression of γ- and α7-nicotinic acetylcholine receptors (nAChR). Although glial cell derived neurotrophic factor (GDNF) has been implicated in repairing and supporting neurons, little is known about the effects of GDNF on demyelination of nerves in sepsis. In this study, we tested the hypothesis that GDNF could alleviate sepsis-induced neuromuscular dysfunction by decreasing the expression of γ- and α7-nAChR in an experimental rat model of neuromyopathy. Rats were randomly divided into a sham group and a sepsis group. Levels of inflammatory factors, muscle function, and nicotinic acetylcholine receptors were tested in rats after cecal ligation and puncture (CLP). At 24 h after CLP, GDNF was injected around the sciatic nerve of sepsis rats, cytokines were detected by enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining was used to detect the expression of nAChRs. GDNF and its downstream effector (Erk1/2 and GFR-α), neuregulin-1 (NRG-1) and γ- and α7-nAChR were measured using Western blot analysis. The expression of GDNF reached a minimum at 24 h after CLP. Compared with the sham group, the release of cytokines and the expression of γ- and α7-nAChR were significantly increased in the sepsis group. The administration of GDNF significantly alleviated sepsis-induced neuromuscular dysfunction, as well as reducing the expression of γ- and α7-nAChR. In addition, the expression of Erk1/2, GFR-α, NRG-1 were significantly increased after GDNF treatment. GDNF administration may improve patient outcomes by reducing the demyelination of nerves and the expression of γ- and α7-nAChR. Copyright © 2018. Published by Elsevier Inc.

Whole-genome sequence-based analysis of thyroid function.

PubMed

Taylor, Peter N; Porcu, Eleonora; Chew, Shelby; Campbell, Purdey J; Traglia, Michela; Brown, Suzanne J; Mullin, Benjamin H; Shihab, Hashem A; Min, Josine; Walter, Klaudia; Memari, Yasin; Huang, Jie; Barnes, Michael R; Beilby, John P; Charoen, Pimphen; Danecek, Petr; Dudbridge, Frank; Forgetta, Vincenzo; Greenwood, Celia; Grundberg, Elin; Johnson, Andrew D; Hui, Jennie; Lim, Ee M; McCarthy, Shane; Muddyman, Dawn; Panicker, Vijay; Perry, John R B; Bell, Jordana T; Yuan, Wei; Relton, Caroline; Gaunt, Tom; Schlessinger, David; Abecasis, Goncalo; Cucca, Francesco; Surdulescu, Gabriela L; Woltersdorf, Wolfram; Zeggini, Eleftheria; Zheng, Hou-Feng; Toniolo, Daniela; Dayan, Colin M; Naitza, Silvia; Walsh, John P; Spector, Tim; Davey Smith, George; Durbin, Richard; Richards, J Brent; Sanna, Serena; Soranzo, Nicole; Timpson, Nicholas J; Wilson, Scott G

2015-03-06

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Chemistry of unsaturated zone gases sampled in open boreholes at the crest of Yucca Mountain, Nevada: Data and basic concepts of chemical and physical processes in the mountain

USGS Publications Warehouse

Thorstenson, Donald C.; Weeks, Edwin P.; Haas, Herbert; Busenberg, Eurybiades; Plummer, Niel; Peters, Charles A.

1998-01-01

Boreholes open to the unsaturated zone at the crest of Yucca Mountain, Nevada, were variously sampled for CO2 (including 13C and 14C), CH4, N2, O2, Ar, CFC-11, CFC-12, and CFC-113 from 1986 to 1993. Air enters the mountain in outcrops, principally on the eastern slope, is enriched in CO2by mixing with soil gas, and is advected to the mountain crest, where it returns to the atmosphere. The CFC data indicate that travel times of the advecting gas in the shallow Tiva Canyon hydrogeologic unit are ≤5 years. The 14C activities are postbomb to depths of 100 m, indicating little retardation of 14CO2 in the shallow flow systems. The 14C activities from 168 to 404 m in the Topopah Spring hydrogeologic unit are 85–90 pMC at borehole USW-UZ6. The CFC data show that the drilling of USW-UZ6 in 1984 has altered the natural system by providing a conduit through the Paintbrush Nonwelded unit, allowing flow from Topopah Spring outcrops in Solitario Canyon on the west to USW-UZ6, upward in the borehole through the Paintbrush, to the shallow Tiva Canyon flow systems, and out of the mountain.

[Comparison on extraction of volatile oils from Lithospermum erythrorhizon by different methods].

PubMed

Yang, Ri-fu; Huang, Ping-ping; Qiu, Tai-qiu; Fan, Xiao-dan

2011-02-01

To extract the volatile oils from Lithospermum erythrorhizon via ultrasound-enhanced sub-critical water extraction (USWE) and compare with ultrasound-enhanced solvent extraction (USE) and steam distillation extraction (SD). The extraction yield of the volatile oils, the containing components of extract, the effect of scanvenging activities on free radical DPPH and reducing activities as well as the inhibitory on escherichia coli and staphylococcus aureus were investigated. The extraction yield of volatile oils by USWE, USE and SD were 2.39%, 1.93% and 0.62%, respectively, the extracts by three methods all contained six major components, but the extracts by SD and USE contained more impurities. The inhibitory effect on escherichia coli and staphylococcus aureus of the extract by SD and its reducing action were the best,but those by USWE were the worst. the extraction yield of volatile oils by USWE is the highest, and it contains less impurities based on the worst in reducing power and inhibitory effects.

Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kyotani, Yoji, E-mail: cd147@naramed-u.ac.jp; Department of Pharmacy, Nara Medical University Hospital, Kashihara 634-8522; Ota, Hiroyo

Obstructive sleep apnea is characterized by intermittent hypoxia (IH), and associated with cardiovascular diseases, such as stroke and heart failure. These cardiovascular diseases have a relation to atherosclerosis marked by the proliferation of vascular smooth muscle cells (VSMCs). In this study, we investigated the influence of IH on cultured rat aortic smooth muscle cell (RASMC). The proliferation of RASMC was significantly increased by IH without changing the level of apoptosis. In order to see what induces RASMC proliferation, we investigated the influence of normoxia (N)-, IH- and sustained hypoxia (SH)-treated cell conditioned media on RASMC proliferation. IH-treated cell conditioned mediummore » significantly increased RASMC proliferation compared with N-treated cell conditioned medium, but SH-treated cell conditioned medium did not. We next investigated the epidermal growth factor (EGF) family as autocrine growth factors. Among the EGF family, we found significant increases in mRNAs for epiregulin (ER), amphiregulin (AR) and neuregulin-1 (NRG1) in IH-treated cells and mature ER in IH-treated cell conditioned medium. We next investigated the changes in erbB family receptors that are receptors for ER, AR and NRG1, and found that erbB2 receptor mRNA and protein expressions were increased by IH, but not by SH. Phosphorylation of erbB2 receptor at Tyr-1248 that mediates intracellular signaling for several physiological effects including cell proliferation was increased by IH, but not by SH. In addition, inhibitor for erbB2 receptor suppressed IH-induced cell proliferation. These results provide the first demonstration that IH induces VSMC proliferation, and suggest that EGF family, such as ER, AR and NRG1, and erbB2 receptor could be involved in the IH-induced VSMC proliferation. - Highlights: ●In vitro system for intermittent hypoxia (IH) and sustained hypoxia (SH). ●IH, but not SH, induces the proliferation of rat vascular smooth muscle cell. ●Epiregulin mRNA and protein are up-regulated in IH, but not in SH. ●IH-induced erbB2 phosphorylation is attenuated by erbB2 inhibitor. ●EGF family and erbB2 receptor may be involved in IH-induced cell proliferation.« less

W.A. Parish Post-Combustion CO{sub 2} Capture and Sequestration Project Phase 1 Definition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Armpriester, Anthony; Smith, Roger; Scheriffius, Jeff

2014-02-01

For a secure and sustainable energy future, the United States (U.S.) must reduce its dependence on imported oil and reduce its emissions of carbon dioxide (CO{sub 2}) and other greenhouse gases (GHGs). To meet these strategic challenges, the U.S. wiU have to create fundamentally new technologies with performance levels far beyond what is now possible. Developing advanced post-combustion clean coal technologies for capturing CO{sub 2} from existing coal-fired power plants can play a major role in the country's transition to a sustainable energy future, especially when coupled with CO{sub 2}-enhanced oil recovery (CO{sub 2}-EOR). Pursuant to these goals, NRG Energy,more » Inc. (NRG) submitted an application and entered into a cost-shared collaboration with the U.S. Department of Energy (DOE) under Round 3 of the Clean Coal Power Initiative (CCPI) to advance low-emission coal technologies. The objective of the NRG W A Parish Post-Combustion CO{sub 2} Capture and Sequestration Demonstration Project is to establish the technical feasibility and economic viability of post-combustion CO{sub 2} capture using flue gas from an existing pulverized coal-fired boiler integrated with geologic sequestration via an enhanced oil recovery (EOR) process. To achieve these objectives, the project will be executed in three phases. Each phase represents a distinct aspect of the project execution. The project phases are: • Phase I. Project Definition/Front-End Engineering Design (FEED) • Phase ll. Detailed Engineering, Procurement & Construction • Phase III. Demonstration and Monitoring The purpose of Phase I is to develop the project in sufficient detail to facilitate the decision-making process in progressing to the next stage of project delivery. Phase n. This report provides a complete summary of the FEED study effort, including pertinent project background information, the scope of facilities covered, decisions, challenges, and considerations made regarding configuration and performance of the facility, along with the conceptual design and estimate results. The findings of this report should be considered conceptual in nature and are conditioned on the statements contained herein. The cost of preparing this report (including the FEED study described herein) was funded in part by a $167-million grant provided by the U.S. DOE.« less

Validation of the Predictive Value of Modeled Human Chorionic Gonadotrophin Residual Production in Low-Risk Gestational Trophoblastic Neoplasia Patients Treated in NRG Oncology/Gynecologic Oncology Group-174 Phase III Trial.

PubMed

You, Benoit; Deng, Wei; Hénin, Emilie; Oza, Amit; Osborne, Raymond

2016-01-01

In low-risk gestational trophoblastic neoplasia, chemotherapy effect is monitored and adjusted with serum human chorionic gonadotrophin (hCG) levels. Mathematical modeling of hCG kinetics may allow prediction of methotrexate (MTX) resistance, with production parameter "hCGres." This approach was evaluated using the GOG-174 (NRG Oncology/Gynecologic Oncology Group-174) trial database, in which weekly MTX (arm 1) was compared with dactinomycin (arm 2). Database (210 patients, including 78 with resistance) was split into 2 sets. A 126-patient training set was initially used to estimate model parameters. Patient hCG kinetics from days 7 to 45 were fit to: [hCG(time)] = hCG7 * exp(-k * time) + hCGres, where hCGres is residual hCG tumor production, hCG7 is the initial hCG level, and k is the elimination rate constant. Receiver operating characteristic (ROC) analyses defined putative hCGRes predictor of resistance. An 84-patient test set was used to assess prediction validity. The hCGres was predictive of outcome in both arms, with no impact of treatment arm on unexplained variability of kinetic parameter estimates. The best hCGres cutoffs to discriminate resistant versus sensitive patients were 7.7 and 74.0 IU/L in arms 1 and 2, respectively. By combining them, 2 predictive groups were defined (ROC area under the curve, 0.82; sensitivity, 93.8%; specificity, 70.5%). The predictive value of hCGres-based groups regarding resistance was reproducible in test set (ROC area under the curve, 0.81; sensitivity, 88.9%; specificity, 73.1%). Both hCGres and treatment arm were associated with resistance by logistic regression analysis. The early predictive value of the modeled kinetic parameter hCGres regarding resistance seems promising in the GOG-174 study. This is the second positive evaluation of this approach. Prospective validation is warranted.

Application for the Drosophila ventral nerve cord standard in neuronal circuit reconstruction and in-depth analysis of mutant morphology

PubMed Central

Boerner, Jana; Godenschwege, Tanja Angela

2010-01-01

The Drosophila standard brain has been a useful tool that provides information about position and size of different brain structures within a wild-type brain and allows the comparison of imaging data that were collected from individual preparations. Therefore the standard can be used to reveal and visualize differences of brain regions between wild-type and mutant brains and can provide spatial description of single neurons within the nervous system. Recently the standard brain was complemented by the generation of a ventral nerve cord (VNC) standard. Here the authors have registered the major components of a simple neuronal circuit, the Giant Fiber System (GFS), into this standard. The authors show that they can also virtually reconstruct the well-characterized synaptic contact of the Giant Fiber with its motorneuronal target when they register the individual neurons from different preparations into the VNC standard. In addition to the potential application for the standard thorax in neuronal circuit reconstruction, the authors show that it is a useful tool for in-depth analysis of mutant morphology of single neurons. The authors find quantitative and qualitative differences when they compared the Giant Fibers of two different neuroglian alleles, nrg849 and nrgG00305, using the averaged wild-type GFS in the standard VNC as a reference. PMID:20615087

Geohydrologic and drill-hole data for test well USW H-1, adjacent to Nevada Test Site, Nye County, Nevada

USGS Publications Warehouse

Rush, F. Eugene; Thordarson, William; Bruckheimer, Laura

1983-01-01

This report presents data collected to determine the hydraulic characteristics of rocks penetrated in test well USW H-1. The well is one of a series of test wells drilled in and near the southwestern part of the Nevada Test Site, Nye County, Nevada, in a program conducted on behalf of the U.S. Department of Energy. These investigations are part of the Nevada Nuclear Waste Storage Investigations to identify suitable sites for storage of high-level radioactive wastes. Data on drilling operations, lithology, borehole geophysics, hydrologic monitoring, core analysis, ground-water chemistry and pumping and injection tests for well USW H-1 are contained in this report.

Graphic comparison of reserve-growth models for conventional oil and accumulation

USGS Publications Warehouse

Klett, T.R.

2003-01-01

The U.S. Geological Survey (USGS) periodically assesses crude oil, natural gas, and natural gas liquids resources of the world. The assessment procedure requires estimated recover-able oil and natural gas volumes (field size, cumulative production plus remaining reserves) in discovered fields. Because initial reserves are typically conservative, subsequent estimates increase through time as these fields are developed and produced. The USGS assessment of petroleum resources makes estimates, or forecasts, of the potential additions to reserves in discovered oil and gas fields resulting from field development, and it also estimates the potential fully developed sizes of undiscovered fields. The term ?reserve growth? refers to the commonly observed upward adjustment of reserve estimates. Because such additions are related to increases in the total size of a field, the USGS uses field sizes to model reserve growth. Future reserve growth in existing fields is a major component of remaining U.S. oil and natural gas resources and has therefore become a necessary element of U.S. petroleum resource assessments. Past and currently proposed reserve-growth models compared herein aid in the selection of a suitable set of forecast functions to provide an estimate of potential additions to reserves from reserve growth in the ongoing National Oil and Gas Assessment Project (NOGA). Reserve growth is modeled by construction of a curve that represents annual fractional changes of recoverable oil and natural gas volumes (for fields and reservoirs), which provides growth factors. Growth factors are used to calculate forecast functions, which are sets of field- or reservoir-size multipliers. Comparisons of forecast functions were made based on datasets used to construct the models, field type, modeling method, and length of forecast span. Comparisons were also made between forecast functions based on field-level and reservoir- level growth, and between forecast functions based on older and newer data. The reserve-growth model used in the 1995 USGS National Assessment and the model currently used in the NOGA project provide forecast functions that yield similar estimates of potential additions to reserves. Both models are based on the Oil and Gas Integrated Field File from the Energy Information Administration (EIA), but different vintages of data (from 1977 through 1991 and 1977 through 1996, respectively). The model based on newer data can be used in place of the previous model, providing similar estimates of potential additions to reserves. Fore-cast functions for oil fields vary little from those for gas fields in these models; therefore, a single function may be used for both oil and gas fields, like that used in the USGS World Petroleum Assessment 2000. Forecast functions based on the field-level reserve growth model derived from the NRG Associates databases (from 1982 through 1998) differ from those derived from EIA databases (from 1977 through 1996). However, the difference may not be enough to preclude the use of the forecast functions derived from NRG data in place of the forecast functions derived from EIA data. Should the model derived from NRG data be used, separate forecast functions for oil fields and gas fields must be employed. The forecast function for oil fields from the model derived from NRG data varies significantly from that for gas fields, and a single function for both oil and gas fields may not be appropriate.

Effect of Zinc Coatings on Joint Properties and Interfacial Reactions in Aluminum to Steel Ultrasonic Spot Welding

NASA Astrophysics Data System (ADS)

Haddadi, F.; Strong, D.; Prangnell, P. B.

2012-03-01

Dissimilar joining of aluminum to steel sheet in multimaterial automotive structures is an important potential application of ultrasonic spot welding (USW). Here, the weldability of different zinc-coated steels with aluminum is discussed, using a 2.5-kW USW welder. Results show that soft hot-dipped zinc (DX56-Z)-coated steel results in better weld performance than hard (galv-annealed) zinc coatings (DX53-ZF). For Al to hard galv-annealed-coated steel welds, lap shear strengths reached a maximum of ~80% of the strength of an Al-Al joint after a 1.0 s welding time. In comparison, welds between Al6111-T4 and hot dipped soft zinc-coated steel took longer to achieve the same maximum strength, but nearly matched the Al-Al joint properties. The reasons for these different behaviors are discussed in terms of the interfacial reactions between the weld members.

A Basis for Excellence: A Plan for the Development of Learning Resource Services. To Accommodate the Northridge and Riverside Campuses: To Develop Collections at Southwest Center, Rutherford and 620 Oaks; To Improve Student Access to the LRS Collections.

ERIC Educational Resources Information Center

Hisle, W. Lee; And Others

Designed by Austin Community College's (ACC's) Learning Resource Services (LRS) Management Team, this plan explores the development of the LRS in preparation for the 1989 closure of the college's Ridgeview (RDV) campus, and the opening of the Northridge (NRG) and Riverside (RVS) campuses. First, the plan's executive summary lays out…

Geohydrologic and drill-hole data for test well USW H-1, adjacent to Nevada Test Site, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rush, F.E.; Thordarson, W.; Bruckheimer, L.

This report presents data collected to determine the hydraulic characteristics of rocks penetrated in test well USW H-1. The well is one of a series of test wells drilled in and near the southwestern part of the Nevada Test Site, Nye County, Nevada, in a program conducted on behalf of the US Department of Energy. These investigations are part of the Nevada Nuclear Waste Storage Investigations to identify suitable sites for storage of high-level radioactive wastes. Data on drilling operations, lithology, borehole geophysics, hydrologic monitoring, core analysis, ground-water chemistry and pumping and injection tests for well USW H-1 are inmore » this report.« less

A Phase 3 Trial of 2 Years of Androgen Suppression and Radiation Therapy With or Without Adjuvant Chemotherapy for High-Risk Prostate Cancer: Final Results of Radiation Therapy Oncology Group Phase 3 Randomized Trial NRG Oncology RTOG 9902

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenthal, Seth A., E-mail: rosents@sutterhealth.org; Hunt, Daniel; Sartor, A. Oliver

Purpose: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS). Methods and Materials: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥7 or clinical stage ≥T2 and GS ≥8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was given as four 21-day cycles, delivered beginning 28 days after 70.2 Gy of RT.more » AS was given as luteinizing hormone-releasing hormone for 24 months, beginning 2 months before RT plus an oral antiandrogen for 4 months before and during RT. The study was designed based on a 6% improvement in OS from 79% to 85% at 5 years, with 90% power and a 2-sided alpha of 0.05. Results: A total of 397 patients (380 eligible) were randomized. The patients had high-risk PCa, 68% with GS 8 to 10 and 34% T3 to T4 tumors, and median prostate-specific antigen of 22.6 ng/mL. The median follow-up period was 9.2 years. The trial closed early because of excess thromboembolic toxicity in the CT arm. The 10-year results for all randomized patients revealed no significant difference between the AS + RT and AS + RT + CT arms in OS (65% vs 63%; P=.81), biochemical failure (58% vs 54%; P=.82), local progression (11% vs 7%; P=.09), distant metastases (16% vs 14%; P=.42), or disease-free survival (22% vs 26%; P=.61). Conclusions: NRG Oncology RTOG 9902 showed no significant differences in OS, biochemical failure, local progression, distant metastases, or disease-free survival with the addition of adjuvant CT to LT AS + RT. The trial results provide valuable data regarding the natural history of high-risk PCa treated with LT AS + RT and have implications for the feasibility of clinical trial accrual and tolerability using CT for PCa.« less

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.

PubMed

Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

2016-03-01

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non–Small Cell Lung Cancer Cells

PubMed Central

Dong, Xuyuan; Fernandez-Salas, Ester; Li, Enxiao; Wang, Shaomeng

2016-01-01

Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non–small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines. Rather, overexpression of phospho-ALK and alternative receptor tyrosine kinases such as phospho-EGFR, phospho-HER3, and phospho-IGFR-1R was observed in both resistant cell lines. Additionally, NRG1, a ligand for HER3, is upregulated and responsible for resistance by activating the EGFR family pathways through the NRG1-HER3-EGFR axis. Combination treatment with EGFR inhibitors, in particular afatinib, was shown to be effective at overcoming resistance. Our study provides new mechanistic insights into adaptive resistance to second-generation ALK inhibitors and suggests a potential clinical strategy to combat resistance to these second-generation ALK inhibitors in NSCLC. PMID:26992917

BRUTON’S TYROSINE KINASE INHIBITORS PREVENT THERAPEUTIC ESCAPE IN BREAST CANCER CELLS

PubMed Central

Wang, Xianhui; Wong, Jason; Sevinsky, Christopher J; Kokabee, Leila; Khan, Faiza; Sun, Yan; Conklin, Douglas S.

2016-01-01

We have reported that a novel isoform of BTK (BTK-C) expressed in breast cancer protects these cells from apoptosis. In this study, we show that recently developed inhibitors of BTK, such as ibrutinib (PCI-32765), AVL-292 and CGI-1746, reduce breast cancer cell survival and prevent drug resistant clones from arising. Ibrutinib treatment impacts HER2+ breast cancer cell viability at lower concentrations than the established breast cancer therapeutic lapatinib. In addition to inhibiting BTK, ibrutinib, but not AVL-292 and CGI-1746, efficiently blocks the activation of EGFR, HER2, ErbB3, and ErbB4. Consequently, the activation of AKT and ERK signaling pathways are also blocked leading to a G1/S cell cycle delay and increased apoptosis. Importantly, inhibition of BTK prevents activation of the AKT signaling pathway by NRG or EGF that has been shown to promote growth factor-driven lapatinib resistance in HER2+ breast cancer cells. HER2+ breast cancer cell proliferation is blocked by ibrutinib even in the presence of these factors. AVL-292, which has no effect on EGFR family activation, prevents NRG- and EGF-dependent growth factor-driven resistance to lapatinib in HER2+ breast cancer cells. In vivo, ibrutinib inhibits HER2+ xenograft tumor growth. Consistent with this, immunofluorescence analysis of xenograft tumors shows that ibrutinib reduces the phosphorylation of HER2, BTK, Akt and Erk and histone H3 and increases cleaved caspase-3 signals. Since BTK-C and HER2 are often co-expressed in human breast cancers, these observations indicate that BTK-C is a potential therapeutic target and that ibrutinib could be an effective drug especially for HER2+ breast cancer. PMID:27256378

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development.

PubMed

Lu, Cecilia S; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-09-26

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins.

MicroRNA-8 promotes robust motor axon targeting by coordinate regulation of cell adhesion molecules during synapse development

PubMed Central

Lu, Cecilia S.; Zhai, Bo; Mauss, Alex; Landgraf, Matthias; Gygi, Stephen; Van Vactor, David

2014-01-01

Neuronal connectivity and specificity rely upon precise coordinated deployment of multiple cell-surface and secreted molecules. MicroRNAs have tremendous potential for shaping neural circuitry by fine-tuning the spatio-temporal expression of key synaptic effector molecules. The highly conserved microRNA miR-8 is required during late stages of neuromuscular synapse development in Drosophila. However, its role in initial synapse formation was previously unknown. Detailed analysis of synaptogenesis in this system now reveals that miR-8 is required at the earliest stages of muscle target contact by RP3 motor axons. We find that the localization of multiple synaptic cell adhesion molecules (CAMs) is dependent on the expression of miR-8, suggesting that miR-8 regulates the initial assembly of synaptic sites. Using stable isotope labelling in vivo and comparative mass spectrometry, we find that miR-8 is required for normal expression of multiple proteins, including the CAMs Fasciclin III (FasIII) and Neuroglian (Nrg). Genetic analysis suggests that Nrg and FasIII collaborate downstream of miR-8 to promote accurate target recognition. Unlike the function of miR-8 at mature larval neuromuscular junctions, at the embryonic stage we find that miR-8 controls key effectors on both sides of the synapse. MiR-8 controls multiple stages of synapse formation through the coordinate regulation of both pre- and postsynaptic cell adhesion proteins. PMID:25135978

Validation of MCNP NPP Activation Simulations for Decommissioning Studies by Analysis of NPP Neutron Activation Foil Measurement Campaigns

NASA Astrophysics Data System (ADS)

Volmert, Ben; Pantelias, Manuel; Mutnuru, R. K.; Neukaeter, Erwin; Bitterli, Beat

2016-02-01

In this paper, an overview of the Swiss Nuclear Power Plant (NPP) activation methodology is presented and the work towards its validation by in-situ NPP foil irradiation campaigns is outlined. Nuclear Research and consultancy Group (NRG) in The Netherlands has been given the task of performing the corresponding neutron metrology. For this purpose, small Aluminium boxes containing a set of circular-shaped neutron activation foils have been prepared. After being irradiated for one complete reactor cycle, the sets have been successfully retrieved, followed by gamma-spectrometric measurements of the individual foils at NRG. Along with the individual activities of the foils, the reaction rates and thermal, intermediate and fast neutron fluence rates at the foil locations have been determined. These determinations include appropriate corrections for gamma self-absorption and neutron self-shielding as well as corresponding measurement uncertainties. The comparison of the NPP Monte Carlo calculations with the results of the foil measurements is done by using an individual generic MCNP model functioning as an interface and allowing the simulation of individual foil activation by predetermined neutron spectra. To summarize, the comparison between calculation and measurement serve as a sound validation of the Swiss NPP activation methodology by demonstrating a satisfying agreement between measurement and calculation. Finally, the validation offers a chance for further improvements of the existing NPP models by ensuing calibration and/or modelling optimizations for key components and structures.

Women psychiatrists and research: so far, no further? An Australasian perspective on factors that encourage and hinder women psychiatrists' involvement in research.

PubMed

Favilla, Amanda; Bloch, Sidney

2004-06-01

Relatively few women psychiatrists conduct research during their careers. Little is known as to what accounts for this consistent finding. We sought to ascertain factors that might be pertinent among women Fellows of the Royal Australian and New Zealand College of Psychiatrists (RANZCP). Our long-term goal is to identify measures that could boost the proportion of women who become involved in research. We submitted a questionnaire to the 670 women Fellows of the RANZCP in which we asked them whether they participated in research and what factors they considered helpful or detrimental to the pursuit of an interest in research. Of the 375 (56%) respondents, 116 (31%) could be assigned to a researcher group (RG). Members of the RG more often identified features in their professional environment and access to mentors as facilitating research involvement compared to the non-researcher group (NRG). The RG had dedicated more time to research as well as to teaching, and less to clinical practice, compared to the NRG. Although family obligations affected both groups, the RG cited these as exerting less of an impact on their career than their non-researching colleagues. Given the factors that distinguish researching from non-researching Fellows, attention needs to be paid to the ethos of the professional environment, mentoring, and training opportunities in research in order to increase the recruitment of women investigators.

Mss11p Is a Central Element of the Regulatory Network That Controls FLO11 Expression and Invasive Growth in Saccharomyces cerevisiae

PubMed Central

van Dyk, Dewald; Pretorius, Isak S.; Bauer, Florian F.

2005-01-01

The invasive and filamentous growth forms of Saccharomyces cerevisiae are adaptations to specific environmental conditions, under particular conditions of limited nutrient availability. Both growth forms are dependent on the expression of the FLO11 gene, which encodes a cell-wall-associated glycoprotein involved in cellular adhesion. A complex regulatory network consisting of signaling pathways and transcription factors has been associated with the regulation of FLO11. Mss11p has been identified as a transcriptional activator of this gene, and here we present an extensive genetic analysis to identify functional relationships between Mss11p and other FLO11 regulators. The data show that Mss11p is absolutely required for the activation of FLO11 by most proteins that have previously been shown to affect FLO11 expression, including the signaling proteins Ras2p, Kss1p, and Tpk2p, the activators Tec1p, Flo8p, and Phd1p, and the repressors Nrg1p, Nrg2p, Sok2p, and Sfl1p. The genetic evidence furthermore suggests that Mss11p activity is not dependent on the presence of any of the above-mentioned factors and that the protein also regulates other genes involved in cellular adhesion phenotypes. Taken together, the data strongly suggest a central role for Mss11p in the regulatory network controlling FLO11 expression, invasive growth, and pseudohyphal differentiation. PMID:15466424

DOE Office of Scientific and Technical Information (OSTI.GOV)

Connolly, J.R.

Petrologic, bulk chemical, and mineralogic data are presented for 49 samples of tuffaceous rocks from core holes USW G-1 and UE-25a{number_sign}1 at Yucca Mountain, Nevada. Included, in descending stratigraphic order, are 11 samples from the Topopah Spring Member of the Paintbrush Tuff, 12 samples from the Tuffaceous Beds of Calico Hills, 3 samples from the Prow Pass Member of the Crater Flat Tuff, 20 samples from the Bullfrog Member of the Crater Flat Tuff and 3 samples from the Tram Member of the Crater Flat Tuff. The suite of samples contains a wide variety of petrologic types, including zeolitized, glassy,more » and devitrified tuffs. Data vary considerably between groups of samples, and include thin section descriptions (some with modal analyses for which uncertainties are estimated), electron microprobe analyses of mineral phases and matrix, mineral identifications by X-ray diffraction, and major element analyses with uncertainty estimates.« less

Ultrasonic Stir Welding Development for Ground-Based and In Situ Fabrication and Repair for In-Space Propulsion Systems/Commercial Space Sector

NASA Technical Reports Server (NTRS)

Ding, Jeff

2015-01-01

The completed Center Innovation Fund (CIF) project used the upgraded Ultrasonic Stir Weld (USW) Prototype System (built in 2013/2014) to begin characterizing the weld process using 2219 aluminum (fig. 1). This work is being done in Bldg. 4755 at NASA Marshall Space Flight Center (MSFC). The capabilities of the USW system provides the means to precisely control and document individual welding parameters. The current upgraded system has the following capabilities: (1) Ability to 'pulse' ultrasonic (US) energy on and off and adjust parameters real-time (travel speed, spindle rpm, US amplitude, X and Z axis positions, and plunge and pin axis force; (2) Means to measure draw force; (3) Ability to record US power versus time; (4) Increasing stiffness of Z axis drive and reduce head deflection using laser technology; (5) Adding linear encoder to better control tool penetration setting; (6) Ultrasonic energy integrated into stir rod and containment plate; (7) Maximum 600 rpm; (8) Maximum Z force 15,000 lb; (9) Real-time data acquisition and logging capabilities at a minimum frequency of 10 Hz; and (10) Two separate transducer power supplies operating at 4.5 kW power.

WE-AB-BRA-07: Quantitative Evaluation of 2D-2D and 2D-3D Image Guided Radiation Therapy for Clinical Trial Credentialing, NRG Oncology/RTOG

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giaddui, T; Yu, J; Xiao, Y

Purpose: 2D-2D kV image guided radiation therapy (IGRT) credentialing evaluation for clinical trial qualification was historically qualitative through submitting screen captures of the fusion process. However, as quantitative DICOM 2D-2D and 2D-3D image registration tools are implemented in clinical practice for better precision, especially in centers that treat patients with protons, better IGRT credentialing techniques are needed. The aim of this work is to establish methodologies for quantitatively reviewing IGRT submissions based on DICOM 2D-2D and 2D-3D image registration and to test the methodologies in reviewing 2D-2D and 2D-3D IGRT submissions for RTOG/NRG Oncology clinical trials qualifications. Methods: DICOM 2D-2Dmore » and 2D-3D automated and manual image registration have been tested using the Harmony tool in MIM software. 2D kV orthogonal portal images are fused with the reference digital reconstructed radiographs (DRR) in the 2D-2D registration while the 2D portal images are fused with DICOM planning CT image in the 2D-3D registration. The Harmony tool allows alignment of the two images used in the registration process and also calculates the required shifts. Shifts calculated using MIM are compared with those submitted by institutions for IGRT credentialing. Reported shifts are considered to be acceptable if differences are less than 3mm. Results: Several tests have been performed on the 2D-2D and 2D-3D registration. The results indicated good agreement between submitted and calculated shifts. A workflow for reviewing these IGRT submissions has been developed and will eventually be used to review IGRT submissions. Conclusion: The IROC Philadelphia RTQA center has developed and tested a new workflow for reviewing DICOM 2D-2D and 2D-3D IGRT credentialing submissions made by different cancer clinical centers, especially proton centers. NRG Center for Innovation in Radiation Oncology (CIRO) and IROC RTQA center continue their collaborative efforts to enhance quality assurance services and to be consistently adaptive to the new advances in radiation therapy. This project was supported by NCI grants U10CA180868, U10CA180822, U24CA180803, U24CA12014 and PA CURE Grant.« less

Long-Term Update of NRG Oncology RTOG 0319: A Phase 1 and 2 Trial to Evaluate 3-Dimensional Conformal Radiation Therapy Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabinovitch, Rachel, E-mail: rachel.rabinovitch@ucdenver.edu; Moughan, Jennifer; Vicini, Frank

Purpose: NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. Methods and Materials: Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breastmore » recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. Results: Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. Conclusions: This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature phase 3 results will determine the appropriateness and limitations of this noninvasive APBI technique.« less

Long-Term Update of NRG Oncology RTOG 0319: A Phase 1 and 2 Trial to Evaluate 3-Dimensional Conformal Radiation Therapy Confined to the Region of the Lumpectomy Cavity for Stage I and II Breast Carcinoma.

PubMed

Rabinovitch, Rachel; Moughan, Jennifer; Vicini, Frank; Pass, Helen; Wong, John; Chafe, Susan; Petersen, Ivy; Arthur, Douglas W; White, Julia

2016-12-01

NRG Oncology RTOG 0319 was the first cooperative group trial in the United States to evaluate 3-dimensional conformal radiation therapy (3D-CRT) accelerated partial breast irradiation (APBI). This report updates secondary endpoints of toxicity and efficacy. Patients with stage I or II invasive breast cancer (tumor size ≤3 cm, ≤3 positive lymph nodes, negative margins) were eligible for 3D-CRT APBI: 38.5 Gy in 10 twice-daily fractions. Patient characteristics and treatment details have previously been reported. Adverse events were graded with CTCAE v3.0 (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). This analysis updates the rates of ipsilateral breast recurrence (IBR), contralateral breast recurrence, ipsilateral node recurrence (INR), metastatic sites (distant metastases [DM]), mastectomy, disease-free survival, mastectomy-free survival, and overall survival. Of 58 enrolled patients, 52 were eligible, with a median age of 61 years; 94% had stage I cancer and 83% had estrogen receptor positive disease. The median follow-up period was 8 years (minimum-maximum, 1.7-9.0 years). The 7-year estimate of isolated IBR (no DM) was 5.9%. The 7-year estimates of all IBRs, INR, mastectomy rate, and DM were 7.7%, 5.8%, 7.7%, and 7.7%, respectively. All 4 IBRs were invasive, of which 3 had a component within the planning target volume. The patterns of failure were as follows: 3 IBRs, 1 INR, 2 DM, 1 INR plus DM, and 1 IBR plus INR plus DM. The 7-year estimates of mastectomy-free survival, disease-free survival, and overall survival were 71.2%, 71.2%, and 78.8%, respectively. Thirteen patients died: 3 of breast cancer and 10 of other causes. Grade 3 (G3) treatment-related adverse events were reported by 4 patients (7.7%). No G3 pain or pulmonary or cardiac toxicities were reported. This phase 1 and 2 trial of 3D-CRT APBI continues to show durable tumor control and minimal G3 toxicity, comparable to other APBI techniques. Mature phase 3 results will determine the appropriateness and limitations of this noninvasive APBI technique. Copyright © 2016. Published by Elsevier Inc.

Comparisons of body size, composition, and whole body bone mass between North American and South African children.

PubMed

Micklesfield, Lisa K; Norris, Shane A; Nelson, Dorothy A; Lambert, Estelle V; van der Merwe, Lize; Pettifor, John M

2007-12-01

We compared whole body BMC of 811 black, white, and mixed ancestral origin children from Detroit, MI; Johannesburg, South Africa; and Cape Town, South Africa. Our findings support the role of genetic and environmental influences in the determination of bone mass in prepubertal children. Higher bone mass and lower fracture rates have been shown in black compared with white children and adults in North America. We compared whole body BMC (WBBMC), whole body fat mass (WBFM), and whole body fat free soft tissue (WBFFST) data between three ethnic groups of children from Detroit, MI (n = 181 white, USW; n = 230 black, USB), Johannesburg, South Africa (n = 73 white, SAW; n = 263 black, SAB), and Cape Town, South Africa (n = 64 mixed ancestral origin, SAM). SAB and SAW groups were slightly older than USW and USB groups (9.5 +/- 0.3 versus 9.3 +/- 0.1 yr); however, USB and USW boys were significantly taller, were heavier, and had a higher BMI than SAM and SAB boys. USB girls were significantly taller than SAB girls and heavier than SAB and SAM girls. In South Africa and the United States, black children had a significantly higher WBBMC than white children, after adjusting for selected best predictors. After adjusting for age, weight, and height, WBBMC was significantly higher in the SAB and SAW boys than in USW and USB and in the SAM group compared with the USW and USB groups. WBFFST and WBFM made significant contributions to a best linear model for log(WBBMC), together with age, height, and ethnicity. The best model accounted for 79% of the WBBMC variance. When included separately in the model, the model containing WBFFST accounted for 76%, and the model containing WBFM accounted for 70%, of the variance in WBBMC. WBBMC is lower in children of European ancestry compared with African ancestry, irrespective of geographical location; however, South African children have significantly higher WBBMC compared with USB and USW groups, thereby acknowledging the possible contribution of environmental factors. Reasons for the significantly higher WBBMC in the children of mixed ancestral origin compared with the other groups need to be studied further.

Results of Hydraulic Tests in Miocene Tuffaceous Rocks at the C-Hole Complex, 1995 to 1997, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Geldon, Arthur L.; Umari, Amjad M.A.; Fahy, Michael F.; Earle, John D.; Gemmell, James M.; Darnell, Jon

2002-01-01

Four hydraulic tests were conducted by the U.S. Geological Survey at the C-hole complex at Yucca Mountain, Nevada, between May 1995 and November 1997. These tests were conducted as part of ongoing investigations to determine the hydrologic and geologic suitability of Yucca Mountain as a potential site for permanent underground storage of high-level nuclear waste. The C-hole complex consists of three 900-meter-deep boreholes that are 30.4 to 76.6 meters apart. The C-holes are completed in fractured, variably welded tuffaceous rocks of Miocene age. Six hydrogeologic intervals occur within the saturated zone in these boreholes - the Calico Hills, Prow Pass, Upper Bullfrog, Lower Bullfrog, Upper Tram, and Lower Tram intervals. The Lower Bullfrog and Upper Tram intervals contributed about 90 percent of the flow during hydraulic tests. The four hydraulic tests conducted from 1995 to 1997 lasted 4 to 553 days. Discharge from the pumping well, UE-25 c #3, ranged from 8.49 to 22.5 liters per second in different tests. Two to seven observation wells, 30 to 3,526 meters from the pumping well, were used in different tests. Observation wells included UE-25 c #1, UE-25 c #2, UE-25 ONC-1, USW H-4, UE-25 WT #14, and UE-25 WT #3 in the tuffaceous rocks and UE-25 p #1 in Paleozoic carbonate rocks. In all hydraulic tests, drawdown in the pumping well was rapid and large (2.9-11 meters). Attributable mostly to frictional head loss and borehole-skin effects, this drawdown could not be used to analyze hydraulic properties. Drawdown and recovery in intervals of UE-25 c #1 and UE-25 c #2 and in other observation wells typically was less than 51 centimeters. These data were analyzed. Hydrogeologic intervals in the C-holes have layered heterogeneity related to faults and fracture zones. Transmissivity, hydraulic conductivity, and storativity generally increase downhole. Transmissivity ranges from 4 to 1,600 meters squared per day; hydraulic conductivity ranges from 0.1 to 50 meters per day; and storativity ranges from 0.00002 to 0.002. Transmissivity in the Miocene tuffaceous rocks decreases from 2,600 to 700 meters squared per day northwesterly across the 21-square-kilometer area affected by hydraulic tests at the C-hole complex. The average transmissivity of the tuffaceous rocks in this area, as determined from plots of drawdown in most or all observation wells as functions of time or distance from the pumping well, is 2,100 to 2,600 meters squared per day. Average storativity determined from these plot ranges is 0.0005 to 0.002. Hydraulic conductivity ranges from less than 2 to more than 10 meters per day; it is largest where prominent northerly trending faults are closely spaced or intersected by northwesterly trending faults. During hydraulic tests, the Miocene tuffaceous rocks functioned as a single aquifer. Drawdown occurred in all monitored intervals of the C-holes and other observation wells, regardless of the hydrogeologic interval being pumped. This hydraulic connection across geologic and lithostratigraphic contacts is believed to result from interconnected faults, fractures, and intervals with large matrix permeability. Samples of UE-25 c #3 water, analyzed from 1995 to 1997, seem to indicate that changes in the quality of the water pumped from that well are probably due solely to lateral variations in water quality within the tuffaceous rocks.

The Effectiveness of Surface Coatings on Preventing Interfacial Reaction During Ultrasonic Welding of Aluminum to Magnesium

NASA Astrophysics Data System (ADS)

Panteli, Alexandria; Robson, Joseph D.; Chen, Ying-Chun; Prangnell, Philip B.

2013-12-01

High power ultrasonic spot welding (USW) is a solid-state joining process that is advantageous for welding difficult dissimilar material couples, like magnesium to aluminum. USW is also a useful technique for testing methods of controlling interfacial reaction in welding as the interface is not greatly displaced by the process. However, the high strain rate deformation in USW has been found to accelerate intermetallic compound (IMC) formation and a thick Al12Mg17 and Al3Mg2 reaction layer forms after relatively short welding times. In this work, we have investigated the potential of two approaches for reducing the IMC reaction rate in dissimilar Al-Mg ultrasonic welds, both involving coatings on the Mg sheet surface to (i) separate the join line from the weld interface, using a 100- μm-thick Al cold spray coating, and (ii) provide a diffusion barrier layer, using a thin manganese physical vapor deposition (PVD) coating. Both methods were found to reduce the level of reaction and increase the failure energy of the welds, but their effectiveness was limited due to issues with coating attachment and survivability during the welding cycle. The effect of the coatings on the joint's interface microstructure, and the fracture behavior have been investigated in detail. Kinetic modeling has been used to show that the benefit of the cold spray coating can be attributed to the reaction rate reverting to that expected under static conditions. This reduces the IMC growth rate by over 50 pct because at the weld line, the high strain rate dynamic deformation in USW normally enhances diffusion through the IMC layer. In comparison, the thin PVD barrier coating was found to rapidly break up early in USW and become dispersed throughout the deformation layer reducing its effectiveness.

Equilibrium dynamics of the sub-Ohmic spin-boson model under bias

NASA Astrophysics Data System (ADS)

Zheng, Da-Chuan; Tong, Ning-Hua

2017-06-01

Using the bosonic numerical renormalization group method, we studied the equilibrium dynamical correlation function C(ω) of the spin operator σ z for the biased sub-Ohmic spin-boson model. The small-ω behavior C(ω )\\propto {ω }s is found to be universal and independent of the bias ɛ and the coupling strength α (except at the quantum critical point α ={α }{{c}} and ɛ = 0). Our NRG data also show C(ω )\\propto {χ }2{ω }s for a wide range of parameters, including the biased strong coupling regime (\\varepsilon \

Identification of Proteins Required for Precise Positioning of Apc2 in Dendrites.

PubMed

Weiner, Alexis T; Seebold, Dylan Y; Michael, Nick L; Guignet, Michelle; Feng, Chengye; Follick, Brandon; Yusko, Brandon A; Wasilko, Nathan P; Torres-Gutierrez, Pedro; Rolls, Melissa M

2018-05-04

In Drosophila neurons, uniform minus-end-out polarity in dendrites is maintained in part by kinesin-2-mediated steering of growing microtubules at branch points. Apc links the kinesin motor to growing microtubule plus ends and Apc2 recruits Apc to branch points where it functions. Because Apc2 acts to concentrate other steering proteins to branch points, we wished to understand how Apc2 is targeted. From an initial broad candidate RNAi screen, we found Miro (a mitochondrial transport protein), Ank2, Axin, spastin and Rac1 were required to position Apc2-GFP at dendrite branch points. YFP-Ank2-L8, Axin-GFP and mitochondria also localized to branch points suggesting the screen identified relevant proteins. By performing secondary screens, we found that energy production by mitochondria was key for Apc2-GFP positioning and spastin acted upstream of mitochondria. Ank2 seems to act independently from other players, except its membrane partner, Neuroglian (Nrg). Rac1 likely acts through Arp2/3 to generate branched actin to help recruit Apc2-GFP. Axin can function in a variety of wnt signaling pathways, one of which includes heterotrimeric G proteins and Frizzleds. Knockdown of Gαs, Gαo, Fz and Fz2, reduced targeting of Apc2 and Axin to branch points. Overall our data suggest that mitochondrial energy production, Nrg/Ank2, branched actin generated by Arp2/3 and Fz/G proteins/Axin function as four modules that control localization of the microtubule regulator Apc2 to its site of action in dendrite branch points. Copyright © 2018 Weiner et al.

Identification of Proteins Required for Precise Positioning of Apc2 in Dendrites

PubMed Central

Weiner, Alexis T.; Seebold, Dylan Y.; Michael, Nick L.; Guignet, Michelle; Feng, Chengye; Follick, Brandon; Yusko, Brandon A.; Wasilko, Nathan P.; Torres-Gutierrez, Pedro; Rolls, Melissa M.

2018-01-01

In Drosophila neurons, uniform minus-end-out polarity in dendrites is maintained in part by kinesin-2-mediated steering of growing microtubules at branch points. Apc links the kinesin motor to growing microtubule plus ends and Apc2 recruits Apc to branch points where it functions. Because Apc2 acts to concentrate other steering proteins to branch points, we wished to understand how Apc2 is targeted. From an initial broad candidate RNAi screen, we found Miro (a mitochondrial transport protein), Ank2, Axin, spastin and Rac1 were required to position Apc2-GFP at dendrite branch points. YFP-Ank2-L8, Axin-GFP and mitochondria also localized to branch points suggesting the screen identified relevant proteins. By performing secondary screens, we found that energy production by mitochondria was key for Apc2-GFP positioning and spastin acted upstream of mitochondria. Ank2 seems to act independently from other players, except its membrane partner, Neuroglian (Nrg). Rac1 likely acts through Arp2/3 to generate branched actin to help recruit Apc2-GFP. Axin can function in a variety of wnt signaling pathways, one of which includes heterotrimeric G proteins and Frizzleds. Knockdown of Gαs, Gαo, Fz and Fz2, reduced targeting of Apc2 and Axin to branch points. Overall our data suggest that mitochondrial energy production, Nrg/Ank2, branched actin generated by Arp2/3 and Fz/G proteins/Axin function as four modules that control localization of the microtubule regulator Apc2 to its site of action in dendrite branch points. PMID:29602811

Fractures in outcrops in the vicinity of drill hole USW G-4. Yucca Mountain, Nevada; data analysis and compilation

USGS Publications Warehouse

Barton, Christopher C.; Page, William R.; Morgan, Terrance L.

1989-01-01

Fractures on outcrops in the vicinity of drill hole USW G-4, Yucca Mountain, Nevada, were studied in order to contribute to characterization of fractures for hydrologjc, geomechanical, and tectonic modeling of the Yucca Mountain block and to characterize fractures prior to the excavation of a proposed exploratory shaft located near USW G-4. Yucca Mountain is a prospective site for the construction of an underground repository for high-level nuclear waste.Measurements were taken and recorded on 5,000 fractures at 50 outcrop stations primarily in the upper lithophysal unit of the Tiva Canyon Member of the Miocene Paintbrush Tuff. Fracture orientation and surface roughness were recorded for each fracture. Additionally, notes were taken on fracture abutting, crossing, and offsetting relations, swarming, curvature, brecciation, slickensides, and fracture fillings. Frequency distributions of orientation and roughness were plotted and analyzed. Fractures with low roughness coefficients (0-4) group tightly into two sets based on orientation. We conclude that such fractures are cooling joints and that all other fractures are tectonic. The development of small-scale fractures adjacent, subparallel, and possibly related to the Ghost Dance fault has been addressed in a preliminary way based on data collected in this study. Such sympathetic fractures are abundant in the upper cliff unit but not in the upper lithophysal unit.

Corrective Action Investigation Plan for Corrective Action Unit 168: Areas 25 and 26 Contaminated Materials and Waste Dumps, Nevada Test Site, Nevada (Rev. 0) includes Record of Technical Change No. 1 (dated 8/28/2002), Record of Technical Change No. 2 (dated 9/23/2002), and Record of Technical Change No. 3 (dated 6/2/2004)

DOE Office of Scientific and Technical Information (OSTI.GOV)

U.S. Department of Energy, National Nuclear Security Administration Nevada

This Corrective Action Investigation Plan contains the U.S. Department of Energy, National Nuclear Security Administration Nevada Operations Office's approach to collect data necessary to evaluate corrective action alternatives appropriate for the closure of Corrective Action Unit 168 under the Federal Facility Agreement and Consent Order. Corrective Action Unit 168 consists of a group of twelve relatively diverse Corrective Action Sites (CASs 25-16-01, Construction Waste Pile; 25-16-03, MX Construction Landfill; 25-19-02, Waste Disposal Site; 25-23-02, Radioactive Storage RR Cars; 25-23-18, Radioactive Material Storage; 25-34-01, NRDS Contaminated Bunker; 25-34-02, NRDS Contaminated Bunker; CAS 25-23-13, ETL - Lab Radioactive Contamination; 25-99-16, USW G3;more » 26-08-01, Waste Dump/Burn Pit; 26-17-01, Pluto Waste Holding Area; 26-19-02, Contaminated Waste Dump No.2). These CASs vary in terms of the sources and nature of potential contamination. The CASs are located and/or associated wit h the following Nevada Test Site (NTS) facilities within three areas. The first eight CASs were in operation between 1958 to 1984 in Area 25 include the Engine Maintenance, Assembly, and Disassembly Facility; the Missile Experiment Salvage Yard; the Reactor Maintenance, Assembly, and Disassembly Facility; the Radioactive Materials Storage Facility; and the Treatment Test Facility Building at Test Cell A. Secondly, the three CASs located in Area 26 include the Project Pluto testing area that operated from 1961 to 1964. Lastly, the Underground Southern Nevada Well (USW) G3 (CAS 25-99-16), a groundwater monitoring well located west of the NTS on the ridgeline of Yucca Mountain, was in operation during the 1980s. Based on site history and existing characterization data obtained to support the data quality objectives process, contaminants of potential concern (COPCs) for CAU 168 are primarily radionuclide; however, the COPCs for several CASs were not defined. To address COPC uncertainty, the analytical program for most CASs will include volatile organic compounds, semivolatile organic compounds, Resource Conservation and Recovery Act metals, total petroleum hydrocarbons, polychlorinated biphenyls, and radionuclides. Upon reviewing historical data and current site conditions, it has been determined that no further characterization is required at USW G3 (CAS 25-99-16) to select the appropriate corrective action. A cesium-137 source was encased in cement within the vadous zone during the drilling of the well (CAS 25-99-16). A corrective action of closure in place with a land-use restriction for drilling near USW G3 is appropriate. This corrective action will be documented in the Corrective Action Decision Document (CADD) for CAU 168. The results of the remaining field investigation will support a defensible evaluation of corrective action alternatives for the other CASs within CAU 168 in this CADD.« less

Geohydrology of test well USW H-3, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Thordarson, William; Rush, F.E.; Waddell, S.J.

1985-01-01

Test well USW H-3 is one of several wells drilled in the southwestern part of the Nevada Test Site for hydraulic testing, hydrologic monitoring, and geophysical logging. The work was performed in cooperation with the U.S. Department of Energy. The rocks penetrated by the well to a total depth of 1,219 meters were volcanic tuffs of Tertiary age. The most transmissive zone in this well is in the upper part of the Tram Member of the Crater Flat Tuff that was penetrated at a depth from 809 to 841 meters; transmissivity is about 7 x 10 -1 meter squared per day. The remainder of the rocks penetrated between the depths of 841 to 1,219 meters have a transmissivity of about 4 x 10 -1 meter squared per day and are predominatly in the Tram Member of the Crater Flat Tuff and the Lithic Ridge Tuff in the depths from 841 to 1,219 meters. (USGS)

The Use of Geographic Information Technologies in Environmental Decision-Making in the State of Michoacan, Mexico

NASA Astrophysics Data System (ADS)

Teodoro, Silva García José; Gustavo, Cruz Cárdenas; Salvador, Ochoa Estrada; Franciso, Estrada Godoy; Fabian, Villalpando Barragán

2008-05-01

One of the most urgent issues facing the human environment, a result of current human evolution is the increase in the production of Urban Solid Waste (USW). The State of Michoacán is no exception; the presence of waste facilities in the area is a very big problem and one with a strong geographical content (Mena et al., 2006). SIGs are one tool for addressing this kind of need. A model which has been commonly used for selecting areas for the final deposit of USW, and which has obtained good results, is so-called multicriterion decision-making. It has been applied in the context of integral USW management, and has generated both a methodology for the determination of safe places for final waste deposit and an Environmental Risk Index (ERI), which fulfills the requirements indicated by the Official Mexican Norm (NOM-083-SEMARNAT-2003). The methodology consists of a quadrant analysis of 25 ha of five factors. A rank was assigned to each of the factors, and this rank was standardized according to a scale from 0 to 10 and subsequently multiplied by a weight (W) which numerically represents the degree of importance and influence of each factor in the environment. Five represented the largest impact, and two represented the smallest impact. The ERI is the sum of the five factors considered and it is represented by means of the following equation: ERI = VVw+UsUsw+FrFrw+ln lnw+Zi Ziw, where ERI is the Environmental Risk Index, V Vw is the aquifer vulnerability, Us Usw represents the use of the soil, Fr Frw refers to the fracturing density, ln lnw represents the domain of the urban and industrial infrastructure, and Zi Ziw refers to flood zones. This was shown to be successful in different regions of Michoacán State, such as the Bajío area, the Paísde la Mariposa Monarca and Tierra Caliente. Another example is its application in the hydrogeologic context, which generated the Aquifer Veda index (a restriction diagram for the opening of new exploitations), and which is intended to regulate and give advice about the design of wells, their depth and optimum slot interval, their appropriate location and caudal, in those cases in which well-drilling is permitted. The above-mentioned approach is fundamental to the sustainable operating schemes for the handling of the underground water in the Ciénega de Chapala. This approach is intended to influence the scientific handling of the hydro resource, promoting sustainable politics and rules of operation.

Microscopic Approach to Magnetism and Superconductivity of f-Electron Systems with Filled Skutterudite Structure

NASA Astrophysics Data System (ADS)

Hotta, Takashi

2005-04-01

In order to gain a deep insight into f-electron properties of filled skutterudite compounds from a microscopic viewpoint, we investigate the multiorbital Anderson model including Coulomb interactions, spin-orbit coupling, and crystalline electric field effect. First we examine the local f-electron state in detail in comparison with the results of LS and j-j coupling schemes. For each case of n=1--13, where n is the number of f electrons per rare-earth ion, the model is analyzed by using the numerical renormalization group (NRG) method to evaluate magnetic susceptibility and entropy of f electron. In particular, for the f 2-electron system corresponding to the Pr-based filled skutterudite, it is found that magnetic fluctuations significantly remain at low temperatures, even when the ground state is Γ1 singlet, if Γ_4(2) triplet is the excited state with small excitation energy. In order to make further step to construct a simplified model which can be treated even in a periodic system, we also analyze the Anderson model constructed based on the j-j coupling scheme by using the NRG method. It is clearly observed that the magnetic properties are quite similar to those of the original Anderson model. Then, we construct an orbital degenerate Hubbard model based on the j-j coupling scheme to investigate the mechanism of superconductivity of filled skutterudites. In the 2-site model, we carefully evaluate the superconducting pair susceptibility for the case of n=2 and find that the susceptibility for off-site Cooper pair is clearly enhanced only in a transition region in which the singlet and triplet ground states are interchanged. We envision a scenario that unconventional superconductivity induced by magnetic fluctuations may occur in the f 2-electron system with Γ1 ground state such as Pr-based filled skutterudite compounds.

Candida species Rewired Hyphae Developmental Programs for Chlamydospore Formation

PubMed Central

Böttcher, Bettina; Pöllath, Christine; Staib, Peter; Hube, Bernhard; Brunke, Sascha

2016-01-01

Chlamydospore formation is a characteristic of many fungal species, among them the closely related human-pathogenic dimorphic yeasts Candida albicans and C. dubliniensis. Whereas function and regulation of filamentation are well-studied in these species, the basis of chlamydospore formation is mostly unknown. Here, we investigate the contribution of environmental and genetic factors and identified central proteins involved in species-specific regulation of chlamydosporulation. We show that specific nutrient levels strongly impact chlamydospore initiation, with starvation favoring sporulation and elevated levels of saccharides or peptone inhibiting it. Thresholds for these nutritional effects differ between C. albicans and C. dubliniensis, which explain species-specific chlamydospore formation on certain diagnostic media. A C. albicans nrg1Δ mutant phenocopied C. dubliniensis, putting Nrg1 regulation at the basis of species-specific chlamydospore formation under various conditions. By screening a series of potential chlamydospore regulators, we identified the TOR and cAMP pathways as crucial for sporulation. As rapamycin treatment blocked chlamydosporulation, a low basal Tor1 activity seems to be essential. In addition, TOR effector pathways play an important role, and loss of the NCR (nitrogen catabolite repression) gene regulators Gat1 and Gln3 reduced chlamydospore formation. A severe reduction was seen for a C. albicans gcn4Δ deletion strain, implicating a link between regulation of amino acid biosynthesis and chlamydospore development. On the other hand, deletion of the GTPase gene RAS1 and the adenylyl cyclase gene CYR1 caused a defect in chlamydospore formation that was mostly rescued by cAMP supplementation. Thus, cAMP-signaling is a second major pathway to control chlamydospore production. Finally, we confirmed light exposure to have a repressive effect on chlamydosporulation. However, permanent illumination only reduced, but not abolished chlamydospore production of C. albicans whereas C. dubliniensis sporulation was unaffected. In summary, we describe novel environmental factors which determine chlamydosporulation and propose a first model for the regulatory network of chlamydospore formation by different Candida species. PMID:27833594

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.

PubMed

Taylor, John C; Bongartz, Tim; Massey, Jonathan; Mifsud, Borbala; Spiliopoulou, Athina; Scott, Ian C; Wang, Jianmei; Morgan, Michael; Plant, Darren; Colombo, Marco; Orchard, Peter; Twigg, Sarah; McInnes, Iain B; Porter, Duncan; Freeston, Jane E; Nam, Jackie L; Cordell, Heather J; Isaacs, John D; Strathdee, Jenna L; Arnett, Donna; de Hair, Maria J H; Tak, Paul P; Aslibekyan, Stella; van Vollenhoven, Ronald F; Padyukov, Leonid; Bridges, S Louis; Pitzalis, Costantino; Cope, Andrew P; Verstappen, Suzanne M M; Emery, Paul; Barnes, Michael R; Agakov, Felix; McKeigue, Paul; Mushiroda, Taisei; Kubo, Michiaki; Weinshilboum, Richard; Barton, Anne; Morgan, Ann W; Barrett, Jennifer H

2018-05-25

Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 -7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

Accelerated Post-Weld Natural Ageing in Ultrasonic Welding Aluminium 6111-T4 Automotive Sheet

NASA Astrophysics Data System (ADS)

Chen, Ying-Chun; Prangnell, Phil

In contrast to previously published reports, it is shown that there is an observable HAZ when ultrasonic spot welding (USW) automotive alloys, like AA6111-T4, the severity of which depends on the welding energy. Immediately after welding, softening is seen relative to the T4 condition, but this is rapidly recovered by natural ageing, which masks the presence of a HAZ, and the weld strength eventually exceeds that of the parent material. This behaviour is caused by dissolution of the solute clusters/GPZs in the T4 sheet, due to the high weld temperatures (> 400 °C), combined with accelerated post-weld natural ageing to a more advanced state than in the parent material. Modelling has demonstrated that this accelerated natural ageing behaviour can be attributed to an excess vacancy concentration generated by the USW process.

Solid State Welding Development at Marshall Space Flight Center

NASA Technical Reports Server (NTRS)

Ding, Robert J.; Walker, Bryant

2012-01-01

What is TSW and USW? TSW is a solid state weld process consisting of an induction coil heating source, a stir rod, and non-rotating containment plates Independent heating, stirring and forging controls Decouples the heating, stirring and forging process elements of FSW. USW is a solid state weld process consisting of an induction coil heating source, a stir rod, and a non-rotating containment plate; Ultrasonic energy integrated into non-rotating containment plate and stir rod; Independent heating, stirring and forging controls; Decouples the heating, stirring and forging process elements of FSW.

Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration.

PubMed

Missinato, Maria A; Saydmohammed, Manush; Zuppo, Daniel A; Rao, Krithika S; Opie, Graham W; Kühn, Bernhard; Tsang, Michael

2018-03-06

Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in dusp6 mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair. © 2018. Published by The Company of Biologists Ltd.

Effect of the Addition of Cetuximab to Paclitaxel, Cisplatin, and Radiation Therapy for Patients With Esophageal Cancer: The NRG Oncology RTOG 0436 Phase 3 Randomized Clinical Trial.

PubMed

Suntharalingam, Mohan; Winter, Kathryn; Ilson, David; Dicker, Adam P; Kachnic, Lisa; Konski, André; Chakravarthy, A Bapsi; Anker, Christopher J; Thakrar, Harish; Horiba, Naomi; Dubey, Ajay; Greenberger, Joel S; Raben, Adam; Giguere, Jeffrey; Roof, Kevin; Videtic, Gregory; Pollock, Jondavid; Safran, Howard; Crane, Christopher H

2017-11-01

The role of epidermal growth factor receptor (EGFR) inhibition in chemoradiation strategies in the nonoperative treatment of patients with esophageal cancer remains uncertain. To evaluate the benefit of cetuximab added to concurrent chemoradiation therapy for patients undergoing nonoperative treatment of esophageal carcinoma. A National Cancer Institute (NCI) sponsored, multicenter, phase 3, randomized clinical trial open to patients with biopsy-proven carcinoma of the esophagus. The study accrued 344 patients from 2008 to 2013. Patients were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation of 50.4 Gy/1.8 Gy fractions with or without weekly cetuximab (400 mg/m2 on day 1 then 250 mg/m2 weekly). Overall survival (OS) was the primary endpoint, with a study designed to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided α = .025. Between June 30, 2008, and February 8, 2013, 344 patients were enrolled. This analysis used all data received at NRG Oncology through April 12, 2015. Sixteen patients were ineligible, resulting in 328 evaluable patients, 159 in the experimental arm and 169 in the control arm. Patients were well matched between the treatment arms for patient and tumor characteristics: 263 (80%) with T3 or T4 disease, 215 (66%) N1, and 62 (19%) with celiac nodal involvement. Incidence of grade 3, 4, or 5 treatment-related adverse events at any time was 71 (46%), 35 (23%), or 6 (4%) in the experimental arm and 83 (50%), 28 (17%), or 2 (1%) in the control arm, respectively. A clinical complete response (cCR) rate of 81 (56%) was observed in the experimental arm vs 92 (58%) in the control arm (Fisher exact test, P = .66). No differences were seen in cCR between treatment arms for either histology (adenocarcinoma or squamous cell). Median follow-up for all patients was 18.6 months. The 24- and 36-month local failure for the experimental arm was 47% (95% CI, 38%-57%) and 49% (95% CI, 40%-59%) vs 49% (95% CI, 41%-58%) and 49% (95% CI, 41%-58%) for the control arm (HR, 0.92; 95% CI, 0.66-1.28; P = .65). The 24- and 36-month OS rates for the experimental arm were 45% (95% CI, 37%-53%) and 34% (95% CI, 26%-41%) vs 44% (95% CI, 36%-51%) and 28% (95% CI, 21%-35%) for the control arm (HR, 0.90; 95% CI, 0.70-1.16; P = .47). The addition of cetuximab to concurrent chemoradiation did not improve OS. These phase 3 trial results point to little benefit to current EGFR-targeted agents in an unselected patient population, and highlight the need for predictive biomarkers in the treatment of esophageal cancer. clinicaltrials.gov Identifier: NCT00655876.

Geohydrologic data from test hole USW UZ-7, Yucca Mountain area, Nye County, Nevada

USGS Publications Warehouse

Kume, Jack; Hammermeister, D.P.

1990-01-01

This report contains a description of the methods used in drilling and coring of the test-hole USW UZ-7, a description of the methods used in collecting, handling, and testing of test-hole samples; Lithologic information from the test hole; and water-content, water-potential, bulk-density, grain-density, porosity, and tritium data for the test hole. Test-hole USW UZ-7 was drilled and cored to a total depth of 62.94 m. The drilling was done using air as a drilling fluid to minimize disturbance to the water content of cores, drill-bit cuttings, and borehole wall-rock. Beginning at the land surface, the unsaturated-zone rock that was penetrated consisted of alluvium; welded and partially to nonwelded ash-flow tuff; bedded and reworked ash-fall tuff; nonwelded ash-flow tuff; and welded ash-flow tuff. Values of gravimetric water content and water potential of alluvium were intermediate between the extreme values in welded and nonwelded units of tuff. Gravimetric water content was largest in bedded and nonwelded ash-fall tuffs and was smallest in welded ash-flow tuff. Values of water potential were more negative in densely welded ash-flow tuffs and were less negative in bedded and nonwelded ash-fall tuffs. Bulk density was largest in densely welded ash-flow tuffs and smallest in nonwelded and bedded ash-fall tuffs. Grain density was uniform but was slightly larger in nonwelded and bedded ash-fall tuffs than in welded ash-flow tuffs. Porosity trends were opposite to bulk-density trends. Tritium content in alluvium was smallest near the alluvium-bedrock contact, markedly increased in the middle of the deposit, and decreased in the near-surface zone of the deposit. (Author 's abstract)

Long-Term Cancer Outcomes From Study NRG Oncology/RTOG 9517: A Phase 2 Study of Accelerated Partial Breast Irradiation With Multicatheter Brachytherapy After Lumpectomy for Early-Stage Breast Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

White, Julia, E-mail: Julia.White@osumc.edu; Winter, Kathryn; Kuske, Robert R.

Purpose: To examine 10-year rates of local, regional, and distant recurrences, patterns of recurrence, and survival rates for breast cancer patients enrolled on Study NRG Oncology/Radiation Therapy Oncology Group 9517, a multi-institutional prospective trial that studied one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT). Methods and Materials: Eligibility included stage I/II unifocal breast cancer <3 cm in size after lumpectomy with negative surgical margins and 0 to 3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 twice-daily fractions over 5 days for high-dose-rate (HDR); and 45 Gy in 3.5 to 5 days formore » low-dose-rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long-term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free, and overall survival. Results: The median follow-up was 12.1 years. One hundred patients were accrued from 1997 to 2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62 years; 88% had T1 tumors; 81% were pN0. Seventy-seven percent were estrogen receptor and/or progesterone receptor positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBRs and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. The 10-year CBE rate was 4.2%, with 5 total events. Eleven patients have developed DM, 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS rates are 69.8% and 78.0%, respectively. Conclusion: This multi-institutional, phase 2 trial studying MCT-APBI continues to report durable in-breast cancer control rates with long-term follow-up.« less

Long-Term Cancer Outcomes From Study NRG Oncology/RTOG 9517: A Phase 2 Study of Accelerated Partial Breast Irradiation With Multicatheter Brachytherapy After Lumpectomy for Early-Stage Breast Cancer.

PubMed

White, Julia; Winter, Kathryn; Kuske, Robert R; Bolton, John S; Arthur, Douglas W; Scroggins, Troy; Rabinovitch, Rachel A; Kelly, Tracy; Toonkel, Leonard M; Vicini, Frank A; McCormick, Beryl

2016-08-01

To examine 10-year rates of local, regional, and distant recurrences, patterns of recurrence, and survival rates for breast cancer patients enrolled on Study NRG Oncology/Radiation Therapy Oncology Group 9517, a multi-institutional prospective trial that studied one of the earliest methods of accelerated partial breast irradiation (APBI), multicatheter brachytherapy (MCT). Eligibility included stage I/II unifocal breast cancer <3 cm in size after lumpectomy with negative surgical margins and 0 to 3 positive axillary nodes without extracapsular extension. The APBI dose delivered was 34 Gy in 10 twice-daily fractions over 5 days for high-dose-rate (HDR); and 45 Gy in 3.5 to 5 days for low-dose-rate (LDR) brachytherapy. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on long-term ipsilateral breast recurrence (IBR), contralateral breast cancer events (CBE), regional recurrence (RR), and distant metastases (DM), disease-free, and overall survival. The median follow-up was 12.1 years. One hundred patients were accrued from 1997 to 2000; 98 were evaluable; 65 underwent HDR and 33 LDR MCT. Median age was 62 years; 88% had T1 tumors; 81% were pN0. Seventy-seven percent were estrogen receptor and/or progesterone receptor positive; 33% received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 4 isolated IBRs and 1 IBR with RR, for 5.2% 10-year IBR without DM. There was 1 isolated RR, 1 with IBR, and 1 with a CBE, for 3.1% 10-year RR without DM. The 10-year CBE rate was 4.2%, with 5 total events. Eleven patients have developed DM, 8 have died of breast cancer, and 22 have died from other causes. The 10-year DFS and OS rates are 69.8% and 78.0%, respectively. This multi-institutional, phase 2 trial studying MCT-APBI continues to report durable in-breast cancer control rates with long-term follow-up. Copyright © 2016 Elsevier Inc. All rights reserved.

Irradiation and post-irradiation examination of uranium-free nitride fuel

NASA Astrophysics Data System (ADS)

Hania, P. R.; Klaassen, F. C.; Wernli, B.; Streit, M.; Restani, R.; Ingold, F.; Fedorov, A. V.; Wallenius, J.

2015-11-01

Two identical Phénix-type 15-15Ti steel pinlets each containing a 70 mm Pu0.3Zr0.7N fuel stack in a 1-bar helium atmosphere have been irradiated in the HFR Petten at medium high linear power (46-47 kW/m at BOL) and an average cladding temperature of 505 °C. The pins were irradiated to a plutonium burn-up of 9.7% (88 MWd/kgHM) in 170 full power days. Both pins remained fully intact. Post-irradiation examination performed at NRG and PSI showed that the overall swelling rate of the fuel was 0.92 vol-%/%FIHMA. Fission gas release was 5-6%, while helium release was larger than 50%. No fuel restructuring was observed, and only mild cracking. EPMA measurements show a burn-up increase toward the pellet edge of up to 4 times. All investigated fission products except to some extent the noble metals were found to be evenly distributed over the matrix, indicating good solubility. Local formation of a secondary phase with high Pu content and hardly any Zr was observed. A general conclusion of this investigation is that ZrN is a suitable inert matrix for burning plutonium at high destruction rates.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

PubMed

McCourt, Carolyn K; Deng, Wei; Dizon, Don S; Lankes, Heather A; Birrer, Michael J; Lomme, Michele M; Powell, Matthew A; Kendrick, James E; Saltzman, Joel N; Warshal, David; Tenney, Meaghan E; Kushner, David M; Aghajanian, Carol

2017-01-01

The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m 2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. Copyright © 2016. Published by Elsevier Inc.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcom a of the uterus, an NRG Oncology/Gynecologic Oncology Group study☆

PubMed Central

McCourt, Carolyn K.; Deng, Wei; Dizon, Don S.; Lankes, Heather A.; Birrer, Michael J.; Lomme, Michele M.; Powell, Matthew A.; Kendrick, James E.; Saltzman, Joel N.; Warshal, David; Tenney, Meaghan E.; Kushner, David M.; Aghajanian, Carol

2017-01-01

Background The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Methods Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40 mg/m2 as a 3 hour IV infusion on day 1 of a 21 day cycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Results Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68 years. ECOGperformance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8%(4/34, 90%CI 4.2–25.1%); all were partial responses. Stable disease for at least 8 weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7 mo and 7.7 mo, respectively, with a median follow-up of 37 mo. Six month PFS was 20.6%. Major grade ≥ 3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. Conclusion In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. PMID:28029447

Genes for psychosis and creativity: a promoter polymorphism of the neuregulin 1 gene is related to creativity in people with high intellectual achievement.

PubMed

Kéri, Szabolcs

2009-09-01

Why are genetic polymorphisms related to severe mental disorders retained in the gene pool of a population? A possible answer is that these genetic variations may have a positive impact on psychological functions. Here, I show that a biologically relevant polymorphism of the promoter region of the neuregulin 1 gene (SNP8NRG243177/rs6994992) is associated with creativity in people with high intellectual and academic performance. Intriguingly, the highest creative achievements and creative-thinking scores were found in people who carried the T/T genotype, which was previously shown to be related to psychosis risk and altered prefrontal activation.

Optimal Shape of a Gamma-ray Collimator: single vs double knife edge

NASA Astrophysics Data System (ADS)

Metz, Albert; Hogenbirk, Alfred

2017-09-01

Gamma-ray collimators in nuclear waste scanners are used for selecting a narrow vertical segment in activity measurements of waste vessels. The system that is used by NRG uses tapered slit collimators of both the single and double knife edge type. The properties of these collimators were investigated by means of Monte Carlo simulations. We found that single knife edge collimators are highly preferable for a conservative estimate of the activity of the waste vessels. These collimators show much less dependence on the angle of incidence of the radiation than double knife edge collimators. This conclusion also applies to cylindrical collimators of the single knife edge type, that are generally used in medical imaging spectroscopy.

Stratigraphy, structure, and some petrographic features of Tertiary volcanic rocks in the USW G-2 drill hole, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Maldonado, Florian; Koether, S.L.

1983-01-01

A continuously cored drill hole designated as USW G-2, located at Yucca Mountain in southwestern Nevada, penetrated 1830.6 m of Tertiary volcanic strata composed of abundant silicic ash-flow tuffs, minor lava and flow breccias, and subordinate volcaniclastic rocks. The volcanic strata penetrated are comprised of the following in descending order: Paintbrush Tuff (Tiva Canyon Member, Yucca Mountain Member, bedded tuff, Pah Canyon Member, and Topopah Spring Member), tuffaceous beds of Calico Hills, Crater Flat Tuff (Prow Pass Member, Bullfrog Member, and Tram unit), lava and flow breccia (rhyodacitic), tuff of Lithic Ridge, bedded and ash-flow tuff, lava and flow breccia (rhyolitic, quartz latitic, and dacitic), bedded tuff, conglomerate and ash-flow tuff, and older tuffs of USW G-2. Comparison of unit thicknesses at USW G-2 to unit thicknesses at previously drilled holes at Yucca Mountain indicate the following: (1) thickening of the Paintbrush Tuff members and tuffaceous beds of Calico Hills toward the northern part of Yucca Mountain; (2) thickening of the Prow Pass Member but thinning of the Bullfrog Member and Tram unit; (3) thinning of the tuff of Lithic Ridge; (4) presence of approximately 280 m of lava and flow breccia not previously penetrated by any drill hole; and (5) presence of an ash-flow tuff unit at the bottom of the drill hole not previously intersected, apparently the oldest unit penetrated at Yucca Mountain to date. Petrographic features of some of the units include: (1) decrease in quartz and K-feldspar and increases in biotite and plagioclase with depth in the tuffaceous beds of Calico Hills; (2) an increase in quartz phenocrysts from the top to the bottom members of the Crater Flat Tuff; (3) a low quartz content in the tuff of Lithic Ridge, suggesting tapping of the magma chamber at quartz-poor levels; (4) a change in zeolitic alteration from heulandite to clinoptilolite to mordenite with increasing depth; (5) lavas characterized by a rhyolitic top and dacitic base, suggesting reverse compositional zoning; and (6) presence of hydrothermal mineralization in the lavas that could be related to an intrusive under Yucca Mountain or to volcanism associated with the Timber Mountain-Claim Canyon caldera complex. A fracture analysis of the core resulted n tabulation of 7,848 fractures, predominately open and high angle. The fractures were filled or coated with material in various combinations and include the following in decreasing abundance: CaCo3, iron oxides and hydroxides, SiO2, manganese oxides and hydroxides, clays and zeolites. An increase in the intensity of fracturing can be correlated with the following: (1) densely welded zones, (2) lithophysal zones, (3) vitrophyre, (4) silicified zones, (5) fault zones, and (6) cooling joints. Numerous fault zones were penetrated by the drill hole, predominately in the lithophysal zone of the Topopah Spring Member and below the tuffaceous beds of Calico Hills. The faults are predominately high angle with both a vertical and lateral component. Three major faults were penetrated, two of which intersect the ground surface, with displacements of at least 20 m and possibly as much as 52 m. The faults and some fractures are probably related to the regional doming of the area associated with the volcanism-tectonism of the Timber Mountain-Claim Canyon caldera complex, and to Basin and Range tectonism.

Geohydrologic and drill-hole data for test well USW H-3, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thordarson, W.; Rush, F.E.; Spengler, R.W.

This report presents data collected to determine the hydraulic characteristics of rocks penetrated in test well USW H-3. The well is one of a series of test wells drilled in and near the southwestern part of the Nevada Test Site, Nye County, Nevada, in a program conducted in cooperation with the US Department of Energy. These investigations are part of the Nevada Nuclear Waste Storage Investigations to identify suitable sites for storage of high-level radioactive wastes. Data on drilling operations, lithology, borehole geophysics, hydrologic monitoring, pumping, swabbing, and injection tests for the well are contained in this report.

Beaked Whale Group Deep Dive Behavior from Passive Acoustic Monitoring

DTIC Science & Technology

2015-09-30

to exploit adversary undersea assets (USW-AA-06). RELATED PROJECTS None REFERENCES Jarvis , S . M., Morrissey, R. P., Moretti, D. J...cavirostris) reveal record-breaking dives. PloS one, 9(3), e92633. 4 Shaffer, J. W., Moretti, D., Jarvis , S ., Tyack, P., & Johnson, M. (2013...I. L. (2011). Beaked whales respond to simulated and actual navy sonar. PLoS One, 6(3), e17009. Ward, J., Jarvis , S ., Moretti, D., Morrissey, R

NRG Oncology Radiation Therapy Oncology Group 0822: A Phase 2 Study of Preoperative Chemoradiation Therapy Using Intensity Modulated Radiation Therapy in Combination With Capecitabine and Oxaliplatin for Patients With Locally Advanced Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Theodore S., E-mail: tshong1@mgh.harvard.edu; Moughan, Jennifer; Garofalo, Michael C.

Purpose: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer. Methods and Materials: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint ofmore » the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided). Results: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively. Conclusion: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity.« less

Diagnostic Performance of Wells Score Combined With Point-of-care Lung and Venous Ultrasound in Suspected Pulmonary Embolism.

PubMed

Nazerian, Peiman; Volpicelli, Giovanni; Gigli, Chiara; Becattini, Cecilia; Sferrazza Papa, Giuseppe Francesco; Grifoni, Stefano; Vanni, Simone

2017-03-01

Lung and venous ultrasound are bedside diagnostic tools increasingly used in the early diagnostic approach of suspected pulmonary embolism (PE). However, the possibility of improving the conventional prediction rule for PE by integrating ultrasound has never been investigated. We performed lung and venous ultrasound in consecutive patients suspected of PE in four emergency departments. Conventional Wells score (Ws) was adjudicated by the attending physician, and ultrasound was performed by one of 20 investigators. Signs of deep venous thrombosis (DVT) at venous ultrasound and signs of pulmonary infarcts or alternative diagnoses at lung ultrasound were considered to recalculate two items of the Ws: signs and symptoms of DVT and alternative diagnosis less likely than PE. The diagnostic performances of the ultrasound-enhanced Ws (USWs) and Ws were then compared after confirmation of the final diagnosis. A total of 446 patients were studied. PE was confirmed in 125 patients (28%). USWs performed significantly better than Ws, with a sensitivity of 69.6% versus 57.6% and a specificity of 88.2% versus 68.2%. In combination with D-dimer, USWs showed an optimal failure rate (0.8%) and a significantly superior efficiency than Ws (32.3% vs. 27.2%). A strategy based on lung and venous ultrasound combined with D-dimer would allow to avoid CT pulmonary angiography in 50.5% of patients with suspected PE, compared to 27.2% when the rule without ultrasound is applied. A pretest risk stratification enhanced by ultrasound of lung and venous performs better than Ws in the early diagnostic process of PE. © 2016 by the Society for Academic Emergency Medicine.

Characterization and mapping of leaf rust resistance in four durum wheat cultivars.

PubMed

Kthiri, Dhouha; Loladze, Alexander; MacLachlan, P R; N'Diaye, Amidou; Walkowiak, Sean; Nilsen, Kirby; Dreisigacker, Susanne; Ammar, Karim; Pozniak, Curtis J

2018-01-01

Widening the genetic basis of leaf rust resistance is a primary objective of the global durum wheat breeding effort at the International Wheat and Maize Improvement Center (CIMMYT). Breeding programs in North America are following suit, especially after the emergence of new races of Puccinia triticina such as BBG/BP and BBBQD in Mexico and the United States, respectively. This study was conducted to characterize and map previously undescribed genes for leaf rust resistance in durum wheat and to develop reliable molecular markers for marker-assisted breeding. Four recombinant inbred line (RIL) mapping populations derived from the resistance sources Amria, Byblos, Geromtel_3 and Tunsyr_2, which were crossed to the susceptible line ATRED #2, were evaluated for their reaction to the Mexican race BBG/BP of P. triticina. Genetic analyses of host reactions indicated that leaf rust resistance in these genotypes was based on major seedling resistance genes. Allelism tests among resistant parents supported that Amria and Byblos carried allelic or closely linked genes. The resistance in Geromtel_3 and Tunsyr_2 also appeared to be allelic. Bulked segregant analysis using the Infinium iSelect 90K single nucleotide polymorphism (SNP) array identified two genomic regions for leaf rust resistance; one on chromosome 6BS for Geromtel_3 and Tunsyr_2 and the other on chromosome 7BL for Amria and Byblos. Polymorphic SNPs identified within these regions were converted to kompetitive allele-specific PCR (KASP) assays and used to genotype the RIL populations. KASP markers usw215 and usw218 were the closest to the resistance genes in Geromtel_3 and Tunsyr_2, while usw260 was closely linked to the resistance genes in Amria and Byblos. DNA sequences associated with these SNP markers were anchored to the wild emmer wheat (WEW) reference sequence, which identified several candidate resistance genes. The molecular markers reported herein will be useful to effectively pyramid these resistance genes with other previously marked genes into adapted, elite durum wheat genotypes.

Characterization and mapping of leaf rust resistance in four durum wheat cultivars

PubMed Central

Kthiri, Dhouha; Loladze, Alexander; MacLachlan, P. R.; N’Diaye, Amidou; Walkowiak, Sean; Nilsen, Kirby; Dreisigacker, Susanne; Ammar, Karim

2018-01-01

Widening the genetic basis of leaf rust resistance is a primary objective of the global durum wheat breeding effort at the International Wheat and Maize Improvement Center (CIMMYT). Breeding programs in North America are following suit, especially after the emergence of new races of Puccinia triticina such as BBG/BP and BBBQD in Mexico and the United States, respectively. This study was conducted to characterize and map previously undescribed genes for leaf rust resistance in durum wheat and to develop reliable molecular markers for marker-assisted breeding. Four recombinant inbred line (RIL) mapping populations derived from the resistance sources Amria, Byblos, Geromtel_3 and Tunsyr_2, which were crossed to the susceptible line ATRED #2, were evaluated for their reaction to the Mexican race BBG/BP of P. triticina. Genetic analyses of host reactions indicated that leaf rust resistance in these genotypes was based on major seedling resistance genes. Allelism tests among resistant parents supported that Amria and Byblos carried allelic or closely linked genes. The resistance in Geromtel_3 and Tunsyr_2 also appeared to be allelic. Bulked segregant analysis using the Infinium iSelect 90K single nucleotide polymorphism (SNP) array identified two genomic regions for leaf rust resistance; one on chromosome 6BS for Geromtel_3 and Tunsyr_2 and the other on chromosome 7BL for Amria and Byblos. Polymorphic SNPs identified within these regions were converted to kompetitive allele-specific PCR (KASP) assays and used to genotype the RIL populations. KASP markers usw215 and usw218 were the closest to the resistance genes in Geromtel_3 and Tunsyr_2, while usw260 was closely linked to the resistance genes in Amria and Byblos. DNA sequences associated with these SNP markers were anchored to the wild emmer wheat (WEW) reference sequence, which identified several candidate resistance genes. The molecular markers reported herein will be useful to effectively pyramid these resistance genes with other previously marked genes into adapted, elite durum wheat genotypes. PMID:29746580

Effect of Long-Term Hormonal Therapy (vs Short-Term Hormonal Therapy): A Secondary Analysis of Intermediate-Risk Prostate Cancer Patients Treated on NRG Oncology RTOG 9202

PubMed Central

Mirhadi, Amin J.; Zhang, Qiang; Hanks, Gerald E.; Lepor, Herbert; Grignon, David J.; Peters, Christopher A.; Rosenthal, Seth A.; Zeitzer, Kenneth; Radwan, John S.; Lawton, Colleen; Parliament, Matthew B.; Reznik, Robert S.; Sandler, Howard M.

2017-01-01

Purpose NRG Oncology RTOG 9202 was a randomized trial testing long-term adjuvant androgen deprivation (LTAD) versus initial androgen deprivation only (STAD) with external beam radiation therapy (RT) in mostly high-risk and some intermediate-risk prostate cancer patients. RTOG 9408 found an overall survival (OS) advantage in patients with cT1b-T2b disease and prostate-specific antigen (PSA) <20 ng/mL, with benefit observed mostly among intermediate-risk patients. It was still unknown whether intermediate-risk patients would experience an additional survival benefit with LTAD; thus, we performed a secondary analysis to explore whether LTAD had any incremental benefit beyond STAD among the intermediate-risk subset of RTOG 9202. The study endpoints were OS, disease-specific survival (DSS), and PSA failure (PSAF). Methods and Materials An analysis was performed for all patients enrolled in RTOG 9202 defined as intermediate-risk (cT2 disease, PSA<10 ng/mL, and Gleason score = 7 or cT2 disease, PSA 10-20 ng/mL, and Gleason score <7). This review yielded 133 patients: 74 (STAD) and 59 (LTAD). The Kaplan-Meier method was used to estimate OS; the cumulative incidence approach was used to estimate DSS and PSAF. A 2-sided test was used, with significance level defined to be .05. Results With over 11 years of median follow-up, 39 STAD patients were alive and 33 LTAD patients were alive. There was no difference in OS (10-year estimates, 61% STAD vs 65% LTAD; P=.53), DSS (10-year DSS, 96% vs 97%; P=.72), or PSAF (10-year PSAF, 53% vs 55%; P=.99) between groups. Conclusion LTAD did not confer a benefit in terms of OS, DSS, or PSAF rates in the intermediate-risk subset in this study. Whereas the subset was relatively small, treatment assignment was randomly applied, and a trend in favor of LTAD would have been of interest. Given the small number of disease-specific deaths observed and lack of benefit with respect to our endpoints, this secondary analysis does not suggest that exploration of longer hormonal therapy is worth testing in the intermediate-risk prostate cancer subset. PMID:28126300

Kinetics and mechanism of bacterial inactivation by ultrasound waves and sonoprotective effect of milk components.

PubMed

Gera, N; Doores, S

2011-03-01

Inactivation of Escherichia coli and Listeria monocytogenes were investigated in buffer and milk upon treatment with ultrasound waves (USW). In addition, sonoprotective effect of milk components and ultrasound-induced changes in bacterial cells were investigated using scanning electron microscopy (SEM). Bacterial cells were added to phosphate buffer, whole milk, skim milk, or simulated milk ultrafiltrate (SMUF). To determine the sonoprotective effect of milk components, lactose (5%), casein (3%), or β lactoglobulin (0.3%) was added to SMUF. Samples were sonicated with 24 kHz pulse USW while maintaining the system temperature between 30 to 35 °C. Aliquots were drawn at set times during sonication and bacteria were enumerated by surface plating appropriate dilutions on selective and nonselective media plates. Escherichia coli exhibited significantly higher D values in whole (2.43 min) and skim milk (2.41 min) than phosphate buffer (2.19 min). Listeria monocytogenes also showed higher D values in whole (9.31 min) and skim milk (8.61 min) compared to phosphate buffer (7.63 min). Data suggest that milk exerts a sonoprotective effect on these bacteria. Escherichia coli exhibited a log-linear inactivation kinetics followed by tailing whereas L. monocytogenes showed 1st-order kinetics throughout. Among the milk components tested, presence of lactose in SMUF resulted in significantly higher D values than SMUF for both organisms suggesting that lactose was exerting a protective effect on bacteria. SEM images showed that USW caused mechanical damage to the cell wall and cell membrane of bacteria leading to their inactivation.

TU-C-9A-01: IROC Organization and Clinical Trial Credentialing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Followill, D; Molineu, A; Xiao, Y

2014-06-15

As a response to recommendations from a report from the Institute of Medicine, NCI is reorganizing it clinical trial groups into a National Clinical Trial Network (NCTN) that consists of four adult groups (Alliance, ECOGACRIN, NRG, and SWOG) and one children’s group (COG). NRG will house CIRO, a center to promote innovative radiation therapy research and intergroup collaboration in radiation. The quality assurance groups that support clinical trials have also been restructured. ITC, OSU Imaging corelab, Philadelphia Imaging core-lab, QARC, RPC, and RTOGQA have joined together to create the Imaging and Radiation Oncology Core (IROC) Group. IROC’s mission is tomore » provide integrated radiation oncology and diagnostic imaging quality control programs in support of the NCI’s NCTN thereby assuring high quality data for clinical trials designed to improve the clinical outcomes for cancer patients worldwide. This will be accomplished through five core services: site qualification, trial design support, credentialing, data management, case review.These changes are important for physicist participating in NCI clinical trials to understand. We will describe in detail the IROC’s activities and five core services so that as a user, the medical physicist can learn how to efficiently utilize this group. We will describe common pitfalls encountered in credentialing for current protocols and present methods to avoid them. These may include the which benchmarks are required for NSABP B-51/RTOG 1304 and how to plan them as well as tips for phantom planning. We will explain how to submit patient and phantom cases in the TRIAD system used by IROC. Learning Objectives: To understand the basic organization of IROC, its mission and five core services To learn how to use TRIAD for patient and phantom data submission To learn how to avoid common pitfalls in credentialing for current trials.« less

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.

PubMed

Engel, Martin; Snikeris, Peta; Matosin, Natalie; Newell, Kelly Anne; Huang, Xu-Feng; Frank, Elisabeth

2016-04-01

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored. We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-D-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia. Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions. In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine. We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Non-equilibrium STLS approach to transport properties of single impurity Anderson model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rezai, Raheleh, E-mail: R_Rezai@sbu.ac.ir; Ebrahimi, Farshad, E-mail: Ebrahimi@sbu.ac.ir

In this work, using the non-equilibrium Keldysh formalism, we study the effects of the electron–electron interaction and the electron-spin correlation on the non-equilibrium Kondo effect and the transport properties of the symmetric single impurity Anderson model (SIAM) at zero temperature by generalizing the self-consistent method of Singwi, Tosi, Land, and Sjolander (STLS) for a single-band tight-binding model with Hubbard type interaction to out of equilibrium steady-states. We at first determine in a self-consistent manner the non-equilibrium spin correlation function, the effective Hubbard interaction, and the double-occupancy at the impurity site. Then, using the non-equilibrium STLS spin polarization function in themore » non-equilibrium formalism of the iterative perturbation theory (IPT) of Yosida and Yamada, and Horvatic and Zlatic, we compute the spectral density, the current–voltage characteristics and the differential conductance as functions of the applied bias and the strength of on-site Hubbard interaction. We compare our spectral densities at zero bias with the results of numerical renormalization group (NRG) and depict the effects of the electron–electron interaction and electron-spin correlation at the impurity site on the aforementioned properties by comparing our numerical result with the order U{sup 2} IPT. Finally, we show that the obtained numerical results on the differential conductance have a quadratic universal scaling behavior and the resulting Kondo temperature shows an exponential behavior. -- Highlights: •We introduce for the first time the non-equilibrium method of STLS for Hubbard type models. •We determine the transport properties of SIAM using the non-equilibrium STLS method. •We compare our results with order-U2 IPT and NRG. •We show that non-equilibrium STLS, contrary to the GW and self-consistent RPA, produces the two Hubbard peaks in DOS. •We show that the method keeps the universal scaling behavior and correct exponential behavior of Kondo temperature.« less

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

PubMed Central

McMeekin, D. Scott; Tritchler, David L.; Cohn, David E.; Mutch, David G.; Lankes, Heather A.; Geller, Melissa A.; Powell, Matthew A.; Backes, Floor J.; Landrum, Lisa M.; Zaino, Richard; Broaddus, Russell D.; Ramirez, Nilsa; Gao, Feng; Ali, Shamshad; Darcy, Kathleen M.; Pearl, Michael L.; DiSilvestro, Paul A.; Lele, Shashikant B.

2016-01-01

Purpose The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. Methods Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. Results A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. Conclusion MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors. PMID:27325856

Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.

PubMed

McMeekin, D Scott; Tritchler, David L; Cohn, David E; Mutch, David G; Lankes, Heather A; Geller, Melissa A; Powell, Matthew A; Backes, Floor J; Landrum, Lisa M; Zaino, Richard; Broaddus, Russell D; Ramirez, Nilsa; Gao, Feng; Ali, Shamshad; Darcy, Kathleen M; Pearl, Michael L; DiSilvestro, Paul A; Lele, Shashikant B; Goodfellow, Paul J

2016-09-01

The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors. © 2016 by American Society of Clinical Oncology.

Relationships of Tubal Ligation to Endometrial Carcinoma Stage and Mortality in the NRG Oncology/Gynecologic Oncology Group 210 Trial

PubMed Central

Brinton, Louise A.; McMeekin, D. Scott; Creasman, William T.; Mutch, David; Cohn, David E.; Walker, Joan L.; Moore, Richard G.; Downs, Levi S.; Soslow, Robert A.; Zaino, Richard; Sherman, Mark E.

2015-01-01

Background: Stage is a critical determinant of treatment among endometrial carcinoma patients; understanding patterns of tumor spread may suggest approaches to improve staging. Specifically, the importance of exfoliation of endometrial carcinoma cells through the fallopian tubes into the peritoneum is ill defined. We assessed the hypothesis that tubal ligation (TL), which should impede transtubal passage of cells, is associated with lower endometrial carcinoma stage at presentation and, consequently, lower mortality. Methods: The NRG Oncology/Gynecologic Oncology Group (GOG) 210 Trial included 4489 endometrial carcinoma patients who completed a risk factor questionnaire that included TL history. Pathology data were derived from clinical reports and central review. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between TL with stage and peritoneal metastasis, overall and by tumor subtype. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for TL and mortality. All statistical tests were two-sided. Results: Compared with stage I, TL was inversely associated with stage III (OR = 0.63, 95% CI = 0.52 to 0.78) and stage IV carcinomas (OR = 0.14, 95% CI = 0.08 to 0.24) overall and among individual tumor subtypes. TL was inversely related to peritoneal metastasis overall (OR = 0.39, 95% CI = 0.22 to 0.68) and among serous carcinomas (OR = 0.28, 95% CI = 0.11 to 0.68). In multivariable models unadjusted for stage, TL was associated with lower endometrial carcinoma-specific mortality (HR = 0.74, 95% CI = 0.61 to 0.91); however, adjustment for stage eliminated the survival advantage. Similar relationships with all-cause mortality were observed. Conclusions: TL is associated with lower stage and mortality among women with aggressive endometrial carcinomas, suggesting transtubal spread is clinically important. Future studies should evaluate whether detection of intraluminal tumor cells is prognostically relevant. PMID:26089540

Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster.

PubMed

Kudumala, Sirisha; Freund, Julie; Hortsch, Michael; Godenschwege, Tanja A

2013-01-01

A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM-mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin-moesin-radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis.

Differential Effects of Human L1CAM Mutations on Complementing Guidance and Synaptic Defects in Drosophila melanogaster

PubMed Central

Kudumala, Sirisha; Freund, Julie; Hortsch, Michael; Godenschwege, Tanja A.

2013-01-01

A large number of different pathological L1CAM mutations have been identified that result in a broad spectrum of neurological and non-neurological phenotypes. While many of these mutations have been characterized for their effects on homophilic and heterophilic interactions, as well as expression levels in vitro, there are only few studies on their biological consequences in vivo. The single L1-type CAM gene in Drosophila, neuroglian (nrg), has distinct functions during axon guidance and synapse formation and the phenotypes of nrg mutants can be rescued by the expression of human L1CAM. We previously showed that the highly conserved intracellular FIGQY Ankyrin-binding motif is required for L1CAM-mediated synapse formation, but not for neurite outgrowth or axon guidance of the Drosophila giant fiber (GF) neuron. Here, we use the GF as a model neuron to characterize the pathogenic L120V, Y1070C, C264Y, H210Q, E309K and R184Q extracellular L1CAM missense mutations and a L1CAM protein with a disrupted ezrin–moesin–radixin (ERM) binding site to investigate the signaling requirements for neuronal development. We report that different L1CAM mutations have distinct effects on axon guidance and synapse formation. Furthermore, L1CAM homophilic binding and signaling via the ERM motif is essential for axon guidance in Drosophila. In addition, the human pathological H210Q, R184Q and Y1070C, but not the E309K and L120V L1CAM mutations affect outside-in signaling via the FIGQY Ankyrin binding domain which is required for synapse formation. Thus, the pathological phenotypes observed in humans are likely to be caused by the disruption of signaling required for both, guidance and synaptogenesis. PMID:24155914

Interfacial Reaction During Dissimilar Joining of Aluminum Alloy to Magnesium and Titanium Alloys

NASA Astrophysics Data System (ADS)

Robson, J. D.; Panteli, A.; Zhang, C. Q.; Baptiste, D.; Cai, E.; Prangnell, P. B.

Ultrasonic welding (USW), a solid state joining process, has been used to produce welds between AA6111 aluminum alloy and AZ31 magnesium alloys or titanium alloy Ti-6Al-4V. The mechanical properties of the welds have been assessed and it has been shown that it is the nature and thickness of the intermetallic compounds (IMCs) at the joint line that are critical in determining joint strength and particularly fracture energy. Al-Mg welds suffer from a very low fracture energy, even when strength is comparable with that of similar metal Mg-Mg welds, due to a thick IMC layer always being formed. It is demonstrated that in USW of Al-Ti alloy the slow interdiffusion kinetics means that an IMC layer does not form during welding, and fracture energy is greater. A model has been developed to predict IMC formation during welding and provide an understanding of the critical factors that determine the IMC thickness. It is predicted that in Al-Mg welds, most of the lMC thickening occurs whilst the IMC regions grow as separate islands, prior to the formation of a continuous layer.

Geohydrologic and drill-hole data for test well USW H-3, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Thordarson, William; Rush, F.E.; Spengler, R.W.; Waddell, S.J.

1984-01-01

Test well USW H-3 is one of a series of test wells drilled in and near the southwestern part of the Nevada Test Site for hydraulic testing, hydrologic monitoring, and geophysical logging. The work was performed in cooperation with the U.S. Department of Energy as part of the Nevada Nuclear Waste Storage investigations. The well penetrated volcanic tuffs of Tertiary age to a depth of 1,219 meters. This report presents data collected to determine the hydraulic characteristics of rocks penetrated. Data on drilling operations, lithology, borehole geophysics, hydrologic monitoring, pumping, swabbing, and injection tests for the well are contained in this report. (USGS)

Preliminary assessment of in-situ geomechanical characteristics in drill hole USW G-1, Yucca Mountain, Nevada

USGS Publications Warehouse

Ellis, William L.; Swolfs, Henri S.

1983-01-01

Observations made during drilling and subsequent testing of the USW G-1 drill hole, Yucca Mountain, Nevada, provide qualitative insights into the in- situ geomechanical characteristics of the layered tuff units penetrated by the hole. Substantial drilling-fluid losses, and the occurrence of drilling-induced fracturing, are understandable in terms of the low, minimum horizontal stress magnitudes interpreted from six hydraulic-fracturing stress measurements conducted between hole depths of 640 and 1,300 meters. Although not confirmed directly by the hydraulic-fracturing data, other observations suggest that the minimum stress magnitudes in the more densely welded and brittle tuff layers may be even smaller than in the less welded and more ductile rocks. Stress-induced borehole ellipticity observed along most of the length of USW G-1 indicates that the horizontal stress components are not equal, and that the concentration of these stresses around the hole is sufficient to locally exceed the yield strength of the rock. The low, minimum horizontal stress magnitudes, perhaps variable with lithology, and the indications from borehole ellipticity of a high in-situ stress/strength ratio, indicate the need for further studies to characterize the structural and geomechanical properties of the rocks at depth in Yucca Mountain.

Non-ambiguous recovery of Biot poroelastic parameters of cellular panels using ultrasonicwaves

NASA Astrophysics Data System (ADS)

Ogam, Erick; Fellah, Z. E. A.; Sebaa, Naima; Groby, J.-P.

2011-03-01

The inverse problem of the recovery of the poroelastic parameters of open-cell soft plastic foam panels is solved by employing transmitted ultrasonic waves (USW) and the Biot-Johnson-Koplik-Champoux-Allard (BJKCA) model. It is shown by constructing the objective functional given by the total square of the difference between predictions from the BJKCA interaction model and experimental data obtained with transmitted USW that the inverse problem is ill-posed, since the functional exhibits several local minima and maxima. In order to solve this problem, which is beyond the capability of most off-the-shelf iterative nonlinear least squares optimization algorithms (such as the Levenberg Marquadt or Nelder-Mead simplex methods), simple strategies are developed. The recovered acoustic parameters are compared with those obtained using simpler interaction models and a method employing asymptotic phase velocity of the transmitted USW. The retrieved elastic moduli are validated by solving an inverse vibration spectroscopy problem with data obtained from beam-like specimens cut from the panels using an equivalent solid elastodynamic model as estimator. The phase velocities are reconstructed using computed, measured resonance frequencies and a time-frequency decomposition of transient waves induced in the beam specimen. These confirm that the elastic parameters recovered using vibration are valid over the frequency range ofstudy.

Geohydrology of rocks penetrated by test well USW H-4, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Whitfield, M.S.; Eshom, E.P.; Thordarson, William; Schaefer, D.H.

1985-01-01

Test well USW H-4 is one of several wells drilled in the southwestern part of the Nevada Test Site for hydraulic testing, hydrologic monitoring, and geophysical logging. The work was performed in cooperation with the U.S. Department of Energy. The rocks penetrated by the well to a total depth of 1,219 m were volcanic tuffs of Tertiary age. Hydraulic coefficients calculated from pumping test data indicate that transmissivity ranged from 200 to 790 sq m/day. A radioactive tracer, borehole flow survey indicated that the two most productive zones during this borehole flow survey occurred in the upper part of the Bullfrog Member of the Crater Flat Tuff, depth interval from 721 to 731.5m, and in the underlying part of the Tram Member, depth interval from 864 to 920m. The water is predominantly a sodium biocarbonate type with small concentrations of calcium, magnesium, and sulfate. The apparent age of this composite water sample was determined by carbon-14 date of 17,200 years before present. (USGS)

A Comparative Study on the Microstructure and Mechanical Properties of Cu6Sn5 and Cu3Sn Joints Formed by TLP Soldering With/Without the Assistance of Ultrasonic Waves

NASA Astrophysics Data System (ADS)

Zhao, H. Y.; Liu, J. H.; Li, Z. L.; Song, X. G.; Zhao, Y. X.; Niu, H. W.; Tian, H.; Dong, H. J.; Feng, J. C.

2018-07-01

In this study, the microstructure and mechanical properties of Cu6Sn5 and Cu3Sn intermetallic joints, formed by the transient liquid phase (TLP) soldering process with and without the assistance of ultrasonic waves (USWs), were compared. After the application of USWs in the TLP soldering process, Cu-Sn intermetallic compounds (IMCs) exhibited a novel noninterfacial growth pattern in the molten solder interlayer. The resulting Cu6Sn5 and Cu3Sn joints consisted of refined equiaxed IMC grains with average sizes of 3 and 2.3 µm, respectively. The Cu6Sn5 grains in the ultrasonically soldered intermetallic joints demonstrated uniform mechanical properties with elastic modulus and hardness values of 123.0 and 5.98 GPa, respectively, while those of Cu3Sn grains were 133.9 and 5.08 GPa, respectively. The shear strengths of ultrasonically soldered Cu6Sn5 and Cu3Sn joints were measured to be 60 and 65 MPa, respectively, higher than that for reflow-soldered intermetallic joints. Ultrasonically soldered Cu6Sn5 and Cu3Sn joints both exhibited a combination of transgranular and intergranular fractures during shear testing.

A Comparative Study on the Microstructure and Mechanical Properties of Cu6Sn5 and Cu3Sn Joints Formed by TLP Soldering With/Without the Assistance of Ultrasonic Waves

NASA Astrophysics Data System (ADS)

Zhao, H. Y.; Liu, J. H.; Li, Z. L.; Song, X. G.; Zhao, Y. X.; Niu, H. W.; Tian, H.; Dong, H. J.; Feng, J. C.

2018-05-01

In this study, the microstructure and mechanical properties of Cu6Sn5 and Cu3Sn intermetallic joints, formed by the transient liquid phase (TLP) soldering process with and without the assistance of ultrasonic waves (USWs), were compared. After the application of USWs in the TLP soldering process, Cu-Sn intermetallic compounds (IMCs) exhibited a novel noninterfacial growth pattern in the molten solder interlayer. The resulting Cu6Sn5 and Cu3Sn joints consisted of refined equiaxed IMC grains with average sizes of 3 and 2.3 µm, respectively. The Cu6Sn5 grains in the ultrasonically soldered intermetallic joints demonstrated uniform mechanical properties with elastic modulus and hardness values of 123.0 and 5.98 GPa, respectively, while those of Cu3Sn grains were 133.9 and 5.08 GPa, respectively. The shear strengths of ultrasonically soldered Cu6Sn5 and Cu3Sn joints were measured to be 60 and 65 MPa, respectively, higher than that for reflow-soldered intermetallic joints. Ultrasonically soldered Cu6Sn5 and Cu3Sn joints both exhibited a combination of transgranular and intergranular fractures during shear testing.

On The Geometric Nature of ``Singlet Fission'' in Certain Crystalline Conjugated Polymers

NASA Astrophysics Data System (ADS)

Rahman, Noah

2013-03-01

In recent years, the coherent fission of low-lying singlet electronic excitations in conjugated polymers has attracted interest as a possible way to exceed the Shockley-Queisser limit in organic photovoltaics. Femtosecond spectroscopic and fluorescence measurements of such singlets and the resulting triplets in crystalline anthracene, tetracene and naphthalene reveal curious phenomena associated with certain vibrational modes, such as ultrafast propagation on a timescale inconsistent with conventional intersystem crossing, long-lived electronic coherence, and triplet magnetic anisotropy whose structure is consistent across all three materials. This conflicts with NRG and quantum chemical simulations, which posit isotropic triplets. I explain this by a dynamical Rashba spin-orbit interaction that decays as R-6. This arises from a geometric SU(2) gauge potential generated by a nuclear-motion-induced parametric near-degeneracy of the molecular electronic states. The anisotropy is shown to follow from the work of Affleck and Oshikawa on spin one-half Heisenberg chains. Possible directions for future work are discussed, especially with regard to adiabatic pumping and topological insulators.

Optimization of Aluminium-to-Magnesium Ultrasonic Spot Welding

NASA Astrophysics Data System (ADS)

Panteli, A.; Chen, Y.-C.; Strong, D.; Zhang, Xiaoyun; Prangnell, P. B.

2012-03-01

The ability to join dissimilar materials in the automotive industry will result in more efficient multimaterial structures. However, welding of aluminium (Al) to magnesium (Mg) alloys is problematic because of the rapid formation of brittle intermetallic phases at the weld interface. Ultrasonic welding (USW) is a solid-state joining technology that may offer a potential solution, but USW of Al to Mg is currently not well understood. Here, we have investigated the effect of process variables and energy input on joint formation between Al-6111 and Mg-AZ31 alloys, and we report on the optimum welding conditions, heat generation, and the formation of a significant intermetallic reaction layer. Furthermore, the factors influencing the interface reaction rate and the advantages of precoating the Mg with Al are discussed.

Egf Signaling Directs Neoblast Repopulation by Regulating Asymmetric Cell Division in Planarians.

PubMed

Lei, Kai; Thi-Kim Vu, Hanh; Mohan, Ryan D; McKinney, Sean A; Seidel, Chris W; Alexander, Richard; Gotting, Kirsten; Workman, Jerry L; Sánchez Alvarado, Alejandro

2016-08-22

A large population of proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and post-injury regeneration in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonal expansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. However, the precise mechanisms regulating the population dynamics of neoblasts remain largely unknown. Here, we uncovered a central role for epidermal growth factor (EGF) signaling during in vivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGF receptor-3 protein localizes asymmetrically on the cytoplasmic membrane of neoblasts, and the ratio of asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarians, but also demonstrate that EGF signaling likely functions as an essential regulator of neoblast clonal expansion. Copyright © 2016 Elsevier Inc. All rights reserved.

Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704.

PubMed

Lawrence, Yaacov R; Moughan, Jennifer; Magliocco, Anthony M; Klimowicz, Alexander C; Regine, William F; Mowat, Rex B; DiPetrillo, Thomas A; Small, William; Simko, Jeffry P; Golan, Talia; Winter, Kathryn A; Guha, Chandan; Crane, Christopher H; Dicker, Adam P

2018-02-01

The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P < .0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P < .0001). In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment. Cancer 2018;124:491-8. © 2017 American Cancer Society. © 2017 American Cancer Society.

Prognostic Value of p16 Status on the Development of a Complete Response in Involved Oropharynx Cancer Neck Nodes After Cisplatin-Based Chemoradiation: A Secondary Analysis of NRG Oncology RTOG 0129

DOE Office of Scientific and Technical Information (OSTI.GOV)

Galloway, Thomas J., E-mail: thomas.galloway@fccc.edu; Zhang, Qiang; Nguyen-Tan, Phuc Felix

Purpose: To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129. Methods and Materials: Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection. Results: Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive:more » n=69; p16-negative: n=30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of chemoradiation. Neither the pretreatment nodal stage (P=.71) nor the postradiation, pre-neck dissection clinical/radiographic neck assessment (P=.42) differed by p16 status. A pCR was more common among p16-positive patients (78%) than p16-negative patients (53%, P=.02) and was associated with a reduced incidence of local–regional failure (hazard ratio 0.33, P=.003). On multivariate analysis of local–regional failure, a test for interaction between pCR and p16 status was not significant (P=.37). One-hundred ninety-three (66%) of 292 of initially node-positive patients were managed without a posttreatment neck dissection. Development of a clinical (cCR) was not significantly influenced by p16-status (P=.42). Observed patients with a clinical nodal CR had disease control outcomes similar to those in patients with a pCR neck dissection. Conclusions: Patients with p16-positive tumors had significantly higher pCR and locoregional control rates than those with p16-negative tumors.« less

Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Standard Radiation Versus Accelerated Radiation Plus Cisplatin for Locally Advanced Head and Neck Carcinoma: NRG Oncology RTOG 0129.

PubMed

Xiao, Canhua; Zhang, Qiang; Nguyen-Tân, Phuc Felix; List, Marcie; Weber, Randal S; Ang, K Kian; Rosenthal, David; Filion, Edith J; Kim, Harold; Silverman, Craig; Raben, Adam; Galloway, Thomas; Fortin, Andre; Gore, Elizabeth; Winquist, Eric; Jones, Christopher U; Robinson, William; Raben, David; Le, Quynh-Thu; Bruner, Deborah

2017-03-15

To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival. Eligible patients were randomized into either an accelerated-fractionation arm or a standard-fractionation arm, and completed the Performance Status Scale for the Head and Neck (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from before treatment to 5 years after treatment. The results from the analysis of area under the curve showed that QOL/PS was not significantly different between the 2 arms from baseline to year after treatment (P ranged from .39 to .98). The results from general linear mixed models further supported the nonsignificant treatment effects until 5 years after treatment (P=.95, .90, and .84 for PSS-HN Diet, Eating, and Speech, respectively). Before treatment and after 1 year after treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than did p16-negative patients (P ranged from .0283 to <.0001 for all questionnaires). However, QOL/PS decreased more significantly from pretreatment to the last 2 weeks of treatment in the p16-positive group than in the p16-negative group (P ranged from .0002 to <.0001). Pretreatment QOL/PS was a significant independent predictor of overall survival, progression-free survival, and local-regional failure but not of distant metastasis (P ranged from .0063 to <.0001). The results indicated that patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after 1 year of follow-up. Patients presenting with better baseline QOL/PS scores had better survival. Copyright © 2016 Elsevier Inc. All rights reserved.

Quality of Life and Performance Status From a Substudy Conducted Within a Prospective Phase 3 Randomized Trial of Concurrent Standard Radiation Versus Accelerated Radiation Plus Cisplatin for Locally Advanced Head and Neck Carcinoma: NRG Oncology RTOG 0129

PubMed Central

Xiao, Canhua; Zhang, Qiang; Nguyen-Tân, Phuc Felix; List, Marcie; Weber, Randal S.; Ang, K. Kian; Rosenthal, David; Filion, Edith J.; Kim, Harold; Silverman, Craig; Raben, Adam; Galloway, Thomas; Fortin, Andre; Gore, Elizabeth; Winquist, Eric; Jones, Christopher U.; Robinson, William; Raben, David; Le, Quynh-Thu; Bruner, Deborah

2016-01-01

Purpose/Objective(s) To analyze quality of life (QOL) and performance status (PS) for head and neck cancer (HNC) patients treated on NRG Oncology RTOG 0129 by treatment (secondary outcome) and p16 status, and to examine the association between QOL/PS and survival. Methods and Materials Eligible patients were randomized into either an accelerated-fractionation arm or a standard-fractionation arm, and completed the Performance Status Scale for the Head and Neck (PSS-HN), the Head and Neck Radiotherapy Questionnaire (HNRQ), and the Spitzer Quality of Life Index (SQLI) at 8 time points from before treatment to 5 years after treatment. Results The results from the analysis of area under the curve showed that QOL/PS was not significantly different between the 2 arms from baseline to year after treatment (P ranged from .39 to .98). The results from general linear mixed models further supported the nonsignificant treatment effects until 5 years after treatment (P=.95, .90, and .84 for PSS-HN Diet, Eating, and Speech, respectively). Before treatment and after 1 year after treatment, p16-positive oropharyngeal cancer (OPC) patients had better QOL than did p16-negative patients (P ranged from .0283 to <.0001 for all questionnaires). However, QOL/PS decreased more significantly from pretreatment to the last 2 weeks of treatment in the p16-positive group than in the p16-negative group (P ranged from .0002 to <.0001). Pretreatment QOL/PS was a significant independent predictor of overall survival, progression-free survival, and local-regional failure but not of distant metastasis (P ranged from .0063 to <.0001). Conclusions The results indicated that patients in both arms may have experienced similar QOL/PS. p16-positive patients had better QOL/PS at baseline and after 1 year of follow-up. Patients presenting with better baseline QOL/PS scores had better survival. PMID:27727063

Prognostic Value of p16 Status on the Development of a Complete Response in Involved Oropharynx Cancer Neck Nodes After Cisplatin-Based Chemoradiation: A Secondary Analysis of NRG Oncology RTOG 0129.

PubMed

Galloway, Thomas J; Zhang, Qiang Ed; Nguyen-Tan, Phuc Felix; Rosenthal, David I; Soulieres, Denis; Fortin, André; Silverman, Craig L; Daly, Megan E; Ridge, John A; Hammond, J Alexander; Le, Quynh-Thu

2016-10-01

To determine the relationship between p16 status and the regional response of patients with node-positive oropharynx cancer treated on NRG Oncology RTOG 0129. Patients with N1-N3 oropharynx cancer and known p16 status who underwent treatment on RTOG 0129 were analyzed. Pathologic complete response (pCR) rates in patients treated with a postchemoradiation neck dissection (with p16-positive or p16-negative cancer) were compared by Fisher exact test. Patients managed expectantly were compared with those treated with a neck dissection. Ninety-nine (34%) of 292 patients with node-positive oropharynx cancer and known p16 status underwent a posttreatment neck dissection (p16-positive: n=69; p16-negative: n=30). The remaining 193 patients with malignant lymphadenopathy at diagnosis were observed. Neck dissection was performed a median of 70 (range, 17-169) days after completion of chemoradiation. Neither the pretreatment nodal stage (P=.71) nor the postradiation, pre-neck dissection clinical/radiographic neck assessment (P=.42) differed by p16 status. A pCR was more common among p16-positive patients (78%) than p16-negative patients (53%, P=.02) and was associated with a reduced incidence of local-regional failure (hazard ratio 0.33, P=.003). On multivariate analysis of local-regional failure, a test for interaction between pCR and p16 status was not significant (P=.37). One-hundred ninety-three (66%) of 292 of initially node-positive patients were managed without a posttreatment neck dissection. Development of a clinical (cCR) was not significantly influenced by p16-status (P=.42). Observed patients with a clinical nodal CR had disease control outcomes similar to those in patients with a pCR neck dissection. Patients with p16-positive tumors had significantly higher pCR and locoregional control rates than those with p16-negative tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Relationships of Tubal Ligation to Endometrial Carcinoma Stage and Mortality in the NRG Oncology/ Gynecologic Oncology Group 210 Trial.

PubMed

Felix, Ashley S; Brinton, Louise A; McMeekin, D Scott; Creasman, William T; Mutch, David; Cohn, David E; Walker, Joan L; Moore, Richard G; Downs, Levi S; Soslow, Robert A; Zaino, Richard; Sherman, Mark E

2015-09-01

Stage is a critical determinant of treatment among endometrial carcinoma patients; understanding patterns of tumor spread may suggest approaches to improve staging. Specifically, the importance of exfoliation of endometrial carcinoma cells through the fallopian tubes into the peritoneum is ill defined. We assessed the hypothesis that tubal ligation (TL), which should impede transtubal passage of cells, is associated with lower endometrial carcinoma stage at presentation and, consequently, lower mortality. The NRG Oncology/Gynecologic Oncology Group (GOG) 210 Trial included 4489 endometrial carcinoma patients who completed a risk factor questionnaire that included TL history. Pathology data were derived from clinical reports and central review. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between TL with stage and peritoneal metastasis, overall and by tumor subtype. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals for TL and mortality. All statistical tests were two-sided. Compared with stage I, TL was inversely associated with stage III (OR = 0.63, 95% CI = 0.52 to 0.78) and stage IV carcinomas (OR = 0.14, 95% CI = 0.08 to 0.24) overall and among individual tumor subtypes. TL was inversely related to peritoneal metastasis overall (OR = 0.39, 95% CI = 0.22 to 0.68) and among serous carcinomas (OR = 0.28, 95% CI = 0.11 to 0.68). In multivariable models unadjusted for stage, TL was associated with lower endometrial carcinoma-specific mortality (HR = 0.74, 95% CI = 0.61 to 0.91); however, adjustment for stage eliminated the survival advantage. Similar relationships with all-cause mortality were observed. TL is associated with lower stage and mortality among women with aggressive endometrial carcinomas, suggesting transtubal spread is clinically important. Future studies should evaluate whether detection of intraluminal tumor cells is prognostically relevant. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Comparison of irradiation behaviour of HTR graphite grades

NASA Astrophysics Data System (ADS)

Heijna, M. C. R.; de Groot, S.; Vreeling, J. A.

2017-08-01

The INNOGRAPH irradiations were executed in the High Flux Reactor (HFR) in Petten by NRG supported by the European Framework programs HTR-M, RAPHAEL, and ARCHER to generate data on the irradiation behaviour of graphite grades for High Temperature Reactor (HTR) application available at that time. Samples of the graphite grades NBG-10, NBG-17, NBG-18, NBG-20, NBG-25, PCEA, PPEA, PCIB, and IG-110 have been irradiated at 750 °C and 950 °C. The inherent scatter induced by the probabilistic material behaviour of graphite requires uncertainty and scatter induced by test conditions and post-irradiation examination to be minimized. The INNOGRAPH irradiations supplied an adequate number of irradiated samples to enable accurate determination of material properties and their evolution under irradiation. This allows comparison of different graphite grades and a qualitative assessment of their appropriateness for HTR applications, as a basis of selection, design and core component lifetime. The results indicate that coarse grained graphite grades exhibit more favourable behaviour for application in HTRs due to their low dimensional anisotropy and fracture propagation resilience.

Forecasting generation of urban solid waste in developing countries--a case study in Mexico.

PubMed

Buenrostro, O; Bocco, G; Vence, J

2001-01-01

Based on a study of the composition of urban solid waste (USW) and of socioeconomic variables in Morelia, Mexico, generation rates were estimated. In addition, the generation of residential solid waste (RSW) and nonresidential solid waste (NRSW) was forecasted by means of a multiple linear regression (MLR) analysis. For residential sources, the independent variables analyzed were monthly wages, persons per dwelling, age, and educational level of the heads of the household. For nonresidential sources, variables analyzed were number of employees, area of facilities, number of working days, and working hours per day. The forecasted values for residential waste were similar to those observed. This approach may be applied to areas in which available data are scarce, and in which there is an urgent need for the planning of adequate management of USW.

Percolation flux and Transport velocity in the unsaturated zone, Yucca Mountain, Nevada

USGS Publications Warehouse

Yang, I.C.

2002-01-01

The percolation flux for borehole USW UZ-14 was calculated from 14C residence times of pore water and water content of cores measured in the laboratory. Transport velocity is calculated from the depth interval between two points divided by the difference in 14C residence times. Two methods were used to calculate the flux and velocity. The first method uses the 14C data and cumulative water content data directly in the incremental intervals in the Paintbrush nonwelded unit and the Topopah Spring welded unit. The second method uses the regression relation for 14C data and cumulative water content data for the entire Paintbrush nonwelded unit and the Topopah Spring Tuff/Topopah Spring welded unit. Using the first method, for the Paintbrush nonwelded unit in boreholeUSW UZ-14 percolation flux ranges from 2.3 to 41.0 mm/a. Transport velocity ranges from 1.2 to 40.6 cm/a. For the Topopah Spring welded unit percolation flux ranges from 0.9 to 5.8 mm/a in the 8 incremental intervals calculated. Transport velocity ranges from 1.4 to 7.3 cm/a in the 8 incremental intervals. Using the second method, average percolation flux in the Paintbrush nonwelded unit for 6 boreholes ranges from 0.9 to 4.0 mm/a at the 95% confidence level. Average transport velocity ranges from 0.6 to 2.6 cm/a. For the Topopah Spring welded unit and Topopah Spring Tuff, average percolation flux in 5 boreholes ranges from 1.3 to 3.2 mm/a. Average transport velocity ranges from 1.6 to 4.0 cm/a. Both the average percolation flux and average transport velocity in the PTn are smaller than in the TS/TSw. However, the average minimum and average maximum values for the percolation flux in the TS/TSw are within the PTn average range. Therefore, differences in the percolation flux in the two units are not significant. On the other hand, average, average minimum, and average maximum transport velocities in the TS/TSw unit are all larger than the PTn values, implying a larger transport velocity for the TS/TSw although there is a small overlap.

The effects of ALG on the murine immune response to sheep erythrocytes

PubMed Central

Anderson, Hilary R.; Dresser, D. W.; Iverson, G. M.; Lance, E. M.; Wortis, H. H.; Zebra, J.

1972-01-01

Antilymphocyte globulin (ALG), and to a lesser extent normal rabbit globulin (NRG), when given to mice prior to immunization with sheep-RBC suppress both the γM and γG2a responses. Globulin injected after the antigen suppresses the γG2a response, augments the γG1 response and has little effect on the γM response. These effects are also observed in mice partially paralysed to rabbit γ globulin. In another system—the response to hapten—protein conjugates precursors of antibody producing cells were found to be more resistant to ALS treatment in vivo than were helper cells. It is concluded that the suppressive effects of ALG treatment are largely due to the direct action of ALG on helper cells (T-cells). The mechanism of the adjuvant-like effect is unclear. PMID:4550853

"Legal highs": safe and legal "heavens"? A study on the diffusion, knowledge and risk awareness of novel psychoactive drugs among students in the UK.

PubMed

Corazza, Ornella; Simonato, Pierluigi; Corkery, John; Trincas, Giuseppina; Schifano, Fabrizio

2014-01-01

The recent emergence of new recreational drugs, combined with the ability of the Internet to disseminate information quickly, have raised a number of concerns in the fields of drug policy, substance use research, and public health. A semi-structured questionnaire was advertised on The Study Room's website from November to December 2010 to explore the awareness, the use and the perception of risks of "legal highs" among student population in the UK. One-third (31.40%) of the 446 participants reported use of these kinds of drugs. Respondents were more likely to have taken were: mephedrone (41.4%), Salvia divinorum (20%), "Spice drugs" (10.7%), methylone (1.4%), naphyrone (NRG) (2.1%) and benzylpiperazine (BZP) (2.1%), while 15.7% did not know what compounds they had ever consumed. The large majority (78.9%) considered these as legal substances, while 74.2% did not consider these safer than illicit drugs. Half (50.8%) of the respondents were aware of the presence of illegal agents in the products they had consumed. The study contributes to an initial assessment of the use and the risks awareness of novel psychoactive compounds among students in the UK. Further research is required, especially in terms of personality and lifestyle attitudes to better profile these new forms of abuse also in non-recreational settings.

Preliminary evaluation of hydrologic properties of cores of unsaturated tuff, test well USW H-1, Yucca Mountain, Nevada

USGS Publications Warehouse

Weeks, E.P.; Wilson, W.E.

1984-01-01

Analyses were made on 19 core samples of unsaturated tuff from test well USW H-1. Moisture-characteristic curves relating saturation and moisture tension were developed from results of mercury-injection tests. Ambient moisture tension estimated from these curves generally was 1 to 2 bars. Values of relative permeability ranging from about 0.002 to 0.1 were determined by fitting an analytical expression to eight of the moisture-characteristic curves, and then integrating to solve for relative permeability. These values of relative permeability were applied to values of saturated hydraulic conductivity of core from a nearby test well to obtain effective hydraulic conductivities of about 8 x 10 to the minus twelfth power to 7 x 10 to the minus tenth power centimeter per second. If a unit hydraulic-head gradient is assumed, these values convert to a vertial matrix flux of 0.003 to 0.2 millimeter per year. The validity of this assumption was not verified due to the sparseness of data and uncertainties in their reliability. Consequently, the results of this study are preliminary and need to be used principally as a guide for future studies. (USGS)

Carbon isotopic data from test hole USW UZ-1, Yucca Mountain, Nevada

USGS Publications Warehouse

Yang, In C.; Peters, C.A.; Thorstenson, D.C.

1993-01-01

Rock-CO2-gas analyses in test hole USW UZ-1 at Yucca Mountain indicate that gas movement in the unsaturated zone is likely through a dry-fracture system with little porewater or caliche-calcite interaction. This is because near-surface ??13C values are of biogenic origin and have changed little throughout the total depth. Post-bomb 14C activity is observed to the depth of about 12 m. An abrupt change in plotted 14C/depth slope is seen at 61 m. The less steep upper segment corresponds to the zone with greater porosity and moisture content, and consequently more tortuosity, with an estimated traveltime of 1.27 cm/yr; the steeper sloped zone corresponding to the lower segment has smaller porosity and moisture content but larger fracture density for gas transport, with an estimated traveltime of 3.26 cm/yr.

Geohydrology of Test Well USW H-3, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thordarson, W.; Rush, F.E.; Waddell, S.J.

Test well USW H-3 is one of several test wells drilled in the southwestern part of the Nevada Test Site in cooperation with the US Department of Energy for investigations related to the isolation of high-level radioactive wastes. All rocks penetrated by the well to a total depth of 1219 meters are volcanic tuff of Tertiary age. The composite hydraulic head in the zone 751 to 1219 meters was 733 meters above sea level, and at a depth below land surface of 751 meters. Below a depth of 1190 meters, the hydraulic head was 754 meters above sea level ormore » higher, suggesting an upward component of groundwater flow at the site. The most transmissive part of the saturated zone is in the upper part of the Tram Member of the Crater Flat Tuff in the depth interval from 809 to 841 meters, with an apparent transmissivity of about 7 x 10{sup -1} meter squared per day. The remainder of the penetrated rocks in the saturated zone, 841 to 1219 meters, has an apparent transmissivity of about 4 x 10{sup -1} meter squared per day. The most transmissive part of the lower depth interval is in the bedded tuff and Lithic Ridge Tuff, in the depth interval from 1108 to 1120 meters. The apparent hydraulic conductivity of the rocks in the lower depth interval from 841 to 1219 meters commonly ranges from about 10{sup -1} to 10{sup -4} meter per day. 32 references, 20 figures, 4 tables.« less

Nerves Regulate Cardiomyocyte Proliferation and Heart Regeneration.

PubMed

Mahmoud, Ahmed I; O'Meara, Caitlin C; Gemberling, Matthew; Zhao, Long; Bryant, Donald M; Zheng, Ruimao; Gannon, Joseph B; Cai, Lei; Choi, Wen-Yee; Egnaczyk, Gregory F; Burns, Caroline E; Burns, C Geoffrey; MacRae, Calum A; Poss, Kenneth D; Lee, Richard T

2015-08-24

Some organisms, such as adult zebrafish and newborn mice, have the capacity to regenerate heart tissue following injury. Unraveling the mechanisms of heart regeneration is fundamental to understanding why regeneration fails in adult humans. Numerous studies have revealed that nerves are crucial for organ regeneration, thus we aimed to determine whether nerves guide heart regeneration. Here, we show using transgenic zebrafish that inhibition of cardiac innervation leads to reduction of myocyte proliferation following injury. Specifically, pharmacological inhibition of cholinergic nerve function reduces cardiomyocyte proliferation in the injured hearts of both zebrafish and neonatal mice. Direct mechanical denervation impairs heart regeneration in neonatal mice, which was rescued by the administration of neuregulin 1 (NRG1) and nerve growth factor (NGF) recombinant proteins. Transcriptional analysis of mechanically denervated hearts revealed a blunted inflammatory and immune response following injury. These findings demonstrate that nerve function is required for both zebrafish and mouse heart regeneration. Copyright © 2015 Elsevier Inc. All rights reserved.

Mott-Hubbard transition and Anderson localization: A generalized dynamical mean-field theory approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuchinskii, E. Z.; Nekrasov, I. A.; Sadovskii, M. V.

The DOS, the dynamic (optical) conductivity, and the phase diagram of a strongly correlated and strongly disordered paramagnetic Anderson-Hubbard model are analyzed within the generalized dynamical mean field theory (DMFT + {sigma} approximation). Strong correlations are taken into account by the DMFT, and disorder is taken into account via an appropriate generalization of the self-consistent theory of localization. The DMFT effective single-impurity problem is solved by a numerical renormalization group (NRG); we consider the three-dimensional system with a semielliptic DOS. The correlated metal, Mott insulator, and correlated Anderson insulator phases are identified via the evolution of the DOS and dynamicmore » conductivity, demonstrating both the Mott-Hubbard and Anderson metal-insulator transition and allowing the construction of the complete zero-temperature phase diagram of the Anderson-Hubbard model. Rather unusual is the possibility of a disorder-induced Mott insulator-to-metal transition.« less

In Spite of It All

ERIC Educational Resources Information Center

Sanchez, Ricardo

1978-01-01

The history of the Chicano and/or Mexicano undocumented worker is one and the same. More than a century of being raped, ravaged, pillaged, and genocidally victimized people has not broken us--we continue surviving in spite and against all odds. (Author/NQ)

Genetic landscape of extreme responders with anaplastic oligodendroglioma.

PubMed

Holdhoff, Matthias; Cairncross, Gregory J; Kollmeyer, Thomas M; Zhang, Ming; Zhang, Peixin; Mehta, Minesh P; Werner-Wasik, Maria; Souhami, Luis; Bahary, Jean-Paul; Kwok, Young; Hartford, Alan C; Chakravarti, Arnab; Yegnasubramanian, Srinivasan; Vogelstein, Bert; Papadopoulos, Nickolas; Kinzler, Kenneth; Jenkins, Robert B; Bettegowda, Chetan

2017-05-30

The NRG Oncology RTOG 9402 trial showed significant survival benefit in patients with 1p/19q co-deleted anaplastic oligodendrogliomas (AO) who received both radiation (RT) and chemotherapy (PCV regimen) versus RT alone. Substantial separation of the survival curves was only seen after 7.3 years. We aimed to determine whether there are specific genetic alterations that distinguish co-deleted AO patients who benefit from the addition of PCV from those who do not. We performed whole exome sequencing on matched tumor and normal DNA from all available short-term (STS) and long-term survivors (LTS) who received RT+PCV. hTERT status and rs55705857 genotypes (G-allele) were analyzed in both cohorts. Six STS (survival of <7.3y) and 7 LTS (survival of ≥7.3y and no progression) had sufficient material for analysis. There was no significant difference between the groups regarding age, performance status and extent of resection. On average, STS had 7 and LTS 4 mutations. Most common mutations in STS vs. LTS were: IDH1 (67 vs. 86%), CIC (50 vs. 71%) and FUBP1 (17 vs. 71%). The hTERT promoter was mutated in 83% STS and 86% LTS. Genotyping of rs55705857 showed a higher prevalence of G allele carriers in LTS than STS (43 vs. 17%). These findings confirm that IDH, CIC, FUBP1 mutations and rs55705857 genotype are common in AO. No distinct genetic signature was identified to differentiate STS and LTS.

Benchmark Credentialing Results for NRG-BR001: The First National Cancer Institute-Sponsored Trial of Stereotactic Body Radiation Therapy for Multiple Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Hallaq, Hania A., E-mail: halhallaq@radonc.uchicago.edu; Chmura, Steven J.; Salama, Joseph K.

Purpose: The NRG-BR001 trial is the first National Cancer Institute–sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. Methods and Materials: The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by <5 cm of normal tissue. Because the planning target volume (PTV) overlaps with organs at risk (OARs), institutions must use the planning priority guidelines to balance PTV coverage (45 Gy in 3 fractions) againstmore » OAR sparing. Submitted plans were processed by the Imaging and Radiation Oncology Core and assessed by the protocol co-chairs by comparing the doses to targets, OARs, and conformity metrics using nonparametric tests. Results: Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm{sup 3} was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. Conclusions: Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements.« less

Benchmark Credentialing Results for NRG-BR001: The First National Cancer Institute-Sponsored Trial of Stereotactic Body Radiation Therapy for Multiple Metastases.

PubMed

Al-Hallaq, Hania A; Chmura, Steven J; Salama, Joseph K; Lowenstein, Jessica R; McNulty, Susan; Galvin, James M; Followill, David S; Robinson, Clifford G; Pisansky, Thomas M; Winter, Kathryn A; White, Julia R; Xiao, Ying; Matuszak, Martha M

2017-01-01

The NRG-BR001 trial is the first National Cancer Institute-sponsored trial to treat multiple (range 2-4) extracranial metastases with stereotactic body radiation therapy. Benchmark credentialing is required to ensure adherence to this complex protocol, in particular, for metastases in close proximity. The present report summarizes the dosimetric results and approval rates. The benchmark used anonymized data from a patient with bilateral adrenal metastases, separated by <5 cm of normal tissue. Because the planning target volume (PTV) overlaps with organs at risk (OARs), institutions must use the planning priority guidelines to balance PTV coverage (45 Gy in 3 fractions) against OAR sparing. Submitted plans were processed by the Imaging and Radiation Oncology Core and assessed by the protocol co-chairs by comparing the doses to targets, OARs, and conformity metrics using nonparametric tests. Of 63 benchmarks submitted through October 2015, 94% were approved, with 51% approved at the first attempt. Most used volumetric arc therapy (VMAT) (78%), a single plan for both PTVs (90%), and prioritized the PTV over the stomach (75%). The median dose to 95% of the volume was 44.8 ± 1.0 Gy and 44.9 ± 1.0 Gy for the right and left PTV, respectively. The median dose to 0.03 cm 3 was 14.2 ± 2.2 Gy to the spinal cord and 46.5 ± 3.1 Gy to the stomach. Plans that spared the stomach significantly reduced the dose to the left PTV and stomach. Conformity metrics were significantly better for single plans that simultaneously treated both PTVs with VMAT, intensity modulated radiation therapy, or 3-dimensional conformal radiation therapy compared with separate plans. No significant differences existed in the dose at 2 cm from the PTVs. Although most plans used VMAT, the range of conformity and dose falloff was large. The decision to prioritize either OARs or PTV coverage varied considerably, suggesting that the toxicity outcomes in the trial could be affected. Several benchmarks met the dose-volume histogram metrics but produced unacceptable plans owing to low conformity. Dissemination of a frequently-asked-questions document improved the approval rate at the first attempt. Benchmark credentialing was found to be a valuable tool for educating institutions about the protocol requirements. Copyright © 2016 Elsevier Inc. All rights reserved.

Discovery of common variants associated with low TSH levels and thyroid cancer risk

PubMed Central

Gudmundsson, Julius; Sulem, Patrick; Gudbjartsson, Daniel F; Jonasson, Jon G; Masson, Gisli; He, Huiling; Jonasdottir, Aslaug; Sigurdsson, Asgeir; Stacey, Simon N; Johannsdottir, Hrefna; Helgadottir, Hafdis Th; Li, Wei; Nagy, Rebecca; Ringel, Matthew D; Kloos, Richard T; de Visser, Marieke C H; Plantinga, Theo S; den Heijer, Martin; Aguillo, Esperanza; Panadero, Angeles; Prats, Enrique; Garcia-Castaño, Almudena; De Juan, Ana; Rivera, Fernando; Walters, G Bragi; Bjarnason, Hjordis; Tryggvadottir, Laufey; Eyjolfsson, Gudmundur I; Bjornsdottir, Unnur S; Holm, Hilma; Olafsson, Isleifur; Kristjansson, Kristleifur; Kristvinsson, Hoskuldur; Magnusson, Olafur T; Thorleifsson, Gudmar; Gulcher, Jeffrey R; Kong, Augustine; Kiemeney, Lambertus ALM; Jonsson, Thorvaldur; Hjartarson, Hannes; Mayordomo, Jose I; Netea-Maier, Romana T; de la Chapelle, Albert; Hrafnkelsson, Jon; Thorsteinsdottir, Unnur; Rafnar, Thorunn; Stefansson, Kari

2013-01-01

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood. PMID:22267200

Quality of life is significantly associated with survival in women with advanced epithelial ovarian cancer: An ancillary data analysis of the NRG Oncology/Gynecologic Oncology Group (GOG-0218) study.

PubMed

Phippen, N T; Secord, A A; Wolf, S; Samsa, G; Davidson, B; Abernethy, A P; Cella, D; Havrilesky, L J; Burger, R A; Monk, B J; Leath, C A

2017-10-01

Evaluate association between baseline quality of life (QOL) and changes in QOL measured by FACT-O TOI with progression-free disease (PFS) and overall survival (OS) in advanced epithelial ovarian cancer (EOC). Patients enrolled in GOG-0218 with completed FACT-O TOI assessments at baseline and at least one follow-up assessment were eligible. Baseline FACT-O TOI scores were sorted by quartiles (Q1-4) and outcomes compared between Q1 and Q2-4 with log-rank statistic and multivariate Cox regression adjusting for age, stage, post-surgical residual disease size, and performance status (PS). Trends in FACT-O TOI scores from baseline to the latest follow-up assessment were evaluated for impact on intragroup (Q1 or Q2-4) outcome by log-rank analysis. Of 1152 eligible patients, 283 formed Q1 and 869 formed Q2-4. Mean baseline FACT-O TOI scores were 47.5 for Q1 vs. 74.7 for Q2-4 (P<0.001). Q1 compared to Q2-4 had worse median OS (37.5 vs. 45.6months, P=0.001) and worse median PFS (12.5 vs. 13.1months, P=0.096). Q2-4 patients had decreased risks of disease progression (HR 0.974, 95% CI 0.953-0.995, P=0.018), and death (HR 0.963, 95% CI 0.939-0.987, P=0.003) for each five-point increase in baseline FACT-O TOI. Improving versus worsening trends in FACT-O TOI scores were associated with longer median PFS (Q1: 12.7 vs. 8.6months, P=0.001; Q2-4: 16.7 vs. 11.1months, P<0.001) and median OS (Q1: 40.8 vs. 16months, P<0.001; Q2-4: 54.4 vs. 33.6months, P<0.001). Baseline FACT-O TOI scores were independently prognostic of PFS and OS while improving compared to worsening QOL was associated with significantly better PFS and OS in women with EOC. Copyright © 2017 Elsevier Inc. All rights reserved.

Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor–Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14

PubMed Central

Wolmark, Norman; Baehner, Frederick L.; Butler, Steven M.; Tang, Gong; Jamshidian, Farid; Sing, Amy P.; Shak, Steven; Paik, Soonmyung

2016-01-01

Purpose We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1–expressing groups. Patients and Methods RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) –positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Results Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (≥ 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B-14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). Conclusion For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis. PMID:27217450

Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14.

PubMed

Wolmark, Norman; Mamounas, Eleftherios P; Baehner, Frederick L; Butler, Steven M; Tang, Gong; Jamshidian, Farid; Sing, Amy P; Shak, Steven; Paik, Soonmyung

2016-07-10

We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1-expressing groups. RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) -positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (≥ 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B-14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis. © 2016 by American Society of Clinical Oncology.

Ultrasonic alignment of bio-functionalized magnetic beads and live cells in PDMS micro-fluidic channel.

PubMed

Islam, Afroja T; Siddique, Ariful H; Ramulu, T S; Reddy, Venu; Eu, Young-Jae; Cho, Seung Hyun; Kim, CheolGi

2012-12-01

In this work, we demonstrated the alignment of polystyrene latex microspheres (diameter of 1 ~45 μm), bio-functionalized superparamagnetic beads (diameter 2.8 μm), and live cells (average diameter 1 ~2 μm) using an ultrasonic standing wave (USW) in a PDMS microfluidic channel (330 μm width) attached on a Si substrate for bio-medical applications. To generate a standing wave inside the channel, ultrasound of 2.25 MHz resonance frequency (for the channel width) was applied by two ultrasound transducers installed at both sides of the channel which caused the radiation force to concentrate the micro-particles at the single pressure nodal plane of USW. By increasing the frequency to the next resonance condition of the channel, the particles were concentrated in dual nodal planes. Migration time of the micro-particles towards the single nodal plane was recorded as 108 s, 17 s, and 115 s for polystyrene particles of 2 μm diameter, bio-functionalized magnetic beads, and live cells, respectively. These successful alignments of the bio-functionalized magnetic beads along the desired part of the channel can enhance the performance of a sensor which is applicable for the bio-hybrid system and the alignment of live cells without any damage can be used for sample pre-treatment for the application of lab-on-a-chip type bioassays.

Volcanotectonic history of Crater Flat, southwestern Nevada, as suggested by new evidence from drill hole USW-VH-1 and vicinity

USGS Publications Warehouse

Carr, W.J.

1982-01-01

New evidence for a possible resurgent dome in the caldera related to eruption of the Bullfrog Member of the Crater Flat Tuff has been provided by recent drilling of a 762-meter (2,501-foot) hole in central Crater Flat. Although no new volcanic units were penetrated by the drill hole (USW-VH-1), the positive aeromagnetic anomaly in the vicinity of the drill hole appears to result in part from the unusually thick, densely welded tuff of the Bullfrog. Major units penetrated include alluvium, basalt of Crater Flat, Tiva Canyon and Topopah Spring Members of the Paintbrush Tuff, and Prow Pass and Bullfrog Members of the Crater Flat Tuff. In addition, the drill hole provided the first subsurface hydrologic information for the area. The water table in the hole is at about 180 meters (600 feet), and the temperature gradient appears slightly higher than normal for the region.

Cognitive function during and six months following chemotherapy for front-line treatment of ovarian, primary peritoneal or fallopian tube cancer: An NRG oncology/gynecologic oncology group study.

PubMed

Hess, Lisa M; Huang, Helen Q; Hanlon, Alexandra L; Robinson, William R; Johnson, Rhonda; Chambers, Setsuko K; Mannel, Robert S; Puls, Larry; Davidson, Susan A; Method, Michael; Lele, Shashikant; Havrilesky, Laura; Nelson, Tina; Alberts, David S

2015-12-01

Changes in cognitive function have been identified in and reported by many cancer survivors. These changes have the potential to impact patient quality of life and functional ability. This prospective longitudinal study was designed to quantify the incidence of change in cognitive function in newly diagnosed ovarian cancer patients throughout and following primary chemotherapy. Eligible patients had newly diagnosed, untreated ovarian cancer and had planned to receive chemotherapy. Web-based and patient reported cognitive assessments and quality of life questionnaires were conducted prior to chemotherapy, prior to cycle four, after cycle six, and six months after completion of primary therapy. Two-hundred-thirty-one evaluable patients entered this study between May 2010 and October 2011. At the cycle 4 time point, 25.2% (55/218) of patients exhibited cognitive impairment in at least one domain. At the post-cycle 6 and 6-month follow up time points, 21.1% (44/208) and 17.8% (30/169) of patients, respectively, demonstrated impairment in at least one domain of cognitive function. There were statistically significant, but clinically small, improvements in processing speed (p<0.001) and attention (p<0.001) but not in motor response time (p=0.066), from baseline through the six-month follow up time period. This was a large, prospective study designed to measure cognitive function in ovarian cancer. A subset of patients had evidence of cognitive decline from baseline during chemotherapy treatment in this study as measured by the web-based assessment; however, changes were generally limited to no more than one domain. Copyright © 2015 Elsevier Inc. All rights reserved.

Smart Nanoparticles Undergo Phase Transition for Enhanced Cellular Uptake and Subsequent Intracellular Drug Release in a Tumor Microenvironment.

PubMed

Ye, Guihua; Jiang, Yajun; Yang, Xiaoying; Hu, Hongxiang; Wang, Beibei; Sun, Lu; Yang, Victor C; Sun, Duxin; Gao, Wei

2018-01-10

Inefficient cellular uptake and intracellular drug release at the tumor site are two major obstacles limiting the antitumor efficacy of nanoparticle delivery systems. To overcome both problems, we designed a smart nanoparticle that undergoes phase transition in a tumor microenvironment (TME). The smart nanoparticle is generated using a lipid-polypetide hybrid nanoparticle, which comprises a PEGylated lipid monolayer shell and a pH-sensitive hydrophobic poly-l-histidine core and is loaded with the antitumor drug doxorubicin (DOX). The smart nanoparticle undergoes a two-step phase transition at two different pH values in the TME: (i) At the TME (pH e : 7.0-6.5), the smart nanoparticle swells, and its surface potential turns from negative to neutral, facilitating the cellular uptake; (ii) After internalization, at the acid endolysosome (pH endo : 6.5-4.5), the smart nanoparticle dissociates and induces endolysosome escape to release DOX into the cytoplasm. In addition, a tumor-penetrating peptide iNRG was modified on the surface of the smart nanoparticle as a tumor target moiety. The in vitro studies demonstrated that the iNGR-modified smart nanoparticles promoted cellular uptake in the acidic environment (pH 6.8). The in vivo studies showed that the iNGR-modified smart nanoparticles exerted more potent antitumor efficacy against late-stage aggressive breast carcinoma than free DOX. These data suggest that the smart nanoparticles may serve as a promising delivery system for sequential uptake and intracellular drug release of antitumor agents. The easy preparation of these smart nanoparticles may also have advantages in the future manufacture for clinical trials and clinical use.

75 FR 10325 - Investigations Regarding Certifications of Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-05

... Systems (Comp) Keller, TX 02/17/10 02/10/10 73477 International Game Reno, NV 02/17/10 02/05/10 Technology.../10 Company (USW). 73495 Perkinelmer Health Sciences, Shelton, CT 02/18/10 02/08/10 Inc. (Wkrs). 73496...

Differences in transcriptional effects of 1α,25 dihydroxyvitamin D3 on fibroblasts associated to breast carcinomas and from paired normal breast tissues.

PubMed

Campos, Laura Tojeiro; Brentani, Helena; Roela, Rosimeire Aparecida; Katayama, Maria Lucia Hirata; Lima, Leandro; Rolim, Cíntia Flores; Milani, Cíntia; Folgueira, Maria Aparecida Azevedo Koike; Brentani, Maria Mitzi

2013-01-01

The effects of 1α,25 dihydroxyvitamin D3 (1,25D) on breast carcinoma associated fibroblasts (CAFs) are still unknown. This study aimed to identify genes whose expression was altered after 1,25D treatment in CAFs and matched adjacent normal mammary associated fibroblasts (NAFs). CAFs and NAFs (from 5 patients) were cultured with or without (control) 1,25D 100 nM. Both CAF and NAF expressed vitamin D receptor (VDR) and 1,25D induction of the genomic pathway was detected through up-regulation of the target gene CYP24A1. Microarray analysis showed that despite presenting 50% of overlapping genes, CAFs and NAFs exhibited distinct transcriptional profiles after 1,25D treatment (FDR<0.05). Functional analysis revealed that in CAFs, genes associated with proliferation (NRG1, WNT5A, PDGFC) were down regulated and those involved in immune modulation (NFKBIA, TREM-1) were up regulated, consistent with anti tumor activities of 1,25D in breast cancer. In NAFs, a distinct subset of genes was induced by 1,25D, involved in anti apoptosis, detoxification, antibacterial defense system and protection against oxidative stress, which may limit carcinogenesis. Co-expression network and interactome analysis of genes commonly regulated by 1,25D in NAFs and CAFs revealed differences in their co-expression values, suggesting that 1,25D effects in NAFs are distinct from those triggered in CAFs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bewertung von Fahrzeuggeräuschen

NASA Astrophysics Data System (ADS)

Genuit, Klaus; Schulte-Fortkamp, Brigitte; Fiebig, André; Haverkamp, Michael

Bei der Wahrnehmung und Beurteilung eines Automobils sind unzählige Merkmale und Eigenschaften von Bedeutung. Dabei können Merkmale objektiv-technisch beschrieben werden, wie Angaben zur Motorisierung, Höchstgeschwindigkeit, Drehmoment, zulässige Zuladung, Verbrauch usw. Daneben sind weitere Eigenschaften von Bedeutung, die sich einer einfachen objektiv-technischen Beschreibung entziehen. Hier sind Begriffe zu nennen, wie Sicherheit, allgemeine Qualitätsanmutung, Design, Ergonomie, Komfort, Haptik, Fahrdynamik, Zuverlässigkeit, die deutlich schwieriger objektiv erfassbar und beschreibbar sind (Abb. 4.1).

Disease Extent at Secondary Cytoreductive Surgery is Predictive of Progression-free and Overall Survival in Advanced Stage Ovarian Cancer: an NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Rose, Peter G.; Java, James J.; Morgan, Mark A.; Secord, Angeles Alvarez; Kesterson, Joshua P.; Stehman, Frederick B.; Warshal, David P.; Creasman, William T.; Hanjani, Parviz; Morris, Robert T.; Copeland, Larry J.

2017-01-01

Purpose GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1 cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). Methods Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3 cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N= 40 (19.9%), no gross disease/microscopically positive N= 8 (4.0%), and gross disease N=153 (76.1%). Results The median PFS for patients with no gross disease/microscopically negative was 16.1 months, no gross disease/microscopically positive was 13.5 months and for gross disease was 11.7 months, p=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5 months, no gross disease/microscopically positive was 42.6 months and for gross disease was 34.9 months, p=0.018. Conclusion Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS. PMID:27692669

Risk factors for readmission in patients with ovarian, fallopian tube, and primary peritoneal carcinoma who are receiving front-line chemotherapy on a clinical trial (GOG 218): an NRG oncology/gynecologic oncology group study (ADS-1236)☆

PubMed Central

Duska, Linda R.; Java, James J.; Cohn, David E.; Burger, Robert A.

2015-01-01

Background Readmission within 30 days is a measure of care quality. Ovarian cancer patients are at high risk for readmission, but specific risk factors are not defined. This study was designed to determine risk factors in patients with ovarian cancer receiving upfront surgery and chemotherapy. Methods The study population was enrolled to GOG 0218. Factors predictive of admission within 30 days of a previous admission or 40 days of cytoreductive surgery were investigated. Categorical variables were compared by Pearson chi-square test, continuous variables by Wilcoxon–Mann–Whitney test. A logistic regression model was used to evaluate independent prognostic factors and to estimate covariate-adjusted odds. All tests were two-tailed, α = 0.05. Results Of 1873 patients, 197 (10.5%) were readmitted, with 59 experiencing >1 readmission. One-hundred-forty-four (73%) readmissions were post-operative (readmission rate 7.7%). Significant risk factors include: disease stage (stage 3 vs 4, p = 0.008), suboptimal cytoreduction (36% vs 64%, p = 0.001), ascites, (p = 0.018), BMI (25.4 vs 27.6, p < 0.001), poor PS (p < 0.001), and higher baseline CA 125 (p = 0.017). Patients readmitted within 40 days of surgery had a significantly shorter interval from surgery to chemotherapy initiation (22 versus 32 days, p < 0.0001). Patients treated with bevacizumab had higher readmission rates in the case of patients with >1 readmission. On multivariate analysis, the odds of re-hospitalization increased with doubling of BMI (OR = 1.81, 95% CI: 1.07–3.07) and PS of 2 (OR = 2.05, 95% CI 1.21–3.48). Conclusion Significant risk factors for readmission in ovarian cancer patients undergoing primary surgery and chemotherapy include stage, residual disease, ascites, high BMI and poor PS. Readmissions are most likely after the initial surgical procedure, a discrete period to target with a prospective intervention. PMID:26335594

Advantages of simulated microgravity in the production of compounds of industrial relevance

NASA Astrophysics Data System (ADS)

Versari, Silvia; Villa, Alessandro; Barenghi, Livia; Bradamante, Silvia

2005-08-01

Glutathione (α-glutamyl-L-cysteinylglycine, GSH) is the most abundant non-protein thiol compound and it is widely distributed in living organisms, mainly, in eukaryotic cells. Inside the cells, GSH assumes pivotal roles in bioreduction processes and protection against oxidative stress. Due to its antioxidant properties, GSH is widely used not only in food and cosmetic area but also as a pharmaceutical compound.The best total GSH production obtained culturing yeast cells in standard conditions is about 3.5% DCW, as the sum of intracellular (mainly) and extracellular GSH. Its production is limited by a feedback inhibition process. Using our patented microgravity (μg) simulator, the NRG bioreactor, we obtained a three-fold increase in total GSH production. In particular we observed an increased GSH extracellular excretion (9%), thus avoiding the feedback inhibition and easing the downstream processing.To confirm the role of μg, we extended our findings on GSH extracellular production using another μg simulator, the Rotating Wall Vessel (RWV).

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

PubMed Central

McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

2017-01-01

Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

Genetic analysis of an overlapping functional requirement for L1- and NCAM-type proteins during sensory axon guidance in Drosophila.

PubMed

Kristiansen, Lars V; Velasquez, Emma; Romani, Susana; Baars, Sigrid; Berezin, Vladimir; Bock, Elisabeth; Hortsch, Michael; Garcia-Alonso, Luis

2005-01-01

L1- and NCAM-type cell adhesion molecules represent distinct protein families that function as specific receptors for different axon guidance cues. However, both L1 and NCAM proteins promote axonal growth by inducing neuronal tyrosine kinase activity and are coexpressed in subsets of axon tracts in arthropods and vertebrates. We have studied the functional requirements for the Drosophila L1- and NCAM-type proteins, Neuroglian (Nrg) and Fasciclin II (FasII), during postembryonic sensory axon guidance. The rescue of the Neuroglian loss-of-function (LOF) phenotype by transgenically expressed L1- and NCAM-type proteins demonstrates a functional interchangeability between these proteins in Drosophila photoreceptor pioneer axons, where both proteins are normally coexpressed. In contrast, the ectopic expression of Fasciclin II in mechanosensory neurons causes a strong enhancement of the axonal misguidance phenotype. Moreover, our findings demonstrate that this functionally redundant specificity to mediate axon guidance has been conserved in their vertebrate homologs, L1-CAM and NCAM.

[Experiment study on ultrashort wave for treating vascular crisis after rat tail replantation].

PubMed

Tan, Long; Gao, Wenshan; Xi, Ali; Wang, Cong; Chen, Shouying; Zhao, Yanyan; Di, Keqian; Yang, Xincai; Weng, Shengbin

2012-10-01

To explore the effect and mechanism of ultrashort wave (USW) for prevention and treatment of vascular crisis after rat tail replantation. Eighty 3-month old female Sprague Dawley rats (weighing 232.8-289.6 g) were randomly divided into 5 groups. In each group, based on the caudal vein and the coccyx was retained, the tail was cut off. The tail artery was ligated in group A; the tail artery was anastomosed in groups B, C, D, and E to establish the tail replantation model. After surgery, the rats of group B were given normal management; the rats of group C were immediately given intraperitoneal injection (3.125 mL/kg) of diluted papaverine hydrochloride injection (1 mg/mL); the rats of groups D and E were immediately given the local USW treatment (once a day) at anastomotic site for 5 days at the dosage of 3 files and 50 mA for 20 minutes (group D) and 2 files and 28 mA for 20 minutes (group E). The survival rate of the rat tails was observed for 10 days after the tail replantation. The tail skin temperature difference between proximal and distal anastomosis was measured at pre- and post-operation; the change between postoperative and preoperative temperature difference was calculated. The blood plasma specimens were collected from the inner canthus before operation and from the tip of the tail at 8 hours after operation to measure the content of nitric oxide (NO). The survival rates of the rat tails were 0 (0/14), 36.4% (8/22), 57.1% (8/14), 22.2% (4/18), and 75.0% (9/12) in groups A, B, C, D, and E, respectively, showing significant overall differences among 5 groups (chi2 = 19.935, P = 0.001); the survival rate of group E was significantly higher than that of group B at 7 days (P < 0.05), but no significant difference was found between the other groups by pairwise comparison (P > 0.05). At preoperation, there was no significant difference in tail skin temperature difference among 5 groups (P > 0.05); at 8 hours, 5 days, 6 days, and 7 days after operation, significant overall difference was found in the change of the skin temperature difference among groups (P < 0.05); pairwise comparison showed significant differences after operation (P < 0.05): group B > group D at 8 hours, group C > group D at 5 days, groups A, B, and C > group D at 6 days, groups B and C > groups A and E, and group B > group D at 7 days; but no significant difference was found between the other groups at the other time points (P > 0.05). Preoperative plasma NO content between each group had no significant difference (P > 0.05). The overall differences had significance in the NO content at postopoerative 8 hours and in the change of the NO content at pre- and post-operation among groups (P < 0.05). Significant differences were found by pairwise comparison (P < 0.05): group D > groups A, B, and C in the plasma NO content, group D > groups A and B in the change of the NO content at pre- and post-operation; but no significant difference was found between the other groups by pairwise comparison (P > 0.05). Rat tail replantation model in this experiment is feasible. USW therapy can increase the survival rate of replanted rat tails, reduce skin temperature at 7 days, improve blood supply, increase the content of nitric oxide at the early period and prevent vascular crisis.

Urban solid waste generation and disposal in Mexico: a case study.

PubMed

Buenrostro, O; Bocco, G; Bernache, G

2001-04-01

The adequate management of municipal solid waste in developing countries is difficult because of the scarcity of studies about their composition. This paper analyses the composition of urban solid waste (USW) in the city of Morelia, Michoacán, Mexico. Residential and non-residential waste sources were sampled, and a structured interview was made to evaluate the socioeconomic characteristics of the studied area. Also, to determine the seasonal patterns of solid waste generation and the efficiency level of the collection service, quantification of solid waste deposited in the dumping ground was measured. Our results show that the recorded amount of SW deposited in the municipal dumping-ground is less than the estimated amount of SW generated; for this reason, the former amount is not recommended as an unbiased indicator for planning public waste collection services. It is essential that dumping-grounds are permanently monitored and that the incoming waste be weighed in order to have a more efficient record of USW deposited in the dumping-ground per day; these data are fundamental for developing adequate managing strategies.

Effect of Brass Interlayer Sheet on Microstructure and Joint Performance of Ultrasonic Spot-Welded Copper-Steel Joints

NASA Astrophysics Data System (ADS)

Satpathy, Mantra Prasad; Kumar, Abhishek; Sahoo, Susanta Kumar

2017-07-01

Solid-state ultrasonic spot welding (USW) inevitably offers a potential solution for joining dissimilar metal combination like copper (Cu) and steel (SS). In this study, the USW has been performed on Cu (UNS C10100) and SS (AISI 304) with brass interlayer by varying various welding parameters, aiming to identify the interfacial reaction, changes in microstructure and weld strength. The highest tensile shear and T-peel failure loads of 1277 and 174 N are achieved at the optimum conditions like 68 µm of vibration amplitude, 0.42 MPa of weld pressure and 1 s of weld time. The fractured surface analysis of brass interlayer and AISI 304 stainless steel samples reveals the features like swirls, voids and intermetallic compounds (IMCs). These IMCs are composed of CuZn and FeZn composite-like structures with 1.0 μm thickness. This confirms that the weld quality is specifically sensitive to the levels of input parameter combinations as well as the type of material present on the sonotrode side.

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Thaker, Premal H.; Brady, William E.; Lankes, Heather A.; Odunsi, Kunle; Bradley, William H.; Moore, Kathleen N.; Muller, Carolyn Y.; Anwer, Khursheed; Schilder, Russell J.; Alvarez, Ronald D.; Fracasso, Paula M.

2017-01-01

Objective The study’s purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID:28802766

Exercise for the heart: signaling pathways

PubMed Central

Zhang, Haifeng; Xiao, Junjie; Li, Xinli

2015-01-01

Physical exercise, a potent functional intervention in protecting against cardiovascular diseases, is a hot topic in recent years. Exercise has been shown to reduce cardiac risk factors, protect against myocardial damage, and increase cardiac function. This improves quality of life and decreases mortality and morbidity in a variety of cardiovascular diseases, including myocardial infarction, cardiac ischemia/reperfusion injury, diabetic cardiomyopathy, cardiac aging, and pulmonary hypertension. The cellular adaptation to exercise can be associated with both endogenous and exogenous factors: 1) exercise induces cardiac growth via hypertrophy and renewal of cardiomyocytes, and 2) exercise induces endothelial progenitor cells to proliferate, migrate and differentiate into mature endothelial cells, giving rise to endothelial regeneration and angiogenesis. The cellular adaptations associated with exercise are due to the activation of several signaling pathways, in particular, the growth factor neuregulin1 (NRG1)-ErbB4-C/EBPβ and insulin-like growth factor (IGF)-1-PI3k-Akt signaling pathways. Of interest, microRNAs (miRNAs, miRs) such as miR-222 also play a major role in the beneficial effects of exercise. Thus, exploring the mechanisms mediating exercise-induced benefits will be instrumental for devising new effective therapies against cardiovascular diseases. PMID:26318584

Geohydrology of test well USW H-1, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rush, F.E.; Thordarson, W.; Pyles, D.G.

This report contains the results of hydraulic testing, hydrologic monitoring, and geophysical logging of test well USW H-1, one of several wells drilled in the southwestern part of the Nevada Test Site in cooperation with the US Department of Energy for investigations related to the isolation of high-level radioactive wastes. All rocks penetrated by the well to a total depth of 1829 meters were of volcanic origin and of Tertiary age. Hydraulic head in the zone 688 to 741 meters below land surface was 730 meters above sea level and at a depth of 572 meters below land surface. Deepermore » zones had hydraulic heads of 781 meters above sea level or higher, indicating an upward component of ground-water flow at the site. The most transmissive zone, with an apparent transmissivity of about 150 meters squared per day, is in the Prow Pass Member of the Crater Flat Tuff in the depth range from 572 to 688 meters below land surface. The remainder of the penetrated rocks in the saturated zone, 688 to 1829 meters, has an apparent transmissivity of about 1 meter squared per day. The most transmissive part of the lower depth range is in the Bullfrog Member of the Crater Flat Tuff in the depth interval from 736 to 741 meters. The apparent hydraulic conductivity of the rocks in this lower depth interval from 688 to 1829 meters commonly ranges between 10{sup -4} and 10{sup -7} meter per day. Water chemistry is typical of tuffaceous rocks of southern Nevada. The water is a sodium bicarbonate type and has an apparent age of 12,000 to 13,000 years before present, as determined by carbon-14 dating.« less

C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W

PubMed Central

2013-01-01

Background Antimicrobial peptides have been the focus of much research over the last decade because of their effectiveness and broad-spectrum activity against microbial pathogens. These peptides also participate in inflammation and the innate host defense system by modulating the immune function that promotes immune cell adhesion and migration as well as the respiratory burst, which makes them even more attractive as therapeutic agents. This has led to the synthesis of various antimicrobial peptides, including KSL-W (KKVVFWVKFK-NH2), for potential clinical use. Because this peptide displays antimicrobial activity against bacteria, we sought to determine its antifungal effect on C. albicans. Growth, hyphal form, biofilm formation, and degradation were thus examined along with EFG1, NRG1, EAP1, HWP1, and SAP 2-4-5-6 gene expression by quantitative RT-PCR. Results This study demonstrates that KSL-W markedly reduced C. albicans growth at both early and late incubation times. The significant effect of KSL-W on C. albicans growth was observed beginning at 10 μg/ml after 5 h of contact by reducing C. albicans transition and at 25 μg/ml by completely inhibiting C. albicans transition. Cultured C. albicans under biofilm-inducing conditions revealed that both KSL-W and amphotericin B significantly decreased biofilm formation at 2, 4, and 6 days of culture. KSL-W also disrupted mature C. albicans biofilms. The effect of KSL-W on C. albicans growth, transition, and biofilm formation/disruption may thus occur through gene modulation, as the expression of various genes involved in C. albicans growth, transition and biofilm formation were all downregulated when C. albicans was treated with KSL-W. The effect was greater when C. albicans was cultured under hyphae-inducing conditions. Conclusions These data provide new insight into the efficacy of KSL-W against C. albicans and its potential use as an antifungal therapy. PMID:24195531

Treatment planning strategy for whole-brain radiotherapy with hippocampal sparing and simultaneous integrated boost for multiple brain metastases using intensity-modulated arc therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, Damodar, E-mail: dpokhrel@kumc.edu; Sood, Sumit; McClinton, Christopher

Purpose: To retrospectively evaluate the accuracy, plan quality and efficiency of intensity-modulated arc therapy (IMAT) for hippocampal sparing whole-brain radiotherapy (HS-WBRT) with simultaneous integrated boost (SIB) in patients with multiple brain metastases (m-BM). Materials and methods: A total of 5 patients with m-BM were retrospectively replanned for HS-WBRT with SIB using IMAT treatment planning. The hippocampus was contoured on diagnostic T1-weighted magnetic resonance imaging (MRI) which had been fused with the planning CT image set. The hippocampal avoidance zone (HAZ) was generated using a 5-mm uniform margin around the paired hippocampi. The m-BM planning target volumes (PTVs) were contoured onmore » T1/T2-weighted MRI registered with the 3D planning computed tomography (CT). The whole-brain planning target volume (WB-PTV) was defined as the whole-brain tissue volume minus HAZ and m-BM PTVs. Highly conformal IMAT plans were generated in the Eclipse treatment planning system for Novalis-TX linear accelerator consisting of high-definition multileaf collimators (HD-MLCs: 2.5-mm leaf width at isocenter) and 6-MV beam. Prescription dose was 30 Gy for WB-PTV and 45 Gy for each m-BM in 10 fractions. Three full coplanar arcs with orbit avoidance sectors were used. Treatment plans were evaluated using homogeneity (HI) and conformity indices (CI) for target coverage and dose to organs at risk (OAR). Dose delivery efficiency and accuracy of each IMAT plan was assessed via quality assurance (QA) with a MapCHECK device. Actual beam-on time was recorded and a gamma index was used to compare dose agreement between the planned and measured doses. Results: All 5 HS-WBRT with SIB plans met WB-PTV D{sub 2%}, D{sub 98%}, and V{sub 30} {sub Gy} NRG-CC001 requirements. The plans demonstrated highly conformal and homogenous coverage of the WB-PTV with mean HI and CI values of 0.33 ± 0.04 (range: 0.27 to 0.36), and 0.96 ± 0.01 (range: 0.95 to 0.97), respectively. All 5 hippocampal sparing patients met protocol guidelines with maximum dose and dose to 100% of hippocampus (D{sub 100%}) less than 16 and 9 Gy, respectively. The dose to the optic apparatus was kept below protocol guidelines for all 5 patients. Highly conformal and homogenous radiosurgical dose distributions were achieved for all 5 patients with a total of 33 brain metastases. The m-BM PTVs had a mean HI = 0.09 ± 0.02 (range: 0.07 to 0.19) and a mean CI = 1.02 ± 0.06 (range: 0.93 to 1.2). The total number of monitor units (MU) was, on average, 1677 ± 166. The average beam-on time was 4.1 ± 0.4 minute . The IMAT plans demonstrated accurate dose delivery of 95.2 ± 0.6%, on average, for clinical gamma passing rate with 2%/2-mm criteria and 98.5 ± 0.9%, on average, with 3%/3-mm criteria. Conclusions: All hippocampal sparing plans were considered clinically acceptable per NRG-CC001 dosimetric compliance criteria. IMAT planning provided highly conformal and homogenous dose distributions for the WB-PTV and m-BM PTVs with lower doses to OAR such as the hippocampus. These results suggest that HS-WBRT with SIB is a clinically feasible, fast, and effective treatment option for patients with a relatively large numbers of m-BM lesions.« less

Screening for depression in cancer patients receiving radiotherapy: Feasibility and identification of effective tools in the NRG Oncology RTOG 0841 trial.

PubMed

Wagner, Lynne I; Pugh, Stephanie L; Small, William; Kirshner, Jeffrey; Sidhu, Kulbir; Bury, Martin J; DeNittis, Albert S; Alpert, Tracy E; Tran, Binh; Bloom, Beatrice F; Mai, Julie; Yeh, Alexander; Sarma, Kalika; Becker, Mark; James, Jennifer; Bruner, Deborah Watkins

2017-02-01

Brief tools are needed to screen oncology outpatients for depressive symptoms. Patients starting radiotherapy for the first diagnosis of any tumor completed distress screening tools, including the 9-item Patient Health Questionnaire (PHQ-9), the 2-item Patient Health Questionnaire (PHQ-2), the National Comprehensive Cancer Network Distress Thermometer (NCCN-DT), and the Hopkins Symptom Checklist (HSCL) (25-item version). Patients exceeding validated cutoff scores and a systematic sample of patients whose screening was negative completed the Structured Clinical Interview for DSM-IV (SCID) mood disorder modules via telephone. Four hundred sixty-three patients from 35 community-based radiation oncology sites and 2 academic radiation oncology sites were recruited. Sixty-six percent of the 455 eligible patients (n = 299) were women, and the eligible patients had breast (45%), gastrointestinal (11%), lung (10%), gynecologic (6%), or other cancers (27%). Seventy-five (16.5%) exceeded screening cutoffs for depressive symptoms. Forty-two of these patients completed the SCID. Another 37 patients whose screening was negative completed the SCID. Among the 79 patients completing the SCID, 8 (10.1%) met the criteria for major depression, 2 (2.5%) met the criteria for dysthymia, and 6 (7.6%) met the criteria for an adjustment disorder. The PHQ-2 demonstrated good psychometric properties for screening for mood disorders with a cutoff score of ≥3 (receiver operating characteristic area under the curve [AUC], 0.83) and was comparable to the PHQ-9 ( > 9; AUC = 0.85). The NCCN-DT did not detect depression (AUC = 0.59). The PHQ-2 demonstrated good psychometric properties for screening for mood disorders, which were equivalent to the PHQ-9 and superior to the NCCN-DT. These findings support using the PHQ-2 to identify patients in need of further assessment for depression, which has a low prevalence but is a clinically significant comorbidity. These findings could inform the implementation of distress screening accreditation standards. Cancer 2017;123:485-493. © 2016 American Cancer Society. © 2016 American Cancer Society.

Prognosis Relevance of Serum Cytokines in Pancreatic Cancer

PubMed Central

Alejandre, Maria José; Palomino-Morales, Rogelio J.; Prados, Jose; Aránega, Antonia; Delgado, Juan R.; Irigoyen, Antonio; Martínez-Galán, Joaquina; Ortuño, Francisco M.

2015-01-01

The overall survival of patients with pancreatic ductal adenocarcinoma is extremely low. Although gemcitabine is the standard used chemotherapy for this disease, clinical outcomes do not reflect significant improvements, not even when combined with adjuvant treatments. There is an urgent need for prognosis markers to be found. The aim of this study was to analyze the potential value of serum cytokines to find a profile that can predict the clinical outcome in patients with pancreatic cancer and to establish a practical prognosis index that significantly predicts patients' outcomes. We have conducted an extensive analysis of serum prognosis biomarkers using an antibody array comprising 507 human cytokines. Overall survival was estimated using the Kaplan-Meier method. Univariate and multivariate Cox's proportional hazard models were used to analyze prognosis factors. To determine the extent that survival could be predicted based on this index, we used the leave-one-out cross-validation model. The multivariate model showed a better performance and it could represent a novel panel of serum cytokines that correlates to poor prognosis in pancreatic cancer. B7-1/CD80, EG-VEGF/PK1, IL-29, NRG1-beta1/HRG1-beta1, and PD-ECGF expressions portend a poor prognosis for patients with pancreatic cancer and these cytokines could represent novel therapeutic targets for this disease. PMID:26346854

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis.

PubMed

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-07-14

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis.

Combined analysis of DNA methylome and transcriptome reveal novel candidate genes with susceptibility to bovine Staphylococcus aureus subclinical mastitis

PubMed Central

Song, Minyan; He, Yanghua; Zhou, Huangkai; Zhang, Yi; Li, Xizhi; Yu, Ying

2016-01-01

Subclinical mastitis is a widely spread disease of lactating cows. Its major pathogen is Staphylococcus aureus (S. aureus). In this study, we performed genome-wide integrative analysis of DNA methylation and transcriptional expression to identify candidate genes and pathways relevant to bovine S. aureus subclinical mastitis. The genome-scale DNA methylation profiles of peripheral blood lymphocytes in cows with S. aureus subclinical mastitis (SA group) and healthy controls (CK) were generated by methylated DNA immunoprecipitation combined with microarrays. We identified 1078 differentially methylated genes in SA cows compared with the controls. By integrating DNA methylation and transcriptome data, 58 differentially methylated genes were shared with differently expressed genes, in which 20.7% distinctly hypermethylated genes showed down-regulated expression in SA versus CK, whereas 14.3% dramatically hypomethylated genes showed up-regulated expression. Integrated pathway analysis suggested that these genes were related to inflammation, ErbB signalling pathway and mismatch repair. Further functional analysis revealed that three genes, NRG1, MST1 and NAT9, were strongly correlated with the progression of S. aureus subclinical mastitis and could be used as powerful biomarkers for the improvement of bovine mastitis resistance. Our studies lay the groundwork for epigenetic modification and mechanistic studies on susceptibility of bovine mastitis. PMID:27411928

Thermal conductivity, bulk properties, and thermal stratigraphy of silicic tuffs from the upper portion of hole USW-G1, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lappin, A.R.; VanBuskirk, R.G.; Enniss, D.O.

1982-03-01

Thermal-conductivity and bulk-property measurements were made on welded and nonwelded silicic tuffs from the upper portion of Hole USW-G1, located near the southwestern margin of the Nevada Test Site. Bulk-property measurements were made by standard techniques. Thermal conductivities were measured at temperatures as high as 280{sup 0}C, confining pressures to 10 MPa, and pore pressures to 1.5 MPa. Extrapolation of measured saturated conductivities to zero porosity suggests that matrix conductivity of both zeolitized and devitrified tuffs is independent of stratigraphic position, depth, and probably location. This fact allows development of a thermal-conductivity stratigraphy for the upper portion of Hole G1.more » Estimates of saturated conductivities of zeolitized nonwelded tuffs and devitrified tuffs below the water table appear most reliable. Estimated conductivities of saturated densely welded devitrified tuffs above the water table are less reliable, due to both internal complexity and limited data presently available. Estimation of conductivity of dewatered tuffs requires use of different air thermal conductivities in devitrified and zeolitized samples. Estimated effects of in-situ fracturing generally appear negligible.« less

The Effect of Early Diagenesis on the 238U/235U Ratio of Platform Carbonates.

NASA Astrophysics Data System (ADS)

Tissot, F.; Chen, C.; Go, B. M.; Naziemiec, M.; Healy, G.; Swart, P. K.; Dauphas, N.

2017-12-01

In the past 15 years, the so-called non-traditional stable isotopes systems (e.g., Mg, Fe, Mo, U) have emerged as powerful tracers of both high-T and low-T geochemical processes (e.g., [1]). Of particular interest for paleoredox studies is the ratio of "stable" isotopes of U (238U/235U), which has the potential to track the global extent of oceanic anoxia (e.g., [2, 3]). Indeed, in the modern ocean, U exists in two main oxidation states, soluble U6+ and insoluble U4+, and has a mean residence time of 400 kyr ([4]), much longer than the global ocean mixing time (1-2 kyr). As such the salinity-normalized ocean is homogeneous with regards to both U concentrations and isotopes (δ238USW = -0.392±0.005 ‰, [2]). The value of δ238USW at any given time is therefore the balance between U input to the ocean, mainly from rivers, and U removal, mostly into biogenic carbonates, anoxic/euxinic sediments and suboxic/hypoxic sediments (e.g., [2, 5]). Because the 238U/235U ratio of the past ocean cannot be measured directly, it has to be estimated from the measurement of the 238U/235U ratio of a sedimentary rock and assuming a constant fractionation factor. Carbonates appear as a promising record since they span most of Earth's history, and the δ238U values of modern primary carbonate precipitates and well-preserved fossil aragonitic coral up to 600 ka are indistinguishable from that of seawater (e.g., [2, 6, 7]). Yet, the effect of secondary processes on the δ238U values of non-coral carbonates, which represent the bulk of the rock record, has only been studied in a handful of shallow samples (down to 40cm, [6]) and remains poorly understood. To investigate the effect of early diagenesis on the 238U/235U ratio of carbonates on the 30kyr to 1Myr timescale, we measured δ13C, δ18O, and δ238U in samples from a 220m long drill core from the Bahamas carbonate platform. In order to separate lattice bound U from secondary U we developed a leaching protocol applicable to carbonate of all ages. We find that early diagenesis results in a 0 to +0.50 ‰ offset between the δ238U of carbonates and that of seawater. [1] Teng et al (2017) RiMG 82. [2] Tissot & Dauphas (2015) GCA 167. [3] Andersen et al. (2016) Chem. Geol. 420. [4] Ku et al (1977) Deep-Sea Research 24. [5] Dunk et al (2002) Chem. Geol. 190. [6] Romaniello et al (2013) Chem. Geol. 362. [7] Andersen et al. (2014) EPSL 400.

Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays

PubMed Central

Chen, Meng; Ye, Yuanqing; Yang, Hushan; Tamboli, Pheroze; Matin, Surena; Tannir, Nizar M.; Wood, Christopher G.; Gu, Jian; Wu, Xifeng

2009-01-01

Purpose The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis, and treatment. Methods We applied Illumina's 317K high-density SNP-arrays to profile chromosomal aberrations in clear cell renal cell carcinoma (ccRCC) from 80 patients and analyzed the association of LOH/amplification events with clinicopathological characteristics and telomere length. Results The most common loss of heterozygosity (LOH) were 3p (69 cases) including 38 whole 3p arm losses, 30 large fragment LOH (spanning 3p21-36), and 1 interstitial LOH (spanning 3p12-14, 3p21-22, 3p24.1-24.2, and 3p24.3), followed by chromosome losses at 8p12-pter, 6q23.3-27, 14q24.1-qter, 9q32-qter, 10q22.3-qter, 9p13.3-pter, 4q28.3-qter, and 13q12.1-21.1. We also found several smallest overlapping regions of LOH that contained tumor suppressor genes. One smallest LOH in 8p12 had a size of 0.29 Mb and only contained one gene (NRG1). The most frequent chromosome gains were at 5q (32 cases), including 10 whole 5q amplification, 21 large amplifications encompassing 5q32-ter, and 1 focal amplification in 5q35.3 (0.42 Mb). The other common chromosome gains were 1q25.1-qter, 7q21.13-qter, 8q24.12-qter, and whole 7p arm. Significant associations of LOH at 9p, 9q, 14q, and 18q were observed with higher nuclear grade. Significant associations with tumor stage were observed for LOH at 14q, 18p, and 21q. Finally, we found that tumors with LOH at 2q, 6p, 6q, 9p, 9q, and 17p had significantly shorter telomere length than those without LOH. Conclusion This is the first study to use Illumina's SNP-CGH array that provides a close estimate of the size and frequency of chromosome LOH and amplifications of ccRCC. The identified regions and genes may become diagnostic and prognostic biomarkers as well as potential targets of therapy. PMID:19521957

Boric acid destabilizes the hyphal cytoskeleton and inhibits invasive growth of Candida albicans.

PubMed

Pointer, Benjamin R; Boyer, Michael P; Schmidt, Martin

2015-04-01

Exposure of Candida albicans to sub-lethal concentrations of boric acid (BA) restricts the dimorphic fungus to its yeast morphology and prevents the formation of invasive hyphae on solid substrates. Exposure to BA causes a rapid and reversible disappearance of polarisome and Spitzenkörper in growing hyphae. In BA-treated hyphae of C. albicans, actin quickly reorganizes from cytoplasmic cables to cortical patches and cell wall growth switches from an apical to an isotropic pattern. As a result of the cytoskeletal changes, the hyphal tips broaden and directional growth of hyphae ceases in the presence of BA. An analysis of homozygous deletion strains showed that mutants with constitutive or enhanced hyphal growth (tup1, nrg1, ssn6, rbf1) are BA-sensitive, demonstrating that cellular morphology is a major determinant of BA tolerance. The screening of deletion mutants also showed that deficiencies of the main activator of hyphal gene expression, Efg1, and the Rim101-signalling cascade, leading to Efg1 activation, cause BA resistance. Taken together, the data presented show that the selective inhibitory effect on BA on C. albicans hyphae is rooted in a disruption of apical cytoskeletal elements of growing hyphae. Copyright © 2015 John Wiley & Sons, Ltd.

Transcription factor ETV1 is essential for rapid conduction in the heart.

PubMed

Shekhar, Akshay; Lin, Xianming; Liu, Fang-Yu; Zhang, Jie; Mo, Huan; Bastarache, Lisa; Denny, Joshua C; Cox, Nancy J; Delmar, Mario; Roden, Dan M; Fishman, Glenn I; Park, David S

2016-12-01

Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.

Transcription factor ETV1 is essential for rapid conduction in the heart

PubMed Central

Shekhar, Akshay; Lin, Xianming; Liu, Fang-Yu; Zhang, Jie; Mo, Huan; Bastarache, Lisa; Denny, Joshua C.; Cox, Nancy J.; Delmar, Mario; Roden, Dan M.; Fishman, Glenn I.; Park, David S.

2016-01-01

Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart. PMID:27775552

WE-E-304-02: Implementing SBRT Protocols: A NRG CIRO Perspective

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Y.

2015-06-15

SBRT is having a dramatic impact on radiation therapy of early-stage, locally advanced cancers. A number of national protocols have been and are being developed to assess the clinical efficacy of SBRT for various anatomical sites, such as lung and spine. Physics credentialing for participating and implementation of trial protocols involve a broad spectrum of requirements from image guidance, motion management, to planning technology and dosimetric constrains. For radiation facilities that do not have extensive experiences in SBRT treatment and protocol credentialing, these complex processes of credentialing and implementation could be very challenging and, sometimes, may lead to ineffective evenmore » unsuccessful execution of these processes. In this proposal, we will provide comprehensive review of some current SBRT protocols, explain the requirements and their underline rationales, illustrate representative failed and successful experiences, related to SBRT credentialing, and discuss strategies for effective SBRT credentialing and implementation. Learning Objectives: Understand requirements and challenges of SBRT credentailing and implentation Discuss processes and strategies of effective SBRT credentailing Discuss practical considerations, potential pitfalls and solutions of SBRT implentation.« less

Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer

PubMed Central

Nakaoku, Takashi; Tsuta, Koji; Tsuchihara, Katsuya; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2015-01-01

Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions. PMID:25870798

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

PubMed

McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

2017-07-01

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients.

PubMed

Kim, Kelly Y; Le, Quynh-Thu; Yom, Sue S; Ng, Raymond H W; Chan, K C Allen; Bratman, Scott V; Welch, John J; Divi, Rao L; Petryshyn, Raymond A; Conley, Barbara A

2017-08-01

Epstein-Barr virus (EBV) DNA analysis has been shown to be useful for early detection, prognostication, and monitoring of treatment response of nasopharyngeal carcinoma (NPC), and the recent literature provides growing evidence of the clinical utility of EBV DNA testing, particularly to inform treatment decisions for NPC patients. Despite the fact that NPC is a rare disease, the NRG Oncology cooperative group has successfully activated a phase 2/3 randomized clinical trial for NPC with international partners and in that process has discovered that the development of a harmonized EBV DNA test is absolutely critical for integration into clinical trials and for future deployment in clinical and central laboratories. In November 2015, the National Cancer Institute (NCI) convened a workshop of international experts in the treatment of NPC and EBV testing to provide a forum for discussing the state of EBV DNA testing and its clinical utility, and to stimulate consideration of future studies and clinical practice guidelines for EBV DNA. This review provides a summary of that discussion. Published by Elsevier Inc.

Donor Hemovigilance during Preparatory Plasmapheresis

PubMed Central

Diekamp, Ulrich; Gneißl, Johannes; Rabe, Angela; Kießig, Stephan T.

2014-01-01

Summary Background Reports on unexpected donor events (UEs) during preparatory plasmapheresis (PPP) are scarce, and rarely consider technical UEs. Methods Defined local and systemic UEs were graded by severity; technical UEs were not graded. On January 1, 2008, E.B.P.S.-Logistics (EBPS) installed the UE module for plasma management software (PMS). Donor room physicians entered UEs daily into the PMS. Medical directors reviewed entries quarterly. EBPS compiled data on donors, donations and UEs from January 1, 2008 to June 30, 2011. Results 66,822 UEs were observed during 1,107,846 PPPs for a corrected incidence of 6.55% (1.4% local, 0.55% systemic, 4.6% technical UEs). 3.36% of PPPs were accompanied by 1 UE and 1.18% by >1 UE (2-5). 13.7% of donors undergoing PPP for the first time, 9.7% of those having a second PPP and 4.0% of those having a third or more PPPs were associated with UEs. Most common UEs were repeated venipuncture, and broken-off collection due to venous access problems and small hematomas. Severe systemic UEs occurred at a rate of 36 per 100,000 PPPs. Conclusions Technical UEs were common with PPP. UEs accompanied first and second donations significantly more frequently than for subsequent donations. PMID:24847188

Normzahlen, Toleranzen, Passungen

NASA Astrophysics Data System (ADS)

Böge, Gert; Böge, Wolfgang

Vor allem wegen der Kosten ist es sinnvoll, sich beim Festlegen von Maßen aller Art auf Vorzugszahlen zu beschränken (Baugrößen, Drehzahlen, Drehmomente, Leistungen, Drücke usw.). Man verwendet dazu eine geometrisch gestufte Zahlenfolge (siehe Teil Mathematik). Abb. 40.1 zeigt, dass bei der geometrischen Stufung die Werte im unteren Bereich fein, im oberen grob gestuft sind. Das ist nicht nur technisch sinnvoll.

A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function.

PubMed

Porcu, Eleonora; Medici, Marco; Pistis, Giorgio; Volpato, Claudia B; Wilson, Scott G; Cappola, Anne R; Bos, Steffan D; Deelen, Joris; den Heijer, Martin; Freathy, Rachel M; Lahti, Jari; Liu, Chunyu; Lopez, Lorna M; Nolte, Ilja M; O'Connell, Jeffrey R; Tanaka, Toshiko; Trompet, Stella; Arnold, Alice; Bandinelli, Stefania; Beekman, Marian; Böhringer, Stefan; Brown, Suzanne J; Buckley, Brendan M; Camaschella, Clara; de Craen, Anton J M; Davies, Gail; de Visser, Marieke C H; Ford, Ian; Forsen, Tom; Frayling, Timothy M; Fugazzola, Laura; Gögele, Martin; Hattersley, Andrew T; Hermus, Ad R; Hofman, Albert; Houwing-Duistermaat, Jeanine J; Jensen, Richard A; Kajantie, Eero; Kloppenburg, Margreet; Lim, Ee M; Masciullo, Corrado; Mariotti, Stefano; Minelli, Cosetta; Mitchell, Braxton D; Nagaraja, Ramaiah; Netea-Maier, Romana T; Palotie, Aarno; Persani, Luca; Piras, Maria G; Psaty, Bruce M; Räikkönen, Katri; Richards, J Brent; Rivadeneira, Fernando; Sala, Cinzia; Sabra, Mona M; Sattar, Naveed; Shields, Beverley M; Soranzo, Nicole; Starr, John M; Stott, David J; Sweep, Fred C G J; Usala, Gianluca; van der Klauw, Melanie M; van Heemst, Diana; van Mullem, Alies; Vermeulen, Sita H; Visser, W Edward; Walsh, John P; Westendorp, Rudi G J; Widen, Elisabeth; Zhai, Guangju; Cucca, Francesco; Deary, Ian J; Eriksson, Johan G; Ferrucci, Luigi; Fox, Caroline S; Jukema, J Wouter; Kiemeney, Lambertus A; Pramstaller, Peter P; Schlessinger, David; Shuldiner, Alan R; Slagboom, Eline P; Uitterlinden, André G; Vaidya, Bijay; Visser, Theo J; Wolffenbuttel, Bruce H R; Meulenbelt, Ingrid; Rotter, Jerome I; Spector, Tim D; Hicks, Andrew A; Toniolo, Daniela; Sanna, Serena; Peeters, Robin P; Naitza, Silvia

2013-01-01

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Pseudogap in normal underdoped phase of Bi2212: LDA + DMFT + Σk

NASA Astrophysics Data System (ADS)

Nekrasov, I. A.; Kuchinskii, E. Z.; Pchelkina, Z. V.; Sadovskii, M. V.

2007-09-01

Pseudogap phenomena are observed for normal underdoped phase of different high- Tc cuprates. Among others Bi 2Sr 2CaCu 2O 8- δ (Bi2212) compound is one of the most studied experimentally [A. Damascelli, Z. Hussain, Z.-X. Shen, Rev. Mod. Phys. 75 (2003) 473; J.C. Campuzano, M.R. Norman, M. Randeria, in: K.H. Bennemann, J.B. Ketterson (Eds.), Physics of Superconductors, vol. 2, Springer, Berlin, 2004, p. 167; J. Fink et al., cond-mat/0512307; X.J. Zhou et al., cond-mat/0604284]. To describe pseudogap regime in Bi2212, we employ novel generalized DMFT + Σk approach [E.Z. Kuchinskii, I.A. Nekrasov, M.V. Sadovskii, JETP Lett. 82 (2005) 198; M.V. Sadovskii et al., Phys. Rev. B 72 (2005) 155105, and these proceedings, doi:10.1016/j.physc.2007.03.367]. This approach gives possibility to preserve conventional dynamical mean-field theory (DMFT) equations [A. Georges et al., Rev. Mod. Phys. 68 (1996) 13] and include an additional (momentum dependent) self-energy Σk. In the present case, Σk describes non-local dynamical correlations induced by short-ranged collective Heisenberg-like antiferromagnetic spin fluctuations [M.V. Sadovskii, Physics-Uspekhi 44 (2001) 515, cond-mat/0408489]. The effective single impurity problem in the DMFT + Σk is solved by numerical renormalization group (NRG) [R. Bulla, A.C. Hewson, Th. Pruschke, J. Phys. Cond. Mat. 10 (1998) 8365; R. Bulla, Phys. Rev. Lett. 83 (1999) 136]. To take into account material specific properties of two neighboring CuO 2 layers of Bi2212 we employ local density approximation (LDA) to calculate necessary model parameters, e.g. the values of intra- and interlayer hopping integrals between Cu-sites. Onsite Coulomb interaction U for x2- y2 orbital was calculated in constrained LDA method [O. Gunnarsson et al., Phys. Rev. B 39 (1989) 1708]. The value of pseudogap potential Δ was obtained within DMFT(NRG) [E.Z. Kuchinskii, I.A. Nekrasov, M.V. Sadovskii, JETP Lett. 82 (2005) 198; M.V. Sadovskii et al., Phys. Rev. B 72 (2005) 155105, and these proceedings, doi:10.1016/j.physc.2007.03.367]. Here, we report theoretical LDA + DMFT + Σk quasiparticle bands dispersion, Fermi surface (FS) and angular resolved photoemission (ARPES) spectra accounting for pseudogap and bilayer splitting effects for normal underdoped Bi2212 ( δ = 0.15). We show that LDA-calculated value of bilayer splitting (BS) is too small to describe experimentally observed peak-dip-hump structure. Fermi surface in presence of the pseudogap fluctuations is almost insensitive to the BS value. Results obtained are in good agreement with recent ARPES experiments.

Recurrent Targeted Genes of Hepatitis B Virus in the Liver Cancer Genomes Identified by a Next-Generation Sequencing–Based Approach

PubMed Central

Ding, Dong; Lou, Xiaoyan; Hua, Dasong; Yu, Wei; Li, Lisha; Wang, Jun; Gao, Feng; Zhao, Na; Ren, Guoping; Li, Lanjuan; Lin, Biaoyang

2012-01-01

Integration of the viral DNA into host chromosomes was found in most of the hepatitis B virus (HBV)–related hepatocellular carcinomas (HCCs). Here we devised a massive anchored parallel sequencing (MAPS) method using next-generation sequencing to isolate and sequence HBV integrants. Applying MAPS to 40 pairs of HBV–related HCC tissues (cancer and adjacent tissues), we identified 296 HBV integration events corresponding to 286 unique integration sites (UISs) with precise HBV–Human DNA junctions. HBV integration favored chromosome 17 and preferentially integrated into human transcript units. HBV targeted genes were enriched in GO terms: cAMP metabolic processes, T cell differentiation and activation, TGF beta receptor pathway, ncRNA catabolic process, and dsRNA fragmentation and cellular response to dsRNA. The HBV targeted genes include 7 genes (PTPRJ, CNTN6, IL12B, MYOM1, FNDC3B, LRFN2, FN1) containing IPR003961 (Fibronectin, type III domain), 7 genes (NRG3, MASP2, NELL1, LRP1B, ADAM21, NRXN1, FN1) containing IPR013032 (EGF-like region, conserved site), and three genes (PDE7A, PDE4B, PDE11A) containing IPR002073 (3′, 5′-cyclic-nucleotide phosphodiesterase). Enriched pathways include hsa04512 (ECM-receptor interaction), hsa04510 (Focal adhesion), and hsa04012 (ErbB signaling pathway). Fewer integration events were found in cancers compared to cancer-adjacent tissues, suggesting a clonal expansion model in HCC development. Finally, we identified 8 genes that were recurrent target genes by HBV integration including fibronectin 1 (FN1) and telomerase reverse transcriptase (TERT1), two known recurrent target genes, and additional novel target genes such as SMAD family member 5 (SMAD5), phosphatase and actin regulator 4 (PHACTR4), and RNA binding protein fox-1 homolog (C. elegans) 1 (RBFOX1). Integrating analysis with recently published whole-genome sequencing analysis, we identified 14 additional recurrent HBV target genes, greatly expanding the HBV recurrent target list. This global survey of HBV integration events, together with recently published whole-genome sequencing analyses, furthered our understanding of the HBV–related HCC. PMID:23236287

Development of a landlside EWS based on rainfall thresholds for Tuscany Region, Italy

NASA Astrophysics Data System (ADS)

Rosi, Ascanio; Segoni, Samuele; Battistini, Alessandro; Rossi, Guglielmo; Catani, Filippo; Casagli, Nicola

2017-04-01

We present the set-up of a landslide EWS based on rainfall thresholds for the Tuscany region (central Italy), that shows a heterogeneous distribution of reliefs and precipitation. The work started with the definition of a single set of thresholds for the whole region, but it resulted unsuitable for EWS purposes, because of the heterogeneity of the Tuscan territory and non-repeatability of the analyses, that were affected by a high degree of subjectivity. To overcome this problem, the work started from the implementation of a software capable of objectively defining the rainfall thresholds, since some of the main issues of these thresholds are the subjectivity of the analysis and therefore their non-repeatability. This software, named MaCumBA, is largely automated and can analyze, in a short time, a high number of rainfall events to define several parameters of the threshold, such as the intensity (I) and the duration (D) of the rainfall event, the no-rain time gap (NRG: how many hours without rain are needed to consider two events as separated) and the equation describing the threshold. The possibility of quickly perform several analyses lead to the decision to divide the territory in 25 homogeneous areas (named alert zones, AZ), so as a single threshold for each AZ could be defined. For the definition of the thresholds two independent datasets (of joint rainfall-landslide occurrences) have been used: a calibration dataset (data from 2000 to 2007) and a validation dataset (2008-2009). Once the thresholds were defined, a WebGIS-based EWS has been implemented. In this system it is possible to focus both on monitoring of real-time data and on forecasting at different lead times up to 48 h; forecasting data are collected from LAMI (Limited Area Model Italy) rainfall forecasts. The EWS works on the basis of the threshold parameters defined by MaCumBA (I, D, NRG). An important feature of the warning system is that the visualization of the thresholds in the WebGIS interface may vary in time depending on when the starting time of the rainfall event is set. Therefore, the starting time of the rainfall event is considered as a variable by the system: whenever new rainfall data are available, a recursive algorithm identifies the starting time for which the rainfall path is closest to or overcomes the threshold. This is considered the most hazardous condition, and it is displayed by the WebGIS interface. One more issue that came to surface, after the EWS implementation, was the time-limited validity of the thresholds. On one hand rainfall thresholds can give good results, on the other hand their validity is limited in time, because of several factors, such as changes of pluviometric regime, land use and urban development. Furthermore, the availability of new landslide data can lead to more robust results. For the aforementioned reasons some of the thresholds defined for Tuscany region were updated, by using new landslide data (from 2010 to march 2013). A comparison between updated and former thresholds clearly shows that the performance of an EWS can be enhanced if the thresholds are constantly updated.

Long-Range Atmosphere-Ocean Forecasting in Support of Undersea Warfare Operations in the Western North Pacific

DTIC Science & Technology

2009-09-01

Forecasts ECS East China Sea ESRL Earth Systems Research Laboratory FA False alarm FARate False alarm rate xviii GDEM Generalized Digital...uses a LTM based, global ocean climatology database called Generalized Digital Environment Model ( GDEM ), in tactical decision aid (TDA) software, such...environment for USW planning. GDEM climatology is derived using temperature and salinity profiles from the Modular Ocean Data Assimilation System

Effective cell trapping using PDMS microspheres in an acoustofluidic chip.

PubMed

Yin, Di; Xu, Gangwei; Wang, Mengyuan; Shen, Mingwu; Xu, Tiegang; Zhu, Xiaoyue; Shi, Xiangyang

2017-09-01

We present a facile particle-based cell manipulation method using acoustic radiation forces. In this work, we selected several representative particles including poly(lactic-co-glycolic acid) (PLGA) microspheres, silica-coated magnetic microbeads, polydimethylsiloxane (PDMS) microspheres and investigated the responses of these particle systems to ultrasonic standing waves (USWs) in a microfluidic chip. We show that depending on the nature (positive or negative acoustic contrast factors) of the particles, these particle systems display different alignment behaviors along the microfluidic channel under USWs. Specifically, PLGA microspheres and silica-coated magnetic microbeads are able to be aligned in the middle of the microfluidic channel, while PDMS microspheres are translocated to the side walls of the channel, which is beneficial for cell trapping and manipulation. Further results demonstrate that the functional PDMS microspheres with a negative acoustic contrast factor can be used to trap cells to the pressure antinodes in the acoustofluidic chip. Cell viability tests reveal that the ultrasonic manipulation does not exert any harmful effect to the cells. This acoustic-based particle and cell manipulation technique may hold a great promise for the development of rapid, noninvasive, continuous assays for detecting of cells and separation of biological samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Patient reported outcomes in NRG Oncology RTOG 0938, evaluating two ultrahypofractionated regimens for prostate cancer.

PubMed

Lukka, Himanshu R; Pugh, Stephanie L; Bruner, Deborah W; Bahary, Jean-Paul; Lawton, Colleen A F; Efstathiou, Jason A; Kudchadker, Rajat J; Ponsky, Lee E; Seaward, Samantha A; Dayes, Ian S; Gopaul, Darindra D; Michalski, Jeff M; Delouya, Guila; Kaplan, Irving D; Horwitz, Eric M; Roach, Mack; Pinover, Wayne H; Beyer, David C; Amanie, John O; Sandler, Howard M; Kachnic, Lisa A

2018-06-15

There is considerable interest in very short (ultrahypofractionated) radiotherapy regimens to treat prostate cancer based on potential radiobiological advantages, patient convenience and resource allocation benefits. To demonstrate that detectable changes in health related quality of life measured by the bowel and urinary domains of the Expanded Prostate Cancer Index Composite (EPIC-50) were not substantially worse than baseline. XXXX is a non-blinded randomized phase II study of NCCN low risk prostate cancer where each arm is compared to a historical control. Patients were randomized to five fractions (7.25Gy in two weeks), or twelve fractions (4.3Gy in 2.5 weeks). The co-primary endpoints were the proportion of patients with a change in EPIC bowel score at one year (baseline to one-year) >five points and in EPIC urinary score >two points tested with a one-sample binomial test. and Limitations: 127 patients were enrolled to five fractions (121 analyzed) and 128 to twelve fractions (125 analyzed). Median follow-up for all patients at the time of analysis was 3.8 years. The one year frequency for >five point change in bowel score for five and twelve fractions were 29.8%(p<0.001) and 28.4%(p<0.001) respectively. The one year frequency for >two point change in urinary score for five and twelve fractions were 45.7%(p<0.001) and 42.2%(p<0.001) respectively. For five and twelve fractions 32.9% of patients had a drop in 1 year EPIC sexual score ≥ 11 points (p=0.34) while 30.9% of patients had a drop in 1 year EPIC sexual score ≥11 points (p=0.20) in the twelve fraction arm respectively. DFS at two years is 93.3% (95% CI: 88.8, 97.8) and 88.3% (95% CI: 82.5, 94.0) in the five and twelve fraction arms, respectively. There was no late grade 4 or 5 treatment-related urinary or bowel toxicity. This study confirms that based on changes in bowel and urinary domains and toxicity (acute and late) the five and twelve fractions regimens are well tolerated. These ultrahypofractionated approaches need to be compared to current standard radiotherapy regimens. Copyright © 2018. Published by Elsevier Inc.

Geohydrology of rocks penetrated by test well USW H-4, Yucca Mountain, Nye County, Nevada

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whitfield, M.S. Jr.; Eshom, E.P.; Thordarson, W.

This report presents the results of hydraulic testing of rocks penetrated by USW H-4, one of several test wells drilled in the southwestern part of the Nevada Test Site, in cooperation with the US Department of Energy, for investigations related to the isolation of high-level radioactive wastes in volcanic tuffs of Tertiary age. All rocks penetrated by the test well to its total depth of 1219 meters were volcanic. Static water level was at a depth of 519 meters below land surface. Hydraulic-head measurements made at successively lower depths during drilling in this test hole indicate no noticeable head change.more » A radioactive-tracer, borehole-flow survey indicated that the two most productive zones in this borehole occurred in the upper part of the Bullfrog Member, depth interval from 721 to 731.5 meters, and in the underlying upper part of the Tram Member, depth interval from 864 to 920 meters, both in the Crater Flat Tuff. Hydraulic coefficients calculated from pumping-test data indicate that transmissivity ranged from 200 to 790 meters squared per day. The hydraulic conductivity ranged from 0.29 to 1.1 meters per day. Chemical analysis of water pumped from the saturated part of the borehole (composite sample) indicates that the water is typical of water produced from tuffaceous rocks in southern Nevada. The water is predominantly a sodium bicarbonate type with small concentrations of calcium, magnesium, and sulfate. The apparent age of this composite water sample was determined by a carbon-14 date to be 17,200 years before present. 24 refs., 10 figs., 8 tabs.« less

Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes.

PubMed

Li, Jiang; Yoshikawa, Akane; Brennan, Mark D; Ramsey, Timothy L; Meltzer, Herbert Y

2018-02-01

Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p<10 -4 , include: 1) synaptic adhesion (PTPRD, LRRC4C, NRXN1, ILIRAPL1, SLITRK1) and scaffolding (MAGI1, MAGI2, NBEA) genes, both essential for synaptic function; 2) other synaptic plasticity-related genes (NRG1/3 and KALRN); 3) the neuron-specific RNA splicing regulator, RBFOX1; and 4) ion channel genes, e.g. KCNA10, KCNAB1, KCNK9 and CACNA2D3). Some genes predicted response for patients with both European and African Ancestries. We replicated some SNPs reported to predict response to other atypical APDs in other GWAS. Although none of the biomarkers reached genome-wide significance, many of the genes and associated pathways have previously been linked to SCZ. Two polygenic modeling approaches, GCTA-GREML and PLINK-Polygenic Risk Score, demonstrated that some risk genes related to neurodevelopment, synaptic biology, immune response, and histones, also contributed to prediction of response. The top hits predicting response to lurasidone did not predict improvement with placebo. This is the first evidence from clinical trials that SCZ risk SNPs are related to clinical response to an AAPD. These results need to be replicated in an independent sample. Copyright © 2017. Published by Elsevier B.V.

A Stable U Isotopic Perspective on the U Budget and Global Extent of Modern Anoxia in the Ocean.

NASA Astrophysics Data System (ADS)

Tissot, F.; Dauphas, N.

2015-12-01

Isotopic fractionation between U4+ and U6+makes U stable isotopes potential tracers of global paleoredox conditions. In this work [1], we put the U-proxy up to a test against a highly constrained system: the modern ocean. We measured a large number of seawater samples from geographically diverse locations and found that the open ocean has a homogenous isotopic composition at δ238USW= -0.392 ± 0.005 ‰ (rel. to CRM-112a). From our measurement of rock samples (n=64) and compilations of literature data (n=380), we then estimated the U isotopic compositions of the various reservoirs involved in the modern oceanic U budget, as well as the fractionation factors associated with U incorporation into those reservoirs. Using a steady-state model, we compared the isotopic composition of the seawater predicted by the four most recent U oceanic budgets [2-5] to the modern seawater value we measured. Three of these budgets [2-4] predict a seawater isotopic composition in very good agreement with the observed δ238USW, which strengthens our confidence in the isotopic fractionation factors associated with each deposition environment and the fact that U is at steady-state in the modern ocean. The U oceanic budget of Henderson and Anderson (2003) does not reproduce the observed seawater composition because the U flux to anoxic/euxinic sediments relative to the total U flux out of the ocean is high in their model, which our analysis shows cannot be correct. The U isotopic composition of seawater is used to constrain the extent of anoxia in the modern ocean (% of seafloor covered by anoxic/euxinic sediments), which is 0.21 ± 0.09 %. This work demonstrates that stable isotopes of U can indeed trace the extent of anoxia in the modern global ocean, thereby validating the application of U isotope measurements to paleoredox reconstructions. Based on the above work, we will present the best estimate of the modern oceanic U budget. [1] Tissot F.L.H., Dauphas N. (2015) Geochim Cosmochim Ac 167, 113-143 [2] Barnes C. E., Cochran J. K. (1990) Earth Planet Sc Lett 97, 94-101 [3] Morford J. L., Emerson S. (1999) Geochim Cosmochim Ac 63, 1735-1750 [4] Dunk R. M., Mills R. A., Jenkins W. J. (2002) Chemical Geology 190, 45-67 [5] Henderson G. M., Anderson R. F. (2003) Rev Mineral Geochem 52, 493-531

Working for America: A Federal Employee Survey

DTIC Science & Technology

1990-06-01

take concerning these is- developed and trained; restructuring the Federal sues. employees ’ health insurance program ; increasing 2 A Report by the U.S...we do that is by periodically conducting surveys of the employees in that system. In developing this questionnaire, we received assistance from...AD-A234 177 I WORKING FOR AMERICA: A FEDERAL EMPLOYEE SURVEY A SPECIAL STUDY (2 THE CHAIRMAN U.S. MERIT SYSTEMS PROTECTION BOARD 1120 Vermont Avenue

Asbestos-associated genome-wide DNA methylation changes in lung cancer.

PubMed

Kettunen, Eeva; Hernandez-Vargas, Hector; Cros, Marie-Pierre; Durand, Geoffroy; Le Calvez-Kelm, Florence; Stuopelyte, Kristina; Jarmalaite, Sonata; Salmenkivi, Kaisa; Anttila, Sisko; Wolff, Henrik; Herceg, Zdenko; Husgafvel-Pursiainen, Kirsti

2017-11-15

Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10 -19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10 -8 , mean Δ -0.09) and TPO (FDR 8.58 × 10 -5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer. © 2017 UICC.

Genetic assessment of additional endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study.

PubMed

Greenwood, Tiffany A; Lazzeroni, Laura C; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Light, Gregory A; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Stone, William S; Sugar, Catherine A; Swerdlow, Neal R; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2016-01-01

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. Copyright © 2015 Elsevier B.V. All rights reserved.

Systematic optimization of human pluripotent stem cells media using Design of Experiments

NASA Astrophysics Data System (ADS)

Marinho, Paulo A.; Chailangkarn, Thanathom; Muotri, Alysson R.

2015-05-01

Human pluripotent stem cells (hPSC) are used to study the early stages of human development in vitro and, increasingly due to somatic cell reprogramming, cellular and molecular mechanisms of disease. Cell culture medium is a critical factor for hPSC to maintain pluripotency and self-renewal. Numerous defined culture media have been empirically developed but never systematically optimized for culturing hPSC. We applied design of experiments (DOE), a powerful statistical tool, to improve the medium formulation for hPSC. Using pluripotency and cell growth as read-outs, we determined the optimal concentration of both basic fibroblast growth factor (bFGF) and neuregulin-1 beta 1 (NRG1β1). The resulting formulation, named iDEAL, improved the maintenance and passage of hPSC in both normal and stressful conditions, and affected trimethylated histone 3 lysine 27 (H3K27me3) epigenetic status after genetic reprogramming. It also enhances efficient hPSC plating as single cells. Altogether, iDEAL potentially allows scalable and controllable hPSC culture routine in translational research. Our DOE strategy could also be applied to hPSC differentiation protocols, which often require numerous and complex cell culture media.

Non-isolated Resolving Sets of certain Graphs Cartesian Product with a Path

NASA Astrophysics Data System (ADS)

Hasibuan, I. M.; Salman, A. N. M.; Saputro, S. W.

2018-04-01

Let G be a connected, simple, and finite graph. For an ordered subset W = {w 1 , w 2 , · · ·, wk } of vertices in a graph G and a vertex v of G, the metric representation of v with respect to W is the k-vector r(v|W ) = (d(v, w 1), d(v, w 2), · · ·, d(v, wk )). The set W is called a resolving set for G if every vertex of G has a distinct representation. The minimum cardinality of W is called the metric dimension of G, denoted by dim(G). If the induced subgraph < W> has no isolated vertices, then W is called a non-isolated resolving set. The minimum cardinality of non-isolated resolving set of G is called the non-isolated resolving number of G, denoted by nr(G). In this paper, we consider H\\square {P}n that is a graph obtained from Cartesian product between a connected graph H and a path Pn . We determine nr(H\\square {P}n), for some classes of H, including cycles, complete graphs, complete bipartite graphs, and friendship graphs.

Basic fibroblast growth factor (bFGF) facilitates differentiation of adult dorsal root ganglia-derived neural stem cells toward Schwann cells by binding to FGFR-1 through MAPK/ERK activation.

PubMed

Gu, Yun; Xue, Chenbin; Zhu, Jianbin; Sun, Hualin; Ding, Fei; Cao, Zheng; Gu, Xiaosong

2014-04-01

Considerable research has been devoted to unraveling the regulation of neural stem cell (NSC) differentiation. The responses of NSCs to various differentiation-inducing stimuli, however, are still difficult to estimate. In this study, we aimed to search for a potent growth factor that was able to effectively induce differentiation of NSCs toward Schwann cells. NSCs were isolated from dorsal root ganglia (DRGs) of adult rats and identified by immunostaining. Three different growth factors were used to stimulate the differentiation of DRG-derived NSCs (DRG-NSCs). We found that among these three growth factors, bFGF was the strongest inducer for the glial differentiation of DRG-NSCs, and bFGF induced the generation of an increased number of Schwann cell-like cells as compared to nerve growth factor (NGF) and neuregulin1-β (NRG). These Schwann cell-like cells demonstrated the same characteristics as those of primary Schwann cells. Furthermore, we noted that bFGF-induced differentiation of DRG-NSCs toward Schwann cells might be mediated by binding to fibroblast growth factor receptor-1 (FGFR-1) through activation of MAPK/ERK signal pathway.

Jab1 regulates Schwann cell proliferation and axonal sorting through p27

PubMed Central

Porrello, Emanuela; Rivellini, Cristina; Dina, Giorgia; Triolo, Daniela; Del Carro, Ubaldo; Ungaro, Daniela; Panattoni, Martina; Feltri, Maria Laura; Wrabetz, Lawrence; Pardi, Ruggero; Quattrini, Angelo

2014-01-01

Axonal sorting is a crucial event in nerve formation and requires proper Schwann cell proliferation, differentiation, and contact with axons. Any defect in axonal sorting results in dysmyelinating peripheral neuropathies. Evidence from mouse models shows that axonal sorting is regulated by laminin211– and, possibly, neuregulin 1 (Nrg1)–derived signals. However, how these signals are integrated in Schwann cells is largely unknown. We now report that the nuclear Jun activation domain–binding protein 1 (Jab1) may transduce laminin211 signals to regulate Schwann cell number and differentiation during axonal sorting. Mice with inactivation of Jab1 in Schwann cells develop a dysmyelinating neuropathy with axonal sorting defects. Loss of Jab1 increases p27 levels in Schwann cells, which causes defective cell cycle progression and aberrant differentiation. Genetic down-regulation of p27 levels in Jab1-null mice restores Schwann cell number, differentiation, and axonal sorting and rescues the dysmyelinating neuropathy. Thus, Jab1 constitutes a regulatory molecule that integrates laminin211 signals in Schwann cells to govern cell cycle, cell number, and differentiation. Finally, Jab1 may constitute a key molecule in the pathogenesis of dysmyelinating neuropathies. PMID:24344238

Two-dimensional Anderson-Hubbard model in the DMFT + {Sigma} approximation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuchinskii, E. Z., E-mail: kuchinsk@iep.uran.ru; Kuleeva, N. A.; Nekrasov, I. A.

The density of states, the dynamic (optical) conductivity, and the phase diagram of the paramagnetic two-dimensional Anderson-Hubbard model with strong correlations and disorder are analyzed within the generalized dynamical mean field theory (DMFT + {Sigma} approximation). Strong correlations are accounted by the DMFT, while disorder is taken into account via the appropriate generalization of the self-consistent theory of localization. We consider the two-dimensional system with the rectangular 'bare' density of states (DOS). The DMFT effective single-impurity problem is solved by numerical renormalization group (NRG). The 'correlated metal,' Mott insulator, and correlated Anderson insulator phases are identified from the evolution ofmore » the density of states, optical conductivity, and localization length, demonstrating both Mott-Hubbard and Anderson metal-insulator transitions in two-dimensional systems of finite size, allowing us to construct the complete zero-temperature phase diagram of the paramagnetic Anderson-Hubbard model. The localization length in our approximation is practically independent of the strength of Hubbard correlations. But the divergence of the localization length in a finite-size two-dimensional system at small disorder signifies the existence of an effective Anderson transition.« less

Quantum criticality of the two-channel pseudogap Anderson model: universal scaling in linear and non-linear conductance.

PubMed

Wu, Tsan-Pei; Wang, Xiao-Qun; Guo, Guang-Yu; Anders, Frithjof; Chung, Chung-Hou

2016-05-05

The quantum criticality of the two-lead two-channel pseudogap Anderson impurity model is studied. Based on the non-crossing approximation (NCA) and numerical renormalization group (NRG) approaches, we calculate both the linear and nonlinear conductance of the model at finite temperatures with a voltage bias and a power-law vanishing conduction electron density of states, ρc(ω) proportional |ω − μF|(r) (0 < r < 1) near the Fermi energy μF. At a fixed lead-impurity hybridization, a quantum phase transition from the two-channel Kondo (2CK) to the local moment (LM) phase is observed with increasing r from r = 0 to r = rc < 1. Surprisingly, in the 2CK phase, different power-law scalings from the well-known [Formula: see text] or [Formula: see text] form is found. Moreover, novel power-law scalings in conductances at the 2CK-LM quantum critical point are identified. Clear distinctions are found on the critical exponents between linear and non-linear conductance at criticality. The implications of these two distinct quantum critical properties for the non-equilibrium quantum criticality in general are discussed.

Drosophila contactin, a homolog of vertebrate contactin, is required for septate junction organization and paracellular barrier function.

PubMed

Faivre-Sarrailh, Catherine; Banerjee, Swati; Li, Jingjun; Hortsch, Michael; Laval, Monique; Bhat, Manzoor A

2004-10-01

Septate junctions (SJs) in epithelial and neuronal cells play an important role in the formation and maintenance of charge and size selective barriers. They form the basis for the ensheathment of nerve fibers in Drosophila and for the attachment of myelin loops to axonal surface in vertebrates. The cell-adhesion molecules NRX IV/Caspr/Paranodin (NCP1), contactin and Neurofascin-155 (NF-155) are all present at the vertebrate axo-glial SJs. Mutational analyses have shown that vertebrate NCP1 and its Drosophila homolog, Neurexin IV (NRX IV) are required for the formation of SJs. In this study, we report the genetic, molecular and biochemical characterization of the Drosophila homolog of vertebrate contactin, CONT. Ultrastructural and dye-exclusion analyses of Cont mutant embryos show that CONT is required for organization of SJs and paracellular barrier function. We show that CONT, Neuroglian (NRG) (Drosophila homolog of NF-155) and NRX IV are interdependent for their SJ localization and these proteins form a tripartite complex. Hence, our data provide evidence that the organization of SJs is dependent on the interactions between these highly conserved cell-adhesion molecules.

Study of five novel non-synonymous polymorphisms in human brain-expressed genes in a Colombian sample.

PubMed

Ojeda, Diego A; Forero, Diego A

2014-10-01

Non-synonymous single nucleotide polymorphisms (nsSNPs) in brain-expressed genes represent interesting candidates for genetic research in neuropsychiatric disorders. To study novel nsSNPs in brain-expressed genes in a sample of Colombian subjects. We applied an approach based on in silico mining of available genomic data to identify and select novel nsSNPs in brain-expressed genes. We developed novel genotyping assays, based in allele-specific PCR methods, for these nsSNPs and genotyped them in 171 Colombian subjects. Five common nsSNPs (rs6855837; p.Leu395Ile, rs2305160; p.Thr394Ala, rs10503929; p.Met289Thr, rs2270641; p.Thr4Pro and rs3822659; p.Ser735Ala) were studied, located in the CLOCK, NPAS2, NRG1, SLC18A1 and WWC1 genes. We reported allele and genotype frequencies in a sample of South American healthy subjects. There is previous experimental evidence, arising from genome-wide expression and association studies, for the involvement of these genes in several neuropsychiatric disorders and endophenotypes, such as schizophrenia, mood disorders or memory performance. Frequencies for these nsSNPSs in the Colombian samples varied in comparison to different HapMap populations. Future study of these nsSNPs in brain-expressed genes, a synaptogenomics approach, will be important for a better understanding of neuropsychiatric diseases and endophenotypes in different populations.

Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Myers, Andrea P.; Filiaci, Virginia L.; Zhang, Yuping; Pearl, Michael; Behbakht, Kian; Makker, Vicky; Hanjani, Parviz; Zweizig, Susan; Burke, James J.; Downey, Gordon; Leslie, Kimberly K.; Van Hummelen, Paul; Birrer, Michael J.; Fleming, Gini F.

2016-01-01

Objective Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. Methods Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next–generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9 months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored. Results Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01–0.78) and RR (response difference 0.83; 95% CI 0.03–0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20–0.97) but not RR (response difference 0.00, 95% CI −0.34–0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR. Conclusions Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus. PMID:27016228

Comparative Evolution of Morphological Regulatory Functions in Candida Species

PubMed Central

Lackey, Erika; Vipulanandan, Geethanjali; Childers, Delma S.

2013-01-01

Morphological transitions play an important role in virulence and virulence-related processes in a wide variety of pathogenic fungi, including the most commonly isolated human fungal pathogen Candida albicans. While environmental signals, transcriptional regulators, and target genes associated with C. albicans morphogenesis are well-characterized, considerably little is known about morphological regulatory mechanisms and the extent to which they are evolutionarily conserved in less pathogenic and less filamentous non-albicans Candida species (NACS). We have identified specific optimal filament-inducing conditions for three NACS (C. tropicalis, C. parapsilosis, and C. guilliermondii), which are very limited, suggesting that these species may be adapted for niche-specific filamentation in the host. Only a subset of evolutionarily conserved C. albicans filament-specific target genes were induced upon filamentation in C. tropicalis, C. parapsilosis, and C. guilliermondii. One of the genes showing conserved expression was UME6, a key filament-specific regulator of C. albicans hyphal development. Constitutive high-level expression of UME6 was sufficient to drive increased filamentation as well as biofilm formation and partly restore conserved filament-specific gene expression in both C. tropicalis and C. parapsilosis, suggesting that evolutionary differences in filamentation ability among pathogenic Candida species may be partially attributed to alterations in the expression level of a conserved filamentous growth machinery. In contrast to UME6, NRG1, an important repressor of C. albicans filamentation, showed only a partly conserved role in controlling NACS filamentation. Overall, our results suggest that C. albicans morphological regulatory functions are partially conserved in NACS and have evolved to respond to more specific sets of host environmental cues. PMID:23913541

Correlation of High-Risk Soft Tissue Sarcoma Biomarker Expression Patterns with Outcome following Neoadjuvant Chemoradiation

PubMed Central

Magliocco, Anthony; Zhang, Qiang; Wang, Dian; Klimowicz, Alex; Harris, Jonathan; Simko, Jeff; DeLaney, Thomas; Kraybill, William; Kirsch, David G.

2018-01-01

Background Sarcoma mortality remains high despite adjuvant chemotherapy. Biomarker predictors of treatment response and outcome could improve treatment selection. Methods Tissue microarrays (TMAs) were created using pre- and posttreatment tumor from two prospective trials (MGH pilot and RTOG 9514) of neoadjuvant/adjuvant MAID chemotherapy and preoperative radiation. Biomarkers were measured using automated computerized imaging (AQUA or ACIS). Expression was correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). Results Specimens from 60 patients included 23 pretreatment (PRE), 40 posttreatment (POST), and 12 matched pairs (MPs). In the MP set, CAIX, GLUT1, and PARP1 expression significantly decreased following neoadjuvant therapy, but p53 nuclear/cytoplasmic (N/C) ratio increased. In the PRE set, no biomarker expression was associated with DFS, DDFS, or OS. In the POST set, increased p53 N/C ratio was associated with a significantly decreased DFS and DDFS (HR 4.13, p=0.017; HR 4.16, p=0.016), while increased ERCC1 and XPF expression were associated with an improved DFS and DDFS. No POST biomarkers were associated with OS. Conclusions PRE biomarker expression did not predict survival outcomes. Expression pattern changes after neoadjuvant chemoradiation supports the concepts of tumor reoxygenation, altered HIF-1α signaling, and a p53 nuclear accumulation DNA damage response. Clinical Trial Registration NRG Oncology RTOG 9514 is registered with ClinicalTrials.gov. The ClinicalTrials.gov Identifier is NCT00002791. PMID:29681762

A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Videtic, Gregory M.M., E-mail: videtig@ccf.org; Hu, Chen; Johns Hopkins University School of Medicine, Baltimore, Maryland

Purpose: To compare 2 stereotactic body radiation therapy (SBRT) schedules for medically inoperable early-stage lung cancer to determine which produces the lowest rate of grade ≥3 protocol-specified adverse events (psAEs) at 1 year. Methods and Materials: Patients with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors were eligible. Patients were randomized to receive either 34 Gy in 1 fraction (arm 1) or 48 Gy in 4 consecutive daily fractions (arm 2). Rigorous central accreditation and quality assurance confirmed treatment per protocol guidelines. This study was designed to detect a psAEsmore » rate >17% at a 10% significance level (1-sided) and 90% power. Secondary endpoints included rates of primary tumor control (PC), overall survival (OS), and disease-free survival (DFS) at 1 year. Designating the better of the 2 regimens was based on prespecified rules of psAEs and PC for each arm. Results: Ninety-four patients were accrued between September 2009 and March 2011. The median follow-up time was 30.2 months. Of 84 analyzable patients, 39 were in arm 1 and 45 in arm 2. Patient and tumor characteristics were balanced between arms. Four (10.3%) patients on arm 1 (95% confidence interval [CI] 2.9%-24.2%) and 6 (13.3%) patients on arm 2 (95% CI 5.1%-26.8%) experienced psAEs. The 2-year OS rate was 61.3% (95% CI 44.2%-74.6%) for arm 1 patients and 77.7% (95% CI 62.5%-87.3%) for arm 2. The 2-year DFS was 56.4% (95% CI 39.6%-70.2%) for arm 1 and 71.1% (95% CI 55.5%-82.1%) for arm 2. The 1-year PC rate was 97.0% (95% CI 84.2%-99.9%) for arm 1 and 92.7% (95% CI 80.1%-98.5%) for arm 2. Conclusions: 34 Gy in 1 fraction met the prespecified criteria and, of the 2 schedules, warrants further clinical research.« less

Quasi-Equilibrium Pairs in Pursuit Games on a Cyclic Graph: Some Modified Cases

DTIC Science & Technology

1989-05-01

CCS Research Report No. 627 QUASI-EQUILIBRIUM PAIRS IN PURSUIT GAMES ON A CYCLIC GRAPH: SOME MODIFIED CASES by A. Charnes D. Zhang i-0 00 CENTER FOR...CCS Research Report No. 627 QUASI-EQUILIBRIUM PAIRS IN PURSUIT GAMES ON A CYCLIC GRAPH: SOME MODIFIED CASES by A. Charnes D. Zhang May 1989 This...University of Texas at Austin Austin, Texas 78712-1177 II (512) 471-1821 APAWNJIZf ] ’ Api, k..s UsW , QUASI-EQUILIBRIUM PAIRS IN PURSUIT GAMES ON A

Microarray Analyses Reveal Marked Differences in Growth Factor and Receptor Expression Between 8-Cell Human Embryos and Pluripotent Stem Cells

PubMed Central

Vlismas, Antonis; Bletsa, Ritsa; Mavrogianni, Despina; Mamali, Georgina; Pergamali, Maria; Dinopoulou, Vasiliki; Partsinevelos, George; Drakakis, Peter; Loutradis, Dimitris

2016-01-01

Previous microarray analyses of RNAs from 8-cell (8C) human embryos revealed a lack of cell cycle checkpoints and overexpression of core circadian oscillators and cell cycle drivers relative to pluripotent human stem cells [human embryonic stem cells/induced pluripotent stem (hES/iPS)] and fibroblasts, suggesting growth factor independence during early cleavage stages. To explore this possibility, we queried our combined microarray database for expression of 487 growth factors and receptors. Fifty-one gene elements were overdetected on the 8C arrays relative to hES/iPS cells, including 14 detected at least 80-fold higher, which annotated to multiple pathways: six cytokine family (CSF1R, IL2RG, IL3RA, IL4, IL17B, IL23R), four transforming growth factor beta (TGFB) family (BMP6, BMP15, GDF9, ENG), one fibroblast growth factor (FGF) family [FGF14(FH4)], one epidermal growth factor member (GAB1), plus CD36, and CLEC10A. 8C-specific gene elements were enriched (73%) for reported circadian-controlled genes in mouse tissues. High-level detection of CSF1R, ENG, IL23R, and IL3RA specifically on the 8C arrays suggests the embryo plays an active role in blocking immune rejection and is poised for trophectoderm development; robust detection of NRG1, GAB1, -2, GRB7, and FGF14(FHF4) indicates novel roles in early development in addition to their known roles in later development. Forty-four gene elements were underdetected on the 8C arrays, including 11 at least 80-fold under the pluripotent cells: two cytokines (IFITM1, TNFRSF8), five TGFBs (BMP7, LEFTY1, LEFTY2, TDGF1, TDGF3), two FGFs (FGF2, FGF receptor 1), plus ING5, and WNT6. The microarray detection patterns suggest that hES/iPS cells exhibit suppressed circadian competence, underexpression of early differentiation markers, and more robust expression of generic pluripotency genes, in keeping with an artificial state of continual uncommitted cell division. In contrast, gene expression patterns of the 8C embryo suggest that it is an independent circadian rhythm-competent equivalence group poised to signal its environment, defend against maternal immune rejection, and begin the rapid commitment events of early embryogenesis. PMID:26493868

Precise spatial control of cavitation erosion in a vessel phantom by using an ultrasonic standing wave.

PubMed

Shi, Aiwei; Huang, Peixuan; Guo, Shifang; Zhao, Lu; Jia, Yingjie; Zong, Yujin; Wan, Mingxi

2016-07-01

In atherosclerotic inducement in animal models, the conventionally used balloon injury is invasive, produces excessive vessel injuries at unpredictable locations and is inconvenient in arterioles. Fortunately, cavitation erosion, which plays an important role in therapeutic ultrasound in blood vessels, has the potential to induce atherosclerosis noninvasively at predictable sites. In this study, precise spatial control of cavitation erosion for superficial lesions in a vessel phantom was realised by using an ultrasonic standing wave (USW) with the participation of cavitation nuclei and medium-intensity ultrasound pulses. The superficial vessel erosions were restricted between adjacent pressure nodes, which were 0.87 mm apart in the USW field of 1 MHz. The erosion positions could be shifted along the vessel by nodal modulation under a submillimetre-scale accuracy without moving the ultrasound transducers. Moreover, the cavitation erosion of the proximal or distal wall could be determined by the types of cavitation nuclei and their corresponding cavitation pulses, i.e., phase-change microbubbles with cavitation pulses of 5 MHz and SonoVue microbubbles with cavitation pulses of 1 MHz. Effects of acoustic parameters of the cavitation pulses on the cavitation erosions were investigated. The flow conditions in the experiments were considered and discussed. Compared to only using travelling waves, the proposed method in this paper improves the controllability of the cavitation erosion and reduces the erosion depth, providing a more suitable approach for vessel endothelial injury while avoiding haemorrhage. Copyright © 2015 Elsevier B.V. All rights reserved.

A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

PubMed Central

Volpato, Claudia B.; Wilson, Scott G.; Cappola, Anne R.; Bos, Steffan D.; Deelen, Joris; den Heijer, Martin; Freathy, Rachel M.; Lahti, Jari; Liu, Chunyu; Lopez, Lorna M.; Nolte, Ilja M.; O'Connell, Jeffrey R.; Tanaka, Toshiko; Trompet, Stella; Arnold, Alice; Bandinelli, Stefania; Beekman, Marian; Böhringer, Stefan; Brown, Suzanne J.; Buckley, Brendan M.; Camaschella, Clara; de Craen, Anton J. M.; Davies, Gail; de Visser, Marieke C. H.; Ford, Ian; Forsen, Tom; Frayling, Timothy M.; Fugazzola, Laura; Gögele, Martin; Hattersley, Andrew T.; Hermus, Ad R.; Hofman, Albert; Houwing-Duistermaat, Jeanine J.; Jensen, Richard A.; Kajantie, Eero; Kloppenburg, Margreet; Lim, Ee M.; Masciullo, Corrado; Mariotti, Stefano; Minelli, Cosetta; Mitchell, Braxton D.; Nagaraja, Ramaiah; Netea-Maier, Romana T.; Palotie, Aarno; Persani, Luca; Piras, Maria G.; Psaty, Bruce M.; Räikkönen, Katri; Richards, J. Brent; Rivadeneira, Fernando; Sala, Cinzia; Sabra, Mona M.; Sattar, Naveed; Shields, Beverley M.; Soranzo, Nicole; Starr, John M.; Stott, David J.; Sweep, Fred C. G. J.; Usala, Gianluca; van der Klauw, Melanie M.; van Heemst, Diana; van Mullem, Alies; H.Vermeulen, Sita; Visser, W. Edward; Walsh, John P.; Westendorp, Rudi G. J.; Widen, Elisabeth; Zhai, Guangju; Cucca, Francesco; Deary, Ian J.; Eriksson, Johan G.; Ferrucci, Luigi; Fox, Caroline S.; Jukema, J. Wouter; Kiemeney, Lambertus A.; Pramstaller, Peter P.; Schlessinger, David; Shuldiner, Alan R.; Slagboom, Eline P.; Uitterlinden, André G.; Vaidya, Bijay; Visser, Theo J.; Wolffenbuttel, Bruce H. R.; Meulenbelt, Ingrid; Rotter, Jerome I.; Spector, Tim D.; Hicks, Andrew A.; Toniolo, Daniela; Sanna, Serena; Peeters, Robin P.; Naitza, Silvia

2013-01-01

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. PMID:23408906

ERBB4 Mutations that Disrupt the Neuregulin-ErbB4 Pathway Cause Amyotrophic Lateral Sclerosis Type 19

PubMed Central

Takahashi, Yuji; Fukuda, Yoko; Yoshimura, Jun; Toyoda, Atsushi; Kurppa, Kari; Moritoyo, Hiroyoko; Belzil, Veronique V.; Dion, Patrick A.; Higasa, Koichiro; Doi, Koichiro; Ishiura, Hiroyuki; Mitsui, Jun; Date, Hidetoshi; Ahsan, Budrul; Matsukawa, Takashi; Ichikawa, Yaeko; Moritoyo, Takashi; Ikoma, Mayumi; Hashimoto, Tsukasa; Kimura, Fumiharu; Murayama, Shigeo; Onodera, Osamu; Nishizawa, Masatoyo; Yoshida, Mari; Atsuta, Naoki; Sobue, Gen; Fifita, Jennifer A.; Williams, Kelly L.; Blair, Ian P.; Nicholson, Garth A.; Gonzalez-Perez, Paloma; Brown, Robert H.; Nomoto, Masahiro; Elenius, Klaus; Rouleau, Guy A.; Fujiyama, Asao; Morishita, Shinichi; Goto, Jun; Tsuji, Shoji

2013-01-01

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3–5 years from onset. Familial ALS (FALS) comprises 5%–10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions. PMID:24119685

Microenvironment-Mediated Mechanisms of Resistance to HER2 Inhibitors Differ between HER2+ Breast Cancer Subtypes.

PubMed

Watson, Spencer S; Dane, Mark; Chin, Koei; Tatarova, Zuzana; Liu, Moqing; Liby, Tiera; Thompson, Wallace; Smith, Rebecca; Nederlof, Michel; Bucher, Elmar; Kilburn, David; Whitman, Matthew; Sudar, Damir; Mills, Gordon B; Heiser, Laura M; Jonas, Oliver; Gray, Joe W; Korkola, James E

2018-03-28

Extrinsic signals are implicated in breast cancer resistance to HER2-targeted tyrosine kinase inhibitors (TKIs). To examine how microenvironmental signals influence resistance, we monitored TKI-treated breast cancer cell lines grown on microenvironment microarrays composed of printed extracellular matrix proteins supplemented with soluble proteins. We tested ∼2,500 combinations of 56 soluble and 46 matrix microenvironmental proteins on basal-like HER2+ (HER2E) or luminal-like HER2+ (L-HER2+) cells treated with the TKIs lapatinib or neratinib. In HER2E cells, hepatocyte growth factor, a ligand for MET, induced resistance that could be reversed with crizotinib, an inhibitor of MET. In L-HER2+ cells, neuregulin1-β1 (NRG1β), a ligand for HER3, induced resistance that could be reversed with pertuzumab, an inhibitor of HER2-HER3 heterodimerization. The subtype-specific responses were also observed in 3D cultures and murine xenografts. These results, along with bioinformatic pathway analysis and siRNA knockdown experiments, suggest different mechanisms of resistance specific to each HER2+ subtype: MET signaling for HER2E and HER2-HER3 heterodimerization for L-HER2+ cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Sec71 functions as a GEF for the small GTPase Arf1 to govern dendrite pruning of Drosophila sensory neurons.

PubMed

Wang, Yan; Zhang, Heng; Shi, Meng; Liou, Yih-Cherng; Lu, Lei; Yu, Fengwei

2017-05-15

Pruning, whereby neurons eliminate their excess neurites, is central for the maturation of the nervous system. In Drosophila , sensory neurons, ddaCs, selectively prune their larval dendrites without affecting their axons during metamorphosis. However, it is unknown whether the secretory pathway plays a role in dendrite pruning. Here, we show that the small GTPase Arf1, an important regulator of the secretory pathway, is specifically required for dendrite pruning of ddaC/D/E sensory neurons but dispensable for apoptosis of ddaF neurons. Analyses of the GTP- and GDP-locked forms of Arf1 indicate that the cycling of Arf1 between GDP-bound and GTP-bound forms is essential for dendrite pruning. We further identified Sec71 as a guanine nucleotide exchange factor for Arf1 that preferentially interacts with its GDP-bound form. Like Arf1, Sec71 is also important for dendrite pruning, but not for apoptosis, of sensory neurons. Arf1 and Sec71 are interdependent for their localizations on Golgi. Finally, we show that the Sec71/Arf1-mediated trafficking process is a prerequisite for Rab5-dependent endocytosis to facilitate endocytosis and degradation of the cell-adhesion molecule Neuroglian (Nrg). © 2017. Published by The Company of Biologists Ltd.

Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer.

PubMed

Hill, Andrew G; Findlay, Michael P; Burge, Matthew E; Jackson, Christopher; Alfonso, Pilar Garcia; Samuel, Leslie; Ganju, Vinod; Karthaus, Meinolf; Amatu, Alessio; Jeffery, Mark; Bartolomeo, Maria Di; Bridgewater, John; Coveler, Andrew L; Hidalgo, Manuel; Kapp, Amy V; Sufan, Roxana I; McCall, Bruce B; Hanley, William D; Penuel, Elicia M; Pirzkall, Andrea; Tabernero, Josep

2018-05-15

Purpose: Duligotuzumab is a dual-action antibody directed against EGFR and HER3. Experimental Design: Metastatic colorectal cancer (mCRC) patients with KRAS ex2 wild-type received duligotuzumab or cetuximab and FOLFIRI until progression or intolerable toxicity. Mandatory tumor samples underwent mutation and biomarker analysis. Efficacy analysis was conducted in patients with RAS exon 2/3 wild-type tumors. Results: Of 134 randomly assigned patients, 98 had RAS ex2/3 wild-type. Duligotuzumab provided no progression-free survival (PFS) or overall survival (OS) benefit compared with cetuximab, although there was a trend for a lower objective response rate (ORR) in the duligotuzumab arm. No relationship was seen between PFS or ORR and ERBB3, NRG1, or AREG expression. There were fewer skin rash events for duligotuzumab but more diarrhea. Although the incidence of grade ≥3 AEs was similar, the frequency of serious AEs was higher for duligotuzumab. Conclusions: Duligotuzumab plus FOLFIRI did not appear to improve the outcomes in patients with RAS exon 2/3 wild-type mCRC compared with cetuximab + FOLFIRI. Clin Cancer Res; 24(10); 2276-84. ©2018 AACR . ©2018 American Association for Cancer Research.

Large-Scale Description of Interacting One-Dimensional Bose Gases: Generalized Hydrodynamics Supersedes Conventional Hydrodynamics

NASA Astrophysics Data System (ADS)

Doyon, Benjamin; Dubail, Jérôme; Konik, Robert; Yoshimura, Takato

2017-11-01

The theory of generalized hydrodynamics (GHD) was recently developed as a new tool for the study of inhomogeneous time evolution in many-body interacting systems with infinitely many conserved charges. In this Letter, we show that it supersedes the widely used conventional hydrodynamics (CHD) of one-dimensional Bose gases. We illustrate this by studying "nonlinear sound waves" emanating from initial density accumulations in the Lieb-Liniger model. We show that, at zero temperature and in the absence of shocks, GHD reduces to CHD, thus for the first time justifying its use from purely hydrodynamic principles. We show that sharp profiles, which appear in finite times in CHD, immediately dissolve into a higher hierarchy of reductions of GHD, with no sustained shock. CHD thereon fails to capture the correct hydrodynamics. We establish the correct hydrodynamic equations, which are finite-dimensional reductions of GHD characterized by multiple, disjoint Fermi seas. We further verify that at nonzero temperature, CHD fails at all nonzero times. Finally, we numerically confirm the emergence of hydrodynamics at zero temperature by comparing its predictions with a full quantum simulation performed using the NRG-TSA-abacus algorithm. The analysis is performed in the full interaction range, and is not restricted to either weak- or strong-repulsion regimes.

Positive Traits in the Bipolar Spectrum: The Space between Madness and Genius

PubMed Central

Greenwood, Tiffany A.

2017-01-01

Bipolar disorder is a severe, lifelong mood disorder for which little is currently understood of the genetic mechanisms underlying risk. By examining related dimensional phenotypes, we may further our understanding of the disorder. Creativity has a historical connection with the bipolar spectrum and is particularly enhanced among unaffected first-degree relatives and those with bipolar spectrum traits. This suggests that some aspects of the bipolar spectrum may confer advantages, while more severe expressions of symptoms negatively influence creative accomplishment. Creativity is a complex, multidimensional construct with both cognitive and affective components, many of which appear to reflect a shared genetic vulnerability with bipolar disorder. It is suggested that a subset of bipolar risk variants confer advantages as positive traits according to an inverted-U-shaped curve with clinically unaffected allele carriers benefitting from the positive traits and serving to maintain the risk alleles in the population. The association of risk genes with creativity in healthy individuals (e.g., NRG1), as well as an overall sharing of common genetic variation between bipolar patients and creative individuals, provides support for this model. Current findings are summarized from a multidisciplinary perspective to demonstrate the feasibility of research in this area to reveal the mechanisms underlying illness. PMID:28277566

Hydrogen-enriched fuels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roser, R.

1998-08-01

NRG Technologies, Inc. is attempting to develop hardware and infrastructure that will allow mixtures of hydrogen and conventional fuels to become viable alternatives to conventional fuels alone. This commercialization can be successful if the authors are able to achieve exhaust emission levels of less than 0.03 g/kw-hr NOx and CO; and 0.15 g/kw-hr NMHC at full engine power without the use of exhaust catalysts. The major barriers to achieving these goals are that the lean burn regimes required to meet exhaust emissions goals reduce engine output substantially and tend to exhibit higher-than-normal total hydrocarbon emissions. Also, hydrogen addition to conventionalmore » fuels increases fuel cost, and reduces both vehicle range and engine output power. Maintaining low emissions during transient driving cycles has not been demonstrated. A three year test plan has been developed to perform the investigations into the issues described above. During this initial year of funding research has progressed in the following areas: (a) a cost effective single-cylinder research platform was constructed; (b) exhaust gas speciation was performed to characterize the nature of hydrocarbon emissions from hydrogen-enriched natural gas fuels; (c) three H{sub 2}/CH{sub 4} fuel compositions were analyzed using spark timing and equivalence ratio sweeping procedures and finally; (d) a full size pick-up truck platform was converted to run on HCNG fuels. The testing performed in year one of the three year plan represents a baseline from which to assess options for overcoming the stated barriers to success.« less

Genomewide Linkage Scan of 409 European-Ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

PubMed Central

Suarez, Brian K.; Duan, Jubao; Sanders, Alan R.; Hinrichs, Anthony L.; Jin, Carol H.; Hou, Cuiping; Buccola, Nancy G.; Hale, Nancy; Weilbaecher, Ann N.; Nertney, Deborah A.; Olincy, Ann; Green, Susan; Schaffer, Arthur W.; Smith, Christopher J.; Hannah, Dominique E.; Rice, John P.; Cox, Nancy J.; Martinez, Maria; Mowry, Bryan J.; Amin, Farooq; Silverman, Jeremy M.; Black, Donald W.; Byerley, William F.; Crowe, Raymond R.; Freedman, Robert; Cloninger, C. Robert; Levinson, Douglas F.; Gejman, Pablo V.

2006-01-01

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees—263 of European ancestry (EA) and 146 of African American ancestry (AA)—together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Zlr] threshold ⩾2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Zlr scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Zlr of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Zlr scores was observed for 5p14.1-q12.1, where the maximum Zlr increased from 2.77 initially to 3.80 after fine mapping in the EA families. PMID:16400611

Genomewide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample.

PubMed

Suarez, Brian K; Duan, Jubao; Sanders, Alan R; Hinrichs, Anthony L; Jin, Carol H; Hou, Cuiping; Buccola, Nancy G; Hale, Nancy; Weilbaecher, Ann N; Nertney, Deborah A; Olincy, Ann; Green, Susan; Schaffer, Arthur W; Smith, Christopher J; Hannah, Dominique E; Rice, John P; Cox, Nancy J; Martinez, Maria; Mowry, Bryan J; Amin, Farooq; Silverman, Jeremy M; Black, Donald W; Byerley, William F; Crowe, Raymond R; Freedman, Robert; Cloninger, C Robert; Levinson, Douglas F; Gejman, Pablo V

2006-02-01

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees--263 of European ancestry (EA) and 146 of African American ancestry (AA)--together with the results of a genome scan (with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia (SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs (ASPs) (279 EA and 124 AA) and 100 all-possible half-sibling ASPs (15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 (empirical Z likelihood-ratio score [Z(lr)] threshold >/=2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >2.0 in 8p were observed from 30.7 cM to 61.7 cM (Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 (equivalent Kong-Cox LOD of 2.30) near D8S1771 (at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 (NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

Measurement campaign for wind power potential in west Greenland

NASA Astrophysics Data System (ADS)

Rønnow Jakobsen, Kasper

2013-04-01

Experiences and results from a wind resource exploring campaign 2003- in west Greenland. Like many other countries, Greenland is trying to reduce its dependency of fossil fuel by implementing renewable energy. The main challenge is that the people live on the coast in scattered settlements, without power infrastructure. Based on this a wind power potential project was established in 2002, funded by the Greenlandic government and the Technical University of Denmark. We present results and experiences of the campaign. 1 Field campaign There were only a few climate stations in or close to settlements and due to their positioning and instrumentation, they were not usable for wind resource estimation. To establish met stations in Arctic areas with complex topography, there are some challenges to face; mast positioning in complex terrain, severe weather conditions, instrumentation, data handling, installation and maintenance budget. The terrain in the ice free and populated part, mainly consists of mountains of different heights and shapes, separated by deep fjords going from the ice cap to the sea. With a generally low wind resource the focus was on the most exposed positions close to the settlements. Data from the nearest existing climate stations was studied for background estimations of predominant wind directions and extreme wind speeds, and based on that the first 10m masts were erected in 2003. 2 Instruments The first installations used standard NRG systems with low cost NRG instruments. For most of the sites this low cost setup did a good job, but there were some problems with the first design, including instrument and boom strains. In subsequent years, the systems were updated several times to be able to operate in the extreme conditions. Different types of instruments, data logger and boom systems were tested to get better data quality and reliability. Today 11 stations with heights ranging from 10-50m are installed and equipped according to the IEC standard. During the first years, the influence of instrument icing was not considered, but recently one of the sites was equipped with an ice rate sensor and a heated ultrasonic anemometer to study the ice influence. 3 Results The predominant wind direction for most sites is away from the ice cap at the center of the continent, but for some coastal sites it is north or south. The north-south wind pattern is expected from the synoptic patterns and the barrier effect of the ice cap. The sites where the predominant wind direction is away from the inland ice are dominated by katabatic wind systems from the ice cap and form valley systems. These sites also seem to have the highest wind resource and will be studied further. A good example of the influence of katabatic and thermal wind systems can be seen in the measurement data from Sarfannguit and Nanortalik 66 and 60 degrees northern latitude respectively. In future work, these katabatic flows and their impact on the wind resource will be studied using mesoscale modelling and microscale downscaling.

Distribution of rubidium, strontium, and zirconium in tuff from two deep coreholes at Yucca Mountain, Nevada

USGS Publications Warehouse

Spengler, Richard W.; Peterman, Zell E.; ,

1991-01-01

Variations in concentrations of trace elements Rb, Sr, and Zr within the sequence of high-silica tuff and dacitic lava beneath Yucca Mountain reflect both primary composition and secondary alteration. Rb and K concentrations have parallel trends. Rb concentrations are significantly lower within intervals containing zeolitic nonwelded to partially welded and bedded tuffs and are higher in thick moderately to densely welded zones. Sr concentrations increase with depth from about 30 ppm in the Topopah Spring Member of the Paintbrush Tuff to almost 300 ppm in the older tuffs. Zr concentrations are about 100 ppm in the Topopah Spring Member and also increase with depth to about 150 ppm in the Lithic Ridge Tuff and upper part of the older tuffs. Conspicuous local high concentrations of Sr in the lower part of the Tram Member, in the dacite lava, and in unit c of the older tuffs in USW G-1, and in the densely welded zone of the Bullfrog Member in USW GU-3/G-3 closely correlate with high concentrations of less-mobile Zr and may reflect either primary composition or elemental redistribution resulting largely from smectitic alteration. Initial 87Sr/86Sr values from composite samples increase upward in units above the Bullfrog Member of the Crater Flat Tuff. The progressive tenfold increase in Sr with depth coupled with the similarity of initial 87Sr/86Sr values within the Bullfrog Member and older units to those of Paleozoic marine carbonates are consistent with a massive influx of Sr from water derived from a Paleozoic carbonate aquifer.

Differential Gene Expression in Colon Tissue Associated With Diet, Lifestyle, and Related Oxidative Stress.

PubMed

Slattery, Martha L; Pellatt, Daniel F; Mullany, Lila E; Wolff, Roger K

2015-01-01

Several diet and lifestyle factors may impact health by influencing oxidative stress levels. We hypothesize that level of cigarette smoking, alcohol, anti-inflammatory drugs, and diet alter gene expression. We analyzed RNA-seq data from 144 colon cancer patients who had information on recent cigarette smoking, recent alcohol consumption, diet, and recent aspirin/non-steroidal anti-inflammatory use. Using a false discovery rate of 0.1, we evaluated gene differential expression between high and low levels of exposure using DESeq2. Ingenuity Pathway Analysis (IPA) was used to determine networks associated with de-regulated genes in our data. We identified 46 deregulated genes associated with recent cigarette use; these genes enriched causal networks regulated by TEK and MAP2K3. Different differentially expressed genes were associated with type of alcohol intake; five genes were associated with total alcohol, six were associated with beer intake, six were associated with wine intake, and four were associated with liquor consumption. Recent use of aspirin and/or ibuprofen was associated with differential expression of TMC06, ST8SIA4, and STEAP3 while a summary oxidative balance score (OBS) was associated with SYCP3, HDX, and NRG4 (all up-regulated with greater oxidative balance). Of the dietary antioxidants and carotenoids evaluated only intake of beta carotene (1 gene), Lutein/Zeaxanthine (5 genes), and Vitamin E (4 genes) were associated with differential gene expression. There were similarities in biological function of de-regulated genes associated with various dietary and lifestyle factors. Our data support the hypothesis that diet and lifestyle factors associated with oxidative stress can alter gene expression. However genes altered were unique to type of alcohol and type of antioxidant. Because of potential differences in associations observed between platforms these findings need replication in other populations.

Fungal Morphogenetic Pathways Are Required for the Hallmark Inflammatory Response during Candida albicans Vaginitis

PubMed Central

Palmer, Glen E.; Nash, Andrea K.; Lilly, Elizabeth A.; Fidel, Paul L.; Noverr, Mairi C.

2014-01-01

Vulvovaginal candidiasis, caused primarily by Candida albicans, presents significant health issues for women of childbearing age. As a polymorphic fungus, the ability of C. albicans to switch between yeast and hyphal morphologies is considered its central virulence attribute. Armed with new criteria for defining vaginitis immunopathology, the purpose of this study was to determine whether the yeast-to-hypha transition is required for the hallmark inflammatory responses previously characterized during murine vaginitis. Kinetic analyses of vaginal infection with C. albicans in C57BL/6 mice demonstrated that fungal burdens remained constant throughout the observation period, while polymorphonuclear leukocyte (PMN), S100A8, and interleukin-1β levels obtained from vaginal lavage fluid increased by day 3 onward. Lactate dehydrogenase activity was also positively correlated with increased effectors of innate immunity. Additionally, immunodepletion of neutrophils in infected mice confirmed a nonprotective role for PMNs during vaginitis. Determination of the importance of fungal morphogenesis during vaginitis was addressed with a two-pronged approach. Intravaginal inoculation of mice with C. albicans strains deleted for key transcriptional regulators (bcr1Δ/Δ, efg1Δ/Δ, cph1Δ/Δ, and efg1Δ/Δ cph1Δ/Δ) controlling the yeast-to-hypha switch revealed a crucial role for morphogenetic signaling through the Efg1 and, to a lesser extent, the Bcr1 pathways in contributing to vaginitis immunopathology. Furthermore, overexpression of transcription factors NRG1 and UME6, to maintain yeast and hyphal morphologies, respectively, confirmed the importance of morphogenesis in generating innate immune responses in vivo. These results highlight the yeast-to-hypha switch and the associated morphogenetic response as important virulence components for the immunopathogenesis of Candida vaginitis, with implications for transition from benign colonization to symptomatic infection. PMID:24478069

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study.

PubMed

Goodfellow, Paul J; Billingsley, Caroline C; Lankes, Heather A; Ali, Shamshad; Cohn, David E; Broaddus, Russell J; Ramirez, Nilsa; Pritchard, Colin C; Hampel, Heather; Chassen, Alexis S; Simmons, Luke V; Schmidt, Amy P; Gao, Feng; Brinton, Louise A; Backes, Floor; Landrum, Lisa M; Geller, Melissa A; DiSilvestro, Paul A; Pearl, Michael L; Lele, Shashikant B; Powell, Matthew A; Zaino, Richard J; Mutch, David

2015-12-20

The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. © 2015 by American Society of Clinical Oncology.

Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

PubMed Central

Goodfellow, Paul J.; Billingsley, Caroline C.; Lankes, Heather A.; Ali, Shamshad; Cohn, David E.; Broaddus, Russell J.; Ramirez, Nilsa; Pritchard, Colin C.; Hampel, Heather; Chassen, Alexis S.; Simmons, Luke V.; Schmidt, Amy P.; Gao, Feng; Brinton, Louise A.; Backes, Floor; Landrum, Lisa M.; Geller, Melissa A.; DiSilvestro, Paul A.; Pearl, Michael L.; Lele, Shashikant B.; Powell, Matthew A.; Zaino, Richard J.; Mutch, David

2015-01-01

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. PMID:26552419

Quercetin Assists Fluconazole to Inhibit Biofilm Formations of Fluconazole-Resistant Candida Albicans in In Vitro and In Vivo Antifungal Managements of Vulvovaginal Candidiasis.

PubMed

Gao, Mei; Wang, Hui; Zhu, LiJuan

2016-01-01

Vulvovaginal candidiasis (VVC) is a common gynecological disease. Candida albicans is believed to be mainly implicated in VVC occurrence, the biofilm of which is one of the virulence factors responsible for resistance to traditional antifungal agents especially to fluconazole (FCZ). Quercetin (QCT) is a dietary flavonoid and has been demonstrated to be antifungal against C. albicans biofilm. 17 C. albicans isolates including 15 clinical ones isolated from VVC patients were employed to investigate the effects of QCT and/or FCZ on the inhibition of C. albicans biofilm. We observed that 64 µg/mL QCT and/or 128 µg/mL FCZ could (i) be synergistic against 10 FCZ-resistant planktonic and 17 biofilm cells of C. albicans, (ii) inhibit fungal adherence, cell surface hydrophobicity (CSH), flocculation, yeast-to-hypha transition, metabolism, thickness and dispersion of biofilms; (iii) down-regulate the expressions of ALS1, ALS3, HWP1, SUN41, UME6 and ECE1 and up-regulate the expressions of PDE2, NRG1 and HSP90, and we also found that (iv) the fungal burden was reduced in vaginal mucosa and the symptoms were alleviated in a murine VVC model after the treatments of 5 mg/kg QCT and/or 20 mg/kg FCZ. Together with these results, it could be demonstrated that QCT could be a favorable antifungal agent and a promising synergist with FCZ in the clinical management of VVC caused by C. albicans biofilm. © 2016 The Author(s) Published by S. Karger AG, Basel.

A cost-utility analysis of NRG Oncology/Gynecologic Oncology Group Protocol 218: incorporating prospectively collected quality-of-life scores in an economic model of treatment of ovarian cancer.

PubMed

Cohn, David E; Barnett, Jason C; Wenzel, Lari; Monk, Bradley J; Burger, Robert A; Straughn, J Michael; Myers, Evan R; Havrilesky, Laura J

2015-02-01

To estimate quality-of-life (QOL)-adjusted cost-utility with addition of bevacizumab (B) to intravenous paclitaxel/carboplatin (PC) for primary treatment of advanced-stage epithelial ovarian cancer. A modified Markov state transition model of 3 regimens evaluated in GOG 218 (PC, PC+concurrent B [PCB], and PCB+maintenance B [PCB+B]) was populated by prospectively collected survival, adverse event, and QOL data from GOG 218. Progression-free survival (PFS) and overall survival (OS) were modeled using primary event data. Costs of grade 4 hypertension, grade 3-5 bowel events, and growth factor support were incorporated. QOL scores were converted to utilities and incorporated into the model. Monte Carlo probabilistic sensitivity analysis was performed to account for uncertainty in estimates. PC was the least expensive ($4044) and least effective (mean 1.1 quality-adjusted progression-free years [QA-PFY]) regimen. PCB ($43,703 and 1.13 QA-PFY) was dominated by a combination of PC and PCB+B. PCB+B ($122,700 and 1.25 QA-PFY) was the most expensive regimen with an incremental cost-effectiveness ratio of $792,380/QA-PFY compared to PC. In a model not incorporating QOL, the incremental cost-effectiveness ratio (ICER) of PCB+B was $632,571/PFY compared to PC. In this cost-utility model, incorporation of QOL into an analysis of GOG 218 led to less favorable ICER (by >$150,000/QA-PFY) in regimens containing B compared with those that do not include B. Continued investigation of populations with ovarian cancer in whom the efficacy of treatment with bevacizumab is expected to be increased (or in whom QOL is expected to increase with use) is critical. Copyright © 2014 Elsevier Inc. All rights reserved.

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction

PubMed Central

Ayalew, M; Le-Niculescu, H; Levey, D F; Jain, N; Changala, B; Patel, S D; Winiger, E; Breier, A; Shekhar, A; Amdur, R; Koller, D; Nurnberger, J I; Corvin, A; Geyer, M; Tsuang, M T; Salomon, D; Schork, N J; Fanous, A H; O'Donovan, M C; Niculescu, A B

2012-01-01

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein–coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. PMID:22584867

Zweitore, Vierpole

NASA Astrophysics Data System (ADS)

Plaßmann, Wilfried

Zweitore (nach DIN 4899; alte Bezeichnung "Vierpole") sind Funktionseinheiten mit zwei Toren, wobei zu jedem Tor ein Klemmenpaar gehört. An eines der Tore wird das Eingangssignal angeschlossen, die zugehörigen Anschlüsse werden mit Eingangsklemmen bezeichnet. Entsprechend wird an den zwei Ausgangsklemmen das Ausgangssignal abgegriffen. Eventuell erforderliche Anschlüsse für eine Stromversorgung werden nicht mitgezählt. Der interne Aufbau besteht aus einer beliebigen Zusammenschaltung von Widerständen, Kondensatoren, Spulen, Transformatoren, Dioden, Transistoren usw. Es wird vorausgesetzt, dass die Zweitore zeitinvariant sind, d. h. die Eigenschaften hängen nicht von der Zeit ab.

Photovoltaics - Where are we going?

NASA Technical Reports Server (NTRS)

Callaghan, W. T.

1984-01-01

The directions that will be followed for solar cell development, production and marketing are projected on the basis of experiences gained during the JPL's Flat-Plate Solar Array project. It is thought that a billion dollar market for Si ribbons can be established by 1990. Thin film technology will yield a product at $2 U.S./W at the end of the 1980s. R&D is growing more focused on central station photovoltaic generators, although the residential market may be the more suitable goal. The intermediate markets, e.g., schools, hospitals and shopping centers may be developed before the central stations.

Genome-wide association and network analysis of lung function in the Framingham Heart Study.

PubMed

Liao, Shu-Yi; Lin, Xihong; Christiani, David C

2014-09-01

Single nucleotide polymorphisms have been found to be associated with pulmonary function using genome-wide association studies. However, lung function is a complex trait that is likely to be influenced by multiple gene-gene interactions besides individual genes. Our goal is to build a cellular network to explore the relationship between pulmonary function and genotypes by combining SNP level and network analyses using longitudinal lung function data from the Framingham Heart Study. We analyzed 2,698 genotyped participants from the Offspring cohort that had an average of 3.35 spirometry measurements per person for a mean length of 13 years. Repeated forced expiratory volume in one second (FEV1 ) and the ratio of FEV1 to forced vital capacity (FVC) were used as outcomes. Data were analyzed using linear-mixed models for the association between lung function and alleles by accounting for the correlation among repeated measures over time within the same subject and within-family correlation. Network analyses were performed using dmGWAS and validated with data from the Third Generation cohort. Analyses identified SMAD3, TGFBR2, CD44, CTGF, VCAN, CTNNB1, SCGB1A1, PDE4D, NRG1, EPHB1, and LYN as contributors to pulmonary function. Most of these genes were novel that were not found previously using solely SNP-level analysis. These novel genes are involving the transforming growth factor beta (TGFB)-SMAD pathway, Wnt/beta-catenin pathway, etc. Therefore, combining SNP-level and network analyses using longitudinal lung function data is a useful alternative strategy to identify risk genes. © 2014 WILEY PERIODICALS, INC.

Failure Behavior of Granite Affected by Confinement and Water Pressure and Its Influence on the Seepage Behavior by Laboratory Experiments.

PubMed

Cheng, Cheng; Li, Xiao; Li, Shouding; Zheng, Bo

2017-07-14

Failure behavior of granite material is paramount for host rock stability of geological repositories for high-level waste (HLW) disposal. Failure behavior also affects the seepage behavior related to transportation of radionuclide. Few of the published studies gave a consistent analysis on how confinement and water pressure affect the failure behavior, which in turn influences the seepage behavior of the rock during the damage process. Based on a series of laboratory experiments on NRG01 granite samples cored from Alxa area, a candidate area for China's HLW disposal, this paper presents some detailed observations and analyses for a better understanding on the failure mechanism and seepage behavior of the samples under different confinements and water pressure. The main findings of this study are as follows: (1) Strength reduction properties were found for the granite under water pressure. Besides, the complete axial stress-strain curves show more obvious yielding process in the pre-peak region and a more gradual stress drop in the post-peak region; (2) Shear fracturing pattern is more likely to form in the granite samples with the effect of water pressure, even under much lower confinements, than the predictions from the conventional triaxial compressive results; (3) Four stages of inflow rate curves are divided and the seepage behaviors are found to depend on the failure behavior affected by the confinement and water pressure.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions.

PubMed

Dahshan, Basem A; Mattes, Malcolm D; Bhatia, Sanjay; Palek, Mary Susan; Cifarelli, Christopher P; Hack, Joshua D; Vargo, John A

2017-12-19

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer.

Efficacy of Stereotactic Radiosurgery in Patients with Multiple Metastases: Importance of Volume Rather Than Number of Lesions

PubMed Central

Mattes, Malcolm D; Bhatia, Sanjay; Palek, Mary Susan; Cifarelli, Christopher P; Hack, Joshua D; Vargo, John A

2017-01-01

The role of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases is controversial. While whole brain radiation therapy (WBRT) has historically been the mainstay of treatment, its value is increasingly being questioned as emerging data supports that SRS alone can provide comparable therapeutic outcomes for limited (one to three) intracranial metastases with fewer adverse effects, including neurocognitive decline. Multiple recent studies have also demonstrated that patients with multiple (> 3) intracranial metastases with a low overall tumor volume have a favorable therapeutic response to SRS, with no significant difference compared to patients with limited metastases. Herein, we present a patient with previously controlled breast cancer who presented with multiple recurrences of intracranial metastases but low total intracranial tumor volume each time. This patient underwent SRS alone for a total of 40 metastatic lesions over three separate procedures with good local control and without any significant cognitive toxicity. The patient eventually opted for enrollment in the NRG-CC001 clinical trial after multiple cranial recurrences. She received conventional WBRT with six months of memantine and developed significant neurocognitive side effects. This case highlights the growing body of literature supporting the role of SRS alone in the management of multiple brain metastases and the importance of maximizing neurocognition as advances in systemic therapies prolong survival in Stage IV cancer. PMID:29492355

Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy

PubMed Central

Rose, Peter G.; Java, James; Whitney, Charles W.; Stehman, Frederick B.; Lanciano, Rachelle; Thomas, Gillian M.; DiSilvestro, Paul A.

2015-01-01

Purpose To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence. Patients and Methods We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five-year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration. Results Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated. Conclusion Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes. PMID:25732170

Evidence That Descending Cortical Axons Are Essential for Thalamocortical Axons to Cross the Pallial-Subpallial Boundary in the Embryonic Forebrain

PubMed Central

Chen, Yijing; Magnani, Dario; Theil, Thomas; Pratt, Thomas; Price, David J.

2012-01-01

Developing thalamocortical axons traverse the subpallium to reach the cortex located in the pallium. We tested the hypothesis that descending corticofugal axons are important for guiding thalamocortical axons across the pallial-subpallial boundary, using conditional mutagenesis to assess the effects of blocking corticofugal axonal development without disrupting thalamus, subpallium or the pallial-subpallial boundary. We found that thalamic axons still traversed the subpallium in topographic order but did not cross the pallial-subpallial boundary. Co-culture experiments indicated that the inability of thalamic axons to cross the boundary was not explained by mutant cortex developing a long-range chemorepulsive action on thalamic axons. On the contrary, cortex from conditional mutants retained its thalamic axonal growth-promoting activity and continued to express Nrg-1, which is responsible for this stimulatory effect. When mutant cortex was replaced with control cortex, corticofugal efferents were restored and thalamic axons from conditional mutants associated with them and crossed the pallial-subpallial boundary. Our study provides the most compelling evidence to date that cortical efferents are required to guide thalamocortical axons across the pallial-subpallial boundary, which is otherwise hostile to thalamic axons. These results support the hypothesis that thalamic axons grow from subpallium to cortex guided by cortical efferents, with stimulation from diffusible cortical growth-promoting factors. PMID:22412988

Dressing the post-Newtonian two-body problem and classical effective field theory

NASA Astrophysics Data System (ADS)

Kol, Barak; Smolkin, Michael

2009-12-01

We apply a dressed perturbation theory to better organize and economize the computation of high orders of the 2-body effective action of an inspiralling post-Newtonian (PN) gravitating binary. We use the effective field theory approach with the nonrelativistic field decomposition (NRG fields). For that purpose we develop quite generally the dressing theory of a nonlinear classical field theory coupled to pointlike sources. We introduce dressed charges and propagators, but unlike the quantum theory there are no dressed bulk vertices. The dressed quantities are found to obey recursive integral equations which succinctly encode parts of the diagrammatic expansion, and are the classical version of the Schwinger-Dyson equations. Actually, the classical equations are somewhat stronger since they involve only finitely many quantities, unlike the quantum theory. Classical diagrams are shown to factorize exactly when they contain nonlinear worldline vertices, and we classify all the possible topologies of irreducible diagrams for low loop numbers. We apply the dressing program to our post-Newtonian case of interest. The dressed charges consist of the dressed energy-momentum tensor after a nonrelativistic decomposition, and we compute all dressed charges (in the harmonic gauge) appearing up to 2PN in the 2-body effective action (and more). We determine the irreducible skeleton diagrams up to 3PN and we employ the dressed charges to compute several terms beyond 2PN.

Signaling through protein kinases and transcriptional regulators in Candida albicans.

PubMed

Dhillon, Navneet K; Sharma, Sadhna; Khuller, G K

2003-01-01

The human fungal pathogen Candida albicans switches from a budding yeast form to a polarized hyphal form in response to various external signals. This morphogenetic switching has been implicated in the development of pathogenicity. Several signaling pathways that regulate morphogenesis have been identified, including various transcription factors that either activate or repress hypha-specific genes. Two well-characterized pathways include the MAP kinase cascade and cAMP-dependent protein kinase pathway that regulate the transcription factors Cph1p and Efg1p, respectively. cAMP also appears to interplay with other second messengers: Ca2+, inositol tri-phosphates in regulating yeast-hyphal transition. Other, less-characterized pathways include two component histidine kinases, cyclin-dependent kinase pathway, and condition specific pathways such as pH and embedded growth conditions. Nrg1 and Rfg1 function as transcriptional repressors of hyphal genes via recruitment of Tup1 co-repressor complex. Different upstream signals converge into a common downstream output during hyphal switch. The levels of expression of several genes have been shown to be associated with hyphal morphogenesis rather than with a specific hypha-inducing condition. Hyphal development is also linked to the expression of a range of other virulence factors. This review explains the relative contribution of multiple pathways that could be used by Candida albican cells to sense subtle differences in the growth conditions of its native host environment.

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

PubMed

Weber, Tobias; Bötticher, Benedikt; Arndt, Michaela A E; Mier, Walter; Sauter, Max; Exner, Evelyn; Keller, Armin; Krämer, Susanne; Leotta, Karin; Wischnjow, Artjom; Grosse-Hovest, Ludger; Strumberg, Dirk; Jäger, Dirk; Gröne, Hermann-Josef; Haberkorn, Uwe; Brem, Gottfried; Krauss, Jürgen

2016-10-28

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813.

PubMed

Chang, Susan; Zhang, Peixin; Cairncross, J Gregory; Gilbert, Mark R; Bahary, Jean-Paul; Dolinskas, Carol A; Chakravarti, Arnab; Aldape, Kenneth D; Bell, Erica H; Schiff, David; Jaeckle, Kurt; Brown, Paul D; Barger, Geoffrey R; Werner-Wasik, Maria; Shih, Helen; Brachman, David; Penas-Prado, Marta; Robins, H Ian; Belanger, Karl; Schultz, Christopher; Hunter, Grant; Mehta, Minesh

2017-02-01

The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Organization of the sleep-related neural systems in the brain of the minke whale (Balaenoptera acutorostrata).

PubMed

Dell, Leigh-Anne; Karlsson, Karl Ae; Patzke, Nina; Spocter, Muhammad A; Siegel, Jerome M; Manger, Paul R

2016-07-01

The current study analyzed the nuclear organization of the neural systems related to the control and regulation of sleep and wake in the basal forebrain, diencephalon, midbrain, and pons of the minke whale, a mysticete cetacean. While odontocete cetaceans sleep in an unusual manner, with unihemispheric slow wave sleep (USWS) and suppressed REM sleep, it is unclear whether the mysticete whales show a similar sleep pattern. Previously, we detailed a range of features in the odontocete brain that appear to be related to odontocete-type sleep, and here present our analysis of these features in the minke whale brain. All neural elements involved in sleep regulation and control found in bihemispheric sleeping mammals and the harbor porpoise were present in the minke whale, with no specific nuclei being absent, and no novel nuclei being present. This qualitative similarity relates to the cholinergic, noradrenergic, serotonergic and orexinergic systems, and the GABAergic elements of these nuclei. Quantitative analysis revealed that the numbers of pontine cholinergic (274,242) and noradrenergic (203,686) neurons, and hypothalamic orexinergic neurons (277,604), are markedly higher than other large-brained bihemispheric sleeping mammals. Small telencephalic commissures (anterior, corpus callosum, and hippocampal), an enlarged posterior commissure, supernumerary pontine cholinergic and noradrenergic cells, and an enlarged peripheral division of the dorsal raphe nuclear complex of the minke whale, all indicate that the suite of neural characteristics thought to be involved in the control of USWS and the suppression of REM in the odontocete cetaceans are present in the minke whale. J. Comp. Neurol. 524:2018-2035, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

MR Spectroscopy to Distinguish between Supratentorial Intraventricular Subependymoma and Central Neurocytoma.

PubMed

Ueda, Fumiaki; Aburano, Hiroyuki; Ryu, Yasuji; Yoshie, Yuichi; Nakada, Mitsutoshi; Hayashi, Yutaka; Matsui, Osamu; Gabata, Toshifumi

2017-07-10

The purpose of this study was to discriminate supratentorial intraventricular subependymoma (SIS) from central neurocytoma (CNC) using magnetic resonance spectroscopy (MRS). Single-voxel proton MRS using a 1.5T or 3T MR scanner from five SISs, five CNCs, and normal controls were evaluated. They were examined using a point-resolved spectroscopy. Automatically calculated ratios comparing choline (Cho), N-acetylaspartate (NAA), myoinositol (MI), and/or glycine (Gly) to creatine (Cr) were determined. Evaluation of Cr to unsuppressed water (USW) was also performed. Mann-Whitney U test was carried out to test the significance of differences in the metabolite ratios. Detectability of lactate (Lac) and alanine (Ala) was evaluated. Although a statistically significant difference (P < 0.0001) was observed in Cho/Cr among SIS, control spectra, and CNC, no statistical difference was noted between SIS and control spectra (P = 0.11). Statistically significant differences were observed in NAA/Cr between SIS and CNC (P = 0.04) or control spectra (P < 0.0001). A statistically significant difference was observed in MI and/or Gly to Cr between SIS and control spectra (P = 0.03), and CNC and control spectra (P < 0.0006). There were no statistical differences between SIS and CNC for MI and/or Gly to Cr (P = 0.32). Significant statistical differences were found between SIS and control spectra (P < 0.0053), control spectra and CNC (P < 0.0016), and SIS and CNC (P < 0.0083) for Cr to USW. Lac inverted doublets were confirmed in two SISs. Triplets of Lac and Ala were detected in four spectra of CNC. The present study showed that MRS can be useful in discriminating SIS from CNC.

An Ultrasound Surface Wave Technique for Assessing Skin and Lung Diseases.

PubMed

Zhang, Xiaoming; Zhou, Boran; Kalra, Sanjay; Bartholmai, Brian; Greenleaf, James; Osborn, Thomas

2018-02-01

Systemic sclerosis (SSc) is a multi-organ connective tissue disease characterized by immune dysregulation and organ fibrosis. Severe organ involvement, especially of the skin and lung, is the cause of morbidity and mortality in SSc. Interstitial lung disease (ILD) includes multiple lung disorders in which the lung tissue is fibrotic and stiffened. The purpose of this study was to translate ultrasound surface wave elastography (USWE) for assessing patients with SSc and/or ILD via measuring surface wave speeds of both skin and superficial lung tissue. Forty-one patients with both SSc and ILD and 30 healthy patients were enrolled in this study. An external harmonic vibration was used to generate the wave propagation on the skin or lung. Three excitation frequencies of 100, 150 and 200 Hz were used. An ultrasound probe was used to measure the wave propagation in the tissue non-invasively. Surface wave speeds were measured on the forearm and upper arm of both left and right arm, as well as the upper and lower lungs, through six intercostal spaces of patients and healthy patients. Viscoelasticity of the skin was calculated by the wave speed dispersion with frequency using the Voigt model. The magnitudes of surface wave speed and viscoelasticity of patients' skin were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. The surface wave speeds of patients' lung were significantly higher than those of healthy patients (p <0.0001) for each location and each frequency. USWE is a non-invasive and non-ionizing technique for measuring both skin and lung surface wave speed and may be useful for quantitative assessment of SSc and/or ILD. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

PubMed

Chen, Kexin; Yang, Da; Li, Xiangchun; Sun, Baocun; Song, Fengju; Cao, Wenfeng; Brat, Daniel J; Gao, Zhibo; Li, Haixin; Liang, Han; Zhao, Yanrui; Zheng, Hong; Li, Miao; Buckner, Jan; Patterson, Scott D; Ye, Xiang; Reinhard, Christoph; Bhathena, Anahita; Joshi, Deepa; Mischel, Paul S; Croce, Carlo M; Wang, Yi Michael; Raghavakaimal, Sreekumar; Li, Hui; Lu, Xin; Pan, Yang; Chang, Han; Ba, Sujuan; Luo, Longhai; Cavenee, Webster K; Zhang, Wei; Hao, Xishan

2015-01-27

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Wind Development on Tribal Lands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ken Haukaas; Dale Osborn; Belvin Pete

Background: The Rosebud Sioux Tribe (RST) is located in south central South Dakota near the Nebraska border. The nearest community of size is Valentine, Nebraska. The RST is a recipient of several Department of Energy grants, written by Distributed Generation Systems, Inc. (Disgen), for the purposes of assessing the feasibility of its wind resource and subsequently to fund the development of the project. Disgen, as the contracting entity to the RST for this project, has completed all the pre-construction activities, with the exception of the power purchase agreement and interconnection agreement, to commence financing and construction of the project. Themore » focus of this financing is to maximize the economic benefits to the RST while achieving commercially reasonable rates of return and fees for the other parties involved. Each of the development activities required and its status is discussed below. Land Resource: The Owl Feather War Bonnet 30 MW Wind Project is located on RST Tribal Trust Land of approximately 680 acres adjacent to the community of St. Francis, South Dakota. The RST Tribal Council has voted on several occasions for the development of this land for wind energy purposes, as has the District of St. Francis. Actual footprint of wind farm will be approx. 50 acres. Wind Resource Assessment: The wind data has been collected from the site since May 1, 2001 and continues to be collected and analyzed. The latest projections indicate a net capacity factor of 42% at a hub height of 80 meters. The data has been collected utilizing an NRG 9300 Data logger System with instrumentation installed at 30, 40 and 65 meters on an existing KINI radio tower. The long-term annual average wind speed at 65-meters above ground level is 18.2 mph (8.1 mps) and 18.7 mph (8.4 mps) at 80-meters agl. The wind resource is excellent and supports project financing.« less

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity.

PubMed

Saleheen, Danish; Natarajan, Pradeep; Armean, Irina M; Zhao, Wei; Rasheed, Asif; Khetarpal, Sumeet A; Won, Hong-Hee; Karczewski, Konrad J; O'Donnell-Luria, Anne H; Samocha, Kaitlin E; Weisburd, Benjamin; Gupta, Namrata; Zaidi, Mozzam; Samuel, Maria; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Ishaq, Madiha; Akhtar, Saba; Trindade, Kevin; Mucksavage, Megan; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Hayyat Mallick, Nadeem; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-Ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Do, Ron; Krauss, Ronald M; MacArthur, Daniel G; Gabriel, Stacey; Lander, Eric S; Daly, Mark J; Frossard, Philippe; Danesh, John; Rader, Daniel J; Kathiresan, Sekar

2017-04-12

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.

Surface Observation Climatic Summaries (SOCS) For Mather AFB, California

DTIC Science & Technology

1992-02-01

1100 SPEND (RTS) CE14 GEIS GE25 OBS GE14 GEl8 GE25 OBS GE14 GEl8 GE25 OBS GE14 GEl8 GE25 OBS CATEGORY A 1.7 .5 .1 930 1.6 .6 .1 930 1.6 .4 930 3.4 1.0...ITS) GE14 0E18 GE25 ORS GE14 GEIS GE25 OS GE14 GEl8 GE25 OBS GE14 GE18 GE25 OBS CATEGORY A 5.7 2.4 930 5.2 1.3 .2 930 1.7 .5 .2 930 1.5 .5 .1 930...TIME (LST) 0600 - 2000 ALL HOURS SPEED K75 GE14 GEl8 GE25 OBS GE14 GEl8 UE25 OS CAT Y A 3.5 1.1 .1 4650 2.8 .9

Is age a prognostic biomarker for survival among women with locally advanced cervical cancer treated with chemoradiation? An NRG Oncology/Gynecologic Oncology Group ancillary data analysis☆

PubMed Central

Moore, Kathleen N.; Java, James J.; Slaughter, Katrina N.; Rose, Peter G.; Lanciano, Rachelle; DiSilvestro, Paul A.; Thigpen, J. Tate; Lee, Yi-Chun; Tewari, Krishnansu S.; Chino, Junzo; Seward, Shelly M.; Miller, David S.; Salani, Ritu; Moore, David H.; Stehman, Frederick B.

2016-01-01

Objective To determine the effect of age on completion of and toxicities following treatment of local regionally advanced cervical cancer (LACC) on Gynecologic Oncology Group (GOG) Phase I–III trials. Methods An ancillary data analysis of GOG protocols 113, 120, 165, 219 data was performed. Wilcoxon, Pearson, and Kruskal-Wallis tests were used for univariate and multivariate analysis. Log rank tests were used to compare survival lengths. Results One-thousand-three-hundred-nineteen women were included; 60.7% were Caucasian, 15% were age 60–70 years and an additional 5% were >70; 87% had squamous histology, 55% had stage IIB disease and 34% had IIIB disease. Performance status declined with age (p = 0.006). Histology and tumor stage did not significantly differ. Number of cycles of chemotherapy received, radiation treatment time, nor dose modifications varied with age. Notably, radiation protocol deviations and failure to complete brachytherapy (BT) did increase with age (p = 0.022 and p < 0.001 respectively). Only all grade lymphatic (p = 0.006) and grade ≥3 cardiovascular toxicities (p= 0.019) were found to vary with age. A 2% increase in the risk of death for every year increase >50 for all-cause mortality (HR 1.02; 95% CI, 1.01–1.04) was found, but no association between age and disease specific mortality was found. Conclusion This represents a large analysis of patients treated for LACC with chemo/radiation, approximately 20% of whom were >60 years of age. Older patients, had higher rates of incomplete brachytherapy which is not explained by collected toxicity data. Age did not adversely impact completion of chemotherapy and radiation or toxicities. PMID:27542967

Genomic and Molecular Screenings Identify Different Mechanisms for Acquired Resistance to MET Inhibitors in Lung Cancer Cells.

PubMed

Gimenez-Xavier, Pol; Pros, Eva; Bonastre, Ester; Moran, Sebastian; Aza, Ana; Graña, Osvaldo; Gomez-Lopez, Gonzalo; Derdak, Sophia; Dabad, Marc; Esteve-Codina, Anna; Hernandez Mora, Jose R; Salinas-Chaparro, Diana; Esteller, Manel; Pisano, David; Sanchez-Cespedes, Montse

2017-07-01

The development of resistance to tyrosine kinase inhibitors (TKI) limits the long-term efficacy of cancer treatments involving them. We aimed to understand the mechanisms that underlie acquired resistance (AR) to MET inhibitors in lung cancer. EBC1 cells, which have MET amplification and are sensitive to TKIs against MET, were used to generate multiple clones with AR to a MET-TKI. Whole-exome sequencing, RNA sequencing, and global DNA methylation analysis were used to scrutinize the genetic and molecular characteristics of the resistant cells. AR to the MET-TKI involved changes common to all resistant cells, that is, phenotypic modifications, specific changes in gene expression, and reactivation of AKT, ERK, and mTOR. The gene expression, global DNA methylation, and mutational profiles distinguished at least two groups of resistant cells. In one of these, the cells have acquired sensitivity to erlotinib, concomitantly with mutations of the KIRREL, HDAC11, HIATL1 , and MAPK1IP1L genes, among others. In the other group, some cells have acquired inactivation of neurofibromatosis type 2 ( NF2 ) concomitantly with strong overexpression of NRG1 and a mutational profile that includes changes in LMLN and TOMM34 Multiple independent and simultaneous strategies lead to AR to the MET-TKIs in lung cancer cells. The acquired sensitivity to erlotinib supports the known crosstalk between MET and the HER family of receptors. For the first time, we show inactivation of NF2 during acquisition of resistance to MET-TKI that may explain the refractoriness to erlotinib in these cells. Mol Cancer Ther; 16(7); 1366-76. ©2017 AACR . ©2017 American Association for Cancer Research.

ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19.

PubMed

Takahashi, Yuji; Fukuda, Yoko; Yoshimura, Jun; Toyoda, Atsushi; Kurppa, Kari; Moritoyo, Hiroyoko; Belzil, Veronique V; Dion, Patrick A; Higasa, Koichiro; Doi, Koichiro; Ishiura, Hiroyuki; Mitsui, Jun; Date, Hidetoshi; Ahsan, Budrul; Matsukawa, Takashi; Ichikawa, Yaeko; Moritoyo, Takashi; Ikoma, Mayumi; Hashimoto, Tsukasa; Kimura, Fumiharu; Murayama, Shigeo; Onodera, Osamu; Nishizawa, Masatoyo; Yoshida, Mari; Atsuta, Naoki; Sobue, Gen; Fifita, Jennifer A; Williams, Kelly L; Blair, Ian P; Nicholson, Garth A; Gonzalez-Perez, Paloma; Brown, Robert H; Nomoto, Masahiro; Elenius, Klaus; Rouleau, Guy A; Fujiyama, Asao; Morishita, Shinichi; Goto, Jun; Tsuji, Shoji

2013-11-07

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by the degeneration of motor neurons and typically results in death within 3-5 years from onset. Familial ALS (FALS) comprises 5%-10% of ALS cases, and the identification of genes associated with FALS is indispensable to elucidating the molecular pathogenesis. We identified a Japanese family affected by late-onset, autosomal-dominant ALS in which mutations in genes known to be associated with FALS were excluded. A whole- genome sequencing and parametric linkage analysis under the assumption of an autosomal-dominant mode of inheritance with incomplete penetrance revealed the mutation c.2780G>A (p. Arg927Gln) in ERBB4. An extensive mutational analysis revealed the same mutation in a Canadian individual with familial ALS and a de novo mutation, c.3823C>T (p. Arg1275Trp), in a Japanese simplex case. These amino acid substitutions involve amino acids highly conserved among species, are predicted as probably damaging, and are located within a tyrosine kinase domain (p. Arg927Gln) or a C-terminal domain (p. Arg1275Trp), both of which mediate essential functions of ErbB4 as a receptor tyrosine kinase. Functional analysis revealed that these mutations led to a reduced autophosphorylation of ErbB4 upon neuregulin-1 (NRG-1) stimulation. Clinical presentations of the individuals with mutations were characterized by the involvement of both upper and lower motor neurons, a lack of obvious cognitive dysfunction, and relatively slow progression. This study indicates that disruption of the neuregulin-ErbB4 pathway is involved in the pathogenesis of ALS and potentially paves the way for the development of innovative therapeutic strategies such using NRGs or their agonists to upregulate ErbB4 functions. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Multiplex Profiling Identifies Distinct Local and Systemic Alterations during Intraperitoneal Chemotherapy for Ovarian Cancer: an NRG Oncology/Gynecologic Oncology Group Study

PubMed Central

Grabosch, Shannon; Tseng, George; Edwards, Robert P; Lankes, Heather A.; Moore, Kathleen; Odunsi, Kunle; Vlad, Anda; Ma, Tianzhou; Strange, Mary; Brozick, Joan; Lugade, Amit; Omilian, Angela; Bshara, Wiam; Stuckey, Ashley R.; Walker, Joan L.; Birrer, Michael

2017-01-01

OBJECTIVES Ovarian cancer leads to abdominal carcinomatosis and late stage (III/IV) diagnosis in 75% of patients. Three randomized phase III trials have demonstrated that intraperitoneal (IP) chemotherapy improves outcomes in epithelial ovarian cancer. While IP treatment is validated by clinical trials, there is a poor understanding of the mechanism(s) leading to the survival advantage other than the increased concentration of cytotoxic drugs within the tumor microenvironment. A better understanding of this process through analysis of dynamic biomarkers should promote novel approaches that may enhance tumor clearance. We propose this pilot study to confirm the feasibility of collecting serial peritoneal samples from implanted catheters in women receiving IP chemotherapy. We believe these specimens may be used for multiplex analysis to reveal unique biomarker fluctuations when compared to peripheral blood. METHODS From 13 women participating on GOG 252, 30 whole blood, 12 peritoneal fluid (PF), and 20 peritoneal wash (PW) with 30 mL saline were obtained. Samples were requested prior to the first three chemotherapy cycles. Samples were assessed for volume, cell populations, protein, RNA, and miRNA content changes. RESULTS Median volume for PF was 1.6 mL and 3.1 mL for PW. PW is a dilution of PF capable of capturing measurable biomarkers. Peritoneal aspirates contain a unique profile of biomarkers distinct from blood. miRNA undergo earlier alteration with chemotherapy than genes. Flow cytometry does not adequately capture biomarker fluctuations. CONCLUSIONS As a proof of principle study, this trial provides evidence that sampling the peritoneal cavity can be adapted for biomarker analysis. PMID:28483269

CD44 variant isoform 9 emerges in response to injury and contributes to the regeneration of the gastric epithelium

PubMed Central

Bertaux-Skeirik, Nina; Wunderlich, Mark; Teal, Emma; Chakrabarti, Jayati; Biesiada, Jacek; Mahe, Maxime; Sundaram, Nambirajan; Gabre, Joel; Hawkins, Jennifer; Jian, Gao; Engevik, Amy C.; Yang, Li; Wang, Jiang; Goldenring, James R.; Qualls, Joseph E.; Medvedovic, Mario; Helmrath, Michael A.; Diwan, Tayyab; Mulloy, James C.; Zavros, Yana

2017-01-01

The CD44 gene encodes several protein isoforms due to alternative splicing and post translational modifications. Given that CD44 variant isoform 9 (CD44v9) is expressed within Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) glands during repair, CD44v9 may be play a functional role during the process of regeneration of the gastric epithelium. Here we hypothesize that CD44v9 marks a regenerative cell lineage responsive to infiltrating macrophages during regeneration of the gastric epithelium. Ulcers were induced in CD44-decient (CD44KO) and C57BL/6 (BL6) mice by a localized application of acetic acid to the serosal surface of the stomach. Gastric organoids expressing CD44v9 were derived from mouse stomachs and transplanted at the ulcer site of CD44KO mice. Ulcers, CD44v9 expression, proliferation and histology were measured 1, 3, 5 and 7-days post-injury. Human-derived gastric organoids were generated from stomach tissue collected from elderly (>55 years) or young (14–20 years) patients. Organoids were transplanted into the stomachs of NOD scid gamma (NSG) mice at the site of injury. Gastric injury was induced in NRG-SGM3 (NRGS) mice harboring human-derived immune cells (hnNRGS) and the immune profile analyzed by CyTOF. CD44v9 expression emerged within regenerating glands the ulcer margin in response to injury. While ulcers in BL6 mice healed within 7-days post-injury, CD44KO mice exhibited loss of repair and epithelial regeneration. Ulcer healing was promoted in CD44KO mice by transplanted CD55v9-expressing gastric organoids. NSG mice exhibited loss of CD44v9 expression and gastric repair. Transplantation of human-derived gastric organoids from young, but not aged stomachs promoted repair in NSG mouse stomachs in response to injury. Finally, compared to NRGS mice, huNRGS animals exhibited reduced ulcer sizes, an infiltration of human CD162+ macrophages and an emergence of CD44v9 expression in SPEM. Thus, during repair of the gastric epithelium CD44v9 emerges within a regenerative cell lineage t hat coincides with macrophage infiltration within the injured mucosa. PMID:28497484

A Randomized Phase 2 Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy–Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fogh, Shannon E., E-mail: Shannon.Fogh@ucsf.edu; Deshmukh, Snehal; Berk, Lawrence B.

Purpose: Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods: The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus <30% or ≥30%) and were then randomized between supportive care, 10 mL of liquid manuka honey 4 times a day, and 2 lozenges (10 mL of dehydrated manuka honey) 4 times a day during concurrent chemotherapy and radiation therapy.more » The primary endpoint was patient-reported pain on swallowing, with the use of an 11-point (0-10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect a 15% relative reduction of change in NRPS score. The secondary endpoints were trend of pain over time, opioid use, clinically graded and patient-reported adverse events, weight loss, dysphagia, nutritional status, and quality of life. Results: 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant (P=.03), with more patients on the supportive care arm taking opioids. Conclusion: Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed.« less

A Randomized Phase 2 Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy-Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012.

PubMed

Fogh, Shannon E; Deshmukh, Snehal; Berk, Lawrence B; Dueck, Amylou C; Roof, Kevin; Yacoub, Sherif; Gergel, Thomas; Stephans, Kevin; Rimner, Andreas; DeNittis, Albert; Pablo, John; Rineer, Justin; Williams, Terence M; Bruner, Deborah

2017-03-15

Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus <30% or ≥30%) and were then randomized between supportive care, 10 mL of liquid manuka honey 4 times a day, and 2 lozenges (10 mL of dehydrated manuka honey) 4 times a day during concurrent chemotherapy and radiation therapy. The primary endpoint was patient-reported pain on swallowing, with the use of an 11-point (0-10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect a 15% relative reduction of change in NRPS score. The secondary endpoints were trend of pain over time, opioid use, clinically graded and patient-reported adverse events, weight loss, dysphagia, nutritional status, and quality of life. 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant (P=.03), with more patients on the supportive care arm taking opioids. Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed. Copyright © 2016. Published by Elsevier Inc.

A Description of the Building Materials Data Base for Pittsburgh, Pennsylvania.

DTIC Science & Technology

1986-04-01

20: 04 21 410.61 1 0 35 -3 ,1 1 0 1 210 6 21 2, 4266 1 0 39 5 1 0 1 0 19 15 1 0 21 4169 1 0 36- 10 72 0 7 1q3 1 0225 252 1 03 L71 0 9 213 1 022 423 0...2 1 1 17 -4 113 4 I I ERR I I ....... ...... . ............. I.......- 00 40s m 210 蓐 ’ 00 --,".7t9 TD ERR .04 . iEDCNT 1...0 0 500~I! 000 sum 111150.000 F-t TLF VO.L.UE PERCENTILE VA. UE PERCENTILE VALUE Gcc 0 oC 25,00 0.0 33.30 C C.. 000 6. 70 50. 000 75 00 60 c0c. A- TD

Effect of Interfacial Reaction on the Mechanical Performance of Steel to Aluminum Dissimilar Ultrasonic Spot Welds

NASA Astrophysics Data System (ADS)

Xu, Lei; Wang, Li; Chen, Ying-Chun; Robson, Joe D.; Prangnell, Philip B.

2016-01-01

The early stages of formation of intermetallic compounds (IMC) have been investigated in dissimilar aluminum to steel welds, manufactured by high power (2.5 kW) ultrasonic spot welding (USW). To better understand the influence of alloy composition, welds were produced between a low-carbon steel (DC04) and two different aluminum alloys (6111 and 7055). The joint strengths were measured in lap shear tests and the formation and growth behavior of IMCs at the weld interface were characterized by electron microscopy, for welding times from 0.2 to 2.4 seconds. With the material combinations studied, the η (Fe2Al5) intermetallic phase was found to form first, very rapidly in the initial stage of welding, with a discontinuous island morphology. Continuous layers of η and then θ (FeAl3) phase were subsequently seen to develop on extending the welding time to greater than 0.7 second. The IMC layer formed in the DC04-AA7055 combination grew thicker than for the DC04-AA6111 welds, despite both weld sets having near identical thermal histories. Zinc was also found to be dissolved in the IMC phases when welding with the AA7055 alloy. After post-weld aging of the aluminum alloy, fracture in the lap shear tests always occurred along the joint interface; however, the DC04-AA6111 welds had higher fracture energy than the DC04-AA7055 combination.

Nonsteroidal Anti-inflammatory Drugs and Endometrial Carcinoma Mortality and Recurrence

PubMed Central

Felix, Ashley S.; Cohn, David E.; McMeekin, D. Scott; Mutch, David G.; Creasman, William T.; Thaker, Premal H.; Walker, Joan L.; Moore, Richard G.; Lele, Shashikant B.; Guntupalli, Saketh R.; Downs, Levi S.; Nagel, Christa I.; Boggess, John F.; Pearl, Michael L.; Ioffe, Olga B.; Park, Kay J.; Ali, Shamshad; Brinton, Louise A.

2017-01-01

Abstract Background: Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods: Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma–specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results: Five hundred fifty endometrial carcinoma–specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma–specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided Ptrend = .01). NSAID use was not associated with recurrence or endometrial carcinoma–specific mortality among women with type II tumors. Conclusions: In this study, use of NSAIDs was associated with increased endometrial carcinoma–specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted. PMID:28376204

Design of the Dutch Obesity Intervention in Teenagers (NRG-DOiT): systematic development, implementation and evaluation of a school-based intervention aimed at the prevention of excessive weight gain in adolescents

PubMed Central

Singh, Amika S; Chin A Paw, Marijke JM; Kremers, Stef PJ; Visscher, Tommy LS; Brug, Johannes; van Mechelen, Willem

2006-01-01

Background Only limited data are available on the development, implementation, and evaluation processes of weight gain prevention programs in adolescents. To be able to learn from successes and failures of such interventions, integral written and published reports are needed. Methods Applying the Intervention Mapping (IM) protocol, this paper describes the development, implementation, and evaluation of the Dutch Obesity Intervention in Teenagers (DOiT), a school-based intervention program aimed at the prevention of excessive weight gain. The intervention focussed on the following health behaviours: (1) reduction of the consumption of sugar-sweetened beverages, (2) reduction of energy intake derived from snacks, (3) decrease of levels of sedentary behaviour, and (4) increase of levels of physical activity (i.e. active transport behaviour and sports participation). The intervention program consisted of an individual classroom-based component (i.e. an educational program, covering 11 lessons of both biology and physical education classes), and an environmental component (i.e. encouraging and supporting changes at the school canteens, as well as offering additional physical education classes). We evaluated the effectiveness of the intervention program using a randomised controlled trial design. We assessed the effects of the intervention on body composition (primary outcome measure), as well as on behaviour, behavioural determinants, and aerobic fitness (secondary outcome measures). Furthermore, we conducted a process evaluation. Discussion The development of the DOiT-intervention resulted in a comprehensive school-based weight gain prevention program, tailored to the needs of Dutch adolescents from low socio-economic background. PMID:17173701

NRG Oncology-Radiation Therapy Oncology Group Study 1014: 1-Year Toxicity Report From a Phase 2 Study of Repeat Breast-Preserving Surgery and 3-Dimensional Conformal Partial-Breast Reirradiation for In-Breast Recurrence.

PubMed

Arthur, Douglas W; Winter, Kathryn A; Kuerer, Henry M; Haffty, Bruce G; Cuttino, Laurie W; Todor, Dorin A; Simone, Nicole L; Hayes, Shelly B; Woodward, Wendy A; McCormick, Beryl; Cohen, Randi J; Sahijdak, Walter M; Canaday, Daniel J; Brown, Doris R; Currey, Adam D; Fisher, Christine M; Jagsi, Reshma; White, Julia

2017-08-01

To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation. Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, <3 cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade ≥3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring ≤1 year from re-treatment completion. A rate of ≥13% for these AEs in a cohort of 55 patients was determined to be unacceptable (86% power, 1-sided α = 0.07). Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 ≤1 cm, 13 >1 to ≤2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 (<2%) grade ≥3 and identified as grade 3 fibrosis of deep connective tissue. Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in-breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare. Copyright © 2017 Elsevier Inc. All rights reserved.

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Michaelson, M. Dror, E-mail: dmichaelson1@partners.org; Hu, Chen; Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Purpose: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab. Methods and Materials: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completionmore » rate, and survival. Results: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2. Conclusions: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.« less

Randomized Phase II Evaluation of Bevacizumab Versus Bevacizumab Plus Fosbretabulin in Recurrent Ovarian, Tubal, or Peritoneal Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study

PubMed Central

Sill, Michael W.; Walker, Joan L.; Darus, Christopher J.; Sutton, Gregory; Tewari, Krishnansu S.; Martin, Lainie P.; Schilder, Jeanne M.; Coleman, Robert L.; Balkissoon, Jai; Aghajanian, Carol

2016-01-01

Purpose The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. Patients and Methods Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m2) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. Results The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. Conclusion On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension. PMID:27217446

Randomized Phase II Evaluation of Bevacizumab Versus Bevacizumab Plus Fosbretabulin in Recurrent Ovarian, Tubal, or Peritoneal Carcinoma: An NRG Oncology/Gynecologic Oncology Group Study.

PubMed

Monk, Bradley J; Sill, Michael W; Walker, Joan L; Darus, Christopher J; Sutton, Gregory; Tewari, Krishnansu S; Martin, Lainie P; Schilder, Jeanne M; Coleman, Robert L; Balkissoon, Jai; Aghajanian, Carol

2016-07-01

The vascular disrupting agent fosbretabulin tromethamine selectively targets pre-existing tumor vasculature, which causes vascular shutdown and leads to cancer cell death and necrosis. Antiangiogenesis agents such as bevacizumab, a humanized antivascular endothelial growth factor monoclonal antibody, might prevent revascularization during and after treatment with a vascular disrupting agent. Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to bevacizumab (15 mg/kg intravenously once every 3 weeks) or the combination of bevacizumab (15 mg/kg) plus fosbretabulin (60 mg/m(2)) intravenously once every 3 weeks until disease progression or toxicity. Randomization was stratified by disease status (measurable v nonmeasurable), prior bevacizumab, and platinum-free interval. The primary end point was progression-free survival (PFS). The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%. The study enrolled 107 patients. Median PFS was 4.8 months for bevacizumab and 7.3 months for bevacizumab plus fosbretabulin (hazard ratio, 0.69; 90% two-sided CI, 0.47 to 1.00; one-sided P = .05). The proportion responding (overall response rate) to bevacizumab was 28.2% among 39 patients with measurable disease and 35.7% among 42 patients treated with the combination. The relative probability of responding was 1.27 (90% CI, 0.74 to 2.17; one-sided P = .24). Adverse events greater than grade 3 were more common in the combination regimen than in bevacizumab only for hypertension (35% v 20%). There was one grade 3 thromboembolic event in the combination arm and one intestinal fistula in the bevacizumab only arm. On the basis of the PFS, overall response rate, and tolerability of these two antivascular therapies, further evaluation is warranted for this chemotherapy-free regimen. Fosbretabulin in combination with bevacizumab increases the risk of hypertension. © 2016 by American Society of Clinical Oncology.

Failure Behavior of Granite Affected by Confinement and Water Pressure and Its Influence on the Seepage Behavior by Laboratory Experiments

PubMed Central

Cheng, Cheng; Li, Xiao; Li, Shouding; Zheng, Bo

2017-01-01

Failure behavior of granite material is paramount for host rock stability of geological repositories for high-level waste (HLW) disposal. Failure behavior also affects the seepage behavior related to transportation of radionuclide. Few of the published studies gave a consistent analysis on how confinement and water pressure affect the failure behavior, which in turn influences the seepage behavior of the rock during the damage process. Based on a series of laboratory experiments on NRG01 granite samples cored from Alxa area, a candidate area for China’s HLW disposal, this paper presents some detailed observations and analyses for a better understanding on the failure mechanism and seepage behavior of the samples under different confinements and water pressure. The main findings of this study are as follows: (1) Strength reduction properties were found for the granite under water pressure. Besides, the complete axial stress–strain curves show more obvious yielding process in the pre-peak region and a more gradual stress drop in the post-peak region; (2) Shear fracturing pattern is more likely to form in the granite samples with the effect of water pressure, even under much lower confinements, than the predictions from the conventional triaxial compressive results; (3) Four stages of inflow rate curves are divided and the seepage behaviors are found to depend on the failure behavior affected by the confinement and water pressure. PMID:28773157

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health.

PubMed

Beaulieu, Jean-Martin

2012-01-01

Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches.

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

PubMed Central

Beaulieu, Jean-Martin

2012-01-01

Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches. PMID:21711983

Retroperitoneal sarcoma (RPS) high risk gross tumor volume boost (HR GTV boost) contour delineation agreement among NRG sarcoma radiation and surgical oncologists.

PubMed

Baldini, Elizabeth H; Bosch, Walter; Kane, John M; Abrams, Ross A; Salerno, Kilian E; Deville, Curtiland; Raut, Chandrajit P; Petersen, Ivy A; Chen, Yen-Lin; Mullen, John T; Millikan, Keith W; Karakousis, Giorgos; Kendrick, Michael L; DeLaney, Thomas F; Wang, Dian

2015-09-01

Curative intent management of retroperitoneal sarcoma (RPS) requires gross total resection. Preoperative radiotherapy (RT) often is used as an adjuvant to surgery, but recurrence rates remain high. To enhance RT efficacy with acceptable tolerance, there is interest in delivering "boost doses" of RT to high-risk areas of gross tumor volume (HR GTV) judged to be at risk for positive resection margins. We sought to evaluate variability in HR GTV boost target volume delineation among collaborating sarcoma radiation and surgical oncologist teams. Radiation planning CT scans for three cases of RPS were distributed to seven paired radiation and surgical oncologist teams at six institutions. Teams contoured HR GTV boost volumes for each case. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. HRGTV boost volume contour agreement between the seven teams was "substantial" or "moderate" for all cases. Agreement was best on the torso wall posteriorly (abutting posterior chest abdominal wall) and medially (abutting ipsilateral para-vertebral space and great vessels). Contours varied more significantly abutting visceral organs due to differing surgical opinions regarding planned partial organ resection. Agreement of RPS HRGTV boost volumes between sarcoma radiation and surgical oncologist teams was substantial to moderate. Differences were most striking in regions abutting visceral organs, highlighting the importance of collaboration between the radiation and surgical oncologist for "individualized" target delineation on the basis of areas deemed at risk and planned resection.

The 'Moskva' satellite television broadcasting system

NASA Astrophysics Data System (ADS)

Kantor, L. Ia.; Minashin, V. P.; Povolotskii, I. S.; Sokolov, A. V.; Talyzin, N. V.

1980-01-01

The Moskva television broadcasting system which uses the high-power links from the Gorizont satellite is described. The transmitting device of the ground station is similar to that of the Ekran and Intersputnik systems. The system includes a special television signal processing unit, a unit for introducing dispersion signals, and transmitting equipment for the sound and radio-broadcasting channels. The signal translated by the satellite is received by a network of ground receiving stations and fed to a television transmitter with a power of 1, 10, or 100 W. The signal in the radio-broadcasting channel can be transmitted into the local radio repeater network or transmitted by a USW FM radio-broadcasting transmitter. The results of system tests are provided.

A Randomized Phase II Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis During the Treatment of Lung Cancer: Results of NRG Oncology RTOG 1012

PubMed Central

Fogh, Shannon; Deshmukh, Snehal; Berk, Lawrence B.; Dueck, Amylou C.; Roof, Kevin; Yacoub, Sherif; Gergel, Thomas; Stephans, Kevin; Rimner, Andreas; DeNittis, Albert; Pablo, John; Rineer, Justin; Williams, Terence M.; Bruner, Deborah

2017-01-01

Purpose Randomized trials have shown that honey is effective for prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods Patients were stratified by percentage of esophagus receiving specific radiation dose (V60Gy esophagus < or ≥ 30%), then randomized between supportive care, 10 ml of liquid Manuka honey four times a day or 2 lozenges (10 ml of dehydrated Manuka honey) four times a day during concurrent chemotherapy and radiotherapy. The primary endpoint was patient-reported pain on swallowing utilizing an eleven point (0–10) scale at 4 weeks (Numerical Rating Pain Scale, NRPS). The study was designed to detect 15% relative reduction of change in NRPS score. Secondary endpoints were trend of pain over time, opioid use, clinically-graded and patient-reported adverse events, weight loss, dysphagia, nutritional status and quality of life. Results 53 patients were randomized to supportive care, 54 randomized to liquid honey and 56 to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms which was found to be significant (p=0.03) with more patients on the supportive care arm taking opioids. Conclusion Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed. PMID:28244415

Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia.

PubMed

Mohammadi, Alireza; Rashidi, Ehsan; Amooeian, Vahid Ghasem

2018-04-13

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1β (IL-1β), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of neurotransmitters and also highlights the strengths and weaknesses of studies attempting to identify candidate biomarkers. Copyright © 2018 Elsevier B.V. All rights reserved.

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin

PubMed Central

WANG, STEPHANIE S.; HSIAO, RUTH; LIMPAR, MARIKO M.; LOMAHAN, SARAH; TRAN, TUAN-ANH; MALONEY, NOLAN J.; IKEGAKI, NAOHIKO; TANG, XAO X.

2014-01-01

In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects. PMID:24190252

Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.

PubMed

Wang, Stephanie S; Hsiao, Ruth; Limpar, Mariko M; Lomahan, Sarah; Tran, Tuan-Anh; Maloney, Nolan J; Ikegaki, Naohiko; Tang, Xao X

2014-01-01

In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.

Petrology and geochemistry of samples from bed-contact zones in Tunnel Bed 5, U12g-Tunnel, Nevada Test Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Connolly, J.R.; Keil, K.; Mansker, W.L.

1984-10-01

This report summarizes the detailed geologic characterization of samples of bed-contact zones and surrounding nonwelded bedded tuffs, both within Tunnel Bed 5, that are exposed in the G-Tunnel complex beneath Rainier Mesa on the Nevada Test Site (NTS). Original planning studies treated the bed-contact zones in Tunnel Bed 5 as simple planar surfaces of relatively high permeability. Detailed characterization, however, indicates that these zones have a finite thickness, are depositional in origin, vary considerably over short vertical and horizontal distances, and are internally complex. Fluid flow in a sequence of nonwelded zeolitized ash-flow or bedded tuffs and thin intervening reworkedmore » zones appears to be a porous-medium phenomenon, regardless of the presence of layering. There are no consistent differences in either bulk composition or detailed mineralogy between bedded tuffs and bed-contact zones in Tunnel Bed 5. Although the original bulk composition of Tunnel Bed 5 was probably peralkaline, extensive zeolitization has resulted in a present peraluminous bulk composition of both bedded tuffs and bed-contact zones. The major zeolite present, clinoptilolite, is intermediate (Ca:K:Na = 26:35:39) and effectively uniform in composition. This composition is similar to that of clinoptilolite from the tuffaceous beds of Calico Hills above the static water level in hole USW G-1, but somewhat different from that reported for zeolites from below the static water level in USW G-2. Tunnel Bed 5 also contains abundant hydrous manganese oxides. The similarity in composition of the clinoptilolites from Tunnel Bed 5 and those above the static water level at Yucca Mountain indicates that many of the results of nuclide-migration experiments in Tunnel Bed 5 would be transferrable to zeolitized nonwelded tuffs above the static water level at Yucca Mountain.« less

Heavy metals, salts and organic residues in old solid urban waste landfills and surface waters in their discharge areas: determinants for restoring their impact.

PubMed

Pastor, J; Hernández, A J

2012-03-01

This study was designed to determine the state of polluted soils in the main landfills of the Community of Madrid (central Spain), as part of a continuous assessment of the impacts of urban solid waste (USW) landfills that were capped with a layer of soil 20 years ago. Our analysis of this problem has been highly conditioned by the constant re-use of many of the USW landfills, since they have never been the target of any specific restoration plan. Our periodical analysis of cover soils and soils from discharge areas of the landfills indicates soil pollution has worsened over the years. Here, we examined heavy metal, salts, and organic compounds in soil and surface water samples taken from 15 landfills in the Madrid region. Impacts of the landfill soil covers on nematode and plant diversity were also evaluated. These analyses continue to reveal the presence of heavy metals (Zn, Cu, Cr, Ni, Pb, Cd) in soils, and salts (sulphates, chlorides and nitrates) in soils and surface waters. In addition, non-agricultural organic compounds, mainly aromatic and aliphatic hydrocarbons, often appeared in very high concentrations, and high levels of insecticides such as gamma-HCH (lindane) were also detected in soils. Around 50% of the water samples collected showed chemical demand of oxygen (CDO) values in excess of 150 mg/l. Traces of phenolic compounds were detected in some landfills, some of which exhibited high levels of 2-chlorophenol and pentachlorophenol. All these factors are conditioning both the revegetation of the landfill systems and the remediation of their slopes and terrestrial ecosystems arising in their discharge areas. This work updates the current situation and discusses risks for the health of the ecosystems, humans, domestic animals and wildlife living close to these landfills. Copyright © 2011 Elsevier Ltd. All rights reserved.

Schreibende Messgeräte

NASA Astrophysics Data System (ADS)

Plaßmann, Wilfried

Die schreibenden Messgeräte werden hauptsächlich eingesetzt, um Vorgänge aufzuzeichnen und zu dokumentieren, die sich im Minuten- und Stunden-Bereich abspielen. Sie sind weitgehend durch Oszilloskope oder elektronische Geräte ähnlich einem Oszilloskop ersetzt worden, die entsprechend für Langzeitaufnahmen ausgelegt sind. Der Vorteil dieser Geräte gegenüber den schreibenden Messgeräten ist der, dass die Daten dauerhaft gespeichert sind, einschließlich der notwendigen Kenngrößen wie Zeitmaßstab, Amplitude, Datum, Aufzeichnungsgerät usw., und sich in dieser Form beliebig oft ausdrucken und vor allem direkt weiterverarbeiten lassen. Weiterhin entfallen die Probleme mit der Mechanik, dem Papier und den Schreibstiften. Deshalb folgt hier eine nur kurze Darstellung der Geräte.

Long-Term Follow-Up of Cardiac Function and Quality of Life for Patients in NSABP Protocol B-31/NRG Oncology: A Randomized Trial Comparing the Safety and Efficacy of Doxorubicin and Cyclophosphamide (AC) Followed by Paclitaxel With AC Followed by Paclitaxel and Trastuzumab in Patients With Node-Positive Breast Cancer With Tumors Overexpressing Human Epidermal Growth Factor Receptor 2.

PubMed

Ganz, Patricia A; Romond, Edward H; Cecchini, Reena S; Rastogi, Priya; Geyer, Charles E; Swain, Sandra M; Jeong, Jong-Hyeon; Fehrenbacher, Louis; Gross, Howard M; Brufsky, Adam M; Flynn, Patrick J; Wahl, Tanya A; Seay, Thomas E; Wade, James L; Biggs, David D; Atkins, James N; Polikoff, Jonathan; Zapas, John L; Mamounas, Eleftherios P; Wolmark, Norman

2017-12-10

Purpose Early cardiac toxicity is a risk associated with adjuvant chemotherapy plus trastuzumab. However, objective measures of cardiac function and health-related quality of life are lacking in long-term follow-up of patients who remain cancer free after completion of adjuvant treatment. Patients and Methods Patients in NSABP Protocol B-31 received anthracycline and taxane chemotherapy with or without trastuzumab for adjuvant treatment of node-positive, human epidermal growth factor receptor 2-positive early-stage breast cancer. A long-term follow-up assessment was undertaken for patients who were alive and disease free, which included measurement of left ventricular ejection fraction by multigated acquisition scan along with patient-reported outcomes using the Duke Activity Status Index (DASI), the Medical Outcomes Study questionnaire, and a review of current medications and comorbid conditions. Results At a median follow-up of 8.8 years among eligible participants, five (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group had a > 10% decline in left ventricular ejection fraction from baseline to a value < 50%. Lower DASI scores correlated with age and use of medications for hypertension, cardiac conditions, diabetes, and hyperlipidemia, but not with whether patients had received trastuzumab. Conclusion In patients without underlying cardiac disease at baseline, the addition of trastuzumab to adjuvant anthracycline and taxane-based chemotherapy does not result in long-term worsening of cardiac function, cardiac symptoms, or health-related quality of life. The DASI questionnaire may provide a simple and useful tool for monitoring patient-reported changes that reflect cardiac function.

High treatment efficacy by dual targeting of Burkitt's lymphoma xenografted mice with a (177)Lu-based CD22-specific radioimmunoconjugate and rituximab.

PubMed

Weber, Tobias; Bötticher, Benedikt; Mier, Walter; Sauter, Max; Krämer, Susanne; Leotta, Karin; Keller, Armin; Schlegelmilch, Anne; Grosse-Hovest, Ludger; Jäger, Dirk; Haberkorn, Uwe; Arndt, Michaela A E; Krauss, Jürgen

2016-03-01

Dual-targeted therapy has been shown to be a promising treatment option in recurrent and/or refractory B-cell non-Hodgkin's lymphoma (B-NHL). We generated radioimmunoconjugates (RICs) comprising either a novel humanized anti-CD22 monoclonal antibody, huRFB4, or rituximab, and the low-energy β-emitter (177)Lu. Both RICs were evaluated as single agents in a human Burkitt's lymphoma xenograft mouse model. To increase the therapeutic efficacy of the anti-CD22 RIC, combination therapy with unlabelled anti-CD20 rituximab was explored. The binding activity of CHX-A″-DTPA-conjugated antibodies to target cells was analysed by flow cytometry. To assess tumour targeting of (177)Lu-labelled antibodies, in vivo biodistribution experiments were performed. For radioimmunotherapy (RIT) studies, non-obese diabetic recombination activating gene-1 (NOD-Rag1 (null) ) interleukin-2 receptor common gamma chain (IL2rγ (null) ) null mice (NRG mice) were xenografted subcutaneously with Raji Burkitt's lymphoma cells. (177)Lu-conjugated antibodies were administered at a single dose of 9.5 MBq per mouse. For dual-targeted therapy, rituximab was injected at weekly intervals (0.5 - 1.0 mg). Tumour accumulation of RICs was monitored by planar scintigraphy. Conjugation of CHX-A"-DTPA resulted in highly stable RICs with excellent antigen-binding properties. Biodistribution experiments revealed higher tumour uptake of the (177)Lu-labelled anti-CD22 IgG than of (177)Lu-labelled rituximab. Treatment with (177)Lu-conjugated huRFB4 resulted in increased tumour growth inhibition and significantly longer survival than treatment with (177)Lu-conjugated rituximab. The therapeutic efficacy of the anti-CD22 RIC could be markedly enhanced by combination with unlabelled rituximab. These findings suggest that dual targeting with (177)Lu-based CD22-specific RIT in combination with rituximab is a promising new treatment option for refractory B-NHL.

Potential Impact of miR-137 and Its Targets in Schizophrenia

PubMed Central

Wright, Carrie; Turner, Jessica A.; Calhoun, Vince D.; Perrone-Bizzozero, Nora

2013-01-01

The significant impact of microRNAs (miRNAs) on disease pathology is becoming increasingly evident. These small non-coding RNAs have the ability to post-transcriptionally silence the expression of thousands of genes. Therefore, dysregulation of even a single miRNA could confer a large polygenic effect. Schizophrenia is a genetically complex illness thought to involve multiple genes each contributing a small risk. Large genome-wide association studies identified miR-137, a miRNA shown to be involved in neuronal maturation, as one of the top risk genes. To assess the potential mechanism of impact of miR-137 in this disorder and identify its targets, we used a combination of literature searches, ingenuity pathway analysis (IPA), and freely accessible bioinformatics resources. Using TargetScan and the schizophrenia gene resource (SZGR) database, we found that in addition to CSMD1, C10orf26, CACNA1C, TCF4, and ZNF804A, five schizophrenia risk genes whose transcripts are also validated miR-137 targets, there are other schizophrenia-associated genes that may be targets of miR-137, including ERBB4, GABRA1, GRIN2A, GRM5, GSK3B, NRG2, and HTR2C. IPA analyses of all the potential targets identified several nervous system (NS) functions as the top canonical pathways including synaptic long-term potentiation, a process implicated in learning and memory mechanisms and recently shown to be altered in patients with schizophrenia. Among the subset of targets involved in NS development and function, the top scoring pathways were ephrin receptor signaling and axonal guidance, processes that are critical for proper circuitry formation and were shown to be disrupted in schizophrenia. These results suggest that miR-137 may indeed play a substantial role in the genetic etiology of schizophrenia by regulating networks involved in neural development and brain function. PMID:23637704

Does parental expressed emotion moderate genetic effects in ADHD? An exploration using a genome wide association scan.

PubMed

Sonuga-Barke, Edmund J S; Lasky-Su, Jessica; Neale, Benjamin M; Oades, Robert; Chen, Wai; Franke, Barbara; Buitelaar, Jan; Banaschewski, Tobias; Ebstein, Richard; Gill, Michael; Anney, Richard; Miranda, Ana; Mulas, Fernando; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Thompson, Margaret; Asherson, Philip; Faraone, Stephen V

2008-12-05

Studies of gene x environment (G x E) interaction in ADHD have previously focused on known risk genes for ADHD and environmentally mediated biological risk. Here we use G x E analysis in the context of a genome-wide association scan to identify novel genes whose effects on ADHD symptoms and comorbid conduct disorder are moderated by high maternal expressed emotion (EE). SNPs (600,000) were genotyped in 958 ADHD proband-parent trios. After applying data cleaning procedures we examined 429,981 autosomal SNPs in 909 family trios. ADHD symptom severity and comorbid conduct disorder was measured using the Parental Account of Childhood Symptoms interview. Maternal criticism and warmth (i.e., EE) were coded by independent observers on comments made during the interview. No G x E interactions reached genome-wide significance. Nominal effects were found both with and without genetic main effects. For those with genetic main effects 36 uncorrected interaction P-values were <10(-5) implicating both novel genes as well as some previously supported candidates. These were found equally often for all of the interactions being investigated. The observed interactions in SLC1A1 and NRG3 SNPs represent reasonable candidate genes for further investigation given their previous association with several psychiatric illnesses. We find evidence for the role of EE in moderating the effects of genes on ADHD severity and comorbid conduct disorder, implicating both novel and established candidates. These findings need replicating in larger independent samples. Copyright 2008 Wiley-Liss, Inc.

Proteus vulgaris and Proteus mirabilis Decrease Candida albicans Biofilm Formation by Suppressing Morphological Transition to Its Hyphal Form.

PubMed

Lee, Kyoung Ho; Park, Su Jung; Choi, Sun Ju; Park, Joo Young

2017-11-01

Candida albicans (C. albicans) and Proteus species are causative agents in a variety of opportunistic nosocomial infections, and their ability to form biofilms is known to be a virulence factor. In this study, the influence of co-cultivation with Proteus vulgaris (P. vulgaris) and Proteus mirabilis (P. mirabilis) on C. albicans biofilm formation and its underlying mechanisms were examined. XTT reduction assays were adopted to measure biofilm formation, and viable colony counts were performed to quantify yeast growth. Real-time reverse transcriptase polymerase chain reaction was used to evaluate the expression of yeast-specific genes (rhd1 and rbe1), filament formation inhibiting genes (tup1 and nrg1), and hyphae-related genes (als3, ece1, hwp1, and sap5). Candida biofilm formation was markedly inhibited by treatment with either living or heat-killed P. vulgaris and P. mirabilis. Proteus-cultured supernatant also inhibited Candida biofilm formation. Likewise, treatment with live P. vulgaris or P. mirabilis or with Proteus-cultured supernatant decreased expression of hyphae-related C. albicans genes, while the expression of yeast-specific genes and the filament formation inhibiting genes of C. albicans were increased. Heat-killed P. vulgaris and P. mirabilis treatment, however, did not affect the expression of C. albicans morphology-related genes. These results suggest that secretory products from P. vulgaris and P. mirabilis regulate the expression of genes related to morphologic changes in C. albicans such that transition from the yeast form to the hyphal form can be inhibited. © Copyright: Yonsei University College of Medicine 2017

Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients.

PubMed

Wang, Rui; Zhang, Yang; Pan, Yunjian; Li, Yuan; Hu, Haichuan; Cai, Deng; Li, Hang; Ye, Ting; Luo, Xiaoyang; Zhang, Yiliang; Li, Bin; Shen, Lei; Sun, Yihua; Chen, Haiquan

2015-10-27

To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients. Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated. Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001). We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.

Numerical renormalization group calculation of impurity internal energy and specific heat of quantum impurity models

NASA Astrophysics Data System (ADS)

Merker, L.; Costi, T. A.

2012-08-01

We introduce a method to obtain the specific heat of quantum impurity models via a direct calculation of the impurity internal energy requiring only the evaluation of local quantities within a single numerical renormalization group (NRG) calculation for the total system. For the Anderson impurity model we show that the impurity internal energy can be expressed as a sum of purely local static correlation functions and a term that involves also the impurity Green function. The temperature dependence of the latter can be neglected in many cases, thereby allowing the impurity specific heat Cimp to be calculated accurately from local static correlation functions; specifically via Cimp=(∂Eionic)/(∂T)+(1)/(2)(∂Ehyb)/(∂T), where Eionic and Ehyb are the energies of the (embedded) impurity and the hybridization energy, respectively. The term involving the Green function can also be evaluated in cases where its temperature dependence is non-negligible, adding an extra term to Cimp. For the nondegenerate Anderson impurity model, we show by comparison with exact Bethe ansatz calculations that the results recover accurately both the Kondo induced peak in the specific heat at low temperatures as well as the high-temperature peak due to the resonant level. The approach applies to multiorbital and multichannel Anderson impurity models with arbitrary local Coulomb interactions. An application to the Ohmic two-state system and the anisotropic Kondo model is also given, with comparisons to Bethe ansatz calculations. The approach could also be of interest within other impurity solvers, for example, within quantum Monte Carlo techniques.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study.

PubMed

Hamilton, C A; Miller, A; Casablanca, Y; Horowitz, N S; Rungruang, B; Krivak, T C; Richard, S D; Rodriguez, N; Birrer, M J; Backes, F J; Geller, M A; Quinn, M; Goodheart, M J; Mutch, D G; Kavanagh, J J; Maxwell, G L; Bookman, M A

2018-02-01

To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors. Published by Elsevier Inc.

EWS-FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma.

PubMed

Shimizu, Rikuka; Tanaka, Miwa; Tsutsumi, Shuichi; Aburatani, Hiroyuki; Yamazaki, Yukari; Homme, Mizuki; Kitagawa, Yoshimasa; Nakamura, Takuro

2018-06-26

EWS-FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS-FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here we clarified the global DNA binding properties of EWS-FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS-FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS-FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS-FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS-FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS-FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co-regulated by EWS-FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS-FLI1 function as well as the importance of GGAA microsatellites. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clinicopathologic characteristics associated with long-term survival in advanced epithelial ovarian cancer: an NRG Oncology/Gynecologic Oncology Group ancillary data study

PubMed Central

Hamilton, C. A.; Miller, A.; Casablanca, Y.; Horowitz, N. S.; Rungruang, B.; Krivak, T. C.; Richard, S. D.; Rodriguez, N.; Birrer, M.J.; Backes, F.J.; Geller, M.A.; Quinn, M.; Goodheart, M.J.; Mutch, D.G.; Kavanagh, J.J.; Maxwell, G. L.; Bookman, M. A.

2018-01-01

Objective To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors. Methods Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (>10 years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC). Results The analysis dataset included 3,010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p<0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors. Conclusions The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors. PMID:29195926

Developmental Regulation of an Adhesin Gene during Cellular Morphogenesis in the Fungal Pathogen Candida albicans▿ †

PubMed Central

Argimón, Silvia; Wishart, Jill A.; Leng, Roger; Macaskill, Susan; Mavor, Abigail; Alexandris, Thomas; Nicholls, Susan; Knight, Andrew W.; Enjalbert, Brice; Walmsley, Richard; Odds, Frank C.; Gow, Neil A. R.; Brown, Alistair J. P.

2007-01-01

Candida albicans expresses specific virulence traits that promote disease establishment and progression. These traits include morphological transitions between yeast and hyphal growth forms that are thought to contribute to dissemination and invasion and cell surface adhesins that promote attachment to the host. Here, we describe the regulation of the adhesin gene ALS3, which is expressed specifically during hyphal development in C. albicans. Using a combination of reporter constructs and regulatory mutants, we show that this regulation is mediated by multiple factors at the transcriptional level. The analysis of ALS3 promoter deletions revealed that this promoter contains two activation regions: one is essential for activation during hyphal development, while the second increases the amplitude of this activation. Further deletion analyses using the Renilla reniformis luciferase reporter delineate the essential activation region between positions −471 and −321 of the promoter. Further 5′ or 3′ deletions block activation. ALS3 transcription is repressed mainly by Nrg1 and Tup1, but Rfg1 contributes to this repression. Efg1, Tec1, and Bcr1 are essential for the transcriptional activation of ALS3, with Tec1 mediating its effects indirectly through Bcr1 rather than through the putative Tec1 sites in the ALS3 promoter. ALS3 transcription is not affected by Cph2, but Cph1 contributes to full ALS3 activation. The data suggest that multiple morphogenetic signaling pathways operate through the promoter of this adhesin gene to mediate its developmental regulation in this major fungal pathogen. PMID:17277173

LH and hCG Action on the Same Receptor Results in Quantitatively and Qualitatively Different Intracellular Signalling

PubMed Central

Casarini, Livio; Lispi, Monica; Longobardi, Salvatore; Milosa, Fabiola; La Marca, Antonio; Tagliasacchi, Daniela; Pignatti, Elisa; Simoni, Manuela

2012-01-01

Human luteinizing hormone (hLH) and chorionic gonadotropin (hCG) act on the same receptor (LHCGR) but it is not known whether they elicit the same cellular and molecular response. This study compares for the first time the activation of cell-signalling pathways and gene expression in response to hLH and hCG. Using recombinant hLH and recombinant hCG we evaluated the kinetics of cAMP production in COS-7 and hGL5 cells permanently expressing LHCGR (COS-7/LHCGR, hGL5/LHCGR), as well as cAMP, ERK1/2, AKT activation and progesterone production in primary human granulosa cells (hGLC). The expression of selected target genes was measured in the presence or absence of ERK- or AKT-pathways inhibitors. In COS-7/LHCGR cells, hCG is 5-fold more potent than hLH (cAMP ED50: 107.1±14.3 pM and 530.0±51.2 pM, respectively). hLH maximal effect was significantly faster (10 minutes by hLH; 1 hour by hCG). In hGLC continuous exposure to equipotent doses of gonadotropins up to 36 hours revealed that intracellular cAMP production is oscillating and significantly higher by hCG versus hLH. Conversely, phospho-ERK1/2 and -AKT activation was more potent and sustained by hLH versus hCG. ERK1/2 and AKT inhibition removed the inhibitory effect on NRG1 (neuregulin) expression by hLH but not by hCG; ERK1/2 inhibition significantly increased hLH- but not hCG-stimulated CYP19A1 (aromatase) expression. We conclude that: i) hCG is more potent on cAMP production, while hLH is more potent on ERK and AKT activation; ii) hGLC respond to equipotent, constant hLH or hCG stimulation with a fluctuating cAMP production and progressive progesterone secretion; and iii) the expression of hLH and hCG target genes partly involves the activation of different pathways depending on the ligand. Therefore, the LHCGR is able to differentiate the activity of hLH and hCG. PMID:23071612

Validating a Local Failure Risk Stratification for Use in Prospective Studies of Adjuvant Radiation Therapy for Bladder Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baumann, Brian C.; He, Jiwei; Hwang, Wei-Ting

Purpose: To inform prospective trials of adjuvant radiation therapy (adj-RT) for bladder cancer after radical cystectomy, a locoregional failure (LF) risk stratification was proposed. This stratification was developed and validated using surgical databases that may not reflect the outcomes expected in prospective trials. Our purpose was to assess sources of bias that may affect the stratification model's validity or alter the LF risk estimates for each subgroup: time bias due to evolving surgical techniques; trial accrual bias due to inclusion of patients who would be ineligible for adj-RT trials because of early disease progression, death, or loss to follow-up shortlymore » after cystectomy; bias due to different statistical methods to estimate LF; and subgrouping bias due to different definitions of the LF subgroups. Methods and Materials: The LF risk stratification was developed using a single-institution cohort (n=442, 1990-2008) and the multi-institutional SWOG 8710 cohort (n=264, 1987-1998) treated with radical cystectomy with or without chemotherapy. We evaluated the sensitivity of the stratification to sources of bias using Fine-Gray regression and Kaplan-Meier analyses. Results: Year of radical cystectomy was not associated with LF risk on univariate or multivariate analysis after controlling for risk group. By use of more stringent inclusion criteria, 26 SWOG patients (10%) and 60 patients from the single-institution cohort (14%) were excluded. Analysis of the remaining patients confirmed 3 subgroups with significantly different LF risks with 3-year rates of 7%, 17%, and 36%, respectively (P<.01), nearly identical to the rates without correcting for trial accrual bias. Kaplan-Meier techniques estimated higher subgroup LF rates than competing risk analysis. The subgroup definitions used in the NRG-GU001 adj-RT trial were validated. Conclusions: These sources of bias did not invalidate the LF risk stratification or substantially change the model's LF estimates.« less

Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Basch, Ethan, E-mail: ebasch@med.unc.edu; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; Pugh, Stephanie L.

Purpose: To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Methods and Materials: Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visitsmore » when an expected PRO-CTCAE assessment was completed. Results: Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling “too sick.” Conclusions: Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies.« less

Feasibility of Patient Reporting of Symptomatic Adverse Events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial.

PubMed

Basch, Ethan; Pugh, Stephanie L; Dueck, Amylou C; Mitchell, Sandra A; Berk, Lawrence; Fogh, Shannon; Rogak, Lauren J; Gatewood, Marcha; Reeve, Bryce B; Mendoza, Tito R; O'Mara, Ann M; Denicoff, Andrea M; Minasian, Lori M; Bennett, Antonia V; Setser, Ann; Schrag, Deborah; Roof, Kevin; Moore, Joan K; Gergel, Thomas; Stephans, Kevin; Rimner, Andreas; DeNittis, Albert; Bruner, Deborah Watkins

2017-06-01

To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling "too sick." Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies. Copyright © 2017 Elsevier Inc. All rights reserved.

Maps showing petroleum exploration intensity and production in major Cambrian to Ordovician reservoir rocks in the Anadarko Basin

USGS Publications Warehouse

Henry, Mitch; Hester, Tim

1996-01-01

The Anadarko basin is a large, deep, two-stage Paleozoic basin (Feinstein, 1981) that is petroleum rich and generally well explored. The Anadarko basin province, a geogrphic area used here mostly for the convenience of mapping and data management, is defined by political boundaries that include the Anadarko basin proper. The boundaries of the province are identical to those used by the U.S. Geological Survey (USGS) in the 1995 National Assessment of United Stated Oil and Gas Resources. The data in this report, also identical to those used in the national assessment, are from several computerized data bases including Nehring Research Group (NRG) Associates Inc., Significant Oil and Gas Fields of the United States (1992); Petroleum Information (PI), Inc., Well History Control System (1991); and Petroleum Information (PI), Inc., Petro-ROM: Production data on CD-ROM (1993). Although generated mostly in response to the national assessment, the data presented here arc grouped differently and arc displayed and described in greater detail. In addition, the stratigraphic sequences discussed may not necessarily correlate with the "plays" of the 1995 national assessment. This report uses computer-generated maps to show drilling intensity, producing wells, major fields, and other geologic information relevant to petroleum exploration and production in the lower Paleozoic part of the Anadarko basin province as defined for the U.S. Geological Survey's 1995 national petroleum assessment. Hydrocarbon accumulations must meet a minimum standard of 1 million barrels of oil (MMBO) or 6 billion cubic feet of gas (BCFG) estimated ultimate recovery to be included in this report as a major field or revoir. Mapped strata in this report include the Upper Cambrian to Lower Ordovician Arbuckle and Low Ordovician Ellenburger Groups, the Middle Ordovician Simpson Group, and the Middle to Upper Ordovician Viola Group.

Analysis of Residual Acceleration Effects on Transport and Segregation During Directional Solidification of Tin-Bismuth in the MEPHISTO Furnace Facility

NASA Technical Reports Server (NTRS)

Alexander, J. Iwan D.

1998-01-01

The research accomplishments summarized in this Final Report during the period from 3/95 to 3/98, which included a 12 months no-cost extension granted at the end of the nominal 2 year period of performance. The report has 5 sections, in section 1 the objectives are presented, a task description is given and the background and significance of the work is outlined. In section 2 the research accomplishments are summarized. In section 3 publications and presentations are listed. Student participation is listed in 4. The work is summarized in section 5. and references for sections 1 and 2 are supplied in section 6. The object of this work, is to approach the problem of determining the transport conditions (and effects of residual acceleration) during the plane-front directional solidification of a tin-bismuth alloy under low gravity conditions. The work involved using a combination of 2- and 3-D numerical models, scaling analyses, ID models and the results of ground-based and low-gravity experiments. The experiments conducted in the MEPHISTO furnace facility during the USW-3 space flight which took place between February 22 through March 6, 199). This experiment represents an unprecedented opportunity to make a quantitative correlation between residual accelerations and the response of an actual experimental solidification

A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill)health. Legal highs or illegal highs?

PubMed

Ayres, Tammy C; Bond, John W

2012-01-01

Public Health England aims to improve the nation's health and acknowledges that unhealthy lifestyles, which include drug use, undermine society's health and well-being. Recreational drug use has changed to include a range of substances sold as 'research chemicals' but known by users as 'legal highs' (legal alternatives to the most popular illicit recreational drugs), which are of an unknown toxicity to humans and often include prohibited substances controlled under the Misuse of Drugs Act (1971). Consequently, the long-term effects on users' health and inconsistent, often illegal ingredients, mean that this group of drugs presents a serious risk to public health both now and in the future. Therefore, the aim of this study was to ascertain what is in legal highs, their legality and safety, while considering the potential impact, these synthetic substances might be having on public health. A total of 22 products were purchased from five different internet sites, 18 months after the UK ban on substituted cathinones, like mephedrone, was introduced in April 2010. Each substance was screened to determine its active ingredients using accepted analytical techniques. The research was conducted in Leicestershire but has implications for the provision of primary and secondary healthcare throughout the UK. Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled 'not for human consumption', they are thinly disguised 'legal highs', available online in quantities that vary from 1 g to 1 kg. Despite amendments to legislation, prohibited class B substances are still readily available in large quantities over the internet. The findings suggest that these prohibited substances are being manufactured or imported into the UK on a large scale, which has serious implications for public health and clinicians who are ill equipped to deal with this newly emerging problem.

A chemical analysis examining the pharmacology of novel psychoactive substances freely available over the internet and their impact on public (ill)health. Legal highs or illegal highs?

PubMed Central

Bond, John W

2012-01-01

Objectives Public Health England aims to improve the nation's health and acknowledges that unhealthy lifestyles, which include drug use, undermine society's health and well-being. Recreational drug use has changed to include a range of substances sold as ‘research chemicals’ but known by users as ‘legal highs’ (legal alternatives to the most popular illicit recreational drugs), which are of an unknown toxicity to humans and often include prohibited substances controlled under the Misuse of Drugs Act (1971). Consequently, the long-term effects on users' health and inconsistent, often illegal ingredients, mean that this group of drugs presents a serious risk to public health both now and in the future. Therefore, the aim of this study was to ascertain what is in legal highs, their legality and safety, while considering the potential impact, these synthetic substances might be having on public health. Design A total of 22 products were purchased from five different internet sites, 18 months after the UK ban on substituted cathinones, like mephedrone, was introduced in April 2010. Each substance was screened to determine its active ingredients using accepted analytical techniques. Setting The research was conducted in Leicestershire but has implications for the provision of primary and secondary healthcare throughout the UK. Results Two products, both sold as NRG-2 from different internet suppliers, were found to contain the banned substituted cathinones 4-methylethcathinone (4-MEC) and 4-methylmethcathinone (4-MMC), the latter being present in much smaller quantities. Although sold as research chemicals and labelled ‘not for human consumption’, they are thinly disguised ‘legal highs’, available online in quantities that vary from 1 g to 1 kg. Conclusions Despite amendments to legislation, prohibited class B substances are still readily available in large quantities over the internet. The findings suggest that these prohibited substances are being manufactured or imported into the UK on a large scale, which has serious implications for public health and clinicians who are ill equipped to deal with this newly emerging problem. PMID:22855623

American Association of Physicists in Medicine Task Group 263: Standardizing Nomenclatures in Radiation Oncology.

PubMed

Mayo, Charles S; Moran, Jean M; Bosch, Walter; Xiao, Ying; McNutt, Todd; Popple, Richard; Michalski, Jeff; Feng, Mary; Marks, Lawrence B; Fuller, Clifton D; Yorke, Ellen; Palta, Jatinder; Gabriel, Peter E; Molineu, Andrea; Matuszak, Martha M; Covington, Elizabeth; Masi, Kathryn; Richardson, Susan L; Ritter, Timothy; Morgas, Tomasz; Flampouri, Stella; Santanam, Lakshmi; Moore, Joseph A; Purdie, Thomas G; Miller, Robert C; Hurkmans, Coen; Adams, Judy; Jackie Wu, Qing-Rong; Fox, Colleen J; Siochi, Ramon Alfredo; Brown, Norman L; Verbakel, Wilko; Archambault, Yves; Chmura, Steven J; Dekker, Andre L; Eagle, Don G; Fitzgerald, Thomas J; Hong, Theodore; Kapoor, Rishabh; Lansing, Beth; Jolly, Shruti; Napolitano, Mary E; Percy, James; Rose, Mark S; Siddiqui, Salim; Schadt, Christof; Simon, William E; Straube, William L; St James, Sara T; Ulin, Kenneth; Yom, Sue S; Yock, Torunn I

2018-03-15

A substantial barrier to the single- and multi-institutional aggregation of data to supporting clinical trials, practice quality improvement efforts, and development of big data analytics resource systems is the lack of standardized nomenclatures for expressing dosimetric data. To address this issue, the American Association of Physicists in Medicine (AAPM) Task Group 263 was charged with providing nomenclature guidelines and values in radiation oncology for use in clinical trials, data-pooling initiatives, population-based studies, and routine clinical care by standardizing: (1) structure names across image processing and treatment planning system platforms; (2) nomenclature for dosimetric data (eg, dose-volume histogram [DVH]-based metrics); (3) templates for clinical trial groups and users of an initial subset of software platforms to facilitate adoption of the standards; (4) formalism for nomenclature schema, which can accommodate the addition of other structures defined in the future. A multisociety, multidisciplinary, multinational group of 57 members representing stake holders ranging from large academic centers to community clinics and vendors was assembled, including physicists, physicians, dosimetrists, and vendors. The stakeholder groups represented in the membership included the AAPM, American Society for Radiation Oncology (ASTRO), NRG Oncology, European Society for Radiation Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), Children's Oncology Group (COG), Integrating Healthcare Enterprise in Radiation Oncology (IHE-RO), and Digital Imaging and Communications in Medicine working group (DICOM WG); A nomenclature system for target and organ at risk volumes and DVH nomenclature was developed and piloted to demonstrate viability across a range of clinics and within the framework of clinical trials. The final report was approved by AAPM in October 2017. The approval process included review by 8 AAPM committees, with additional review by ASTRO, European Society for Radiation Oncology (ESTRO), and American Association of Medical Dosimetrists (AAMD). This Executive Summary of the report highlights the key recommendations for clinical practice, research, and trials. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Prospective Validation of Pooled Prognostic Factors in Women with Advanced Cervical Cancer Treated with Chemotherapy with/without Bevacizumab: NRG Oncology/GOG Study

PubMed Central

Tewari, Krishnansu S.; Sill, Michael W.; Monk, Bradley J.; Penson, Richard T.; Long, Harry J.; Poveda, Andrés; Landrum, Lisa M.; Leitao, Mario M.; Brown, Jubilee; Reid, Thomas J.A.; Michael, Helen E.; Moore, David H.

2016-01-01

Purpose In the randomized phase III trial, Gynecologic Oncology Group protocol 240, the incorporation of bevacizumab with chemotherapy significantly increased overall survival (OS) in women with advanced cervical cancer. A major objective of GOG-240 was to prospectively analyze previously identified pooled clinical prognostic factors known as the Moore criteria. Experimental Design Potential negative factors included black race, performance status 1, pelvic disease, prior cisplatin, and progression-free interval <365 days. Risk categories included low-risk (0-1 factor); intermediate-risk (2-3 factors); high-risk (4-5 factors). Each test of association was conducted at the 5% level of significance. Logistic regression and survival analysis was used to determine whether factors were prognostic or could be used to guide therapy. Results For the entire population (n=452), high-risk patients had significantly worse OS (p<0.0001). The hazard ratios of death for treating with topotecan in low-risk, mid-risk, and high-risk subsets are 1.18 (95% CI 0.63-2.24), 1.11 (95% CI 0.82-1.5), and 0.84 (95% CI 0.50-1.42), respectively. The hazard ratios of death for treating with bevacizumab in low-risk, mid-risk, and high-risk subsets are 0.96 (95% CI 0.51-1.83; p=0.9087), 0.673 (95% CI 0.5-0.91; p=0.0094), and 0.536 (95% CI 0.32-0.905; p=0.0196), respectively. Conclusions This is the first prospectively validated scoring system in cervical cancer. The Moore criteria have real world clinical applicability. Toxicity concerns may justify omission of bevacizumab in some low-risk patients where survival benefit is small. The benefit to receiving bevacizumab appears to be greatest in the moderate- and high-risk subgroups (5.8 month increase in median OS). PMID:26672085

Preliminary hydrogeologic assessment of boreholes UE-25c #1, UE-25c #2, and UE-25c #3, Yucca Mountain, Nye County, Nevada

USGS Publications Warehouse

Geldon, A.L.

1993-01-01

Boreholes UE-25c #1, UE-25c #2, and UE-25c #3 (collectively called the C-holes) each were drilled to a depth of 914.4 meters at Yucca Mountain, on the Nevada Test Site, in 1983 and 1984 for the purpose of conducting aquifer and tracer tests. Each of the boreholes penetrated the Paintbrush Tuff and the tuffs and lavas of Calico Hills and bottomed in the Crater Flat Tuff. The geologic units penetrated consist of devitrified to vitrophyric, nonwelded to densely welded, ash-flow tuff, tuff breccia, ash-fall tuff, and bedded tuff. Below the water table, which is at an average depth of 401.6 meters below land surface, the rocks are argillic and zeolitic. The geologic units at the C-hole complex strike N. 2p W. and dip 15p to 21p NE. They are cut by several faults, including the Paintbrush Canyon Fault, a prominent normal fault oriented S. 9p W., 52.2p NW. The rocks at the C-hole complex are fractured extensively, with most fractures oriented approximately perpendicular to the direction of regional least horizontal principal stress. In the Crater Flat Tuff and the tuffs and lavas of Calico Hills, fractures strike predominantly between S. 20p E. and S. 20p W. and secondarily between S. 20p E. and S. 60p E. In the Topopah Spring Member of the Paintbrush Tuff, however, southeasterly striking fractures predominate. Most fractures are steeply dipping, although shallowly dipping fractures occur in nonwelded and reworked tuff intervals of the Crater Flat Tuff. Mineral-filled fractures are common in the tuff breccia zone of the Tram Member of the Crater Flat Tuff, and, also, in the welded tuff zone of the Bullfrog Member of the Crater Flat Tuff. The fracture density of geologic units in the C-holes was estimated to range from 1.3 to 7.6 fractures per cubic meter. Most of these estimates appear to be the correct order of magnitude when compared to transect measurements and core data from other boreholes 1.3 orders of magnitude too low. Geophysical data and laboratory analyses were used to determine matrix hydrologic properties of the tuffs and lavas of Calico Hills and the Crater Flat Tuff in the C-holes. The porosity ranged from 12 to 43 percent and, on the average, was larger in nonwelded to partially welded, ash-flow tuff, ashfall tuff, and reworked tuff than in moderately to densely welded ash-flow tuff. The pore-scale horizontal permeability of nine samples ranged from 5.7x10'3 to 2.9 millidarcies, and the pore-scale vertical permeability of these samples ranged from 3.7x10'* to 1.5 millidarcies. Ratios of pore-scale horizontal to vertical permeability generally ranged from 0.7 to 2. Although the number of samples was small, values of pore-scale permeability determined were consistent with samples from other boreholes at Yucca Mountain. The specific storage of nonwelded to partially welded ash-flow tuff, ash-fall tuff, and reworked tuff was estimated from porosity and elasticity to' be 2xlO'6 per meter, twice the specific storage of moderately to densely welded ash-flow tuff and tuff breccia. The storativity of geologic units, based on their average thickness (corrected for bedding dip) and specific storage, was estimated to range from 1xlO's to 2xlO'4. Ground-water flow in the Tertiary rocks of the Yucca Mountain area is not confined by strata but appears to result from the random intersection of water-bearing fractures and faults. Even at the C-hole complex, an area of only 1,027 square meters, water-producing zones during pumping tests vary from borehole to borehole. In borehole UE-25c #1, water is produced mainly from the lower, nonwelded to welded zone of the Bullfrog Member of the Crater Flat Tuff and secondarily from the tuff-breccia zone of the Tram Member of the Crater Flat Tuff. In borehole UE-25c #3, water is produced in nearly equal proportions from these two intervals and the central, moderately to densely welded zone of the Bullfrog Member. In borehole UE-25c #2, almost all production comes from the moderately to dense

Preclinical imaging characteristics and quantification of Platinum-195m SPECT.

PubMed

Aalbersberg, E A; de Wit-van der Veen, B J; Zwaagstra, O; Codée-van der Schilden, K; Vegt, E; Vogel, Wouter V

2017-08-01

In vivo biodistribution imaging of platinum-based compounds may allow better patient selection for treatment with chemo(radio)therapy. Radiolabeling with Platinum-195m ( 195m Pt) allows SPECT imaging, without altering the chemical structure or biological activity of the compound. We have assessed the feasibility of 195m Pt SPECT imaging in mice, with the aim to determine the image quality and accuracy of quantification for current preclinical imaging equipment. Enriched (>96%) 194 Pt was irradiated in the High Flux Reactor (HFR) in Petten, The Netherlands (NRG). A 0.05 M HCl 195m Pt-solution with a specific activity of 33 MBq/mg was obtained. Image quality was assessed for the NanoSPECT/CT (Bioscan Inc., Washington DC, USA) and U-SPECT + /CT (MILabs BV, Utrecht, the Netherlands) scanners. A radioactivity-filled rod phantom (rod diameter 0.85-1.7 mm) filled with 1 MBq 195m Pt was scanned with different acquisition durations (10-120 min). Four healthy mice were injected intravenously with 3-4 MBq 195m Pt. Mouse images were acquired with the NanoSPECT for 120 min at 0, 2, 4, or 24 h after injection. Organs were delineated to quantify 195m Pt concentrations. Immediately after scanning, the mice were sacrificed, and the platinum concentration was determined in organs using a gamma counter and graphite furnace - atomic absorption spectroscopy (GF-AAS) as reference standards. A 30-min acquisition of the phantom provided visually adequate image quality for both scanners. The smallest visible rods were 0.95 mm in diameter on the NanoSPECT and 0.85 mm in diameter on the U-SPECT + . The image quality in mice was visually adequate. Uptake was seen in the kidneys with excretion to the bladder, and in the liver, blood, and intestine. No uptake was seen in the brain. The Spearman correlation between SPECT and gamma counter was 0.92, between SPECT and GF-AAS it was 0.84, and between GF-AAS and gamma counter it was0.97 (all p < 0.0001). Preclinical 195m Pt SPECT is feasible with acceptable tracer doses and acquisition times, and provides good image quality and accurate signal quantification.

FGFR2 mutations are associated with poor outcomes in endometrioid endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Jeske, Yvette W.; Ali, Shamshad; Byron, Sara A; Gao, Feng; Mannel, Robert S; Ghebre, Rahel G; DiSilvestro, Paul A; Lele, Shashikant B; Pearl, Michael L; Schmidt, Amy P; Lankes, Heather A; Ramirez, Nilsa C; Rasty, Golnar; Powell, Matthew; Goodfellow, Paul J; Pollock, Pamela M

2017-01-01

Purpose Activating FGFR2 mutations have been identified in ~10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. Methods Tumors were collected as part of the GOG 210 clinical trial “Molecular Staging of Endometrial Cancer” where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. Results Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p = 0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p < 0.001, Chi-square test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p < 0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177–3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096–3.696). Conclusion In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted. PMID:28314589

Rising to the Forensic Analytical Challenges Associated with the Global Increase in Seizures of Cathinone-derived "Legal Highs"

NASA Astrophysics Data System (ADS)

Sutcliffe, O.; Daeid, N. Nic; Kemp, H. F.; Meier-Augenstein, W.

2012-04-01

Substances touted as "legal highs" and known by names such as "ivory wave" or "NRG-1" mimic the effects of illegal drugs such as amphetamine, cocaine and ecstasy. Sold as "bath salts", plant food or incense these so-called "designer drugs" can be dangerous but despite this health danger many have not yet been made illegal and are difficult to detect with current drug tests. These "bath salts" can cause euphoria, paranoia, anxiety and hallucinations. They often contain mephedrone, a synthetic compound structurally related to methcathinone, which is found in Khat - a plant that, like mephedrone itself, is illegal to possess in many countries. "Bath salts" are usually labelled as being "not for human consumption" and the name "bath salts" is used by those who sell these substances as a way of circumventing legislation when supplying them. Mephedrone (a synthetic cathinone) was legal (or at least not illegal) in the UK until April 2010 when it was classified as a Class B, Schedule 1 substance (UK Misuse of Drugs Act 1971). The current challenges to law enforcement agencies are: (1) Identification and quantification of new and emerging illicit substances. (2) Tracing or linking product to precursor (i.e. source identification). Here, we present as a potential way of tracing the source of the raw materials, and consequently providing information as to who is making the "bath salts", which is based on identification of products and/or adulterants/excipients by GCMS in combination with isotopic profiling of both precursor and product to determine characteristic shifts or linkages in isotopic composition between starting material used, synthetic processes employed and resultant drug produced.

Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.

PubMed

Fledrich, Robert; Mannil, Manoj; Leha, Andreas; Ehbrecht, Caroline; Solari, Alessandra; Pelayo-Negro, Ana L; Berciano, José; Schlotter-Weigel, Beate; Schnizer, Tuuli J; Prukop, Thomas; Garcia-Angarita, Natalia; Czesnik, Dirk; Haberlová, Jana; Mazanec, Radim; Paulus, Walter; Beissbarth, Tim; Walter, Maggie C; Triaal, Cmt-; Hogrel, Jean-Yves; Dubourg, Odile; Schenone, Angelo; Baets, Jonathan; De Jonghe, Peter; Shy, Michael E; Horvath, Rita; Pareyson, Davide; Seeman, Pavel; Young, Peter; Sereda, Michael W

2017-11-01

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Disruption of the ErbB signaling in adolescence increases striatal dopamine levels and affects learning and hedonic-like behavior in the adult mouse.

PubMed

Golani, Idit; Tadmor, Hagar; Buonanno, Andres; Kremer, Ilana; Shamir, Alon

2014-11-01

The ErbB signaling pathway has been genetically and functionally implicated in schizophrenia. Numerous findings support the dysregulation of Neuregulin (NRG) and epidermal growth factor (EGF) signaling in schizophrenia. However, it is unclear whether alterations of these pathways in the adult brain or during development are involved in the pathophysiology of schizophrenia. Herein we characterized the behavioral profile and molecular changes resulting from pharmacologically blocking the ErbB signaling pathway during a critical period in the development of decision making, planning, judgments, emotions, social cognition and cognitive skills, namely adolescence. We demonstrate that chronic administration of the pan-ErbB kinase inhibitor JNJ-28871063 (JNJ) to adolescent mice elevated striatal dopamine levels and reduced preference for sucrose without affecting locomotor activity and exploratory behavior. In adulthood, adolescent JNJ-treated mice continue to consume less sucrose and needed significantly more correct-response trials to reach the learning criterion during the discrimination phase of the T-maze reversal learning task than their saline-injected controls. In addition, JNJ mice exhibited deficit in reference memory but not in working memory as measured in the radial arm maze. Inhibition of the pathway during adolescence did not affect exploratory behavior and locomotor activity in the open field, social interaction, social memory, and reversal learning in adult mice. Our data suggest that alteration of ErbB signaling during adolescence resulted in changes in the dopaminergic systems that emerge in pathological learning and hedonic behavior in adulthood, and pinpoints the possible role of the pathway in the development of cognitive skills and motivated behavior. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Optimization of liposomal topotecan for use in treating neuroblastoma.

PubMed

Chernov, Lina; Deyell, Rebecca J; Anantha, Malathi; Dos Santos, Nancy; Gilabert-Oriol, Roger; Bally, Marcel B

2017-06-01

The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

The nuclear OXPHOS genes in insecta: a common evolutionary origin, a common cis-regulatory motif, a common destiny for gene duplicates

PubMed Central

Porcelli, Damiano; Barsanti, Paolo; Pesole, Graziano; Caggese, Corrado

2007-01-01

Background When orthologous sequences from species distributed throughout an optimal range of divergence times are available, comparative genomics is a powerful tool to address problems such as the identification of the forces that shape gene structure during evolution, although the functional constraints involved may vary in different genes and lineages. Results We identified and annotated in the MitoComp2 dataset the orthologs of 68 nuclear genes controlling oxidative phosphorylation in 11 Drosophilidae species and in five non-Drosophilidae insects, and compared them with each other and with their counterparts in three vertebrates (Fugu rubripes, Danio rerio and Homo sapiens) and in the cnidarian Nematostella vectensis, taking into account conservation of gene structure and regulatory motifs, and preservation of gene paralogs in the genome. Comparative analysis indicates that the ancestral insect OXPHOS genes were intron rich and that extensive intron loss and lineage-specific intron gain occurred during evolution. Comparison with vertebrates and cnidarians also shows that many OXPHOS gene introns predate the cnidarian/Bilateria evolutionary split. The nuclear respiratory gene element (NRG) has played a key role in the evolution of the insect OXPHOS genes; it is constantly conserved in the OXPHOS orthologs of all the insect species examined, while their duplicates either completely lack the element or possess only relics of the motif. Conclusion Our observations reinforce the notion that the common ancestor of most animal phyla had intron-rich gene, and suggest that changes in the pattern of expression of the gene facilitate the fixation of duplications in the genome and the development of novel genetic functions. PMID:18315839

Does time interval between surgery and intraperitoneal chemotherapy administration in advanced ovarian cancer carry a prognostic impact? An NRG Oncology/Gynecologic Oncology Group study ancillary study

PubMed Central

Garcia-Soto, Arlene E; Java, James J; Neira, Wilberto Nieves; Pearson, J Matthew; Cohn, David E.; Lele, Shashikant B; Tewari, Krishnansu S; Walker, Joan L; Secord, Angeles Alvarez; Armstrong, Deborah K; Copeland, Larry J

2016-01-01

Objectives To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. Methods Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. Results The median TSIC was 62.5 days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26 days, p <0.001). TSIC was significantly associated (P = 0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R2 -0.141, 95%CI -0.217, -0.064, p < 0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. Conclusions In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further. PMID:27726923

Retroperitoneal Sarcoma Target Volume and Organ at Risk Contour Delineation Agreement Among NRG Sarcoma Radiation Oncologists

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baldini, Elizabeth H., E-mail: ebaldini@partners.org; Abrams, Ross A.; Bosch, Walter

Purpose: The purpose of this study was to evaluate the variability in target volume and organ at risk (OAR) contour delineation for retroperitoneal sarcoma (RPS) among 12 sarcoma radiation oncologists. Methods and Materials: Radiation planning computed tomography (CT) scans for 2 cases of RPS were distributed among 12 sarcoma radiation oncologists with instructions for contouring gross tumor volume (GTV), clinical target volume (CTV), high-risk CTV (HR CTV: area judged to be at high risk of resulting in positive margins after resection), and OARs: bowel bag, small bowel, colon, stomach, and duodenum. Analysis of contour agreement was performed using the simultaneousmore » truth and performance level estimation (STAPLE) algorithm and kappa statistics. Results: Ten radiation oncologists contoured both RPS cases, 1 contoured only RPS1, and 1 contoured only RPS2 such that each case was contoured by 11 radiation oncologists. The first case (RPS 1) was a patient with a de-differentiated (DD) liposarcoma (LPS) with a predominant well-differentiated (WD) component, and the second case (RPS 2) was a patient with DD LPS made up almost entirely of a DD component. Contouring agreement for GTV and CTV contours was high. However, the agreement for HR CTVs was only moderate. For OARs, agreement for stomach, bowel bag, small bowel, and colon was high, but agreement for duodenum (distorted by tumor in one of these cases) was fair to moderate. Conclusions: For preoperative treatment of RPS, sarcoma radiation oncologists contoured GTV, CTV, and most OARs with a high level of agreement. HR CTV contours were more variable. Further clarification of this volume with the help of sarcoma surgical oncologists is necessary to reach consensus. More attention to delineation of the duodenum is also needed.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greg Retzlaff

In January 2006 the Smith River Rancheria (SRR), located in Smith River, California, contracted with the team of Strategic Energy Solutions (SES) and Evergreen NRG to conduct a study for the community. The objective of the study was to identify renewable generation opportunities that would facilitate Rancheria energy independence through SRR owned and operated power projects. These generation facilities were to be located either on or near the reservation. Specifically, the Rancheria was interested in the viability of generating electric power using biomass and wind fuel resources. Initial research identified that a very small portion of the community's energy couldmore » be offset by renewable energy generation due to the low solar resource in this area, and the lack of significant wind or biomass resources on or near reservation land. Some larger projects were identified which offered little or no benefit to the Rancheria. As a result, the scope of this study was changed in October 2006 to focus on energy efficiency opportunities for key reservation facilities, with a continued analysis of smaller renewable energy opportunities within reservation boundaries. The consulting team initially performed a resource analysis for biomass and solar generation opportunities in the region of the Rancheria. It was quickly concluded that none of these options would yield renewable power for the Rancheria at costs competitive with current utility sources, and that any larger installations would require substantial funding that may not be available. Having made these conclusions early on, the study effort was redirected and the team investigated each of the major Rancheria buildings to look for solar, wind and conservation opportunities. The buildings were audited for energy use and the roof areas were examined for exposure of solar radiation. Wind resources were also investigated to determine if smaller wind turbines would offer power generation at a reasonable cost.« less

A three-way parallel ICA approach to analyze links among genetics, brain structure and brain function.

PubMed

Vergara, Victor M; Ulloa, Alvaro; Calhoun, Vince D; Boutte, David; Chen, Jiayu; Liu, Jingyu

2014-09-01

Multi-modal data analysis techniques, such as the Parallel Independent Component Analysis (pICA), are essential in neuroscience, medical imaging and genetic studies. The pICA algorithm allows the simultaneous decomposition of up to two data modalities achieving better performance than separate ICA decompositions and enabling the discovery of links between modalities. However, advances in data acquisition techniques facilitate the collection of more than two data modalities from each subject. Examples of commonly measured modalities include genetic information, structural magnetic resonance imaging (MRI) and functional MRI. In order to take full advantage of the available data, this work extends the pICA approach to incorporate three modalities in one comprehensive analysis. Simulations demonstrate the three-way pICA performance in identifying pairwise links between modalities and estimating independent components which more closely resemble the true sources than components found by pICA or separate ICA analyses. In addition, the three-way pICA algorithm is applied to real experimental data obtained from a study that investigate genetic effects on alcohol dependence. Considered data modalities include functional MRI (contrast images during alcohol exposure paradigm), gray matter concentration images from structural MRI and genetic single nucleotide polymorphism (SNP). The three-way pICA approach identified links between a SNP component (pointing to brain function and mental disorder associated genes, including BDNF, GRIN2B and NRG1), a functional component related to increased activation in the precuneus area, and a gray matter component comprising part of the default mode network and the caudate. Although such findings need further verification, the simulation and in-vivo results validate the three-way pICA algorithm presented here as a useful tool in biomedical data fusion applications. Copyright © 2014 Elsevier Inc. All rights reserved.

Retroperitoneal Sarcoma Target Volume and Organ at Risk Contour Delineation Agreement Among NRG Sarcoma Radiation Oncologists

PubMed Central

Baldini, Elizabeth H.; Abrams, Ross A.; Bosch, Walter; Roberge, David; Haas, Rick L.M.; Catton, Charles N.; Indelicato, Daniel J.; Olsen, Jeffrey R.; Deville, Curtiland; Chen, Yen-Lin; Finkelstein, Steven E.; DeLaney, Thomas F.; Wang, Dian

2015-01-01

Purpose The purpose of this study was to evaluate the variability in target volume and organ at risk (OAR) contour delineation for retroperitoneal sarcoma (RPS) among 12 sarcoma radiation oncologists. Methods and Materials Radiation planning computed tomography (CT) scans for 2 cases of RPS were distributed among 12 sarcoma radiation oncologists with instructions for contouring gross tumor volume (GTV), clinical target volume (CTV), high-risk CTV (HR CTV: area judged to be at high risk of resulting in positive margins after resection), and OARs: bowel bag, small bowel, colon, stomach, and duodenum. Analysis of contour agreement was performed using the simultaneous truth and performance level estimation (STAPLE) algorithm and kappa statistics. Results Ten radiation oncologists contoured both RPS cases, 1 contoured only RPS1, and 1 contoured only RPS2 such that each case was contoured by 11 radiation oncologists. The first case (RPS 1) was a patient with a de-differentiated (DD) liposarcoma (LPS) with a predominant well-differentiated (WD) component, and the second case (RPS 2) was a patient with DD LPS made up almost entirely of a DD component. Contouring agreement for GTV and CTV contours was high. However, the agreement for HR CTVs was only moderate. For OARs, agreement for stomach, bowel bag, small bowel, and colon was high, but agreement for duodenum (distorted by tumor in one of these cases) was fair to moderate. Conclusions For preoperative treatment of RPS, sarcoma radiation oncologists contoured GTV, CTV, and most OARs with a high level of agreement. HR CTV contours were more variable. Further clarification of this volume with the help of sarcoma surgical oncologists is necessary to reach consensus. More attention to delineation of the duodenum is also needed. PMID:26194680

With Great Power Comes Great Responsibility-A Personal Philosophy for Communicating Science in Society.

PubMed

Zehr, E Paul

2016-01-01

Many think that communicating science is a necessary and rewarding activity. Yet finding compelling, relevant, and timely points of linkage between challenging scientific concepts and the experiences and interests of the general public can be difficult. Since science continues to influence more and more aspects of daily life and knowledge, there is a parallel need for communication about science in our society. Here I discuss the "middle-ground hypothesis" using popular culture for science communication and applying the "FUNnel model," where popular culture is used as a lead-in and wrap-up when discussing science. The scientific knowledge we find in our hands does not belong to us-we just had it first. We can honor that knowledge best by sharing it as widely as possible using the most creative means at our disposal.

Whole-genome association analysis of pork meat pH revealed three significant regions and several potential genes in Finnish Yorkshire pigs.

PubMed

Verardo, Lucas L; Sevón-Aimonen, Marja-Liisa; Serenius, Timo; Hietakangas, Ville; Uimari, Pekka

2017-02-13

One of the most commonly used quality measurements of pork is pH measured 24 h after slaughter. The most probable mode of inheritance for this trait is oligogenic with several known major genes, such as PRKAG3. In this study, we used whole-genome SNP genotypes of over 700 AI boars; after a quality check, 42,385 SNPs remained for association analysis. All the boars were purebred Finnish Yorkshire. To account for relatedness of the animals, a pedigree-based relationship matrix was used in a mixed linear model to test the effect of SNPs on pH measured from loin. A bioinformatics analysis was performed to identify the most promising genes in the significant regions related to meat quality. Genome-wide association study (GWAS) revealed three significant chromosomal regions: one on chromosome 3 (39.9 Mb-40.1 Mb) and two on chromosome 15 (58.5 Mb-60.5 Mb and 132 Mb-135 Mb including PRKAG3). A conditional analysis with a significant SNP in the PRKAG3 region, MARC0083357, as a covariate in the model retained the significant SNPs on chromosome 3. Even though linkage disequilibrium was relatively high over a long distance between MARC0083357 and other significant SNPs on chromosome 15, some SNPs retained their significance in the conditional analysis, even in the vicinity of PRKAG3. The significant regions harbored several genes, including two genes involved in cyclic AMP (cAMP) signaling: ADCY9 and CREBBP. Based on functional and transcription factor-gene networks, the most promising candidate genes for meat pH are ADCY9, CREBBP, TRAP1, NRG1, PRKAG3, VIL1, TNS1, and IGFBP5, and the key transcription factors related to these genes are HNF4A, PPARG, and Nkx2-5. Based on SNP association, pathway, and transcription factor analysis, we were able to identify several genes with potential to control muscle cell homeostasis and meat quality. The associated SNPs can be used in selection for better pork. We also showed that post-GWAS analysis reveals important information about the genes' potential role on meat quality. The gained information can be used in later functional studies.

Detection and quantification of new psychoactive substances (NPSs) within the evolved "legal high" product, NRG-2, using high performance liquid chromatography-amperometric detection (HPLC-AD).

PubMed

Zuway, Khaled Y; Smith, Jamie P; Foster, Christopher W; Kapur, Nikil; Banks, Craig E; Sutcliffe, Oliver B

2015-09-21

The global increase in the production and abuse of cathinone-derived New Psychoactive Substances (NPSs) has developed the requirement for rapid, selective and sensitive protocols for their separation and detection. Electrochemical sensing of these compounds has been demonstrated to be an effective method for the in-field detection of these substances, either in their pure form or in the presence of common adulterants, however, the technique is limited in its ability to discriminate between structurally related cathinone-derivatives (for example: (±)-4′-methylmethcathinone (4-MMC, 2a) and (±)-4′-methyl-N-ethylmethcathinone (4-MEC, 2b) when they are both present in a mixture. In this paper we demonstrate, for the first time, the combination of HPLC-UV with amperometric detection (HPLC-AD) for the qualitative and quantitative analysis of 4-MMC and 4-MEC using either a commercially available impinging jet (LC-FC-A) or custom-made iCell channel (LC-FC-B) flow-cell system incorporating embedded graphite screen-printed macroelectrodes. The protocol offers a cost-effective, reproducible and reliable sensor platform for the simultaneous HPLC-UV and amperometric detection of the target analytes. The two systems have similar limits of detection, in terms of amperometric detection [LC-FC-A: 14.66 μg mL(-1) (2a) and 9.35 μg mL(-1) (2b); LC-FC-B: 57.92 μg mL(-1) (2a) and 26.91 μg mL(-1) (2b)], to the previously reported oxidative electrochemical protocol [39.8 μg mL(-1) (2a) and 84.2 μg mL(-1) (2b)], for two synthetic cathinones, prevalent on the recreational drugs market. Though not as sensitive as standard HPLC-UV detection, both flow cells show a good agreement, between the quantitative electroanalytical data, thereby making them suitable for the detection and quantification of 4-MMC and 4-MEC, either in their pure form or within complex mixtures. Additionally, the simultaneous HPLC-UV and amperometric detection protocol detailed herein shows a marked improvement and advantage over previously reported electroanalytical methods, which were either unable to selectively discriminate between structurally related synthetic cathinones (e.g. 4-MMC and 4-MEC) or utilised harmful and restrictive materials in their design.