Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model

PubMed Central

Gabbita, S. Prasad; Johnson, Ming F.; Kobritz, Naomi; Eslami, Pirooz; Poteshkina, Aleksandra; Varadarajan, Sridhar; Turman, John; Zemlan, Frank; Harris-White, Marni E.

2015-01-01

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer’s Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression. In this study, 3xTgAD mice, age 6 months, were treated orally with 3 doses of the TNFα modulating compound isoindolin-1,3 dithione (IDT) for 10 months. We demonstrate that IDT is a TNFα modulating compound both in vitro and in vivo. Following long-term IDT administration, mice were assessed for learning & memory and tissue and serum were collected for analysis. Results demonstrate that IDT is safe for long-term treatment and significantly improves learning and memory in the 3xTgAD mouse model. IDT significantly reduced paired helical filament tau and fibrillar amyloid accumulation. Flow cytometry of brain cell populations revealed that IDT increased the infiltrating neutrophil population while reducing TNFα expression in this population. IDT is a safe and effective TNFα and innate immune system modulator. Thus small molecule, orally bioavailable modulators are promising therapeutics for Alzheimer’s disease. PMID:26436670

Bioremediation and phytoremediation: Chlorinated and recalcitrant compounds

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

NONE

1998-12-31

Bioremediation and phytoremediation have progressed, especially with regard to the treatment of hydrocarbon-contaminated sites. Sites contaminated with chlorinated and recalcitrant compounds have proven more resistant to these approaches, but exciting progress is being made both in the laboratory and in the field. This book brings together the latest breakthrough thinking and results in bioremediation, with chapters on cometabolic processes, aerobic and anaerobic mechanisms, biological reductive dechlorination processes, bioaugmentation, biomonitoring, and phytoremediation of recalcitrant organic compounds.

Biocidal Properties of Anti-Icing Additives for Aircraft Fuels

PubMed Central

Neihof, R. A.; Bailey, C. A.

1978-01-01

The biocidal and biostatic activities of seven glycol monoalkyl ether compounds were evaluated as part of an effort to find an improved anti-icing additive for jet aircraft fuel. Typical fuel contaminants, Cladosporium resinae, Gliomastix sp., Candida sp., Pseudomonas aeruginosa, and a mixed culture containing sulfate-reducing bacteria were used as assay organisms. Studies were carried out over 3 to 4 months in two-phase systems containing jet fuel and aqueous media. Diethylene glycol monomethyl ether, triethylene glycol monomethyl ether, triethylene glycol monoethyl ether, and 2-methoxyethanol were generally biocidal in aqueous concentrations of 10 to 17% for all organisms except Gliomastix, which required 25% or more. 2-Ethoxyethanol, 2-propoxyethanol, and 2-butoxyethanol were biocidal at progressively lower concentrations down to 1 to 2% for 2-butoxyethanol. The enhanced antimicrobial activity of these three compounds was attributed to cytoplasmic membrane damage because of the correlation between surface tension measurements and lytic activity with P. aeruginosa cells. The mechanism of action of the less active compounds appeared to be due to osmotic (dehydrating) effects. When all requirements are taken into account, diethylene glycol monomethyl ether appears to be the most promising replacement for the currently used additive, 2-methoxyethanol. PMID:646356

Autoxidation of packed almonds as affected by maillard reaction volatile compounds derived from roasting.

PubMed

Severini, C; Gomes, T; De Pilli, T; Romani, S; Massini, R

2000-10-01

Shelled almonds of two Italian varieties, Romana and Pizzuta, peeled and unpeeled, were roasted and packed under different conditions: air (control), vacuum, and Maillard reaction volatile compounds (MRVc) derived from the roasting process. Samples were stored for approximately 8 months at room temperature, without light, and, at regular intervals, were collected and analyzed to evaluate the progress of lipid oxidation. Peroxide values, triglyceride oligopolymers, and oxidized triglycerides were evaluated during the storage time. Results showed that, although the MRVc atmosphere did not protect the lipid fraction of almonds as well as the vacuum condition; nevertheless, it was more protective than the control atmosphere, showing an antioxidant effect. The effect of the natural coating was a strong protection against lipid oxidation; in fact, only the unpeeled samples showed peroxide values lower than the threshold of acceptability (25 milliequiv of O(2)/kg of oil). Moreover, at the end of the storage period, Pizzuta almonds showed a greater deterioration than those of the Romana variety.

Inter-laboratory assessment of a harmonized zebrafish developmental toxicology assay - progress report on phase I.

PubMed

Gustafson, A-L; Stedman, D B; Ball, J; Hillegass, J M; Flood, A; Zhang, C X; Panzica-Kelly, J; Cao, J; Coburn, A; Enright, B P; Tornesi, M B; Hetheridge, M; Augustine-Rauch, K A

2012-04-01

This report provides a progress update of a consortium effort to develop a harmonized zebrafish developmental toxicity assay. Twenty non-proprietary compounds (10 animal teratogens and 10 animal non-teratogens) were evaluated blinded in 4 laboratories. Zebrafish embryos from pond-derived and cultivated strain wild types were exposed to the test compounds for 5 days and subsequently evaluated for lethality and morphological changes. Each of the testing laboratories achieved similar overall concordance to the animal data (60-70%). Subsequent optimization procedures to improve the overall concordance focused on compound formulation and test concentration adjustments, chorion permeation and number of replicates. These optimized procedures were integrated into a revised protocol and all compounds were retested in one lab using embryos from pond-derived zebrafish and achieved 85% total concordance. To further assess assay performance, a study of additional compounds is currently in progress at two laboratories using embryos from pond-derived and cultivated-strain wild type zebrafish. Copyright © 2011 Elsevier Inc. All rights reserved.

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

PubMed

Sharpe, Martyn A; Livingston, Andrew D; Gist, Taylor L; Ghosh, Pardip; Han, Junyan; Baskin, David S

2015-09-01

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

PubMed Central

Sharpe, Martyn A.; Livingston, Andrew D.; Gist, Taylor L.; Ghosh, Pardip; Han, Junyan; Baskin, David S.

2015-01-01

The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID:26501110

Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

PubMed

Akram, Afia Muhammad; Iqbal, Zafar; Akhtar, Tanveer; Khalid, Ahmed Mukhtar; Sabar, Muhammad Farooq; Qazi, Mahmood Hussain; Aziz, Zeba; Sajid, Nadia; Aleem, Aamer; Rasool, Mahmood; Asif, Muhammad; Aloraibi, Saleh; Aljamaan, Khaled; Iqbal, Mudassar

2017-04-03

BCR-ABL kinase domain (K D ) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-K D mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was used for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which 8 (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-K D . Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 y respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-K D mutation screening in late chronic phase CML patients for improved clinical management of disease.

Role of Macrophage-Induced Inflammation in Mesothelioma

DTIC Science & Technology

2011-07-01

particularly the Plexxikon compound PLX -3397, a blocker of the CSF1 receptor. This compound has already entered clinical trials in some tumors...begun incubating hybrid spheroids and macrophages alone with the PLX - 3397 compound. After 24-48 h of PLX -3397, we have confirmed that macrophages...months 12-24). These studies are ongoing and will be completed in a few months, using the PLX -3397 compound instead of the more toxic clodronate

Stability of bioactive compounds in butiá (Butia odorata) fruit pulp and nectar.

PubMed

Hoffmann, Jessica Fernanda; Zandoná, Giovana Paula; Dos Santos, Priscila Silveira; Dallmann, Camila Müller; Madruga, Francine Bonemann; Rombaldi, Cesar Valmor; Chaves, Fábio Clasen

2017-12-15

Butia odorata is a palm tree native to southern Brazil whose fruit (known as butiá) and leaves are used to make many food products and crafts. Butiá contain several biologically active compounds with potential health benefits. However, processing conditions can alter quality attributes including bioactive compound content. This study evaluated the stability of bioactive compounds in butiá pulp upon pasteurization, during 12months of frozen storage, and in butiá nectar after a 3-month storage period. Pulp pasteurization resulted in a reduction in phenolic, flavonoid, carotenoid, and ascorbic acid contents. After a 12-month frozen storage period, flavonoid, phenolic, and ascorbic acid contents decreased while carotenoid content remained unaltered. Carotenoid, ascorbic acid, and phenolic contents were unaffected by the 3-month storage of butiá nectar; however, flavonoid content and antioxidant potential were reduced. Despite bioactive compound degradation upon heat treatment and storage, butiá nectar remained rich in phenolics, especially (-)-epicatechin, rutin, and (+)-catechin. Copyright © 2017 Elsevier Ltd. All rights reserved.

Maiorchino Cheese: Physico-Chemical, Hygienic and Safety Characteristics

PubMed Central

Ravidà, Andrea; Mandanici, Alessandro; Ferrantelli, Vincenzo; Chetta, Michele; Verzera, Antonella

2015-01-01

This study assessed the physical, chemical, and microbiological characteristics of traditional Maiorchino cheese (Italy) made from raw ewe’s milk or from a mixture with goat’s milk. Cheese samples from the same batch were analyzed after 20 days and 6, 8, 12, 17 and 24 months of ripening. A decrease in moisture level lead to progressive total solids concentration (fat, total nitrogen, total solids and chloride) during ripening. Aw values decreased from 0.97 (day 20) to 0.85 (month 24), while pH increased from 4.99 to 5.41 (6 months) followed a by reduction until 4.85 (month 24). In samples analysed 20 days after cheesemaking, aerobic mesophilic count was 1.8•107 CFU/g, Enterobacteriaceae were 2.7•106 CFU/g, Staphylococcus spp. were 1.8•104 CFU/g, and yeasts 4.5•105 CFU/g. Sulphite reducing bacteria were not found. Lactic bacteria count at 30°C (LAB30) and 42°C (LAB42) was about 108 CFU/g (day 20); LAB30 reduced until month 8; LAB 42 reduced until month 12; both were not detectable at months 17 and 24. Cheese-making process does not consider commercial starter cultures and LAB group is heterogeneous because of its natural microflora. Yeasts were considered as typical microflora of Maiorchino. Volatile compounds were examined at 6, 12 and 24 months of ripening; 54 components were identified. Statistical analysis showed that the seasoning period of 12 months was the best for Maiorchino flavour attributes. The characterisation of Maiorchino traditional cheese may be considered as significant for this old traditional product, with the aim of obtaining the PDO certification. PMID:27800379

Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA).

PubMed

Horváth, R; Abicht, A; Holinski-Feder, E; Laner, A; Gempel, K; Prokisch, H; Lochmüller, H; Klopstock, T; Jaksch, M

2006-01-01

Detailed clinical, neuroradiological, histological, biochemical, and genetic investigations were undertaken in a child suffering from Leigh syndrome. The clinical symptoms started at age five months and led to a severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity. Biochemical measurement of skeletal muscle showed a severe decrease in mitochondrial complex II. Sequencing of SDHA revealed compound heterozygosity for a nonsense mutation in exon 4 (W119X) and a missense mutation in exon 3 (A83V), both absent in normal controls. In six additional patients--five with Leigh or Leigh-like syndrome and one with neuropathy and ataxia associated with isolated deficiency of complex II--mutations in SDHA were not detected, indicating genetic heterogeneity.

Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss.

PubMed

Bonafede, Lucas; Ficicioglu, Can H; Serrano, Leona; Han, Grace; Morgan, Jessica I W; Mills, Monte D; Forbes, Brian J; Davidson, Stefanie L; Binenbaum, Gil; Kaplan, Paige B; Nichols, Charles W; Verloo, Patrick; Leroy, Bart P; Maguire, Albert M; Aleman, Tomas S

2015-12-01

To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC.

Cobalamin C Deficiency Shows a Rapidly Progressing Maculopathy With Severe Photoreceptor and Ganglion Cell Loss

PubMed Central

Bonafede, Lucas; Ficicioglu, Can H.; Serrano, Leona; Han, Grace; Morgan, Jessica I. W.; Mills, Monte D.; Forbes, Brian J.; Davidson, Stefanie L.; Binenbaum, Gil; Kaplan, Paige B.; Nichols, Charles W.; Verloo, Patrick; Leroy, Bart P.; Maguire, Albert M.; Aleman, Tomas S.

2015-01-01

Purpose To describe in detail the retinal structure and function of a group of patients with cobalamin C (cblC) disease. Methods Patients (n = 11, age 4 months to 15 years) with cblC disease (9/11, early onset) diagnosed by newborn screening underwent complete ophthalmic examinations, fundus photography, near-infrared reflectance imaging, and spectral-domain optical coherence tomography (SD-OCT). Electroretinograms (ERGs) were performed in a subset of patients. Results Patients carried homozygous or compound heterozygote mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Late-onset patients had a normal exam. All early-onset patients showed a maculopathy; older subjects had a retina-wide degeneration (n = 4; >7 years of age). In general, retinal changes were first observed before 1 year of age and progressed within months to a well-established maculopathy. Pseudocolobomas were documented in three patients. Measurable visual acuities ranged from 20/200 to 20/540. Nystagmus was present in 8/11 patients; 5/6 patients had normal ERGs; 1/6 had reduced rod-mediated responses. Spectral-domain OCT showed macular thinning, with severe ganglion cell layer (GCL) and outer nuclear layer (ONL) loss. Inner retinal thickening was observed in areas of total GCL/ONL loss. A normal lamination pattern in the peripapillary nasal retina was often seen despite severe central and/or retina-wide disease. Conclusions Patients with early-onset cblC and MMACHC mutations showed an early-onset, unusually fast-progressing maculopathy with severe central ONL and GCL loss. An abnormally thickened inner retina supports a remodeling response to both photoreceptor and ganglion cell degeneration and/or an interference with normal development in early-onset cblC. PMID:26658511

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

PubMed

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M; Michl, Patrick; Rinke, Anja

2017-05-01

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor

PubMed Central

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice

2016-01-01

Purpose To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. Patients and methods ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Results Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. Conclusion ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted. PMID:27801670

Kinetics, prognostic and predictive values of ESR1 circulating mutations in metastatic breast cancer patients progressing on aromatase inhibitor.

PubMed

Clatot, Florian; Perdrix, Anne; Augusto, Laetitia; Beaussire, Ludivine; Delacour, Julien; Calbrix, Céline; Sefrioui, David; Viailly, Pierre-Julien; Bubenheim, Michael; Moldovan, Cristian; Alexandru, Cristina; Tennevet, Isabelle; Rigal, Olivier; Guillemet, Cécile; Leheurteur, Marianne; Gouérant, Sophie; Petrau, Camille; Théry, Jean-Christophe; Picquenot, Jean-Michel; Veyret, Corinne; Frébourg, Thierry; Jardin, Fabrice; Sarafan-Vasseur, Nasrin; Di Fiore, Frédéric

2016-11-15

To assess the prognostic and predictive value of circulating ESR1 mutation and its kinetics before and after progression on aromatase inhibitor (AI) treatment. ESR1 circulating D538G and Y537S/N/C mutations were retrospectively analyzed by digital droplet PCR after first-line AI failure in patients treated consecutively from 2010 to 2012 for hormone receptor-positive metastatic breast cancer. Progression-free survival (PFS) and overall survival (OS) were analyzed according to circulating mutational status and subsequent lines of treatment. The kinetics of ESR1 mutation before (3 and 6 months) and after (3 months) AI progression were determined in the available archive plasmas. Circulating ESR1 mutations were found at AI progression in 44/144 patients included (30.6%). Median follow-up from AI initiation was 40 months (range 4-94). The median OS was decreased in patients with circulating ESR1 mutation than in patients without mutation (15.5 versus 23.8 months, P=0.0006). The median PFS was also significantly decreased in patients with ESR1 mutation than in patients without mutation (5.9 vs 7 months, P=0.002). After AI failure, there was no difference in outcome for patients receiving chemotherapy (n = 58) versus non-AI endocrine therapy (n=51) in patients with and without ESR1 mutation. ESR1 circulating mutations were detectable in 75% of all cases before AI progression, whereas the kinetics 3 months after progression did not correlate with outcome. ESR1 circulating mutations are independent risk factors for poor outcome after AI failure, and are frequently detectable before clinical progression. Interventional studies based on ESR1 circulating status are warranted.

Language Assessment in a Snap: Monitoring Progress up to 36 Months

ERIC Educational Resources Information Center

Gilkerson, Jill; Richards, Jeffrey A.; Greenwood, Charles R.; Montgomery, Judy K.

2017-01-01

This article describes the development and validation of the Developmental Snapshot, a 52-item parent questionnaire on child language and vocal communication development that can be administered monthly and scored automatically. The Snapshot was created to provide an easily administered monthly progress monitoring tool that enables parents to…

Tau Pathology is Present In Vivo and Develops In Vitro in Sensory Neurons from Human P301S Tau Transgenic Mice: A System for Screening Drugs against Tauopathies

PubMed Central

Mellone, Manuela; Kestoras, Dimitra; Andrews, Melissa R.; Dassie, Elisa; Crowther, R. Anthony; Stokin, Gorazd B.; Tinsley, Jon; Horne, Graeme; Goedert, Michel

2013-01-01

Intracellular tau aggregates are the neuropathological hallmark of several neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and cases of frontotemporal dementia, but the link between these aggregates and neurodegeneration remains unclear. Neuronal models recapitulating the main features of tau pathology are necessary to investigate the molecular mechanisms of tau malfunction, but current models show little and inconsistent spontaneous tau aggregation. We show that dorsal root ganglion (DRG) neurons in transgenic mice expressing human P301S tau (P301S-htau) develop tau pathology similar to that found in brain and spinal cord and a significant reduction in mechanosensation occurs before detectable fibrillar tau formation. DRG neuronal cultures established from adult P301S-htau mice at different ages retained the pattern of aberrant tau found in vivo. Moreover, htau became progressively hyperphosphorylated over 2 months in vitro beginning with nonsymptomatic neurons, while hyperphosphorylated P301S-htau-positive neurons from 5-month-old mice cultured for 2 months died preferentially. P301S-htau-positive neurons grew aberrant axons, including spheroids, typically found in human tauopathies. Neurons cultured at advanced stages of tau pathology showed a 60% decrease in the fraction of moving mitochondria. SEG28019, a novel O-GlcNAcase inhibitor, reduced steady-state pSer396/pSer404 phosphorylation over 7 weeks in a significant proportion of DRG neurons showing for the first time the possible beneficial effect of prolonged dosing of O-GlcNAcase inhibitor in vitro. Our system is unique in that fibrillar tau forms without external manipulation and provides an important new tool for understanding the mechanisms of tau dysfunction and for screening of compounds for treatment of tauopathies. PMID:24227726

Compositional and functional dynamics of dried papaya as affected by storage time and packaging material.

PubMed

Udomkun, Patchimaporn; Nagle, Marcus; Argyropoulos, Dimitrios; Mahayothee, Busarakorn; Latif, Sajid; Müller, Joachim

2016-04-01

Papaya has been identified as a valuable source of nutrients and antioxidants, which are beneficial for human health. To preserve the nutritional properties after drying, appropriate storage specifications should be considered. This study aimed to investigate the quality and stability of air-dried papaya in terms of quality dynamics and behavior of bio-active compounds during storage for up to 9 months in two packaging materials: aluminum laminated polyethylene and polyamide/polyethylene. Samples with moisture content (MC) of 0.1328 g g(-1) and water activity (aw) of 0.5 were stored at 30 °C and relative humidity (RH) of 40-50%. The MC, aw, degree of browning (DB) and 5-hydroxymethylfurfural (HMF) content were found to notably increase as storage progressed. On the contrary, there was a significant decrease in antioxidant capacity (DPPH, FRAP and ABTS), total phenolic (TP) and ascorbic acid (AA) contents. Packaging in aluminum laminated polyethylene under ambient conditions was found to better preserve bio-active compounds and retard increases in MC, aw and DB, when compared to polyamide/polyethylene. Copyright © 2015 Elsevier Ltd. All rights reserved.

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

PubMed Central

Chen, Qi; Quan, Qi; Ding, Lingyu; Hong, Xiangchan; Zhou, Ningning; Liang, Ying; Wu, Haiying

2015-01-01

Objectives Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy. Materials and Methods Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded. Results and Conclusion PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control. PMID:26172562

Survival benefit for patients with diffuse intrinsic pontine glioma (DIPG) undergoing re-irradiation at first progression: A matched-cohort analysis on behalf of the SIOP-E-HGG/DIPG working group.

PubMed

Janssens, Geert O; Gandola, Lorenza; Bolle, Stephanie; Mandeville, Henry; Ramos-Albiac, Monica; van Beek, Karen; Benghiat, Helen; Hoeben, Bianca; Morales La Madrid, Andres; Kortmann, Rolf-Dieter; Hargrave, Darren; Menten, Johan; Pecori, Emilia; Biassoni, Veronica; von Bueren, Andre O; van Vuurden, Dannis G; Massimino, Maura; Sturm, Dominik; Peters, Max; Kramm, Christof M

2017-03-01

Overall survival (OS) of patients with diffuse intrinsic pontine glioma (DIPG) is poor. The purpose of this study is to analyse benefit and toxicity of re-irradiation at first progression. At first progression, 31 children with DIPG, aged 2-16 years, underwent re-irradiation (dose 19.8-30.0 Gy) alone (n = 16) or combined with systemic therapy (n = 15). At initial presentation, all patients had typical symptoms and characteristic MRI features of DIPG, or biopsy-proven high-grade glioma. An interval of ≥3 months after upfront radiotherapy was required before re-irradiation. Thirty-nine patients fulfilling the same criteria receiving radiotherapy at diagnosis, followed by best supportive care (n = 20) or systemic therapy (n = 19) at progression but no re-irradiation, were eligible for a matched-cohort analysis. Median OS for patients undergoing re-irradiation was 13.7 months. For a similar median progression-free survival after upfront radiotherapy (8.2 versus 7.7 months; P = .58), a significant benefit in median OS (13.7 versus 10.3 months; P = .04) was observed in favour of patients undergoing re-irradiation. Survival benefit of re-irradiation increased with a longer interval between end-of-radiotherapy and first progression (3-6 months: 4.0 versus 2.7; P < .01; 6-12 months: 6.4 versus 3.3; P = .04). Clinical improvement with re-irradiation was observed in 24/31 (77%) patients. No grade 4-5 toxicity was recorded. On multivariable analysis, interval to progression (corrected hazard ratio = .27-.54; P < .01) and re-irradiation (corrected hazard ratio = .18-.22; P < .01) remained prognostic for survival. A risk score (RS), comprising 5 categories, was developed to predict survival from first progression (ROC: .79). Median survival ranges from 1.0 month (RS-1) to 6.7 months (RS-5). The majority of patients with DIPG, responding to upfront radiotherapy, do benefit of re-irradiation with acceptable tolerability. Copyright © 2017 Elsevier Ltd. All rights reserved.

Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

PubMed Central

Wang, Jun; Wang, Baocheng; Chu, Huili; Yao, Yunfeng

2016-01-01

Identifying activating EGFR mutations is a useful predictive strategy that helps select a population of advanced non-small-cell lung cancer (NSCLC) patients for treatment with EGFR tyrosine kinase inhibitors (TKIs). Patients with sensitizing EGFR mutations (predominantly an in-frame deletion in exon 19 and an L858R substitution) are highly responsive to first-generation EGFR TKIs, such as gefitinib and erlotinib, and show improved progression-free survival without serious side effects. However, all patients with activating EGFR mutations who are initially responsive to EGFR TKIs eventually develop acquired resistance after a median progression-free survival of 10–16 months, followed by disease progression. Moreover, ~20%–30% of NSCLC patients have no objective tumor regression on initial EGFR TKI treatment, although they harbor an activating EGFR mutation. These patients represent an NSCLC subgroup that is defined as having intrinsic or primary resistance to EGFR TKIs. Different mechanisms of acquired EGFR TKI resistance have been identified, and several novel compounds have been developed to reverse acquired resistance, but little is known about EGFR TKI intrinsic resistance. In this review, we summarize the latest findings involving mechanisms of intrinsic resistance to EGFR TKIs in advanced NSCLC with activating EGFR mutations and present possible therapeutic strategies to overcome this resistance. PMID:27382309

Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9.

PubMed

Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio; Tack, Ivan; Doublier, Sophie; Elliot, Sharon J; Vlassara, Helen; Striker, Gary E

2012-02-01

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis.

Pentosan polysulfate inhibits atherosclerosis in Watanabe heritable hyperlipidemic rabbits: differential modulation of metalloproteinase-2 and -9

PubMed Central

Lupia, Enrico; Zheng, Feng; Grosjean, Fabrizio; Tack, Ivan; Doublier, Sophie; Elliot, Sharon J; Vlassara, Helen; Striker, Gary E

2013-01-01

Pentosan polysulfate (PPS), a heparinoid compound essentially devoid of anticoagulant activity, modulates cell growth and decreases inflammation. We investigated the effect of PPS on the progression of established atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. After severe atherosclerosis developed on an atherogenic diet, WHHL rabbits were treated with oral PPS or tap water for 1 month. The aortic intima-to-media ratio and macrophage infiltration were reduced, plaque collagen content was increased, and plaque fibrous caps were preserved by PPS treatment. Plasma lipid levels and post-heparin hepatic lipase activity remained unchanged. However, net collagenolytic activity in aortic extracts was decreased, and the levels of matrix metalloproteinase (MMP)-2 and tissue inhibitor of metalloproteinase (TIMP) activity were increased by PPS. Moreover, PPS treatment decreased tumor necrosis factor α (TNFα)-stimulated proinflammatory responses, in particular activation of nuclear factor-κB and p38, and activation of MMPs in macrophages. In conclusion, oral PPS treatment prevents progression of established atherosclerosis in WHHL rabbits. This effect may be partially mediated by increased MMP-2 and TIMP activities in the aortic wall and reduced TNFα-stimulated inflammation and MMP activation in macrophages. Thus, PPS may be a useful agent in inhibiting the progression of atherosclerosis. PMID:22042083

Age or experience? The influence of age at implantation and social and linguistic environment on language development in children with cochlear implants.

PubMed

Szagun, Gisela; Stumper, Barbara

2012-12-01

The authors investigated the influence of social environmental variables and age at implantation on language development in children with cochlear implants. Participants were 25 children with cochlear implants and their parents. Age at implantation ranged from 6 months to 42 months ( M (age) = 20.4 months, SD = 22.0 months). Linguistic progress was assessed at 12, 18, 24, and 30 months after implantation. At each data point, language measures were based on parental questionnaire and 45-min spontaneous speech samples. Children's language and parents' child-directed language were analyzed. On all language measures, children displayed considerable vocabulary and grammatical growth over time. Although there was no overall effect of age at implantation, younger and older children had different growth patterns. Children implanted by age 24 months made the most marked progress earlier on, whereas children implanted thereafter did so later on. Higher levels of maternal education were associated with faster linguistic progress; age at implantation was not. Properties of maternal language input, mean length of utterance, and expansions were associated with children's linguistic progress independently of age at implantation. In children implanted within the sensitive period for language learning, children's home language environment contributes more crucially to their linguistic progress than does age at implantation.

Development and operations of the astrophysics data system

NASA Technical Reports Server (NTRS)

Murray, S. S.

1996-01-01

Monthly progress reports are given for the period April 1994 through September 1994. Each month's progress includes a general summary and overviews of Administrative functions, Systems Engineering, User Committee, User Support, Test and QA, System Integration, Development, Operations, and Suppliers of Data. These overviews include user and query statistics for the month.

Development and operations of the astrophysics data system

NASA Technical Reports Server (NTRS)

Murray, S. S.

1996-01-01

Monthly progress reports are given for the period October 1993 through March 1994. Each month's progress includes a general summary and overviews of Administrative functions, Systems Engineering, User Committee, User Support, Test and QA, System Integration, Development, Operations, and Suppliers of Data. These overviews include user and query statistics for the month.

Compound Libraries: Recent Advances and Their Applications in Drug Discovery.

PubMed

Gong, Zhen; Hu, Guoping; Li, Qiang; Liu, Zhiguo; Wang, Fei; Zhang, Xuejin; Xiong, Jian; Li, Peng; Xu, Yan; Ma, Rujian; Chen, Shuhui; Li, Jian

2017-01-01

Hit identification is the starting point of small-molecule drug discovery and is therefore very important to the pharmaceutical industry. One of the most important approaches to identify a new hit is to screen a compound library using an in vitro assay. High-throughput screening has made great contributions to drug discovery since the 1990s but requires expensive equipment and facilities, and its success depends on the size of the compound library. Recent progress in the development of compound libraries has provided more efficient ways to identify new hits for novel drug targets, thereby helping to promote the development of the pharmaceutical industry, especially for firstin- class drugs. A multistage and systematic research of articles published between 1986 and 2017 has been performed, which was organized into 5 sections and discussed in detail. In this review, the sources and classification of compound libraries are summarized. The progress made in combinatorial libraries and DNA-encoded libraries is reviewed. Library design methods, especially for focused libraries, are introduced in detail. In the final part, the status of the compound libraries at WuXi is reported. The progress related to compound libraries, especially drug template libraries, DELs, and focused libraries, will help to identify better hits for novel drug targets and promote the development of the pharmaceutical industry. Moreover, these libraries can facilitate hit identification, which benefits most research organizations, including academics and small companies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The role of BRAF V600 mutation in melanoma

PubMed Central

2012-01-01

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors. PMID:22554099

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.

PubMed

Antonia, Scott J; Villegas, Augusto; Daniel, Davey; Vicente, David; Murakami, Shuji; Hui, Rina; Yokoi, Takashi; Chiappori, Alberto; Lee, Ki H; de Wit, Maike; Cho, Byoung C; Bourhaba, Maryam; Quantin, Xavier; Tokito, Takaaki; Mekhail, Tarek; Planchard, David; Kim, Young-Chul; Karapetis, Christos S; Hiret, Sandrine; Ostoros, Gyula; Kubota, Kaoru; Gray, Jhanelle E; Paz-Ares, Luis; de Castro Carpeño, Javier; Wadsworth, Catherine; Melillo, Giovanni; Jiang, Haiyi; Huang, Yifan; Dennis, Phillip A; Özgüroğlu, Mustafa

2017-11-16

Most patients with locally advanced, unresectable, non-small-cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti-programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based chemoradiotherapy. We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression-free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12-month and 18-month progression-free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression-free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month progression-free survival rate was 55.9% versus 35.3%, and the 18-month progression-free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

Plants and their bioactive compounds with the potential to enhance mechanisms of inherited cardiac regeneration.

PubMed

Zhou, Zhen; Li, Dianbin; Zhou, Hua; Lin, Xiaoli; Li, Censing; Tang, Mingfeng; Feng, Zhou; Li, Ming

2015-06-01

This article reviews the current progress and research indications in the application of natural plant compounds with the potential for the treatment of cardiovascular diseases. Our understanding of how to apply natural plant compounds to enhance mechanisms of inherited cardiac regeneration, which is physiologically pertinent to myocyte turnover or minor cardiac repair, for substantial cardiac regeneration to repair pathological heart injuries is discussed. Although significant progress has been made in the application of natural plant compounds for therapy of heart diseases, the understanding or the application of these compounds specifically for enhancing mechanisms of inherited cardiac regeneration for the treatment of cardiovascular diseases is little. Recent recognition of some natural plant compounds that can repair damaged myocardial tissues through enhancing mechanisms of inherited cardiac regeneration has offered an alternative for clinical translation. Application of natural plant compounds, which show the activity of manipulating gene expressions in such a way to enhance mechanisms of inherited cardiac regeneration for cardiac repair, may provide a promising strategy for the reconstruction of damaged cardiac tissues due to cardiovascular diseases. Georg Thieme Verlag KG Stuttgart · New York.

Long-term outcomes for patients with chronic lymphocytic leukemia who discontinue ibrutinib.

PubMed

Jain, Preetesh; Thompson, Philip A; Keating, Michael; Estrov, Zeev; Ferrajoli, Alessandra; Jain, Nitin; Kantarjian, Hagop; Burger, Jan A; O'Brien, Susan; Wierda, William G

2017-06-15

Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported. Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed. Long-term outcomes among patients with CLL after they discontinued ibrutinib were analyzed. Ninety of 320 patients (28%) who were treated on ibrutinib-based regimens discontinued ibrutinib. Of these, 80 had relapsed/refractory disease, and 10 were treatment-naive. The median time to discontinuation was 15 months (range, 1.2-54 months). After a median follow-up of 38 months after starting ibrutinib, 40 patients (44%) remained alive. Major reasons for ibrutinib discontinuation were intolerance (n = 29; 32%), miscellaneous (n = 28; 31%), progression (n = 19; 21%), and Richter transformation (RT) (n = 9; 10%). The median survival according to the reason for discontinuation was 33 months for ibrutinib intolerance, 11 months for miscellaneous causes, 16 months for progressive CLL, and 2 months for RT. Among the 19 patients who had progressive CLL, 42% responded to subsequent therapy. Ibrutinib discontinuation was observed during therapy. Patients with CLL who had disease transformation had especially poor outcomes, whereas those who developed progressive disease during ibrutinib therapy had a median survival of <1.5 years. Survival was associated with the reason for discontinuation; patients who had progressive CLL had better survival compared with those who had disease transformation. Effective salvage strategies for patients with CLL who progress on ibrutinib therapy is of critical importance. Cancer 2017;123:2268-2273. © 2017 American Cancer Society. © 2017 American Cancer Society.

Andrographolide reduces cognitive impairment in young and mature AβPPswe/PS-1 mice.

PubMed

Serrano, Felipe G; Tapia-Rojas, Cheril; Carvajal, Francisco J; Hancke, Juan; Cerpa, Waldo; Inestrosa, Nibaldo C

2014-12-18

Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Aβ oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3β (GSK-3β). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AβPPswe/PS-1 Alzheimer's model. ANDRO reduces the Aβ levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Aβ oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression.

Analyzing compound and project progress through multi-objective-based compound quality assessment.

PubMed

Nissink, J Willem M; Degorce, Sébastien

2013-05-01

Compound-quality scoring methods designed to evaluate multiple drug properties concurrently are useful to analyze and prioritize output from drug-design efforts. However, formalized multiparameter optimization approaches are not widely used in drug design. We rank molecules synthesized in drug-discovery projects using simple and aggregated desirability functions reflecting medicinal chemistry 'rules'. Our quality score deals transparently with missing data, a key requirement in drug-hunting projects where data availability is often limited. We further estimate confidence in the interpretation of such a compound-quality measure. Scores and associated confidences provide systematic insight in the quality of emerging chemical equity. Tracking quality of synthetic output over time yields valuable insight into the progress of drug-design teams, with potential applications in risk and resource management of a drug portfolio.

Vemurafenib for BRAF V600 mutated advanced melanoma: results of treatment beyond progression.

PubMed

Scholtens, A; Geukes Foppen, M H; Blank, C U; van Thienen, J V; van Tinteren, H; Haanen, J B

2015-03-01

Selective BRAF inhibition (BRAFi) by vemurafenib or dabrafenib has become approved standard treatment in BRAF V600 mutated advanced stage melanoma. While the response rate is high, the response duration is limited with a progression-free survival (PFS) of 5-6months. Our observation of accelerated disease progression within some patients after stopping vemurafenib treatment has fostered the idea of treatment beyond progression (BRAFi TBP). In this retrospective study, we analysed 70 metastatic melanoma patients, treated at our institute, who experienced progression after prior objective response upon treatment with vemurafenib. Thirty-five patients that continued treatment beyond progression are compared with 35 patients who stopped BRAFi treatment at disease progression. Median overall survival beyond documented progression was found to be 5.2months versus 1.4months (95% confidence interval (CI): 3.8-7.4 versus 0.6-3.4; Log-Rank p=0.002) in favour of BRAFi TBP. In the multivariate survival analysis, stopping treatment at disease progression was significantly associated with shorter survival (hazard ratio: 1.92; 95% CI: 1.04-3.55; p=0.04). Our results suggest that continuing vemurafenib treatment beyond progression may be beneficial in advanced melanoma patients, who prior to progression responded to vemurafenib. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Radiographic Comparison of Progressive and Conventional Loading on Crestal Bone Loss and Density in Single Dental Implants: A Randomized Controlled Trial Study

PubMed Central

Ghoveizi, Rahab; Alikhasi, Marzieh; Siadat, Mohammad-Reza; Siadat, Hakimeh; Sorouri, Majid

2013-01-01

Objective: Crestal bone loss is a biological complication in implant dentistry. The aim of this study was to compare the effect of progressive and conventional loading on crestal bone height and bone density around single osseointegrated implants in the posterior maxilla by a longitudinal radiographic assessment technique. Materials and Methods: Twenty micro thread implants were placed in 10 patients (two implants per patient). One of the two implants in each patient was assigned to progressive and the other to conventional loading groups. Eight weeks after surgery, conventional implants were restored with a metal ceramic crown and the progressive group underwent a progressive loading protocol. The progressive loading group took different temporary acrylic crowns at 2, 4 and 6 months. After eight months, acrylic crowns were replaced with a metal ceramic crown. Computer radiography of both progressive and conventional implants was taken at 2, 4, 6, and 12 months. Image analysis was performed to measure the height of crestal bone loss and bone density. Results: The mean values of crestal bone loss at month 12 were 0.11 (0.19) mm for progressively and 0.36 (0.36) mm for conventionally loaded implants, with a statistically significant difference (P < 0.05) using Wilcoxon sign rank. Progressively loaded group showed a trend for higher bone density gain compared to the conventionally loaded group, but when tested with repeated measure ANOVA, the differences were not statistically significant (P > 0.05). Conclusion: The progressive group showed less crestal bone loss in single osseointegrated implant than the conventional group. Bone density around progressively loaded implants showed increase in crestal, middle and apical areas. PMID:23724215

USSR Report, Chemistry

DTIC Science & Technology

1984-01-06

Sep-Oct 83) ................................. ANALYTICAL CHEMISTRY Ionometric Determination of Copper in Organic Compounds S(S. L. Davydova, et al...Committee Reviews Progress in Fertilizer Industry (EKONOMICHESKAYA GAZETA, No 42, Oct 83) .................. 30 INORGANIC COMPOUNDS Speed of Ultrasound...Sep 83).. ........... .......... . . .. . . . . .... 39 NITROGEN COMPOUNDS Phototropy of Quaternary Ammonium Salts of N,N’-Bis- Substituted Diimides

Progressive central puberty in a toddler with partial androgen insensitivity.

PubMed

Dougan, Grace C; Uli, Naveen; Shulman, Dorothy I

2014-03-01

A male infant was diagnosed with partial androgen insensitivity caused by a novel mutation in the androgen receptor. At 3.5 months of age, he received 100 mg of testosterone intramuscularly over the course of 3 months to increase phallic size. He developed pubic hair after 5 months and signs of progressive central precocious puberty when re-examined at 17.5 months, which subsequently was suppressed with depot leuprolide. Copyright © 2014 Mosby, Inc. All rights reserved.

Economic impact of disease progression in follicular non-Hodgkin lymphoma

PubMed Central

Beveridge, Roy; Satram-Hoang, Sacha; Sail, Kavita; Darragh, Joseph; Chen, Clara; Forsyth, Michael; Reyes, Carolina

2011-01-01

Using a retrospective claims database, we estimated the economic costs of progression among patients with follicular non-Hodgkin lymphoma (f-NHL) treated in an outpatient community-based setting. Patients with f-NHL who received care between 1 July 2006 and 31 December 2009 were categorized into two cohorts based on whether they experienced progressive disease (PD) or not. Costs per patient per month (PPPM) were compared between patients with PD versus non-PD. Follow-up time was censored at the last entry for disease status or 6 months after the date of remission/stable disease or progression. Of the 1002 patients with f-NHL identified, 268 progressed and 734 did not. The mean overall costs PPPM over the 6-month follow-up period were significantly higher for patients with PD versus non-PD ($3527 vs. $860; difference = $2667; p < 0.001). This cost difference persisted within all resource categories evaluated. Results of this study indicate that therapies which delay progression for patients with f-NHL may result in potential cost savings. PMID:21745172

Eribulin mesylate (halichondrin B Analog E7389) in platinum-resistant and platinum-sensitive ovarian cancer: a two-cohort, phase II study

PubMed Central

Hensley, Martee L.; Kravetz, Sara; Jia, Xiaoyu; Iasonos, Alexia; Tew, William; Pereira, Lauren; Sabbatini, Paul; Whalen, Christin; Aghajanian, Carol A.; Zarwan, Corinne; Berlin, Suzanne

2011-01-01

Background Eribulin mesylate is a tubulin inhibitor with activity superior to paclitaxel in NIH:OVCAR-3 human epithelial ovarian cancer xenograft models. We sought to assess the efficacy of eribulin in platinum-resistant and platinum-sensitive recurrent ovarian cancer. Methods Patients with recurrent measurable epithelial ovarian cancer, ≤2 prior cytotoxic regimens, and adequate organ function were enrolled into two separate cohorts: 1) Platinum resistant (progression-free interval from last platinum-based therapy <6 months); and 2) Platinum sensitive (progression-free interval from last platinum-based therapy ≥6 months). Treatment: Eribulin 1.4 mg/m2 over 15 minutes by vein on days 1 and 8, every 21 days. Efficacy was determined by objective response by computed tomography. Results Platinum-resistant cohort: Thirty-seven patients enrolled. Thirty-six patients were evaluable for response and toxicity. Two patients achieved partial response (PR, 5.5%). Sixteen (44%) had a best response of stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.4–2.8 months). Platinum-sensitive cohort: Thirty-seven patients enrolled, and all were evaluable for response. Seven patients achieved partial response (PR, 19%). Median progression-free survival was 4.1 months (95% confidence interval, 2.8–5.8 months). The major toxicity was grade 3 or 4 neutropenia (42% in platinum-resistant patients; 54% in platinum-sensitive patients). Conclusions Eribulin achieved objective response in 5.5% of women with platinum-resistant recurrent ovarian cancer and in 19% of women with platinum-sensitive disease. Median progression-free survival was 1.8 months in the platinum-resistant group and 4.1 months in the platinum-sensitive group. PMID:21935916

Review on comparative efficacy of bevacizumab, panitumumab and cetuximab antibody therapy with combination of FOLFOX-4 in KRAS-mutated colorectal cancer patients.

PubMed

Pathak, Surajit; S, Sushmitha; Banerjee, Antara; Marotta, Francesco; Gopinath, Madhumala; Murugesan, Ramachandran; Zhang, Hong; B, Bhavani; Girigoswami, Agnishwar; Sollano, Jose; Sun, Xiao-Feng

2018-01-26

Colorectal cancer, fourth leading form of cancer worldwide and is increasing in alarming rate in the developing countries. Treating colorectal cancer has become a big challenge worldwide and several antibody therapies such as bevacizumab, panitumumab and cetuximab are being used with limited success. Moreover, mutation in KRAS gene which is linked with the colorectal cancer initiation and progression further interferes with the antibody therapies. Considering median progression free survival and overall survival in account, this review focuses to identify the most efficient antibody therapy in combination with chemotherapy (FOLFOX-4) in KRAS mutated colorectal cancer patients. The bevacizumab plus FOLFOX-4 therapy shows about 9.3 months and 8.7 months of progression free survival for KRAS wild and mutant type, respectively. The overall survival is about 34.8 months for wild type whereas for the mutant it is inconclusive for the same therapy. In comparison, panitumumab results in better progression-free survival which is about (9.6 months) and overall survival is about (23.9 months) for the wild type KRAS and the overall survival is about 15.5 months for the mutant KRAS . Cetuximab plus FOLFOX-4 therapy shows about 7.7 months and 5.5 months of progression-free survival for wild type KRAS and mutant type, respectively. Thus, panitumumab shows significant improvement in overall survival rate for wild type KRAS , validating as a cost effective therapeutic for colorectal cancer therapy. This review depicts that panitumumab along with FOLFOX-4 has a higher response in colorectal cancer patients than the either of the two monoclonal antibodies plus FOLFOX-4.

Next Generation Attenuation Relationships for the Eastern United States (NGA-East)

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

Mahin, Stephen; Bozorgnia, Yousef

2016-04-11

This is a progress report to DOE for project Next Generation Attenuation for Central & Eastern US (NGA-East).This progress report consists of numerous monthly progress segments starting June 1, 2010 until December 31, 2015. Please note: the December 2015 progress report was issued in January 2016 due to the final university financial reporting at the end of this project. For each month, there is a technical progress list, and an update on the financial progress of the project. As you know, this project is jointly funded by the DOE, US Nuclear Regulatory Commission (NRC) and Electric Power Research Institute (EPRI).more » Thus, each segment includes financial progress for these three funding agencies.« less

Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension.

PubMed

Schuster, Cornelia; Eikesdal, Hans P; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E; Akslen, Lars A; Straume, Oddbjørn

2012-01-01

VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. ClinicalTrials.gov NCT00139360.

Combined vemurafenib and fotemustine in patients with BRAF V600 melanoma progressing on vemurafenib.

PubMed

Queirolo, Paola; Spagnolo, Francesco; Picasso, Virginia; Spano, Laura; Tanda, Enrica; Fontana, Valeria; Giorello, Laura; Merlo, Domenico Franco; Simeone, Ester; Grimaldi, Antonio Maria; Curvietto, Marcello; Del Vecchio, Michele; Bruzzi, Paolo; Ascierto, Paolo Antonio

2018-02-23

BRAF inhibitor vemurafenib achieves high response rate and an improvement in survival in patients with BRAF-mutated metastatic melanoma. However, median progression-free survival is only 6.9 months in the phase 3 study. Retrospective analyses suggest that treatment with BRAF inhibitors beyond initial progression might be associated with improved overall survival. We aimed to prospectively investigate the activity of prolonged treatment with vemurafenib and the addition of fotemustine in patients with systemic progression on prior single-agent BRAF inhibitor. In this two-centres, single-arm Phase 2 trial, we enrolled patients with systemic progressive disease during single-agent vemurafenib treatment. Participants received vemurafenib 960 mg twice daily or dose administered at time of disease progression with vemurafenib previous treatment and fotemustine 100 mg/m2 intravenously every three weeks. The primary endpoint was PFS. Thirty-one patients were enrolled in the study; 16 patients had brain metastases at baseline. Median PFS was 3.9 months and 19 patients (61.3%) achieved disease control (1 CR, 4 PR, 14 SD). For patients achieving disease control, median duration of treatment was 6 months. Median OS was 5.8 months from enrolment and 15.4 months from start of previous vemurafenib. Five patients (16.1%) had a G3-4 AE, the most common being thrombocytopenia, which occurred in 3 patients.This trial is registered with ClinicalTrials.gov number NCT01983124. The combination of vemurafenib plus fotemustine has clinical activity and an acceptable safety profile in BRAF-refractory patients.

Extraction of oak volatiles and ellagitannins compounds and sensory profile of wine aged with French winewoods subjected to different toasting methods: behaviour during storage.

PubMed

Chira, Kleopatra; Teissedre, Pierre-Louis

2013-09-01

In Merlot wines the evolution of volatile and non-volatile (ellagitannins) compounds extracted from winewoods while being macerated for 12 months was studied. Seven types of winewoods subjected to different toasting methods were used. Different rates of extraction, depending mainly on wood compounds origin (toasting or naturally present in wood) and on the watering process during toasting, were observed, which were reflected in sensory differences. Globally, volatile phenols together with aldehydes, phenols and lactones showed an increase with increasing maceration time. Ellagitannins were extracted faster during the first 3 months; after 6 months an important decrease was observed. Wines with winewoods subjected to watering during toasting were lower in ellagitannins concentrations and demonstrated the greatest decrease of these compounds during maceration. Astringency and bitterness intensified with increasing ellagitannins. Lactones induced positive sweetness sensations, whereas furanic and guaiacol compounds influenced bitterness and astringency. Spicy and vanilla descriptors were related to eugenol, vanillin and other odorous chemicals. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of packaging material on enological parameters and volatile compounds of dry white wine.

PubMed

Revi, M; Badeka, A; Kontakos, S; Kontominas, M G

2014-01-01

The enological parameters and volatile compounds of white wine packaged in dark coloured glass and two commercial bag-in-box (BIB) pouches (low density polyethylene - LDPE and ethylene vinyl acetate - EVA lined) were determined for a period of 6 months at 20 °C. Parameters monitored included: titratable acidity, volatile acidity, pH, total SO2, free SO2, colour, volatile compounds and sensory attributes. The BIB packaging materials affected the titratable acidity, total and free SO2 and colour of wine. A substantial portion of the wine aroma compounds was adsorbed by the plastic materials or lost to the environment through leakage of the valve fitment. Between the two plastics, the LDPE lined pouch showed a considerably higher aroma sorption as compared to EVA. Wine packaged in glass retained the largest portion of its aroma compounds. Sensory evaluation showed that white wine packaged in both plastics was of acceptable quality for 3 months vs. at least 6 months for that in glass bottles. Copyright © 2013 Elsevier Ltd. All rights reserved.

Thermal and Kinetic Modelling of Elastomer Flow—Application to an Extrusion Die

NASA Astrophysics Data System (ADS)

Launay, J.; Allanic, N.; Mousseau, P.; Deterre, R.

2011-05-01

This paper reports and discusses the thermal and kinetic behaviour of elastomer flow inside an extrusion die. The reaction progress through the runner was modeled by using a particle tracking technique. The aim is to analyze viscous dissipation phenomena to control scorch arisen, improve the rubber compound curing homogeneity and reduce the heating time in the mould using the progress of the induction time. The heat and momentum equations were solved in three dimensions with Ansys Polyflow. A particle tracking technique was set up to calculate the reaction progress. Several simulations were performed to highlight the influence of process parameters and geometry modifications on the rubber compound thermal and cure homogeneity.

Are We There Yet? Applying Thermodynamic and Kinetic Profiling on Embryonic Ectoderm Development (EED) Hit-to-Lead Program.

PubMed

Wang, Ying; Edalji, Rohinton P; Panchal, Sanjay C; Sun, Chaohong; Djuric, Stevan W; Vasudevan, Anil

2017-10-26

It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (k off ) of the lead compounds were observed as the program progressed. Analysis of the kinetic data indicated that compound cellular activity correlated with both K i and k off . Our analysis revealed that ITC data should be interpreted in the context of chiral purity of the compounds. The thermodynamic signatures of the EED aminopyrrolidine compounds were found to be mainly enthalpy driven with improved enthalpic contributions as the program progressed. Our study also demonstrated that significant challenges still exist in utilizing kinetic and thermodynamic parameters for hit selection.

Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma.

PubMed

Kaseb, Ahmed O; Morris, Jeffrey S; Iwasaki, Michiko; Al-Shamsi, Humaid O; Raghav, Kanwal Pratap Singh; Girard, Lauren; Cheung, Sheree; Nguyen, Van; Elsayes, Khaled M; Xiao, Lianchun; Abdel-Wahab, Reham; Shalaby, Ahmed S; Hassan, Manal; Hassabo, Hesham M; Wolff, Robert A; Yao, James C

2016-01-01

Clinicaltrials.gov #NCT01180959. Early clinical studies of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) have a tolerable toxicity and a promising clinical outcome. We evaluated the efficacy and tolerability of this combination as a second-line therapy for HCC refractory to sorafenib. For this single-arm, Phase II study, we recruited patients with Child-Pugh class A or B liver disease, Eastern Cooperative Oncology Group performance status 0-2, and advanced HCC that was not amenable to surgical or regional therapies and treatment with sorafenib had failed (disease progressed or patient could not tolerate sorafenib). Patients received 10 mg/kg intravenous bevacizumab every 14 days and 150 mg oral erlotinib daily for 28-day cycles until progression. Tumor response was evaluated every two cycles using Response Evaluation Criteria in Solid Tumors. The primary end point was the 16-week progression-free survival rate. Secondary end points included time to progression and overall survival. A total of 44 patients were enrolled and had a median follow-up time of 33.8 months (95% confidence interval [CI]: 23.5 months - not defined). The 16-week progression-free survival rate was 43% (95% CI: 28%-59%), median time to progression was 3.9 months (95% CI: 2.0-8.3 months), and median overall survival duration was 9.9 months (95% CI: 8.3-15.5 months). Grade 3-4 adverse events included fatigue (13%), acne (11%), diarrhea (9%), anemia (7%), and upper gastrointestinal hemorrhage (7%). Bevacizumab plus erlotinib was tolerable and showed a signal of survival benefit in the second-line setting for patients with advanced HCC. Because standard-of-care options are lacking in this setting, further studies to identify predictors of response to this regimen are warranted.

Predictive Value of Early Tumor Shrinkage and Density Reduction of Lung Metastases in Patients With Metastatic Colorectal Cancer Treated With Regorafenib.

PubMed

Vanwynsberghe, Hannes; Verbeke, Xander; Coolen, Johan; Van Cutsem, Eric

2017-12-01

The benefit of regorafenib in colorectal cancer is not very pronounced. At present, there is lack of predictive biological or radiological markers. We studied if density reduction or small changes in size of lung metastases could be a predictive marker. We retrospectively measured density in size of lung metastases of all patients included in the CORRECT and CONSIGN trials at our center. Contrast-enhanced CT scan at baseline and at week 8 were compared. Data of progressive-free survival and overall survival were collected from the CORRECT and CONSIGN trials. A significant difference in progressive-free survival was seen in 3 groups: response or stable disease in size (5.36 vs. 3.96 months), response in density (6.03 vs. 2.72 months), and response in corrected density (6.14 vs. 3.08 months). No difference was seen for response in size versus stable disease or progressive disease in size. For overall survival, a difference was observed in the same 3 groups: response or stable disease in size (9.89 vs. 6.44 months), response in density (9.59 vs. 7.04 months), and response in corrected density (9.09 vs. 7.16 months). No difference was seen for response in size versus stable disease or progressive disease in size. Density reduction in lung metastases might be a good predictive parameter to predict outcome for regorafenib. Early tumor progression might be a negative predictive factor. If further validated, density reduction and early tumor progression might be useful to ameliorate the cost-benefit of regorafenib. Copyright © 2017 Elsevier Inc. All rights reserved.

Influence of physicochemical parameters and high pressure processing on the volatile compounds of Serrano dry-cured ham after prolonged refrigerated storage.

PubMed

Martínez-Onandi, N; Rivas-Cañedo, A; Picon, A; Nuñez, M

2016-12-01

One hundred and three volatile compounds were detected by solid-phase microextraction followed by gas chromatography-mass spectrometry in 30 ripened Serrano dry-cured hams, submitted or not to high pressure processing (HPP) and afterwards held for 5months at 4°C. The effect of ham physicochemical parameters and HPP (600MPa for 6min) on volatile compounds was assessed. Physicochemical parameters primarily affected the levels of acids, alcohols, alkanes, esters, benzene compounds, sulfur compounds and some miscellaneous compounds. Intramuscular fat content was the physicochemical parameter with the most pronounced effect on the volatile fraction of untreated Serrano ham after refrigerated storage, influencing the levels of 38 volatile compounds while aw, salt content and salt-in-lean ratio respectively influenced the levels of 4, 4 and 5 volatile compounds. HPP treatment affected 21 volatile compounds, resulting in higher levels of alkanes and ketones and lower levels of esters and secondary alcohols, what might affect Serrano ham odor and aroma after 5months of refrigerated storage. Copyright © 2016 Elsevier Ltd. All rights reserved.

A novel canine model for Duchenne muscular dystrophy (DMD): single nucleotide deletion in DMD gene exon 20.

PubMed

Mata López, Sara; Hammond, James J; Rigsby, Madison B; Balog-Alvarez, Cynthia J; Kornegay, Joe N; Nghiem, Peter P

2018-05-29

Boys with Duchenne muscular dystrophy (DMD) have DMD gene mutations, with associated loss of the dystrophin protein and progressive muscle degeneration and weakness. Corticosteroids and palliative support are currently the best treatment options. The long-term benefits of recently approved compounds such as eteplirsen and ataluren remain to be seen. Dogs with naturally occurring dystrophinopathies show progressive disease akin to that of DMD. Accordingly, canine DMD models are useful for studies of pathogenesis and preclinical therapy development. A dystrophin-deficient, male border collie dog was evaluated at the age of 5 months for progressive muscle weakness and dysphagia. Dramatically increased serum creatine kinase levels (41,520 U/L; normal range 59-895 U/L) were seen on a biochemistry panel. Histopathologic changes characteristic of dystrophinopathy were seen. Dystrophin was absent in the skeletal muscle on immunofluorescence microscopy and western blot. Whole genome sequencing, polymerase chain reaction, and Sanger sequencing revealed a frameshift, single nucleotide deletion in canine DMD exon 20, position 27,626,466 (c.2841delT mRNA), resulting in a stop codon six nucleotides downstream. Semen was archived for future line perpetuation. This spontaneous canine dystrophinopathy occurred due to a novel mutation in the minor DMD mutation hotspot (between exons 2 through 20). Perpetuating this line could allow for preclinical testing of genetic therapies targeted to this area of the DMD gene.

Stereotactic Radiosurgery for the Treatment of Primary and Metastatic Spinal Sarcomas

PubMed Central

Balagamwala, Ehsan H.; Angelov, Lilyana; Suh, John H.; Djemil, Toufik; Magnelli, Anthony; Qi, Peng; Zhuang, Tingliang; Godley, Andrew

2016-01-01

Purpose: Despite advancements in local and systemic therapy, metastasis remains common in the natural history of sarcomas. Unfortunately, such metastases are the most significant source of morbidity and mortality in this heterogeneous disease. As a classically radioresistant histology, stereotactic radiosurgery has emerged to control spinal sarcomas and provide palliation. However, there is a lack of data regarding pain relief and relapse following stereotactic radiosurgery. Methods: We queried a retrospective institutional database of patients who underwent spine stereotactic radiosurgery for primary and metastatic sarcomas. The primary outcome was pain relief following stereotactic radiosurgery. Secondary outcomes included progression of pain, radiographic failure, and development of toxicities following treatment. Results: Forty treatment sites were eligible for inclusion; the median prescription dose was 16 Gy in a single fraction. Median time to radiographic failure was 14 months. At 6 and 12 months, radiographic control was 63% and 51%, respectively. Among patients presenting with pain, median time to pain relief was 1 month. Actuarial pain relief at 6 months was 82%. Median time to pain progression was 10 months; at 12 months, actuarial pain progression was 51%. Following multivariate analysis, presence of neurologic deficit at consult (hazard ratio: 2.48, P < .01) and presence of extraspinal bone metastases (hazard ratio: 2.83, P < .01) were associated with pain relief. Greater pain at consult (hazard ratio: 1.92, P < .01), prior radiotherapy (hazard ratio: 4.65, P = .02), and greater number of irradiated vertebral levels were associated with pain progression. Conclusions: Local treatment of spinal sarcomas has remained a challenge for decades, with poor rates of local control and limited pain relief following conventional radiotherapy. In this series, pain relief was achieved in 82% of treatments at 6 months, with half of patients experiencing pain progression by 12 months. Given minimal toxicity and suboptimal pain control at 12 months, dose escalation beyond 16 Gy is warranted. PMID:27074915

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience

PubMed Central

Vici, Patrizia; Pizzuti, Laura; Michelotti, Andrea; Sperduti, Isabella; Natoli, Clara; Mentuccia, Lucia; Lauro, Luigi Di; Sergi, Domenico; Marchetti, Paolo; Santini, Daniele; Magnolfi, Emanuela; Iezzi, Laura; Moscetti, Luca; Fabbri, Agnese; Cassano, Alessandra; Grassadonia, Antonino; Omarini, Claudia; Piacentini, Federico; Botticelli, Andrea; Bertolini, Ilaria; Scinto, Angelo Fedele; Zampa, Germano; Mauri, Maria; D’Onofrio, Loretta; Sini, Valentina; Barba, Maddalena; Maugeri-Saccà, Marcello; Rossi, Ernesto; Landucci, Elisabetta; Tomao, Silverio; Alberti, Antonio Maria; Giotta, Francesco; Ficorella, Corrado; Adamo, Vincenzo; Russo, Antonio; Lorusso, Vito; Cannita, Katia; Barni, Sandro; Laudadio, Lucio; Greco, Filippo; Garrone, Ornella; Giulia, Marina Della; Marolla, Paolo; Sanguineti, Giuseppe; Cocco, Barbara Di; Ciliberto, Gennaro; Maria, Ruggero De; Gamucci, Teresa

2017-01-01

We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order. PMID:28915642

Continuous passive motion and its effects on knee flexion after total knee arthroplasty in patients with knee osteoarthritis.

PubMed

Liao, Chun-De; Huang, Yi-Ching; Lin, Li-Fong; Chiu, Yen-Shuo; Tsai, Jui-Chen; Chen, Chun-Lung; Liou, Tsan-Hon

2016-08-01

This study evaluated the effects of continuous passive motion (CPM) on accelerated flexion after total knee arthroplasty (TKA) and whether CPM application measures (i.e. initial angle and daily increment) are associated with functional outcomes. A retrospective investigation was conducted at the rehabilitation centre of a university-based teaching hospital. Patients who received CPM therapy immediately after TKA surgery were categorized into rapid-, normal-, and slow-progress groups according to their response to CPM during their acute inpatient stay. Knee pain, passive knee flexion, and knee function-measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-were assessed preoperatively at discharge and at 3- and 6-month outpatient follow-up visits. A total of 354 patients were followed for 6 months after inpatient-stay discharge. The patients in the rapid-progress group (n = 119) exhibited significantly greater knee flexions than those in the slow-progress group did (n = 103) at the 3-month follow-up [mean difference (MD) = 10.3°, 95 % confidence interval (CI) 4.3°-16.3°, p < 0.001] and 6-month follow-up (MD = 10.9°, 95 % CI 6.3°-15.6°, p < 0.001). Significant WOMAC score differences between the rapid- and slow-progress groups were observed at the 3-month follow-up (MD = 7.2, 95 % CI 5.4-9.1, p < 0.001) and 6-month follow-up (MD = 16.1, 95 % CI 13.4-18.7, p < 0.001). CPM initial angles and rapid progress significantly predicted short- and long-term outcomes in knee flexion and WOMAC scores (p < 0.001). When CPM is used, early application with initial high flexion and rapid progress benefits knee function up to 6 months after TKA. II.

Identification of novel drugs to target dormant micrometastases.

PubMed

Hurst, Robert E; Hauser, Paul J; You, Youngjae; Bailey-Downs, Lora C; Bastian, Anja; Matthews, Stephen M; Thorpe, Jessica; Earle, Christine; Bourguignon, Lilly Y W; Ihnat, Michael A

2015-05-14

Cancer-specific survival has changed remarkably little over the past half century, mainly because metastases that are occult at diagnosis and generally resistant to chemotherapy subsequently develop months, years or even decades following definitive therapy. Targeting the dormant micrometastases responsible for these delayed or occult metastases would represent a major new tool in cancer patient management. Our hypothesis is that these metastases develop from micrometastatic cells that are suppressed by normal extracellular matrix (ECM). A new screening method was developed that compared the effect of drugs on the proliferation of cells grown on a normal ECM gel (small intestine submucosa, SISgel) to cells grown on plastic cell culture plates. The desired endpoint was that cells on SISgel were more sensitive than the same cells grown as monolayers. Known cancer chemotherapeutic agents show the opposite pattern. Screening 13,000 compounds identified two leads with low toxicity in mice and EC50 values in the range of 3-30 μM, depending on the cell line, and another two leads that were too toxic to mice to be useful. In a novel flank xenograft method of suppressed/dormant cells co-injected with SISgel into the flank, the lead compounds significantly eliminated the suppressed cells, whereas conventional chemotherapeutics were ineffective. Using a 4T1 triple negative breast cancer model, modified for physiological metastatic progression, as predicted, both lead compounds reduced the number of large micrometastases/macrometastases in the lung. One of the compounds also targeted cancer stem cells (CSC) isolated from the parental line. The CSC also retained their stemness on SISgel. Mechanistic studies showed a mild, late apoptotic response and depending on the compound, a mild arrest either at S or G2/M in the cell cycle. In summary we describe a novel, first in class set of compounds that target micrometastatic cells and prevent their reactivation to form recurrent tumors/macrometastases.

Crevicular Fluid Biomarkers and Periodontal Disease Progression

PubMed Central

Oh, Min; Braun, Thomas M.; Ramseier, Christoph A.; Sugai, Jim V.; Giannobile, William V.

2014-01-01

Aim Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). Materials and Methods 100 individuals participated in a 12-month longitudinal investigation and categorized into 4 groups according to their periodontal status. GCF, clinical parameters, and saliva were collected bi-monthly. Sub-gingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6-months, patients received periodontal therapy and continued participation from 6-12 months. GCF samples were analyzed by ELISA for MMP-8, MMP-9, OPG, CRP and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p=0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Results Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61,86). Conclusions Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). PMID:24303954

The impact of fruit maturation on bioactive microconstituents, inhibition of serum oxidation and inflammatory markers in stimulated PBMCs and sensory characteristics of Koroneiki virgin olive oils from Messenia, Greece.

PubMed

Kaliora, Andriana C; Artemiou, Anna; Giogios, Ioannis; Kalogeropoulos, Nick

2013-08-01

Olive fruits from the Koroneiki cultivar (Olea europaea L.) grown in Messenia, Greece, were hand-picked from the same trees in progressive maturity stages, covering three months, and processed identically with a commercial olive mill and a three-phase decanter. Data on quality parameters, and antioxidant activity of the obtained oils were collected by employing the conventional analytical methods set by European Union Commission Regulation no. 61/2011. Additionally, the potential of oils' polar extract to inhibit total serum lipid oxidation and inflammatory markers in stimulated human mononuclear cells was assayed. The results showed that ripening caused an increase in monounsaturated and decrease in polyunsaturated fatty acids, as well as an increase in phenolic compounds - mainly hydroxytyrosol - and in squalene. The extracts' ferric reducing power was in line with the increase of phenolic compounds. In later stages of maturation, lipoprotein oxidation was less potent and the decrease of inflammatory markers in stimulated human mononuclear cells was more powerful. Sensory evaluation detected differences in oils' "bitter" attributes, while the analysis of oils' volatiles revealed quantitative differences.

Social Reconstructionism or Child-Centered Progressivism? Difficulties Defining Progressive Education from the PEA's 1939 Documentary Film, School

ERIC Educational Resources Information Center

Kridel, Craig

2013-01-01

In "The Transformation of the School", Lawrence Cremin warned against formulating any capsule definition of progressive education: "None exists, and none ever will; for throughout its history progressive education meant different things to different people, and these differences were only compounded by the remarkable diversity of…

Progress in the field of physiologically active lanosterol compounds

NASA Astrophysics Data System (ADS)

Reshetova, I. G.; Tkhaper, R. K.; Kamernitskii, Alexey V.

1992-08-01

This review correlates the studies (up to 1991) on the isolation, structural determination, biological activity, and synthesis of physiologically active polyoxidised lanosterol derivatives of vegetable (inotodiol, ganoderic acids) and animal (seychellogenin) origin. The cytotoxic, cardiovascular, and other forms of activity of compounds of this type are of considerable interest in relation to their medical use. It is noted that the functionalised side chain (in an open form or containing lactones, lactols, etc.) is generally responsible for the activity exhibited by lanosterol derivatives. Two basic approaches to the derivation of these structures are defined: either by complete reconstruction of the side chain of lanosterol (degradation and rebuilding with oxygen-containing residues) or by progressive functionalisation of the Δ24-side chain of lanosterol. The synthesis of the known anticancer compound "inotodiol", seychellogenins, ganoderic acids, and other compounds are described. The bibliography includes 105 references.

Mass Transportation in Massachusetts : demonstration project progress report no. 5 - tentative conclusions

DOT National Transportation Integrated Search

1963-11-22

This fifth progress report is submitted twelve months after the initiation of the first MTC-HHFA experiment, and ten months after the start of the large Boston and Maine Railroad. Because of the urgent need to present comprehensive analyses in some d...

Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients.

PubMed

Conry, Robert M; Rodriguez, Michael G; Pressey, Joseph G

2016-01-01

Zoledronic acid (ZA) is a third-generation bisphosphonate in widespread clinical use to reduce pain and skeletal events in patients from a variety of malignancies with bone metastases. Pre-clinical studies indicate that ZA inhibits osteosarcoma through direct anti-proliferative effects, immune activation and anti-angiogenic activity. The purpose of this study was to evaluate the antitumor efficacy of ZA at standard dose until progression in patients with stage IV osteosarcoma lacking a standard of care treatment option proven to influence survival. Researchers retrospectively reviewed medical records of all patients at our institution with high-grade osteosarcoma presumed to be incurable due to metastases progressive after primary combination chemotherapy who received single agent ZA in an effort to delay progression. In our four-patient cohort following initiation of ZA, the median progression-free survival was 19 months, and median overall survival was 56+ months. Two of four patients have remained progression-free since starting ZA. The other two initially progressed after 18-20 months on ZA followed by metastasectomy of lung or dural metastases and further stability for over a year following resumption of ZA. After a 20-month progression-free interval on ZA alone, one patient had partial response following addition of pazopanib to ZA that likely contributed to long term disease control. The four patients experienced no significant toxicities despite protracted dosing of ZA for up to 5 years, and none have required chemotherapy since beginning ZA. Single agent ZA was associated with encouraging progression-free survival in four consecutive patients with metastatic osteosarcoma. Prospective trials of single agent ZA are warranted as protracted maintenance therapy in surgically incurable osteosarcoma relapsed or refractory to first line combination chemotherapy with radiographically measurable metastases.

Low-Dose Radiotherapy in Indolent Lymphoma

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

Rossier, Christine; Schick, Ulrike; Miralbell, Raymond

Purpose: To assess the response rate, duration of response, and overall survival after low-dose involved-field radiotherapy in patients with recurrent low-grade lymphoma or chronic lymphocytic leukemia (CLL). Methods and Materials: Forty-three (24 women, 19 men) consecutive patients with indolent lymphoma or CLL were treated with a total dose of 4 Gy (2 x 2 Gy) using 6- 18-MV photons. The median age was 73 years (range, 39-88). Radiotherapy was given either after (n = 32; 75%) or before (n = 11; 25%) chemotherapy. The median time from diagnosis was 48 months (range, 1-249). The median follow-up period was 20 monthsmore » (range, 1-56). Results: The overall response rate was 90%. Twelve patients (28%) had a complete response, 15 (35%) had a partial response, 11 (26%) had stable disease, and 5 (11%) had progressive disease. The median overall survival for patients with a positive response (complete response/partial response/stable disease) was 41 months; for patients with progressive disease it was 6 months (p = 0.001). The median time to in-field progression was 21 months (range, 0-24), and the median time to out-field progression was 8 months (range, 0-40). The 3-year in-field control was 92% in patients with complete response (median was not reached). The median time to in-field progression was 9 months (range, 0.5-24) in patients with partial response and 6 months (range, 0.6-6) in those with stable disease (p < 0.05). Younger age, positive response to radiotherapy, and no previous chemotherapy were the best factors influencing the outcome. Conclusions: Low-dose involved-field radiotherapy is an effective treatment in the management of patients with recurrent low-grade lymphoma or CLL.« less

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study

PubMed Central

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Background Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. Patients and methods This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Results Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63–7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Conclusion Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects. PMID:29075129

Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study.

PubMed

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-01-01

Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63-7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.

Clinical Efficacy and Safety of Bevacizumab Monotherapy in Patients with Metastatic Melanoma: Predictive Importance of Induced Early Hypertension

PubMed Central

Schuster, Cornelia; Eikesdal, Hans P.; Puntervoll, Hanne; Geisler, Jürgen; Geisler, Stephanie; Heinrich, Daniel; Molven, Anders; Lønning, Per E.; Akslen, Lars A.; Straume, Oddbjørn

2012-01-01

Background VEGF driven angiogenesis plays a key role in cancer progression. We determined the clinical efficacy of bevacizumab monotherapy in patients with metastatic melanoma. Methods and Findings Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated as objective response, disease control (DC), and survival. We observed one complete (3%) and 5 partial (14%) responses. In addition, 5 patients experienced stable disease >6 months (14%) while 24 patients had progressive disease (PD, 69%), corresponding to a total DC at 6 months in 11 out of 35 patients (31%). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12–49). Seven of the 11 patients experiencing DC developed early hypertension (<2 months) compared to 3/24 of patients with PD (P = 0.001), and hypertension was associated with PFS (P = 0.005) and OS (P = 0.013). Conclusion Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. Induced early hypertension was a marker for clinical efficacy of bevacizumab. Trial Registration ClinicalTrials.gov NCT00139360. PMID:22719881

Outcome prediction in plasmacytoma of bone: a risk model utilizing bone marrow flow cytometry and light-chain analysis.

PubMed

Hill, Quentin A; Rawstron, Andy C; de Tute, Ruth M; Owen, Roger G

2014-08-21

The purpose of this study was to use multiparameter flow cytometry to detect occult marrow disease (OMD) in patients with solitary plasmacytoma of bone and assess its value in predicting outcome. Aberrant phenotype plasma cells were demonstrable in 34 of 50 (68%) patients and comprised a median of 0.52% of bone marrow leukocytes. With a median follow-up of 3.7 years, 28 of 50 patients have progressed with a median time to progression (TTP) of 18 months. Progression was documented in 72% of patients with OMD vs 12.5% without (median TTP, 26 months vs not reached; P = .003). Monoclonal urinary light chains (ULC) were similarly predictive of outcome because progression was documented in 91% vs 44% without (median TTP, 16 vs 82 months; P < .001). By using both parameters, it was possible to define patients with an excellent outcome (lacking both OMD and ULC, 7.7% progression) and high-risk patients (OMD and/or ULC, 75% progression; P = .001). Trials of systemic therapy are warranted in high-risk patients. © 2014 by The American Society of Hematology.

Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment.

PubMed

Cesini, Laura; Siniscalchi, Agostina; Grammatico, Sara; Andriani, Alessandro; Fiorini, Alessia; De Rosa, Luca; Za, Tommaso; Rago, Angela; Caravita, Tommaso; Petrucci, Maria Teresa

2018-05-02

The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predictors of Clinical Progression in HIV-1-Infected Adults Initiating Combination Antiretroviral Therapy with Advanced Disease in the Asia-Pacific Region: Results from the TREAT Asia HIV Observational Database

PubMed Central

Byakwaga, H.; Petoumenos, K.; Ananworanich, J.; Zhang, F.; Boyd, M. A.; Sirisanthana, T.; Li, P. C. K.; Lee, C.; Mean, C. V.; Saphonn, V.; Omar, S. F. S.; Pujari, S.; Phanuphak, P.; Lim, P. L.; Kumarasamy, N.; Chen, Y. M. A.; Merati, T. P.; Sungkanuparph, S.; Ditangco, R.; Oka, S.; Tau, G.; Zhou, J.; Law, M. G.; Emery, S.

2013-01-01

The majority of HIV-infected patients in developing countries commences combination antiretroviral therapy (cART) with advanced disease. We examined predictors of disease progression in patients initiating cART with CD4 count ≤200 cells/mm3 in the TREAT Asia HIV Observational Database. The main outcome measure was progression to either an AIDS-defining illness or death occurring 6 months after initiation of cART. We used survival analysis methods. A total of 1255 patients contributed 2696 person years of follow-up; 73 were diagnosed with AIDS and 9 died. The rate of progression to the combined end point was 3.0 per 100 person years. The factors significantly associated with a higher risk of disease progression were Indian ethnicity, infection through intravenous drug use, lower CD4 count, and hemoglobin ≤130 g/dL at 6 months. In conclusion, measurements of CD4 count and hemoglobin at month 6 may be useful for early identification of disease progression in resource-limited settings. PMID:23422741

Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study.

PubMed

von Minckwitz, Gunter; du Bois, Andreas; Schmidt, Marcus; Maass, Nicolai; Cufer, Tanja; de Jongh, Felix E; Maartense, Eduard; Zielinski, Christoph; Kaufmann, Manfred; Bauer, Wolfgang; Baumann, Klaus H; Clemens, Michael R; Duerr, Ralph; Uleer, Christoph; Andersson, Michael; Stein, Robert C; Nekljudova, Valentina; Loibl, Sibylle

2009-04-20

Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)-positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Patients with HER-2-positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m(2) body-surface area on days 1 through 14 [1,250 mg/m(2) semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2-positive breast cancer who experienced progression during trastuzumab treatment.

Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice

PubMed Central

Dunkelmann, Tina; Schemmert, Sarah; Honold, Dominik; Teichmann, Kerstin; Butzküven, Elke; Demuth, Hans-Ulrich; Shah, Nadim Joni; Langen, Karl-Josef; Kutzsche, Janine; Willbold, Dieter; Willuweit, Antje

2018-01-01

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models. PMID:29578479

Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour.

PubMed

Stacchiotti, S; Saponara, M; Frapolli, R; Tortoreto, M; Cominetti, D; Provenzano, S; Negri, T; Dagrada, G P; Gronchi, A; Colombo, C; Vincenzi, B; Badalamenti, G; Zuco, V; Renne, S L; Collini, P; Morosi, C; Dei Tos, A P; Bello, E; Pilotti, S; Casali, P G; D'Incalci, M; Zaffaroni, N

2017-05-01

Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments. Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT. Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin. Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diet rich in date palm fruits improves memory, learning and reduces beta amyloid in transgenic mouse model of Alzheimer's disease.

PubMed

Subash, Selvaraju; Essa, Musthafa Mohamed; Braidy, Nady; Awlad-Thani, Kathyia; Vaishnav, Ragini; Al-Adawi, Samir; Al-Asmi, Abdullah; Guillemin, Gilles J

2015-01-01

At present, the treatment options available to delay the onset or slow down the progression of Alzheimer's disease (AD) are not effective. Recent studies have suggested that diet and lifestyle factors may represent protective strategies to minimize the risk of developing AD. Date palm fruits are a good source of dietary fiber and are rich in total phenolics and natural antioxidants, such as anthocyanins, ferulic acid, protocatechuic acid and caffeic acid. These polyphenolic compounds have been shown to be neuroprotective in different model systems. We investigated whether dietary supplementation with 2% and 4% date palm fruits (grown in Oman) could reduce cognitive and behavioral deficits in a transgenic mouse model for AD (amyloid precursor protein [APPsw]/Tg2576). The experimental groups of APP-transgenic mice from the age of 4 months were fed custom-mix diets (pellets) containing 2% and 4% date fruits. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in all the animals at the age of 4 months and after 14 months of treatment using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. We have also analyzed the levels of amyloid beta (Aβ) protein (1-40 and 1-42) in plasma of control and experimental animals. Standard diet-fed Tg mice showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability and motor coordination when compared to wild-type on the same diet and Tg mice fed 2% and 4% date supplementation at the age of 18 months. The levels of both Aβ proteins were significantly lowered in date fruits supplemented groups than the Tg mice without the diet supplement. The neuroprotective effect offered by 4% date fruits diet to AD mice is higher than 2% date fruits diet. Our results suggest that date fruits dietary supplementation may have beneficial effects in lowering the risk, delaying the onset or slowing down the progression of AD.

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

48 CFR 2052.211-71 - Technical progress report.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Technical progress report... Technical progress report. As prescribed at 2011.104-70(b), the contracting officer shall insert the... solicitation. Technical Progress Report (JAN 1993) The contractor shall provide a monthly Technical Progress...

Crevicular fluid biomarkers and periodontal disease progression.

PubMed

Kinney, Janet S; Morelli, Thiago; Oh, Min; Braun, Thomas M; Ramseier, Christoph A; Sugai, Jim V; Giannobile, William V

2014-02-01

Assess the ability of a panel of gingival crevicular fluid (GCF) biomarkers as predictors of periodontal disease progression (PDP). In this study, 100 individuals participated in a 12-month longitudinal investigation and were categorized into four groups according to their periodontal status. GCF, clinical parameters and saliva were collected bi-monthly. Subgingival plaque and serum were collected bi-annually. For 6 months, no periodontal treatment was provided. At 6 months, patients received periodontal therapy and continued participation from 6 to 12 months. GCF samples were analysed by ELISA for MMP-8, MMP-9, Osteoprotegerin, C-reactive Protein and IL-1β. Differences in median levels of GCF biomarkers were compared between stable and progressing participants using Wilcoxon Rank Sum test (p = 0.05). Clustering algorithm was used to evaluate the ability of oral biomarkers to classify patients as either stable or progressing. Eighty-three individuals completed the 6-month monitoring phase. With the exception of GCF C-reactive protein, all biomarkers were significantly higher in the PDP group compared to stable patients. Clustering analysis showed highest sensitivity levels when biofilm pathogens and GCF biomarkers were combined with clinical measures, 74% (95% CI = 61, 86). Signature of GCF fluid-derived biomarkers combined with pathogens and clinical measures provides a sensitive measure for discrimination of PDP (ClinicalTrials.gov NCT00277745). © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Novel Transition Metal Compounds with Promising Thermoelectric Properties

NASA Technical Reports Server (NTRS)

Caillat, T.; Borshchevsky, A.; Fleurial, J. -P.

1993-01-01

Progress in the search for new high temperature thermoelectric materials at the Jet Propulsion Laboratory is reviewed. Novel transition metal compounds were selected as potential new high performance thermoelectric materials and criteria of selection are presented and discussed. Samples of these new compounds were prepared at JPL by a variety of techniques. Encouraging experimental results obtained on several of these compounds are reported and show that they have the potential to be the next generation of thermoelectric materials.

High doses of biotin in chronic progressive multiple sclerosis: a pilot study.

PubMed

Sedel, Frédéric; Papeix, Caroline; Bellanger, Agnès; Touitou, Valérie; Lebrun-Frenay, Christine; Galanaud, Damien; Gout, Olivier; Lyon-Caen, Olivier; Tourbah, Ayman

2015-03-01

No drug has been found to have any impact on progressive multiple sclerosis (MS). Biotin is a vitamin acting as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acids synthesis. Among others, biotin activates acetylCoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. The aim of this pilot study is to assess the clinical efficacy and safety of high doses of biotin in patients suffering from progressive MS. Uncontrolled, non-blinded proof of concept study 23 consecutive patients with primary and secondary progressive MS originated from three different French MS reference centers were treated with high doses of biotin (100-300mg/day) from 2 to 36 months (mean=9.2 months). Judgement criteria varied according to clinical presentations and included quantitative and qualitative measures. In four patients with prominent visual impairment related to optic nerve injury, visual acuity improved significantly. Visual evoked potentials in two patients exhibited progressive reappearance of P100 waves, with normalization of latencies in one case. Proton magnetic resonance spectroscopy (H-MRS) in one case showed a progressive normalization of the Choline/Creatine ratio. One patient with left homonymous hemianopia kept on improving from 2 to 16 months following treatment׳s onset. Sixteen patients out of 18 (89%) with prominent spinal cord involvement were considered as improved as confirmed by blinded review of videotaped clinical examination in 9 cases. In all cases improvement was delayed from 2 to 8 months following treatment׳s onset. These preliminary data suggest that high doses of biotin might have an impact on disability and progression in progressive MS. Two double-blind placebo-controlled trials are on going. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

29 CFR 4022.81 - General rules.

Code of Federal Regulations, 2010 CFR

2010-07-01

... thereon for that month using— (i) For months after May 1998, the applicable federal mid-term rate (as... (or, where the rate for a month is not available at the time the PBGC calculates the amount to be recouped or reimbursed, the most recent month for which the rate is available) based on monthly compounding...

Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters

PubMed Central

2011-01-01

Background Diagnosis of primary HIV infection (PHI) has important clinical and public health implications. HAART initiation at this stage remains controversial. Methods Our objective was to identify predictors of disease progression among Argentinean seroconverters during the first year of infection, within a multicentre registry of PHI-patients diagnosed between 1997 and 2008. Cox regression was used to analyze predictors of progression (LT-CD4 < 350 cells/mm3, B, C events or death) at 12 months among untreated patients. Results Among 134 subjects, 74% presented with acute retroviral syndrome (ARS). Seven opportunistic infections (one death), nine B events, and 10 non-AIDS defining serious events were observed. Among the 92 untreated patients, 24 (26%) progressed at 12 months versus three (7%) in the treated group (p = 0.01). The 12-month progression rate among untreated patients with ARS was 34% (95% CI 22.5-46.3) versus 13% (95% CI 1.1-24.7) in asymptomatic patients (p = 0.04). In univariate analysis, ARS, baseline LT-CD4 < 350 cells/mm3, and baseline and six-month viral load (VL) > 100,000 copies/mL were associated with progression. In multivariate analysis, only ARS and baseline VL > 100,000 copies/mL remained independently associated; HR: 8.44 (95% CI 0.97-73.42) and 9.44 (95% CI 1.38-64.68), respectively. Conclusions In Argentina, PHI is associated with significant morbidity. HAART should be considered in PHI patients with ARS and high baseline VL to prevent disease progression. PMID:21831310

Treatment of mycosis fungoides with topical nitrosourea compounds: Further studies.

PubMed

Zackheim, H S; Epstein, E H

1975-12-01

Twenty-six patients with mycosis fungoides were treated topically with three nitrosourea compounds: carmustine (BCNU), lomustine (CCNU), and 1-methyl-1-nitrosourea. A high percentage experienced good to excellent results. Remissions following treatment of individual lesions varied from one month to at least three years. Remissions following total body surface treatment varied from two weeks to at least four months. Two of 13 patients treated over the entire body suffered temporary bone marrow depression, indluding one with severe pancytopenia. This toxic effect was attributed to lomustine and was not seen in patients treated with carmustine alone. Thirteen patients highly allergic to mechlorethamine hydrochloride showed no cross-sensitivity to nitrosourea compounds. A primary irritant dermatitis occurred in about one half of the patients and telangiectasia in two. Two patients developed hypersensitivity to nitrosourea compounds. Carmustine is the preferred nitrosourea compound for topical therapy of mycosis fungoides.

Salvage Stereotactic Body Radiotherapy for Isolated Lymph Node Recurrent Prostate Cancer: Single Institution Series of 94 Consecutive Patients and 124 Lymph Nodes.

PubMed

Jereczek-Fossa, Barbara Alicja; Fanetti, Giuseppe; Fodor, Cristiana; Ciardo, Delia; Santoro, Luigi; Francia, Claudia Maria; Muto, Matteo; Surgo, Alessia; Zerini, Dario; Marvaso, Giulia; Timon, Giorgia; Romanelli, Paola; Rondi, Elena; Comi, Stefania; Cattani, Federica; Golino, Federica; Mazza, Stefano; Matei, Deliu Victor; Ferro, Matteo; Musi, Gennaro; Nolè, Franco; de Cobelli, Ottavio; Ost, Piet; Orecchia, Roberto

2017-08-01

The purpose of the study was to evaluate the prostate serum antigen (PSA) response, local control, progression-free survival (PFS), and toxicity of stereotactic body radiotherapy (SBRT) for lymph node (LN) oligorecurrent prostate cancer. Between May 2012 and October 2015, 124 lesions were treated in 94 patients with a median dose of 24 Gy in 3 fractions. Seventy patients were treated for a single lesion and 25 for > 1 lesion. In 34 patients androgen deprivation (AD) was combined with SBRT. We evaluated biochemical response according to PSA level every 3 months after SBRT: a 3-month PSA decrease from pre-SBRT PSA of more than 10% identified responder patients. In case of PSA level increase, imaging was performed to evaluate clinical progression. Toxicity was assessed every 6 to 9 months after SBRT. Median follow-up was 18.5 months. In 13 patients (14%) Grade 1 to 2 toxicity was reported without any Grade 3 to 4 toxicity. Biochemical response, stabilization, and progression were observed in 64 (68%), 10 (11%), and 20 (21%) of 94 evaluable patients. Clinical progression was observed in 31 patients (33%) after a median time of 8.1 months. In-field progression occurred in 12 lesions (9.7%). Two-year local control and PFS rates were 84% and 30%, respectively. Age older than 75 years correlated with better biochemical response rate. Age older than 75 years, concomitant AD administered up to 12 months, and pelvic LN involvement correlated with longer PFS. SBRT is safe and offers good in-field control. At 2 years after SBRT, 1 of 3 patients is progression-free. Further investigation is warranted to identify patients who benefit most from SBRT and to define the optimal combination with AD. Copyright © 2017 Elsevier Inc. All rights reserved.

Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

PubMed

Robin, Tyler P; Breeze, Robert E; Smith, Derek E; Rusthoven, Chad G; Lewis, Karl D; Gonzalez, Rene; Brill, Amanda; Saiki, Robin; Stuhr, Kelly; Gaspar, Laurie E; Karam, Sana D; Raben, David; Kavanagh, Brian D; Nath, Sameer K; Liu, Arthur K

2018-06-16

Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Sorafenib for the Treatment of Progressive Metastatic Medullary Thyroid Cancer: Efficacy and Safety Analysis.

PubMed

de Castroneves, Luciana Audi; Negrão, Marcelo Vailati; de Freitas, Ricardo Miguel Costa; Papadia, Carla; Lima, José Viana; Fukushima, Julia T; Simão, Eduardo Furquim; Kulcsar, Marco Aurélio Vamondes; Tavares, Marcos Roberto; Jorge, Alexander Augusto de Lima; de Castro, Gilberto; Hoff, Paulo Marcelo; Hoff, Ana Oliveira

2016-03-01

Treatment of advanced medullary thyroid carcinoma (MTC) was recently improved with the approval of vandetanib and cabozantinib. However, there is still a need to explore sequential therapy with more than one tyrosine kinase inhibitor (TKI) and to explore alternative therapies when vandetanib and cabozantinib are not available. This study reports the authors' experience with sorafenib as a treatment for advanced MTC. This is a retrospective longitudinal study of 13 patients with progressive metastatic MTC treated with sorafenib 400 mg twice daily between December 2011 and January 2015. The primary endpoints were to evaluate response and progression-free survival (PFS) in patients treated with sorafenib outside a clinical trial. The secondary endpoint was an assessment of the toxicity profile. One patient was excluded because of a serious allergic skin rash one week after starting sorafenib. The analysis included 12 patients with metastatic MTC (median age 48 years), 10 with sporadic and 2 with hereditary disease. The median duration of treatment was 11 months, and the median follow-up was 15.5 months. At data cutoff, 2/12 (16%) patients were still on treatment for 16 and 34 months. According to Response Evaluation Criteria in Solid Tumors analysis, 10 (83.3%) patients showed stable disease, and two (16.6%) had progression of disease; no partial response was observed. The median PFS was nine months. However, three patients with extensive and rapidly progressive disease died within three months of sorafenib treatment. The median PFS excluding these three patients was 12 months. Adverse events (AE) occurred in nine (75%) patients. The main AEs were skin toxicity, weight loss, and fatigue. Five (41.6%) patients needed dose reduction, and one patient discontinued treatment because of toxicity. Treatment with sorafenib in progressive metastatic MTC is well tolerated and resulted in disease control and durable clinical benefit in 75% of patients. Sorafenib treatment could be considered when vandetanib and cabozantinib are not available or after failing these drugs.

Detection Progress of Selected Drugs in TLC

PubMed Central

Pyka, Alina

2014-01-01

This entry describes applications of known indicators and dyes as new visualizing reagents and various visualizing systems as well as photocatalytic reactions and bioautography method for the detection of bioactive compounds including drugs and compounds isolated from herbal extracts. Broadening index, detection index, characteristics of densitometric band, modified contrast index, limit of detection, densitometric visualizing index, and linearity range of detected compounds were used for the evaluation of visualizing effects of applied visualizing reagents. It was shown that visualizing effect depends on the chemical structure of the visualizing reagent, the structure of the substance detected, and the chromatographic adsorbent applied. The usefulness of densitometry to direct detection of some drugs was also shown. Quoted papers indicate the detection progress of selected drugs investigated by thin-layer chromatography (TLC). PMID:24551853

Exercise Improves Cognition in Parkinson’s Disease: the PRET-PD Randomized Clinical Trial

PubMed Central

David, Fabian J.; Robichaud, Julie A.; Leurgans, Sue E.; Poon, Cynthia; Kohrt, Wendy M.; Goldman, Jennifer G.; Comella, Cynthia L.; Vaillancourt, David E.; Corcos, Daniel M.

2015-01-01

Background This paper reports on the findings of the effect of two structured exercise interventions on secondary cognitive outcomes which were gathered as part of the Progressive Resistance Exercise Training in Parkinson’s disease randomized controlled trial. Methods This study was a prospective, parallel-group, single-center trial. Fifty-one non-demented patients with mild-to-moderate Parkinson’s disease were randomly assigned either to modified Fitness Counts or to Progressive Resistance Exercise, and were followed for 24 months. Cognitive outcomes were the Digit Span, Stroop, and Brief Test of Attention. Results Eighteen patients in modified Fitness Counts and 20 patients in Progressive Resistance Exercise completed the trial. At 12 and at 24 months no differences between groups were observed. At 12 months, relative to baseline, modified Fitness Counts improved on the Digit Span (estimated change, 0.3; Inter-Quartile Range, 0, 0.7; p=0.04) and Stroop (0.3; 0, 0.6; p=0.04), and Progressive Resistance Exercise improved only on the Digit Span (0.7; 0.3, 1; p<0.01). At 24 months, relative to baseline, modified Fitness Counts improved on the Digit Span (0.7; 0.3, 1.7; p<0.01) and Stroop (0.3; 0.1, 0.5; p=0.03), while Progressive Resistance Exercise improved on the Digit Span (0.5; 0.2, 0.8; p<0.01), Stroop (0.2; −0.1, 0.6; p=0.048), and Brief Test of Attention (0.3; 0, 0.8; p=0.048). No neurologic or cognitive adverse events were seen. Conclusions This study provides Class IV level of evidence that 24 months of Progressive Resistance Exercise or modified Fitness Counts may improve attention and working memory in non-demented patients with mild-to-moderate Parkinson’s disease. PMID:26148003

HER2-Specific Chimeric Antigen Receptor-Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial.

PubMed

Ahmed, Nabil; Brawley, Vita; Hegde, Meenakshi; Bielamowicz, Kevin; Kalra, Mamta; Landi, Daniel; Robertson, Catherine; Gray, Tara L; Diouf, Oumar; Wakefield, Amanda; Ghazi, Alexia; Gerken, Claudia; Yi, Zhongzhen; Ashoori, Aidin; Wu, Meng-Fen; Liu, Hao; Rooney, Cliona; Dotti, Gianpietro; Gee, Adrian; Su, Jack; Kew, Yvonne; Baskin, David; Zhang, Yi Jonathan; New, Pamela; Grilley, Bambi; Stojakovic, Milica; Hicks, John; Powell, Suzanne Z; Brenner, Malcolm K; Heslop, Helen E; Grossman, Robert; Wels, Winfried S; Gottschalk, Stephen

2017-08-01

Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014. The duration of follow-up was 10 weeks to 29 months (median, 8 months). Monotherapy with autologous VSTs specific for cytomegalovirus, Epstein-Barr virus, or adenovirus and genetically modified to express HER2-CARs with a CD28.ζ-signaling endodomain (HER2-CAR VSTs). Primary end points were feasibility and safety. The key secondary end points were T-cell persistence and their antiglioblastoma activity. A total of 17 patients (8 females and 9 males; 10 patients ≥18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion. Infusions were well tolerated, with no dose-limiting toxic effects. HER2-CAR VSTs were detected in the peripheral blood for up to 12 months after the infusion by quantitative real-time polymerase chain reaction. Of 16 evaluable patients (9 adults and 7 children), 1 had a partial response for more than 9 months, 7 had stable disease for 8 weeks to 29 months, and 8 progressed after T-cell infusion. Three patients with stable disease are alive without any evidence of progression during 24 to 29 months of follow-up. For the entire study cohort, median overall survival was 11.1 months (95% CI, 4.1-27.2 months) from the first T-cell infusion and 24.5 months (95% CI, 17.2-34.6 months) from diagnosis. Infusion of autologous HER2-CAR VSTs is safe and can be associated with clinical benefit for patients with progressive glioblastoma. Further evaluation of HER2-CAR VSTs in a phase 2b study is warranted as a single agent or in combination with other immunomodulatory approaches for glioblastoma.

Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study.

PubMed

Lin, Chia-Chi; Shih, Jin-Yuan; Yu, Chong-Jen; Ho, Chao-Chi; Liao, Wei-Yu; Lee, Jih-Hsing; Tsai, Tzu-Hsiu; Su, Kang-Yi; Hsieh, Min-Shu; Chang, Yih-Leong; Bai, Ya-Ying; Huang, Derek De-Rui; Thress, Kenneth S; Yang, James Chih-Hsin

2018-02-01

Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4-13·9) and overall survival was 16·9 months (11·7-29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1-10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6-not reached, and 10·8 months, 7·2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3-not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. AstraZeneca, Taiwan Ministry of Science and Technology. Copyright © 2018 Elsevier Ltd. All rights reserved.

Degradation of organic pollutants in Mediterranean forest soils amended with sewage sludge.

PubMed

Francisca Gomez-Rico, M; Font, Rafael; Vera, Jose; Fuentes, David; Disante, Karen; Cortina, Jordi

2008-05-01

The degradation of two groups of organic pollutants in three different Mediterranean forest soils amended with sewage sludge was studied for nine months. The sewage sludge produced by a domestic water treatment plant was applied to soils developed from limestone, marl and sandstone, showing contrasting alkalinity and texture. The compounds analysed were: linear alkylbenzene sulphonates (LAS) with a 10-13 carbon alkylic chain, and nonylphenolic compounds, including nonylphenol (NP) and nonylphenol ethoxylates with one and two ethoxy groups (NP1EO+NP2EO). These compounds were studied because they frequently exceed the limits proposed for sludge application to land in Europe. After nine months, LAS decomposition was 86-96%, and NP+NP1EO+NP2EO decomposition was 61-84%, which can be considered high. Temporal trends in LAS and NP+NP1EO+NP2EO decomposition were similar, and the concentrations of both types of compounds were highly correlated. The decomposition rates were higher in the period of 6-9 months (summer period) than in the period 0-6 months (winter+spring period) for total LAS and NP+NP1EO+NP2EO. Differences in decay rates with regard to soil type were not significant. The average values of decay rates found are similar to those observed in agricultural soils.

The Effects of 6 Months of Progressive High Effort Resistance Training Methods upon Strength, Body Composition, Function, and Wellbeing of Elderly Adults.

PubMed

Steele, James; Raubold, Kristin; Kemmler, Wolfgang; Fisher, James; Gentil, Paulo; Giessing, Jürgen

2017-01-01

The present study examined the progressive implementation of a high effort resistance training (RT) approach in older adults over 6 months and through a 6-month follow-up on strength, body composition, function, and wellbeing of older adults. Twenty-three older adults (aged 61 to 80 years) completed a 6-month supervised RT intervention applying progressive introduction of higher effort set end points. After completion of the intervention participants could choose to continue performing RT unsupervised until 6-month follow-up. Strength, body composition, function, and wellbeing all significantly improved over the intervention. Over the follow-up, body composition changes reverted to baseline values, strength was reduced though it remained significantly higher than baseline, and wellbeing outcomes were mostly maintained. Comparisons over the follow-up between those who did and those who did not continue with RT revealed no significant differences for changes in any outcome measure. Supervised RT employing progressive application of high effort set end points is well tolerated and effective in improving strength, body composition, function, and wellbeing in older adults. However, whether participants continued, or did not, with RT unsupervised at follow-up had no effect on outcomes perhaps due to reduced effort employed during unsupervised RT.

EVALUATION OF PATCHY ATROPHY SECONDARY TO HIGH MYOPIA BY SEMIAUTOMATED SOFTWARE FOR FUNDUS AUTOFLUORESCENCE ANALYSIS.

PubMed

Miere, Alexandra; Capuano, Vittorio; Serra, Rita; Jung, Camille; Souied, Eric; Querques, Giuseppe

2017-05-31

To evaluate the progression of patchy atrophy in high myopia using semiautomated software for fundus autofluorescence (FAF) analysis. The medical records and multimodal imaging of 21 consecutive highly myopic patients with macular chorioretinal patchy atrophy (PA) were retrospectively analyzed. All patients underwent repeated fundus autofluorescence and spectral domain optical coherence tomography over at least 12 months. Color fundus photography was also performed in a subset of patients. Total atrophy area was measured on FAF images using Region Finder semiautomated software embedded in Spectralis (Heidelberg Engineering, Heidelberg, Germany) at baseline and during follow-up visits. Region Finder was compared with manually measured PA on FAF images. Twenty-two eyes of 21 patients (14 women, 7 men; mean age 62.8 + 13.0 years, range 32-84 years) were included. Mean PA area using Region Finder was 2.77 ± 2.91 SD mm at baseline, 3.12 ± 2.68 mm at Month 6, 3.43 ± 2.68 mm at Month 12, and 3.73 ± 2.74 mm at Month 18 (overall P < 0.005); this accounts for PA progression rate of 0.821 mm/year. Atrophy progression was significantly greater among eyes with larger PA compared with smaller baseline PA at Months 6, 12, and 18. There was no statistically significant difference between semiautomated Region Finder PA area and manually measured PA area on FAF images. Fundus autofluorescence analysis by Region Finder semiautomated software provides accurate measurements of lesion area and allows us to quantify the progression of PA in high myopia. In our series, PA enlarged significantly over at least 12 months, and its progression seemed to be related to the lesion size at baseline.

Abiraterone and increased survival in metastatic prostate cancer.

PubMed

de Bono, Johann S; Logothetis, Christopher J; Molina, Arturo; Fizazi, Karim; North, Scott; Chu, Luis; Chi, Kim N; Jones, Robert J; Goodman, Oscar B; Saad, Fred; Staffurth, John N; Mainwaring, Paul; Harland, Stephen; Flaig, Thomas W; Hutson, Thomas E; Cheng, Tina; Patterson, Helen; Hainsworth, John D; Ryan, Charles J; Sternberg, Cora N; Ellard, Susan L; Fléchon, Aude; Saleh, Mansoor; Scholz, Mark; Efstathiou, Eleni; Zivi, Andrea; Bianchini, Diletta; Loriot, Yohann; Chieffo, Nicole; Kheoh, Thian; Haqq, Christopher M; Scher, Howard I

2011-05-26

Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group. The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).

Bax/Tubulin/Epithelial-Mesenchymal Pathways Determine the Efficacy of Silybin Analog HM015k in Colorectal Cancer Cell Growth and Metastasis.

PubMed

Amawi, Haneen; Hussein, Noor A; Ashby, Charles R; Alnafisah, Rawan; Sanglard, Leticia M; Manivannan, Elangovan; Karthikeyan, Chandrabose; Trivedi, Piyush; Eisenmann, Kathryn M; Robey, Robert W; Tiwari, Amit K

2018-01-01

The inhibition of apoptosis, disruption of cellular microtubule dynamics, and over-activation of the epithelial mesenchymal transition (EMT), are involved in the progression, metastasis, and resistance of colorectal cancer (CRC) to chemotherapy. Therefore, the design of a molecule that can target these pathways could be an effective strategy to reverse CRC progression and metastasis. In this study, twelve novel silybin derivatives, HM015a-HM015k (15a-15k) and compound 17, were screened for cytotoxicity in CRC cell lines. Compounds HM015j and HM015k (15k and 15j) significantly decreased cell proliferation, inhibited colony formation, and produced cell cycle arrest in CRC cells. Furthermore, 15k significantly induced the formation of reactive oxygen species and apoptosis. It induced the cleavage of the intrinsic apoptotic protein (Bax p21) to its more efficacious fragment, p18. Compound 15k also inhibited tubulin expression and disrupted its structure. Compound 15k significantly decreased metastatic LOVO cell migration and invasion. Furthermore, 15k reversed mesenchymal morphology in HCT116 and LOVO cells. Additionally, 15k significantly inhibited the expression of the mesenchymal marker N-cadherin and upregulated the expression of the epithelial marker, E-cadherin. Compound 15k inhibited the expression of key proteins known to induce EMT (i.e., DVL3, β-catenin, c-Myc) and upregulated the anti-metastatic protein, cyclin B1. Overall, in vitro , 15k significantly inhibited CRC progression and metastasis by inhibiting apoptosis, tubulin activity and the EMT pathways. Overall, these data suggest that compound 15k should be tested in vivo in a CRC animal model for further development.

PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

PubMed

Hammerer, Peter; Al-Batran, Salah-Eddin; Windemuth-Kieselbach, Christine; Keller, Martin; Hofheinz, Ralf-Dieter

2018-03-01

To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P < 0.0001). Overall survival (50% cut-off) was 23.3 months in responders and 16.0 months in non-responders (P = 0.068); corresponding data at the 30% cut-off are 21.7 and 16.0 months (P = 0.057). Overall, 55.4% of men experienced ≥ 1 adverse event, 59.6% of whom had a serious adverse event. PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

Whole lung lavage: the salvage therapy for pulmonary alveolar proteinosis.

PubMed

Indira, K S Kumari; Rajesh, V; Darsana, V; Ranjit, U; John, Jiju; Vengadakrishnaraj, S P; Dharmadhikari, Shubhada Amol

2007-01-01

A 53-year-old school teacher presented with progressive exertional breathlessness and dry cough of three months duration. His diagnosis was confirmed as pulmonary alveolar proteinosis on open lung biopsy. In about three months, the disease progressed to life threatening respiratory failure. He was subjected to whole lung lavage (WLL) as a salvage therapy. The technical details of WLL performed on this patient are described. At six months follow up, he was clinically and functionally stable and leading a near normal life.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

PubMed

Ratzer, Rikke; Iversen, Pernille; Börnsen, Lars; Dyrby, Tim B; Romme Christensen, Jeppe; Ammitzbøll, Cecilie; Madsen, Camilla Gøbel; Garde, Ellen; Lyksborg, Mark; Andersen, Birgit; Hyldstrup, Lars; Sørensen, Per Soelberg; Siebner, Hartwig R; Sellebjerg, Finn

2016-06-01

There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS. © The Author(s), 2015.

Target identification of small molecules based on chemical biology approaches.

PubMed

Futamura, Yushi; Muroi, Makoto; Osada, Hiroyuki

2013-05-01

Recently, a phenotypic approach-screens that assess the effects of compounds on cells, tissues, or whole organisms-has been reconsidered and reintroduced as a complementary strategy of a target-based approach for drug discovery. Although the finding of novel bioactive compounds from large chemical libraries has become routine, the identification of their molecular targets is still a time-consuming and difficult process, making this step rate-limiting in drug development. In the last decade, we and other researchers have amassed a large amount of phenotypic data through progress in omics research and advances in instrumentation. Accordingly, the profiling methodologies using these datasets expertly have emerged to identify and validate specific molecular targets of drug candidates, attaining some progress in current drug discovery (e.g., eribulin). In the case of a compound that shows an unprecedented phenotype likely by inhibiting a first-in-class target, however, such phenotypic profiling is invalid. Under the circumstances, a photo-crosslinking affinity approach should be beneficial. In this review, we describe and summarize recent progress in both affinity-based (direct) and phenotypic profiling (indirect) approaches for chemical biology target identification.

Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

PubMed Central

Hoose, Scott A.; Duran, Camille; Malik, Indranil; Eslamfam, Shabnam; Shasserre, Samantha C.; Downing, S. Sabina; Hoover, Evelyn M.; Dowd, Katherine E.; Smith, Roger; Polymenis, Michael

2012-01-01

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation. PMID:22567160

Systematic analysis of cell cycle effects of common drugs leads to the discovery of a suppressive interaction between gemfibrozil and fluoxetine.

PubMed

Hoose, Scott A; Duran, Camille; Malik, Indranil; Eslamfam, Shabnam; Shasserre, Samantha C; Downing, S Sabina; Hoover, Evelyn M; Dowd, Katherine E; Smith, Roger; Polymenis, Michael

2012-01-01

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation.

40 CFR 60.441 - Definitions and symbols.

Code of Federal Regulations, 2014 CFR

2014-07-01

... = the weight fraction of organics applied of each coating (i) applied during a calendar month as.... Fugitive volatile organic compounds means any volatile organic compounds which are emitted from the coating... capture fugitive volatile organic compounds. Oven means a chamber which uses heat or irradiation to bake...

Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib

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

Gan, Gregory N., E-mail: gregory.gan@ucdenver.edu; Weickhardt, Andrew J.; Scheier, Benjamin

Purpose: To analyze the durability and toxicity of radiotherapeutic local ablative therapy (LAT) applied to extra-central nervous system (eCNS) disease progression in anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) patients. Methods and Materials: Anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib and manifesting ≤4 discrete sites of eCNS progression were classified as having oligoprogressive disease (OPD). If subsequent progression met OPD criteria, additional courses of LAT were considered. Crizotinib was continued until eCNS progression was beyond OPD criteria or otherwise not suitable for further LAT. Results: Of 38 patients, 33 progressed while taking crizotinib. Of these, 14 had eCNS progressionmore » meeting OPD criteria suitable for radiotherapeutic LAT. Patients with eCNS OPD received 1-3 courses of LAT with radiation therapy. The 6- and 12-month actuarial local lesion control rates with radiation therapy were 100% and 86%, respectively. The 12-month local lesion control rate with single-fraction equivalent dose >25 Gy versus ≤25 Gy was 100% versus 60% (P=.01). No acute or late grade >2 radiation therapy-related toxicities were observed. Median overall time taking crizotinib among those treated with LAT versus those who progressed but were not suitable for LAT was 28 versus 10.1 months, respectively. Patients continuing to take crizotinib for >12 months versus ≤12 months had a 2-year overall survival rate of 72% versus 12%, respectively (P<.0001). Conclusions: Local ablative therapy safely and durably eradicated sites of individual lesion progression in anaplastic lymphoma kinase-positive NSCLC patients receiving crizotinib. A dose–response relationship for local lesion control was observed. The suppression of OPD by LAT in patients taking crizotinib allowed an extended duration of exposure to crizotinib, which was associated with longer overall survival.« less

Component Identification and Item Difficulty of Raven's Matrices Items.

ERIC Educational Resources Information Center

Green, Kathy E.; Kluever, Raymond C.

Item components that might contribute to the difficulty of items on the Raven Colored Progressive Matrices (CPM) and the Standard Progressive Matrices (SPM) were studied. Subjects providing responses to CPM items were 269 children aged 2 years 9 months to 11 years 8 months, most of whom were referred for testing as potentially gifted. A second…

In vivo measurements of tooth wear over 12 months.

PubMed

Rodriguez, J M; Austin, R S; Bartlett, D W

2012-01-01

The aim of this study was to measure the progression of tooth wear in a cohort of 63 patients, 43 males and 20 females with a mean age of 39.1 years. Recruitment followed referral from general practice to Guy's Hospital for advice/management of tooth wear. Addition silicone impressions were taken at 6-month intervals for a total of 12 months; impressions were subsequently poured in type IV gypsum. Casts were scanned using a non-contacting laser profilometer and then superimposed using Geomagic® Qualify 11. Wear was measured in μm by tooth per time interval. A questionnaire highlighting dietary, parafunctional and gastric risk factors was obtained from each participant. Clustered multiple regression analysis was used to determine the relationship between tooth wear progression and risk factors. Maximum follow-up times were 6 months for 63 participants and 12 months for 30 participants. The measurement error was 15 μm. At the tooth level, 72.2% of 1,078 teeth wore <15 μm over a 6-month period. At the subject level, 77.7% of 63 participants showed median wear <15 μm over a 6-month period. There was a statistical trend towards tooth wear progression being associated with gastric risk factors (p < 0.05). The lower molars and the upper anterior teeth were the most commonly affected teeth; the lower molars and the upper central incisors were the most severely affected teeth. Tooth wear progression was slow in this cohort, suggesting that tooth wear may be cyclical and inactive in the majority of participants. Copyright © 2011 S. Karger AG, Basel.

UNIT OPERATIONS SECTION MONTHLY PROGRESS REPORT, OCTOBER 1961

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

Whatley, M.E.; Haas, P.A.; Horton, R.W.

1962-04-01

Additional runs were made in the 6-in.-dia. separation column. The kinetics of the methane --copper oxide reaction was investigated in deep bed tests. The work on the development of the shear included a satisfactory method of ng, preliminary test of an outer gag faced with rubber, and a metallic inner gsg contoured to the shape of a sheared assembly. The mechanical dejacketing of the SRE Core I fuel, NaK-bonded, stainless steel-clad uranium slugs, was successfully completed. The effective therrnal conductivity of a packed bed of 0.023-in. steel shot was approximately 0.33 Btu/hr- deg Fft at 200 deg F. Flow capacitymore » for the compound extraction scrub column equipped with sieve plates (0.125-in.-dia. was determined. Average waste calcination rates for Purex were higher by a factor of 1.5 to 2.0 than rates for TBP-25. (auth)« less

Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.

PubMed

Watanabe, Satomi; Hayashi, Hidetoshi; Okamoto, Kunio; Fujiwara, Kimiko; Hasegawa, Yoshikazu; Kaneda, Hiroyasu; Tanaka, Kaoru; Takeda, Masayuki; Nakagawa, Kazuhiko

2016-11-01

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC. Copyright © 2016 Elsevier Inc. All rights reserved.

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.

PubMed

Yao, James C; Pavel, Marianne; Lombard-Bohas, Catherine; Van Cutsem, Eric; Voi, Maurizio; Brandt, Ulrike; He, Wei; Chen, David; Capdevila, Jaume; de Vries, Elisabeth G E; Tomassetti, Paola; Hobday, Timothy; Pommier, Rodney; Öberg, Kjell

2016-11-10

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.

PubMed

Ou, Sai-Hong Ignatius; Ahn, Jin Seok; De Petris, Luigi; Govindan, Ramaswamy; Yang, James Chih-Hsin; Hughes, Brett; Lena, Hervé; Moro-Sibilot, Denis; Bearz, Alessandra; Ramirez, Santiago Viteri; Mekhail, Tarek; Spira, Alexander; Bordogna, Walter; Balas, Bogdana; Morcos, Peter N; Monnet, Annabelle; Zeaiter, Ali; Kim, Dong-Wan

2016-03-01

Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases. © 2015 by American Society of Clinical Oncology.

Effect of volatile compounds on excimer laser power delivery.

PubMed

Van Horn, Stewart D; Hovanesian, John A; Maloney, Robert K

2002-01-01

To determine whether vapors from perfume, hairspray, oil-based paint, or water-based paint affect excimer laser beam power delivery at the corneal surface. We measured the power delivery of an Apex Plus laser before, during, and after exposure to vapors from the following volatile compounds: three types of perfume, hair spray, an oil-based paint, and a water-based paint. A digital calorimeter was used to measure the steady-state beam power of the laser during laser discharge at the corneal plane. Multiple trials were run with each compound, and the change in laser energy over time was examined to determine if any of the compounds caused degradation of the laser optics. The presence of a volatile compound in the room caused no change in mean laser energy in comparison to before and after the compound was present. However, perfumes caused a progressive decline in laser beam power throughout the trials. Controlling for this progressive decline, there was no significant difference from perfume to perfume. None of the compounds tested caused a decline in laser beam power while present in the room. However, the presence of any perfume caused a deterioration in beam power over time, suggesting a degradation of the laser optics for all perfumes. Laser centers should consider advising their patients and staff to not wear perfumes in the laser suite.

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL

PubMed Central

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-01-01

Background: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Methods: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Results: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Conclusions: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression. PMID:28117385

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

PubMed

Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

2017-06-01

Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Increasing Psychotherapists’ Adoption and Implementation of the Evidence-based Practice of Progress Monitoring

PubMed Central

Persons, Jacqueline B.; Koerner, Kelly; Eidelman, Polina; Thomas, Cannon; Liu, Howard

2015-01-01

Evidence-based practices (EBPs) reach consumers slowly because practitioners are slow to adopt and implement them. We hypothesized that giving psychotherapists a tool + training intervention that was designed to help the therapist integrate the EBP of progress monitoring into his or her usual way of working would be associated with adoption and sustained implementation of the particular progress monitoring tool we trained them to use (the Depression Anxiety Stress Scales on our Online Progress Tracking tool) and would generalize to all types of progress monitoring measures. To test these hypotheses, we developed an online progress monitoring tool and a course that trained psychotherapists to use it, and we assessed progress monitoring behavior in 26 psychotherapists before, during, immediately after, and 12 months after they received the tool and training. Immediately after receiving the tool + training intervention, participants showed statistically significant increases in use of the online tool and of all types of progress monitoring measures. Twelve months later, participants showed sustained use of any type of progress monitoring measure but not the online tool. PMID:26618237

Increasing psychotherapists' adoption and implementation of the evidence-based practice of progress monitoring.

PubMed

Persons, Jacqueline B; Koerner, Kelly; Eidelman, Polina; Thomas, Cannon; Liu, Howard

2016-01-01

Evidence-based practices (EBPs) reach consumers slowly because practitioners are slow to adopt and implement them. We hypothesized that giving psychotherapists a tool + training intervention that was designed to help the therapist integrate the EBP of progress monitoring into his or her usual way of working would be associated with adoption and sustained implementation of the particular progress monitoring tool we trained them to use (the Depression Anxiety Stress Scales on our Online Progress Tracking tool) and would generalize to all types of progress monitoring measures. To test these hypotheses, we developed an online progress monitoring tool and a course that trained psychotherapists to use it, and we assessed progress monitoring behavior in 26 psychotherapists before, during, immediately after, and 12 months after they received the tool and training. Immediately after receiving the tool + training intervention, participants showed statistically significant increases in use of the online tool and of all types of progress monitoring measures. Twelve months later, participants showed sustained use of any type of progress monitoring measure but not the online tool. Copyright © 2015 Elsevier Ltd. All rights reserved.

Imbricatolic acid from Juniperus communis L. prevents cell cycle progression in CaLu-6 cells.

PubMed

De Marino, Simona; Cattaneo, Fabio; Festa, Carmen; Zollo, Franco; Iaccio, Annalisa; Ammendola, Rosario; Incollingo, Filomena; Iorizzi, Maria

2011-11-01

Imbricatolic acid was isolated from the methanolic extract of the fresh ripe berries of Juniperus communis (Cupressaceae) together with sixteen known compounds and a new dihydrobenzofuran lignan glycoside named juniperoside A. Their structures were determined by spectroscopic methods and by comparison with the spectral data reported in literature. Imbricatolic acid was evaluated for its ability to prevent cell cycle progression in p53-null CaLu-6 cells. This compound induces the upregulation of cyclin-dependent kinase inhibitors and their accumulation in the G1 phase of the cell cycle, as well as the degradation of cyclins A, D1, and E1. Furthermore, no significant imbricatolic acid-induced apoptosis was observed. Therefore, this plant-derived compound may play a role in the control of cell cycle. © Georg Thieme Verlag KG Stuttgart · New York.

Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

PubMed

Couillard, S; Gutman, M; Labrie, C; Bélanger, A; Candas, B; Labrie, F

1998-01-01

Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

Processing and thermodynamics research. Volume II. Monthly progress report, October 1984

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

Not Available

1984-11-15

A detailed list of materials was prepared, data and information that will be gathered for analysis in the study (Project BPT1) that relates feedstock to product slate. A meeting of the sponsors Steering Committee gave broad support to the research direction presented. Discussions were held with Professor Lloyd Lee at the University of Oklahoma on possible future cooperation of this work with his correlation and model studies. Mass spectrometry efforts (Project BPT2) centered on establishing the performance characteristics of the MS-50 as pertains to quantitative ultra-high dynamic resolution low voltage EI analysis with this system. A complete review of allmore » chemical separations done to date on Wilmington and Mayan crudes revealed a few inconsistencies, and a few repeat experiments are in progress to resolve them (Project OPT2). Preparations are being made for thiophene separations from the 425/sup 0/ to 550/sup 0/C Cerro Negro neutrals (Project OPT2). A review of the progress on the chemistry of contaminated fuels project (Project OPT4) was held with DOD personnel. The acid fractions of the various distillates from contaminated diesel fuel have been shown to be corrosive in copper strip testing. Biological activity was also established as one source of corrosion problems. Stability test technique development focused on the type of filter materials that will withstand the accelerated aging conditions (65/sup 0/C) for several weeks. Thermodynamic studies on hetero-atom compounds continued with experimental work in progress on 2,5-dimethylpyridine, 2,5-dimethylpyrrole, 2,3-benzofuran, and 3-methylpyrrolidine (Project BPT3A and BPT3B). Vapor liquid-equilibria measurements continue on hydrogen and a 450/sup 0/ to 950/sup 0/F cut from the Wilsonville, AL coal liquefaction plant (Project OPT3).« less

THE DEVELOPMENT OF PRE-VOCATIONAL EDUCATION LITERACY COURSES FOR USE WITH COMPUTER ASSISTED INSTRUCTION OF DISADVANTAGED YOUTH AND ADULTS. TECHNICAL PROGRESS REPORT.

ERIC Educational Resources Information Center

HANKIN, EDWARD K.; AND OTHERS

THIS TECHNICAL PROGRESS REPORT COVERS THE FIRST THREE MONTHS OF A PROJECT TO DEVELOP COMPUTER ASSISTED PREVOCATIONAL READING AND ARITHMETIC COURSES FOR DISADVANTAGED YOUTHS AND ADULTS. DURING THE FIRST MONTH OF OPERATION, PROJECT PERSONNEL CONCENTRATED ON SUCH ADMINISTRATIVE MATTERS AS TRAINING STAFF AND PREPARING FACILITIES. AN ARITHMETIC PROGRAM…

COSMIC monthly progress report

NASA Technical Reports Server (NTRS)

1994-01-01

Activities of the Computer Software Management and Information Center (COSMIC) are summarized for the month of January 1994. Tables showing the current inventory of programs available from COSMIC are presented and program processing and evaluation activities are discussed. Marketing and customer service activities in this period are presented as is the progress report of NASTRAN maintenance and support. Tables of disseminations and budget summary conclude the report.

miR-21 is associated with fibrosis and right ventricular failure

PubMed Central

Hu, Dong-Qing; Zhao, Mingming; Blay, Eddie; Sandeep, Nefthi; Ong, Sang-Ging; Jung, Gwanghyun; Kooiker, Kristina B.; Coronado, Michael; Fajardo, Giovanni; Bernstein, Daniel

2017-01-01

Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement. PMID:28469078

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer.

PubMed

Forsythe, Anna; Chandiwana, David; Barth, Janina; Thabane, Marroon; Baeck, Johan; Tremblay, Gabriel

2018-01-01

Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P =0.000; Spearman =0.650, P =0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R 2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R 2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC.

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone.

PubMed

Palmerini, E; Jones, R L; Marchesi, E; Paioli, A; Cesari, M; Longhi, A; Meazza, C; Coccoli, L; Fagioli, F; Asaftei, S; Grignani, G; Tamburini, A; Pollack, S M; Picci, P; Ferrari, S

2016-04-20

Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). Patients receiving G 900 mg/m(2) d 1, 8; D 75 mg/m(2) d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate. Fifty-one patients were included, with a median age of 17 years (8-71), 26 (51%) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49%) patients had metastases limited to lungs, 26 (51%) multiple sites. 40 (78%) osteosarcoma, 11 (22%) HGS. Eight (16%) patients achieved surgical complete response (sCR2) after GD. Four-month PFS rate was 46%, and significantly better for patients with ECOG 0 (ECOG 0: 54% vs ECOG 1: 43% vs ECOG 2: 0%; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75% vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56% vs HGS 18%; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases. Forty-six cases had RECIST measurable disease: 6 (13%) patients had a partial response (PR), 20 (43%) had stable disease (SD) and 20 (43%) had progressive disease (PD). The 1-year OS was 30%: 67% for PR, 54% for SD and 20% for PD (p = 0.005). GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma.

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax.

PubMed

Anderson, Mary Ann; Tam, Constantine; Lew, Thomas E; Juneja, Surender; Juneja, Manu; Westerman, David; Wall, Meaghan; Lade, Stephen; Gorelik, Alexandra; Huang, David C S; Seymour, John F; Roberts, Andrew W

2017-06-22

The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) ( P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not ( P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy. © 2017 by The American Society of Hematology.

Knee Injuries Are Associated with Accelerated Knee Osteoarthritis Progression: Data from the Osteoarthritis Initiative

PubMed Central

Driban, Jeffrey B.; Eaton, Charles B.; Lo, Grace H.; Ward, Robert J.; Lu, Bing; McAlindon, Timothy E.

2014-01-01

Objective We aimed to evaluate if a recent knee injury was associated with accelerated knee osteoarthritis (KOA) progression. Methods In the Osteoarthritis Initiative (OAI) we studied participants free of KOA on their baseline radiographs (Kellgren-Lawrence [KL]<2). We compared three groups: 1) individuals with accelerated progression of KOA: defined as having at least one knee that progressed to end-stage KOA (KL Grade 3 or 4) within 48 months, 2) common KOA progression: at least one knee increased in radiographic scoring within 48 months (excluding those defined as accelerated KOA), and 3) no KOA: no change in KL grade in either knee. At baseline, participants were asked if their knees had ever been injured and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine if a new knee injury was associated with the outcome of accelerated KOA or common KOA progression after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure. Results A knee injury during the total observation period was associated with accelerated KOA progression (n=54, odds ratio [OR]=3.14) but not common KOA progression (n=187, OR=1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR=8.46) and common KOA progression (OR=3.12). Conclusion Recent knee injuries are associated with accelerated KOA. Most concerning is that certain injuries may be associated with a rapid cascade towards joint failure in less than one year. PMID:24782446

Letrozole in advanced breast cancer: the PO25 trial

PubMed Central

2007-01-01

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS. PMID:17333340

Chemopreventive potential of natural compounds in head and neck cancer.

PubMed

Rahman, Mohammad Aminur; Amin, A R M Ruhul; Shin, Dong M

2010-01-01

Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers worldwide. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development, which underscore the importance of novel strategies for cancer prevention. Cancer chemoprevention, the use of natural or synthetic compounds to prevent, arrest, or reverse the process of carcinogenesis at its earliest stages, aims to reverse premalignancies and prevent second primary tumors. Genomics and proteomics information including initial mutation, cancer promotion, progression, and susceptibility has brought molecularly targeted therapies for drug development. The development of preventive approaches using specific natural or synthetic compounds, or both, requires a depth of understanding of the cross-talk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Many natural dietary compounds have been identified with multiple molecular targets, effective in the prevention and treatment of cancer. This review describes recent advances in the understanding of the complex signaling networks driving cancer progression and of molecularly targeted natural compounds under preclinical and clinical investigation.

Laser-assisted in situ keratomileusis with optimized, fast-repetition, and cyclotorsion control excimer laser to treat hyperopic astigmatism with high cylinder.

PubMed

Alió Del Barrio, Jorge L; Tiveron, Mauro; Plaza-Puche, Ana B; Amesty, María A; Casanova, Laura; García, María J; Alió, Jorge L

2017-10-18

To evaluate the visual outcomes after femtosecond laser-assisted laser in situ keratomileusis (LASIK) surgery to correct primary compound hyperopic astigmatism with high cylinder using a fast repetition rate excimer laser platform with optimized aspheric profiles and cyclotorsion control. Eyes with primary simple or compound hyperopic astigmatism and a cylinder power ≥3.00 D had uneventful femtosecond laser-assisted LASIK with a fast repetition rate excimer laser ablation, aspheric profiles, and cyclotorsion control. Visual, refractive, and aberrometric results were evaluated at the 3- and 6-month follow-up. The astigmatic outcome was evaluated using the Alpins method and ASSORT software. This study enrolled 80 eyes at 3 months and 50 eyes at 6 months. The significant reduction in refractive sphere and cylinder 3 and 6 months postoperatively (p<0.01) was associated with an improved uncorrected distance visual acuity (p<0.01). A total of 23.75% required retreatment 3 months after surgery. Efficacy and safety indices at 6 months were 0.90 and 1.00, respectively. At 6 months, 80% of eyes had an SE within ±0.50 D and 96% within ±1.00 D. No significant differences were detected between the third and the sixth postoperative months in refractive parameters. A significant increase in the spherical aberration was detected, but not in coma. The correction index was 0.94 at 3 months. Laser in situ keratomileusis for primary compound hyperopic astigmatism with high cylinder (>3.00 D) using the latest excimer platforms with cyclotorsion control, fast repetition rate, and optimized aspheric profiles is safe, moderately effective, and predictable.

Bioactive Compound Contents and Antioxidant Activity in Aronia (Aronia melanocarpa) Leaves Collected at Different Growth Stages.

PubMed

Thi, Nhuan Do; Hwang, Eun-Sun

2014-09-01

The bioactive compounds and antioxidant activity of aronia leaves at different stages of maturity were identified and evaluated. Young and old leaves were approximately 2 months of age and 4 months of age, respectively. The young leaves contained more polyphenols and flavonoids than the old leaves. Three phenolic compounds (i.e., chlorogenic acid, p-coumaric acid, and rutin) were detected by HPLC. Antioxidant activity was measured using 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radical, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical, and superoxide anion radical scavenging assays. The reducing power of aronia leaf extracts increased in a concentration-dependent manner (0~100 μg/mL). The antioxidant activity of the 80% ethanol extract was greater than that of distilled water extract. The high phenolic compound content indicated that these compounds contribute to antioxidant activity. The overall results indicate that aronia leaves contain bioactive compounds, and that younger aronia leaves may be more favorable for extracting antioxidative ingredients because they contain more polyphenols.

Bioactive Compound Contents and Antioxidant Activity in Aronia (Aronia melanocarpa) Leaves Collected at Different Growth Stages

PubMed Central

Thi, Nhuan Do; Hwang, Eun-Sun

2014-01-01

The bioactive compounds and antioxidant activity of aronia leaves at different stages of maturity were identified and evaluated. Young and old leaves were approximately 2 months of age and 4 months of age, respectively. The young leaves contained more polyphenols and flavonoids than the old leaves. Three phenolic compounds (i.e., chlorogenic acid, p-coumaric acid, and rutin) were detected by HPLC. Antioxidant activity was measured using 2,2-di-phenyl-1-picrylhydrazyl (DPPH) radical, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical, and superoxide anion radical scavenging assays. The reducing power of aronia leaf extracts increased in a concentration-dependent manner (0~100 μg/mL). The antioxidant activity of the 80% ethanol extract was greater than that of distilled water extract. The high phenolic compound content indicated that these compounds contribute to antioxidant activity. The overall results indicate that aronia leaves contain bioactive compounds, and that younger aronia leaves may be more favorable for extracting antioxidative ingredients because they contain more polyphenols. PMID:25320718

Vitamin D compounds inhibit cancer stem-like cells and induce differentiation in triple negative breast cancer.

PubMed

Shan, Naing Lin; Wahler, Joseph; Lee, Hong Jin; Bak, Min Ji; Gupta, Soumyasri Das; Maehr, Hubert; Suh, Nanjoo

2017-10-01

Triple-negative breast cancer is one of the least responsive breast cancer subtypes to available targeted therapies due to the absence of hormonal receptors, aggressive phenotypes, and the high rate of relapse. Early breast cancer prevention may therefore play an important role in delaying the progression of triple-negative breast cancer. Cancer stem cells are a subset of cancer cells that are thought to be responsible for tumor progression, treatment resistance, and metastasis. We have previously shown that vitamin D compounds, including a Gemini vitamin D analog BXL0124, suppress progression of ductal carcinoma in situ in vivo and inhibit cancer stem-like cells in MCF10DCIS mammosphere cultures. In the present study, the effects of vitamin D compounds in regulating breast cancer stem-like cells and differentiation in triple-negative breast cancer were assessed. Mammosphere cultures, which enriches for breast cancer cells with stem-like properties, were used to assess the effects of 1α,25(OH) 2 D 3 and BXL0124 on cancer stem cell markers in the triple-negative breast cancer cell line, SUM159. Vitamin D compounds significantly reduced the mammosphere forming efficiency in primary, secondary and tertiary passages of mammospheres compared to control groups. Key markers of cancer stem-like phenotype and pluripotency were analyzed in mammospheres treated with 1α,25(OH) 2 D 3 and BXL0124. As a result, OCT4, CD44 and LAMA5 levels were decreased. The vitamin D compounds also down-regulated the Notch signaling molecules, Notch1, Notch2, Notch3, JAG1, JAG2, HES1 and NFκB, which are involved in breast cancer stem cell maintenance. In addition, the vitamin D compounds up-regulated myoepithelial differentiating markers, cytokeratin 14 and smooth muscle actin, and down-regulated the luminal marker, cytokeratin 18. Cytokeratin 5, a biomarker associated with basal-like breast cancer, was found to be significantly down-regulated by the vitamin D compounds. These results suggest that vitamin D compounds may serve as potential preventive agents to inhibit triple negative breast cancer by regulating cancer stem cells and differentiation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of characteristics of compounds on maintenance of an amorphous state in solid dispersion with crospovidone.

PubMed

Shibata, Yusuke; Fujii, Makiko; Kokudai, Makiko; Noda, Shinobu; Okada, Hideko; Kondoh, Masuo; Watanabe, Yoshiteru

2007-06-01

Solid dispersion (SD) of indomethacin with crospovidone (CrosPVP) shows useful characteristics for preparation of dosage forms. This study aimed to determine the types of drugs that could adopt a stable amorphous form in SD. Twenty compounds with various melting points (70-218 degrees C), molecular weights (135-504) and functional groups (amide, amino, carbonyl, hydroxyl, ketone etc.) were prepared in SD with CrosPVP. The CrosPVP SDs were prepared using a mechanical mixing and heating method. Melting point and molecular weight were found to have no influence on the ability of a compound to maintain an amorphous state in SD. All compounds containing hydrogen-bond-donor functional groups existed in an amorphous state in SD for at least 6 months. Infrared spectra suggested an interaction between the functional groups of these compounds and amide carbonyl group of CrosPVP. Compounds without hydrogen-bond-donor groups could not maintain an amorphous state and underwent recrystallization within 1 month. It was suggested that the presence of a hydrogen-bond-donor functional group in a compound is an important factor affecting the stable formation of SD with CrosPVP, which contains a hydrogen-bond acceptor.

Quality-adjusted survival with combination nal-IRI+5-FU/LV vs 5-FU/LV alone in metastatic pancreatic cancer patients previously treated with gemcitabine-based therapy: a Q-TWiST analysis.

PubMed

Pelzer, Uwe; Blanc, Jean-Frédéric; Melisi, Davide; Cubillo, Antonio; Von Hoff, Daniel D; Wang-Gillam, Andrea; Chen, Li-Tzong; Siveke, Jens T; Wan, Yin; Solem, Caitlyn T; Botteman, Marc F; Yang, Yoojung; de Jong, Floris A; Hubner, Richard A

2017-05-09

In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST). Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0. Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months). Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Evaluation of baseline structural factors for predicting glaucomatous visual-field progression using optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy.

PubMed

Sehi, M; Bhardwaj, N; Chung, Y S; Greenfield, D S

2012-12-01

The objective of this study is to assess whether baseline optic nerve head (ONH) topography and retinal nerve fiber layer thickness (RNFLT) are predictive of glaucomatous visual-field progression in glaucoma suspect (GS) and glaucomatous eyes, and to calculate the level of risk associated with each of these parameters. Participants with ≥28 months of follow-up were recruited from the longitudinal Advanced Imaging for Glaucoma Study. All eyes underwent standard automated perimetry (SAP), confocal scanning laser ophthalmoscopy (CSLO), time-domain optical coherence tomography (TDOCT), and scanning laser polarimetry using enhanced corneal compensation (SLPECC) every 6 months. Visual-field progression was assessed using pointwise linear-regression analysis of SAP sensitivity values (progressor) and defined as significant sensitivity loss of >1 dB/year at ≥2 adjacent test locations in the same hemifield at P<0.01. Cox proportional hazard ratios (HR) were calculated to determine the predictive ability of baseline ONH and RNFL parameters for SAP progression using univariate and multivariate models. Seventy-three eyes of 73 patients (43 GS and 30 glaucoma, mean age 63.2±9.5 years) were enrolled (mean follow-up 51.5±11.3 months). Four of 43 GS (9.3%) and 6 of 30 (20%) glaucomatous eyes demonstrated progression. Mean time to progression was 50.8±11.4 months. Using multivariate models, abnormal CSLO temporal-inferior Moorfields classification (HR=3.76, 95% confidence interval (CI): 1.02-6.80, P=0.04), SLPECC inferior RNFLT (per -1 μm, HR=1.38, 95% CI: 1.02-2.2, P=0.02), and TDOCT inferior RNFLT (per -1 μm, HR=1.11, 95% CI: 1.04-1.2, P=0.001) had significant HRs for SAP progression. Abnormal baseline ONH topography and reduced inferior RNFL are predictive of SAP progression in GS and glaucomatous eyes.

Evaluation of baseline structural factors for predicting glaucomatous visual-field progression using optical coherence tomography, scanning laser polarimetry and confocal scanning laser ophthalmoscopy

PubMed Central

Sehi, M; Bhardwaj, N; Chung, Y S; Greenfield, D S

2012-01-01

Purpose The objective of this study is to assess whether baseline optic nerve head (ONH) topography and retinal nerve fiber layer thickness (RNFLT) are predictive of glaucomatous visual-field progression in glaucoma suspect (GS) and glaucomatous eyes, and to calculate the level of risk associated with each of these parameters. Methods Participants with ≥28 months of follow-up were recruited from the longitudinal Advanced Imaging for Glaucoma Study. All eyes underwent standard automated perimetry (SAP), confocal scanning laser ophthalmoscopy (CSLO), time-domain optical coherence tomography (TDOCT), and scanning laser polarimetry using enhanced corneal compensation (SLPECC) every 6 months. Visual-field progression was assessed using pointwise linear-regression analysis of SAP sensitivity values (progressor) and defined as significant sensitivity loss of >1 dB/year at ≥2 adjacent test locations in the same hemifield at P<0.01. Cox proportional hazard ratios (HR) were calculated to determine the predictive ability of baseline ONH and RNFL parameters for SAP progression using univariate and multivariate models. Results Seventy-three eyes of 73 patients (43 GS and 30 glaucoma, mean age 63.2±9.5 years) were enrolled (mean follow-up 51.5±11.3 months). Four of 43 GS (9.3%) and 6 of 30 (20%) glaucomatous eyes demonstrated progression. Mean time to progression was 50.8±11.4 months. Using multivariate models, abnormal CSLO temporal-inferior Moorfields classification (HR=3.76, 95% confidence interval (CI): 1.02–6.80, P=0.04), SLPECC inferior RNFLT (per −1 μm, HR=1.38, 95% CI: 1.02–2.2, P=0.02), and TDOCT inferior RNFLT (per −1 μm, HR=1.11, 95% CI: 1.04–1.2, P=0.001) had significant HRs for SAP progression. Conclusion Abnormal baseline ONH topography and reduced inferior RNFL are predictive of SAP progression in GS and glaucomatous eyes. PMID:23060026

Progressive Occlusion of Small Saccular Aneurysms Incompletely Occluded After Stent-Assisted Coil Embolization : Analysis of Related Factors and Long-Term Outcomes.

PubMed

Lim, Jeong Wook; Lee, Jeongjun; Cho, Young Dae

2017-08-08

Incompletely occluded aneurysms after coil embolization are subject to recanalization but occasionally progress to a totally occluded state. Deployed stents may actually promote thrombosis of coiled aneurysms. We evaluated outcomes of small aneurysms (<10 mm) wherein saccular filling with contrast medium was evident after stent-assisted coiling, assessing factors implicated in subsequent progressive occlusion. Between September 2012 and June 2016, a total of 463 intracranial aneurysms were treated by stent-assisted coil embolization. Of these, 132 small saccular aneurysms displayed saccular filling with contrast medium in the immediate aftermath of coiling. Progressive thrombosis was defined as complete aneurysmal occlusion at the 6‑month follow-up point. Rates of progressive occlusion and factors predisposing to this were analyzed via binary logistic regression. In 101 (76.5%) of the 132 intracranial aneurysms, complete occlusion was observed in follow-up imaging studies at 6 months. Binary logistic regression analysis indicated that progressive occlusion was linked to smaller neck diameter (odds ratio [OR] = 1.533; p = 0.003), hyperlipidemia (OR = 3.329; p = 0.036) and stent type (p = 0.031). The LVIS stent is especially susceptible to progressive thrombosis, more so than Neuroform (OR = 0.098; p = 0.008) or Enterprise (OR = 0.317; p = 0.098) stents. In 57 instances of progressive thrombosis, followed for ≥12 months (mean 25.0 ± 10.7 months), 56 (98.2%) were stable, with minor recanalization noted once (1.8%) and no major recanalization. Aneurysms associated with smaller diameter necks, hyperlipidemic states and LVIS stent deployment may be inclined to possible thrombosis, if occlusion immediately after stent-assisted coil embolization is incomplete. In such instances, excellent long-term durability is anticipated.

Survival after failure of first-line chemotherapy in advanced gastric cancer patients: differences between Japan and the rest of the world.

PubMed

Takashima, Atsuo; Iizumi, Sakura; Boku, Narikazu

2017-07-01

In this review, we focus on post-progression survival after first-line chemotherapy of advanced gastric cancer, and particularly the differences between Japan and the rest of the world. We reviewed 15 recent phase III trials of which 4 were solely recruited from Japanese and 11 from rest of the world. The patient characteristics age, performance status, previous gastrectomy and the number of metastatic sites were similar in Japan and rest of the world. However, the diffuse histological type was more common in Japan. While overall survival was longer in Japan (10.5-14.1 vs. 7.9-12.2 months), progression-free survival tended to be shorter in Japan (3.6-6.0 vs. 3.1-7.4 months). Post-progression survival calculated as the difference between median overall survival and progression-free survival was clearly longer in Japan (6.9-8.6 vs. 2.4-6.2 months). The proportion of patients receiving second-line chemotherapy (%2nd-CX) was quite different in Japan and rest of the world (69-85% vs. 11-59%). Correlations between %2nd-CX and post-progression survival were strong (Spearman's rank correlation coefficient; ρ = 0.86, P < 0.001). Correlations between %2nd-CX and ratio of post-progression survival to total overall survival were also strong (ρ = 0.84, P < 0.001). Because a survival benefit of second-CX was documented in several phase III trials, it can be concluded that higher %2nd-CX partly contributed to extended post-progression survival. However, considering that second-CX increased survival only by ~1.5 months at median, other factors such as third-line chemotherapy may have some influences to prolonged post-progression survival. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Extemporaneous compounding in a sample of New Zealand hospitals: a retrospective survey.

PubMed

Kairuz, Therése; Chhim, Srey; Hasan, Fhazeel; Kumar, Karishma; Lal, Aarti; Patel, Roshni; Singh, Ranjani; Dogra, Mridula; Garg, Sanjay

2007-03-23

To determine the extent and nature of extemporaneous compounding of liquid preparations in a sample of New Zealand hospitals. Retrospective data were collected from eight hospitals known to provide compounding services during the period 1 June 2004 to 31 December 2004; including dosage form, volume, and quantity prepared. Data were collected on site from compounding logbooks and batch sheets. Demographic patient data was limited to age and was only collected from pharmacy departments where this information was readily available. Off-label use was analysed where appropriate data were available. 2015 products were compounded over the 7-month period; an average of 251.9 per month. More oral dosage forms were compounded (n=152) compared to topical dosage forms (n=100); 74 drugs required extemporaneous preparation for oral use. There were 16 drugs used in an off-label manner on 144 occasions for paediatric patients. Most off-label drugs were reformulated as suspensions; omeprazole suspension was compounded at all of the hospitals. Off-label use of four drugs (sotalol, labetalol, diazoxide, and clonidine) was analysed for different paediatric age groups. Suspensions are the most frequently compounded dosage form and omeprazole is the drug that is most frequently reformulated. Off-label medicines form a small but integral role in the supply of medicinal products.

Characterization of phenolic compounds in Pinus laricio needles and their responses to prescribed burnings.

PubMed

Cannac, Magali; Pasqualini, Vanina; Greff, Stéphane; Fernandez, Catherine; Ferrat, Lila

2007-07-30

Fire is a dominant ecological factor in Mediterranean-type ecosystems. Management strategies include prescribed (controlled) burning, which has been used in the management of several species, such as Pinus nigra ssp laricio var. Corsicana, a pine endemic to Corsica of great ecological and economic importance. The effects of prescribed burning on Pinus laricio have been little studied. The first aim of this study was to characterize total and simple phenolic compounds in Pinus laricio. The second aim was to understand: i) the short term (one to three months) and medium term (three years) effects of prescribed burning, and ii) the effects of periodic prescribed burning on the production of phenolic compounds in Pinus laricio. The first result of this study is the presence of total and simple phenolic compounds in the needles of Pinus laricio. 3-Vanillyl propanol is the major compound. After a prescribed burning, the synthesis of total phenolic compounds increases in Pinus laricio for a period of three months. Total phenolic compounds could be used as bioindicators for the short-term response of Pinus laricio needles to prescribed burning. Simple phenolic compounds do not seem to be good indicators of the impact of prescribed burning because prescribed burnings are low in intensity.

Recurrent endometrial carcinoma: prognosis for patients with recurrence within 6 to 12 months is worse relative to those relapsing at 12 months or later.

PubMed

Miyake, Takahito; Ueda, Yutaka; Egawa-Takata, Tomomi; Matsuzaki, Shinya; Yokoyama, Takuhei; Miyoshi, Yukari; Kimura, Toshihiro; Yoshino, Kiyoshi; Fujita, Masami; Yamasaki, Masato; Enomoto, Takayuki; Kimura, Tadashi

2011-06-01

We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs). We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC). Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months). Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy. Copyright © 2011 Mosby, Inc. All rights reserved.

Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature.

PubMed

Jurecka, Agnieszka; Zikanova, Marie; Jurkiewicz, Elżbieta; Tylki-Szymańska, Anna

2014-02-01

We present a 9-year follow-up of a patient with an attenuated (type II) adenylosuccinate lyase deficiency with no obvious signs of disease progression and degradation. We also review the literature, focusing on attenuated phenotype, and we report a positive effect of a ketogenic diet on seizure control. The patient presented at the age of 5 months with a history of global developmental delay. Screening of urinary purine metabolites revealed elevation of succinyladenosine and succinylaminoimidazolecarboxamide riboside (a ratio of 2:1). Mutation analysis revealed a compound heterozygosity for missense mutations: p.R426H and p.D268H. She began to walk independently at the age of 3 years. From the age of 4 years, her communication skills improved and she presented fewer autistic features. Due to poor results in seizure control, the ketogenic diet was introduced at the age of 7 years, resulting in reduction of seizure frequency. Currently, at the age of 9 years, the girl is attending a special kindergarten and is functioning very well in her preschool group. She began to make statements that form a logical continuity and make progress in simple manual operations. The patient participates in therapies such as pet therapy, hippotherapy, speech therapy, physiotherapy, hydrotherapy, and music therapy. Georg Thieme Verlag KG Stuttgart · New York.

78 FR 26215 - Jewish American Heritage Month, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-03

... American Heritage Month, 2013 By the President of the United States of America A Proclamation In his second... American shores. We take this month to celebrate the progress that followed, and the bright future that... May 2013 as Jewish American Heritage Month. I call upon all Americans to visit www.JewishHeritageMonth...

Monitoring Indicators of Scholarly Language: A Progress-Monitoring Instrument for Measuring Narrative Discourse Skills

ERIC Educational Resources Information Center

Gillam, Sandra Laing; Gillam, Ronald B.; Fargo, Jamison D.; Olszewski, Abbie; Segura, Hugo

2017-01-01

The purpose of this study was to assess the basic psychometric properties of a progress-monitoring tool designed to measure narrative discourse skills in school-age children with language impairments (LI). A sample of 109 children with LI between the ages of 5 years 7 months and 9 years 9 months completed the "Test of Narrative Language"…

Progression of Structural Change in the Breast Cancer Genome

DTIC Science & Technology

2013-08-01

CNV !(months!143,!samples!have!already!been!approved!for!use)!.............................!6! 2b:!Develop!and!test!FISH!probes!to! detect !SMRT! CNV ...hormone+ therapy+resistance+–+likely+in+combination+with+some+of+the+other+mutations+identified+here.+ 2b:%Develop%and%test%FISH%probes%to% detect %SMRT% CNV ...4! Task!2:!Determine!impact!of!NCOR2/SMRT! CNV !on!breast!cancer!progression!(months!1424

Progress Monitoring in Reading: Comparison of Weekly, Bimonthly, and Monthly Assessments for Students at Risk for Reading Difficulties in Grades 2-4

ERIC Educational Resources Information Center

January, Stacy-Ann A.; Van Norman, Ethan R.; Christ, Theodore J.; Ardoin, Scott P.; Eckert, Tanya L.; White, Mary Jane

2018-01-01

The present study examined the utility of two progress monitoring assessment schedules (bimonthly and monthly) as alternatives to monitoring once weekly with curriculum-based measurement in reading (CBM-R). General education students (N = 93) in Grades 2-4 who were at risk for reading difficulties but not yet receiving special education services…

29 CFR 4022.81 - General rules.

Code of Federal Regulations, 2011 CFR

2011-07-01

... after May 1998, the applicable federal mid-term rate (as determined by the Secretary of the Treasury pursuant to section 1274(d)(1)(C)(ii) of the Code) for that month (or, where the rate for a month is not... which the rate is available) based on monthly compounding; and (ii) For May 1998 and earlier months, the...

29 CFR 4022.81 - General rules.

Code of Federal Regulations, 2012 CFR

2012-07-01

... after May 1998, the applicable federal mid-term rate (as determined by the Secretary of the Treasury pursuant to section 1274(d)(1)(C)(ii) of the Code) for that month (or, where the rate for a month is not... which the rate is available) based on monthly compounding; and (ii) For May 1998 and earlier months, the...

29 CFR 4022.81 - General rules.

Code of Federal Regulations, 2014 CFR

2014-07-01

... after May 1998, the applicable federal mid-term rate (as determined by the Secretary of the Treasury pursuant to section 1274(d)(1)(C)(ii) of the Code) for that month (or, where the rate for a month is not... which the rate is available) based on monthly compounding; and (ii) For May 1998 and earlier months, the...

29 CFR 4022.81 - General rules.

Code of Federal Regulations, 2013 CFR

2013-07-01

... after May 1998, the applicable federal mid-term rate (as determined by the Secretary of the Treasury pursuant to section 1274(d)(1)(C)(ii) of the Code) for that month (or, where the rate for a month is not... which the rate is available) based on monthly compounding; and (ii) For May 1998 and earlier months, the...

Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis.

PubMed

Fogarty, Emer; Schmitz, Susanne; Tubridy, Niall; Walsh, Cathal; Barry, Michael

2016-09-01

Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis (RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies. To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS. A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted within a Bayesian framework to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome. The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome. Interferon-beta-1b 250mcg ranked among the most efficacious treatments for disability progression confirmed after six months (92%) and among the least efficacious when the outcome was confirmed after three months (30%). No significant modification of relative treatment effects was identified from study-level covariates or baseline risk. Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS. Copyright © 2016 Elsevier B.V. All rights reserved.

The perspective crops for the bioregenerative human life support systems

NASA Astrophysics Data System (ADS)

Polonskiy, Vadim; Polonskaya, Janna

The perspective crops for the bioregenerative human life support systems V.I. Polonskiy, J.E. Polonskaya aKrasnoyarsk State Agrarian University, 660049, Krasnoyarsk, Russia In the nearest future the space missions will be too long. In this case it is necessary to provide the crew by vitamins, antioxidants, and water-soluble dietary fibers. These compounds will be produced by higher plants. There was not enough attention at present to increasing content of micronutrients in edible parts of crops candidates for CELSS. We suggested to add the new crops to this list. 1. Barley -is the best crop for including to food crops (wheat, rice, soybean). Many of the health effects of barley are connected to dietary fibers beta-glucan of barley grains. Bar-ley is the only seed from cereals including wheat with content of all eight tocopherols (vitamin E, important antioxidant). Barley grains contain much greater amounts of phenolic compounds (potential antioxidant activities) than other cereal grains. Considerable focus is on supplement-ing wheat-based breads with barley to introduce the inherent nutritional advantages of barley flour, currently only 20We have selected and tested during 5 generations two high productive barley lines -1-K-O and 25-K-O. Our investigations (special breeding program for improving grain quality of barley) are in progress. 2. Volatile crops. Young leaves and shoots of these crops are edible and have a piquant taste. A lot of organic volatile compounds, oils, vitamins, antioxidants are in their biomass. These micronutrients are useful for good appetite and health of the crew. We have investigated 11 species: basil (Ocimum basilicum), hyssop (Hyssopus officinalis), marjoram (Origanum majorana), sweet-Mary (Melissa officinalis), common thyme (Thymus vulgaris), creeping thyme (Thymus serpyllum), summer savory (Satureja hortensis), catnip (Nepeta cataria), rue (Ruta graveolens), coriander (Coriandrum Ativum), sulfurwort (Levisticum officinale). These plants were grown under artificial light conditions from 5 to 7 months. All crops were cut periodically in every month. On the base of our investigations it is possible to recommend for using in CELSS the next crops: marjoram, sweet-Mary and common thyme. The micronutrients containing in barley and above mentioned volatile crops will be useful for good appetite and health of the crew.

Progressive Hearing Impairment in Children with Congenital Cytomegalovirus Infection.

ERIC Educational Resources Information Center

Dahle, Arthur J.; And Others

1979-01-01

Audiological assessment of 86 children (mean age 38 months at last evaluation time) with congenital cytomegalovirus infection revealed progressive hearing loss in four of 12 Ss with sensorineural hearing impairments. Case descriptions documented the progression of the hearing loss. (Author)

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas.

PubMed

Desjardins, Annick; Quinn, Jennifer A; Vredenburgh, James J; Sathornsumetee, Sith; Friedman, Allan H; Herndon, James E; McLendon, Roger E; Provenzale, James M; Rich, Jeremy N; Sampson, John H; Gururangan, Sridharan; Dowell, Jeannette M; Salvado, August; Friedman, Henry S; Reardon, David A

2007-05-01

Recent reports demonstrate the activity of imatinib mesylate, an ATP-mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme. We performed the current phase 2 study to evaluate this regimen among patients with recurrent WHO grade III malignant glioma (MG). Patients with grade III MG at any recurrence, received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme inducing anti-epileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Clinical assessments were performed monthly and radiographic assessments were obtained at least every 2 months. The primary endpoint was 6-month progression-free survival (PFS) rate. Thirty-nine patients were enrolled. All patients had progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. The median number of episodes of prior progression was 2 (range, 1-7) and the median number of prior treatment regimens was 3 (range, 1-8). With a median follow-up of 82.9 weeks, 24% of patients were progression-free at 6 months. The radiographic response rate was 10%, while 33% achieved stable disease. Among patients who achieved at least stable disease at first evaluation, the 6-month and 12-month PFS rates were 53% and 29%, respectively. The most common grade 3 or greater toxicities were hematologic and complicated less than 4% of administered courses. Imatinib mesylate plus hydroxyurea, is well tolerated and associated with anti-tumor activity in some patients with recurrent grade 3 MG.

Isolated lower brachial plexus (Klumpke) palsy with compound arm presentation: case report.

PubMed

Buchanan, Edward P; Richardson, Randal; Tse, Raymond

2013-08-01

Klumpke palsy has yet to be clearly documented in the newborn, because previous reports lack any description of the obstetrical history, clinical progression, or outcome. Based on a high incidence of breach presentation in the few clinical series that report Klumpke palsy, hyperabduction with arm overhead during delivery has been the presumed mechanism. We report a child with isolated lower brachial plexus palsy and Horner syndrome who presented at birth with a vertex compound arm presentation. Recognition of this condition and details of the clinical progression and outcome are important, because guidelines for management are currently not available. Copyright © 2013. Published by Elsevier Inc.

Transition Metal Compounds Towards Holography

PubMed Central

Dieckmann, Volker; Eicke, Sebastian; Springfeld, Kristin; Imlau, Mirco

2012-01-01

We have successfully proposed the application of transition metal compounds in holographic recording media. Such compounds feature an ultra-fast light-induced linkage isomerization of the transition-metal–ligand bond with switching times in the sub-picosecond regime and lifetimes from microseconds up to hours at room temperature. This article highlights the photofunctionality of two of the most promising transition metal compounds and the photophysical mechanisms that are underlying the hologram recording. We present the latest progress with respect to the key measures of holographic media assembled from transition metal compounds, the molecular embedding in a dielectric matrix and their impressive potential for modern holographic applications. PMID:28817028

The recent progress of isoxazole in medicinal chemistry.

PubMed

Zhu, Jie; Mo, Jun; Lin, Hong-Zhi; Chen, Yao; Sun, Hao-Peng

2018-05-28

Isoxazole compounds exhibit a wide spectrum of targets and broad biological activities. Developing compounds with heterocycle rings has been one of the trends. The integration of isoxazole ring can offer improved physical-chemical properties. Because of the unique profiles, isoxazole ring becomes a popular moiety in compounds design. In this review article, the major focus has been paid to the applications of isoxazole compounds in treating multiple diseases, including anticancer, antimicrobial, anti-inflammatory, etc. Strategies for compounds design for preclinical, clinical, and FDA approved drugs were discussed. Also, the emphasis has been addressed to the future perspectives and trend for the application. Copyright © 2018 Elsevier Ltd. All rights reserved.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study

PubMed Central

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-01-01

Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. ‘Progressors’ were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. PMID:29306872

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms.

PubMed

Baum, Richard P; Kulkarni, Harshad R; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-03-30

Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. In our center, 2294 patients were screened between 2004 and 2014 by 68 Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90 Yttrium or 177 Lutetium-based PRRT. Progression free survival was determined by 68 Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68 Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048 patients with neuroendocrine neoplasms

PubMed Central

Baum, Richard P.; Kulkarni, Harshad R.; Singh, Aviral; Kaemmerer, Daniel; Mueller, Dirk; Prasad, Vikas; Hommann, Merten; Robiller, Franz C.; Niepsch, Karin; Franz, Holger; Jochems, Arthur; Lambin, Philippe; Hörsch, Dieter

2018-01-01

Introduction Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. Methods In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Results Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. Conclusion PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy. PMID:29682195

Proton Therapy for Reirradiation of Progressive or Recurrent Chordoma

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

McDonald, Mark W., E-mail: mmcdona2@iuhealth.org; Indiana University Health Proton Therapy Center, Bloomington, Indiana; Linton, Okechuckwu R.

2013-12-01

Purpose: To report the results in patients reirradiated with proton therapy for recurrent or progressive chordoma, with or without salvage surgery. Methods and Materials: A retrospective review of 16 consecutive patients treated from 2005 to 2012 was performed. All patients had received at least 1 prior course of radiation therapy to the same area, and all but 1 patient had at least 1 surgical resection for disease before receiving reirradiation. At the time of recurrence or progression, half of the patients underwent additional salvage surgery before receiving reirradiation. The median prior dose of radiation was 75.2 Gy (range, 40-79.2 Gy).more » Six patients had received prior proton therapy, and the remainder had received photon radiation. The median gross tumor volume at the time of reirradiation was 71 cm{sup 3} (range, 0-701 cm{sup 3}). Reirradiation occurred at a median interval of 37 months after prior radiation (range, 12-129 months), and the median dose of reirradiation was 75.6 Gy (relative biological effectiveness [RBE]) (range. 71.2-79.2 Gy [RBE]), given in standard daily fractionation (n=14) or hyperfractionation (n=2). Results: The median follow-up time was 23 months (range, 6-63 months); it was 26 months in patients alive at the last follow-up visit (range, 12-63 months). The 2-year estimate for local control was 85%, overall survival 80%, chordoma-specific survival 88%, and development of distant metastases 20%. Four patients have had local progression: 3 in-field and 1 marginal. Late toxicity included grade 3 bitemporal lobe radionecrosis in 1 patient that improved with hyperbaric oxygen, a grade 4 cerebrospinal fluid leak with meningitis in 1 patient, and a grade 4 ischemic brainstem stroke (out of radiation field) in 1 patient, with subsequent neurologic recovery. Conclusions: Full-dose proton reirradiation provided encouraging initial disease control and overall survival for patients with recurrent or progressive chordoma, although additional toxicities may develop with longer follow-up times.« less

A retrospective study of correlation of morphologic patterns, MIB1 proliferation index, and survival analysis in 134 cases of plasmacytoma.

PubMed

Ghodke, Kiran; Shet, Tanuja; Epari, Sridhar; Sengar, Manju; Menon, Hari; Gujral, Sumeet

2015-06-01

Plasmacytoma classified into solitary plasmacytoma of bone (SPB) and extramedullary plasmacytoma (EMP) is characterized by infiltrate of plasma cells of diverse maturity and by their monoclonal immunoglobulin products. Both SPB and EMP represent different groups of neoplasm in terms of location, tumor progression, and overall survival rate. There is a need for features that indicate likelihood of myeloma in patients with plasmacytoma without other manifestations. This study was an attempt to study the morphologic patterns of plasmacytoma (SPB and EMP), MIB1 proliferation index, and correlation of these with clinicopathologic features and survival of the patients. The study group comprised of 134 cases of plasmacytoma (88 SPB and 46 EMP) over duration of 8 years and were graded as per Bartl's histologic grading system. Commonest site was vertebral body in SPB (36%) and upper aerodigestive tract in EMP (48%). On serum electrophoresis, overall M band was detected in 41% cases. Both SPB and EMP on histology revealed similar morphologic features. MIB1 proliferation index ranged from less than 1% to 80%. It was slightly higher in EMP in comparison with SPB (P value = .002). Seventy percent of cases, which progressed to multiple myeloma (MM) showed MIB1 labeling index more than 10%; however, it was not statistically significant in predicting the disease progression. With the median follow-up of 19 months (range, 1-99 months), 10 SPB had disease progression of which 7 converted to MM, and 3 developed EMP, with a median interval of 21 months (range, 8-75 months) for the development of MM and 3 months (range, 3-9 months) for the progression to EMP. Five-year survival for EMP varied by site, with poorest survival in brain/central nervous system EMP as compared with EMP at other sites. To conclude, grade and MIB1 proliferation index help in predicting aggressive course in plasmacytoma. Copyright © 2015 Elsevier Inc. All rights reserved.

Some dissociating factors in the analysis of structural and functional progressive damage in open-angle glaucoma.

PubMed

Hudson, C J W; Kim, L S; Hancock, S A; Cunliffe, I A; Wild, J M

2007-05-01

To identify the presence, and origin, of any "dissociating factors" inherent to the techniques for evaluating progression that mask the relationship between structural and functional progression in open-angle glaucoma (OAG). 23 patients (14 with OAG and 9 with ocular hypertension (OHT)) who had received serial Heidelberg Retina Tomograph (HRT II) and Humphrey Field Analyser (HFA) examinations for >or=5 years (mean 78.4 months (SD 9.5), range 60-101 months) were identified. Evidence of progressive disease was retrospectively evaluated in one eye of each patient using the Topographic Change Analysis (TCA) and Glaucoma Progression Analysis (GPA) for the HRT II and HFA, respectively. Six patients were stable by both techniques; four exhibited both structural and functional progression; seven exhibited structural progression, only, and six showed functional progression, only. Three types of dissociating factors were identified. TCA failed to identify progressive structural damage in the presence of advanced optic nerve head damage. GPA failed to identify progressive functional damage at stimulus locations, with sensitivities exhibiting test-retest variability beyond the maximum stimulus luminance of the perimeter, and where a perimetric learning effect was apparent. The three dissociating factors accounted for nine of the 13 patients who exhibited a lack of concordance between structural and functional progressive damage.

Detoxification of Mycotoxins and Other Compounds of Military Interest

DTIC Science & Technology

1987-01-14

h to A conclusion. A newly recognized naturally occurring gILLathione derivative y ltmlguttin)hs enpnae and methods for large scale preparation of...whereas ochers contained as much as 50-70% of the new material. An effort is currently in progress in order to determine the nature of the new compound

Quinazoline derivatives as potential anticancer agents: a patent review (2007 - 2010).

PubMed

Marzaro, Giovanni; Guiotto, Adriano; Chilin, Adriana

2012-03-01

Due to the increase in knowledge about cancer pathways, there is a growing interest in finding novel potential drugs. Quinazoline is one of the most widespread scaffolds amongst bioactive compounds. A number of patents and papers appear in the literature regarding the discovery and development of novel promising quinazoline compounds for cancer chemotherapy. Although there is a progressive decrease in the number of patents filed, there is an increasing number of biochemical targets for quinazoline compounds. This paper provides a comprehensive review of the quinazolines patented in 2007 - 2010 as potential anticancer agents. Information from articles published in international peer-reviewed journals was also included, to give a more exhaustive overview. From about 1995 to 2006, the anticancer quinazolines panorama has been dominated by the 4-anilinoquinazolines as tyrosine kinase inhibitors. The extensive researches conducted in this period could have caused the progressive reduction in the ability to file novel patents as shown in the 2007 - 2010 period. However, the growing knowledge of cancer-related pathways has recently highlighted some novel potential targets for therapy, with quinazolines receiving increasing attention. This is well demonstrated by the number of different targets of the patents considered in this review. The structural heterogeneity in the patented compounds makes it difficult to derive general pharmacophores and make comparisons among claimed compounds. On the other hand, the identification of multi-target compounds seems a reliable goal. Thus, it is reasonable that quinazoline compounds will be studied and developed for multi-target therapies.

ATG4B inhibitors with a benzotropolone core structure block autophagy and augment efficiency of chemotherapy in mice.

PubMed

Kurdi, Ammar; Cleenewerck, Matthias; Vangestel, Christel; Lyssens, Sophie; Declercq, Wim; Timmermans, Jean-Pierre; Stroobants, Sigrid; Augustyns, Koen; De Meyer, Guido R Y; Van Der Veken, Pieter; Martinet, Wim

2017-08-15

Autophagy is a cell survival mechanism hijacked by advanced tumors to endure a rough microenvironment. Late autophagy inhibitors such as (hydroxy)chloroquine have been used clinically to halt tumor progression with modest success. However, given the toxic nature of these compounds and their lack of specificity, novel targets should be considered. We recently identified a benzotropolone derivative that significantly inhibited the essential autophagy protein ATG4B. Therefore, we synthesized and tested additional benzotropolone compounds to identify a promising ATG4B inhibitor that impairs autophagy both in vitro and in vivo. A compound library containing 27 molecules with a benzotropolone backbone was synthesized and screened for inhibition of recombinant ATG4B. Depending on the benzotropolone compound, inhibition of recombinant ATG4B ranged from 3 to 82%. Active compounds were evaluated in cellular assays to confirm inhibition of ATG4B and suppression of autophagy. Seven compounds inhibited processing of the autophagy protein LC3 and autophagosome formation. Compound UAMC-2526 was selected for further in vivo use because of its fair plasma stability. This compound abolished autophagy both in nutrient-deprived GFP-LC3 mice and in CD1 -/- Foxn1nu mice bearing HT29 colorectal tumor xenografts. Moreover, addition of UAMC-2526 to the chemotherapy drug oxaliplatin significantly improved inhibition of tumor growth. Our data indicate that suppression of autophagy via ATG4B inhibition is a feasible strategy to augment existing chemotherapy efficacy and to halt tumor progression. Copyright © 2017 Elsevier Inc. All rights reserved.

Induction gemcitabine and oxaliplatin therapy followed by a twice-weekly infusion of gemcitabine and concurrent external-beam radiation for neoadjuvant treatment of locally advanced pancreatic cancer: a single institutional experience.

PubMed

Leone, Francesco; Gatti, Marco; Massucco, Paolo; Colombi, Federica; Sperti, Elisa; Campanella, Delia; Regge, Daniele; Gabriele, Pietro; Capussotti, Lorenzo; Aglietta, Massimo

2013-01-15

Chemoradiotherapy (CRT) may render curative resection feasible in patients with locally advanced pancreatic carcinoma (LAPC). The authors previously demonstrated the achievement of significant disease control and a median survival of 14 months by CRT in patients with LAPC. In this study, they evaluated the use of induction chemotherapy followed by a CRT neoadjuvant protocol. Patients first received induction gemcitabine and oxaliplatin (GEMOX) (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)). Patients without disease progression then received gemcitabine twice weekly (50 mg/m(2) daily) concurrent with radiotherapy (50.4 grays) and were re-evaluated for resectability. Thirty-nine patients (15 with borderline resectable disease and 24 with unresectable disease) entered the study. The treatment was well tolerated. Disease control was obtained in 29 of 39 patients. Two patients progressed after GEMOX, and 7 progressed after CRT. After a median follow-up of 13 months, the median progression-free survival (PFS) was 10.2 months. The median PFS of patients with borderline resectable and unresectable disease was 16.6 and 9.1 months, respectively (P = .056). For the whole group, the median overall survival (OS) was 16.7 months (27.8 months for patients with borderline resectable disease, 13.3 for patients with unresectable disease; P = .045). Eleven patients (9 with borderline resectable disease and 2 with unresectable disease at diagnosis) underwent successful resection. Patients who underwent resection had a significantly longer median PFS compared with nonresected patients (19.7 months vs 7.6 months, respectively). The median OS among resected and nonresected patients was 31.5 months and 12.3 months, respectively (P < .001). The current results indicated that induction GEMOX followed by CRT is feasible in patients with LAPC. Both those with borderline resectable disease and those with unresectable disease received clinical benefit, a chance to obtain resectability, and improved survival. The authors concluded that this protocol warrants further evaluation. Copyright © 2012 American Cancer Society.

Selected ground-water data, Chester County, Pennsylvania

USGS Publications Warehouse

Sloto, Ronald A.

1989-01-01

Hydrologic data for Chester County, Pennsylvania are given for 3,010 wells and 32 springs. Water levels are given for 48 observation wells measured monthly during 1936-86. Chemical analyses of ground water are given for major ions, physical properties, nutrients, metals and other trace constituents, volatile organic compounds, acid organic compounds, base-neutral organic compounds, organochlorine insecticides, polychlorinated biphenyls, polychlorinated napthalenes, organophosphorous insecticides, organic acid herbicides, triazine herbicides, other organic compounds, and radionuclides.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

PubMed

Tourbah, Ayman; Lebrun-Frenay, Christine; Edan, Gilles; Clanet, Michel; Papeix, Caroline; Vukusic, Sandra; De Sèze, Jerome; Debouverie, Marc; Gout, Olivier; Clavelou, Pierre; Defer, Gilles; Laplaud, David-Axel; Moreau, Thibault; Labauge, Pierre; Brochet, Bruno; Sedel, Frédéric; Pelletier, Jean

2016-11-01

Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated. © The Author(s), 2016.

Vemurafenib beyond progression in a patient with metastatic melanoma: a case report.

PubMed

Grimaldi, Antonio M; Simeone, Ester; Palla, Marco; Festino, Lucia; Caracò, Corrado; Mozzillo, Nicola; Petrillo, Antonella; Muto, Paolo; Ascierto, Paolo A

2015-04-01

The prognosis of metastatic melanoma has changed markedly in recent years because of the advent of newer targeted therapies such as BRAF inhibitors. However, the response to BRAF inhibitor therapy is frequently nondurable in patients with advanced melanoma. Novel approaches are thus needed to overcome resistance to these agents and to improve the management of advanced melanoma patients after disease progression. Here, we present the case of a 44-year-old man diagnosed with advanced melanoma in July 2010, harboring a BRAF mutation. Melanoma progressed during first-line chemotherapy with dacarbazine, but showed significant benefit after the initiation of vemurafenib on August 2011. Six months later, the patient experienced disease progression in left-obturator lymphadenopathy; still, anti-BRAF treatment was continued together with stereotactic radiotherapy, and was interrupted only shortly for intestinal occlusion secondary to melanoma metastasis of the bowel. When his conditions were stable, after 1 month of vemurafenib treatment discontinuation, anti-BRAF therapy was reinitiated, with a positive outcome. Vemurafenib treatment was definitively discontinued for disease progression in the brain, peritoneum, lymph node, intestine, and skin in March 2013, after about 20 months from initiation, and the patient died a few weeks later. The clinical case presented here shows that treatment beyond progression with vemurafenib can yield a survival benefit in melanoma patients whose disease progresses in a few sites, which can be treated with locoregional therapies. This clinical strategy needs further validation in prospective clinical trials.

Behavioural characterisation of the alpha-mannosidosis guinea pig.

PubMed

Robinson, A J; Crawley, A C; Auclair, D; Weston, P F; Hirte, C; Hemsley, K M; Hopwood, J J

2008-01-25

alpha-Mannosidosis is a lysosomal storage disorder resulting from a functional deficiency of the lysosomal enzyme alpha-mannosidase. This deficiency results in the accumulation of various oligosaccharides in the lysosomes of affected individuals, causing somatic pathology and progressive neurological degeneration that results in cognitive deficits, ataxia, and other neurological symptoms. We have a naturally occurring guinea pig model of this disease which exhibits a deficiency of lysosomal alpha-mannosidase and has a similar clinical presentation to human alpha-mannosidosis. Various tests were developed in the present study to characterise and quantitate the loss of neurological function in alpha-mannosidosis guinea pigs and to follow closely the progression of the disease. General neurological examinations showed progressive differences in alpha-mannosidosis animals from approximately 1 month of age. Significant differences were observed in hind limb gait width from 2 months of age and significant cognitive (memory and learning) deficits were observed from 3 months of age. Evoked response tests showed an increase in somatosensory P1 peak latency in alpha-mannosidosis guinea pigs from approximately 2 months of age, as well as progressive hearing loss using auditory brainstem evoked responses. The alpha-mannosidosis guinea pig therefore appears to exhibit many of the characteristics of the human disease, and will be useful in evaluating therapies for treatment of central nervous system pathology.

Meniscal Extrusion Progresses Shortly after the Medial Meniscus Posterior Root Tear.

PubMed

Furumatsu, Takayuki; Kodama, Yuya; Kamatsuki, Yusuke; Hino, Tomohito; Okazaki, Yoshiki; Ozaki, Toshifumi

2017-12-01

Medial meniscus posterior root tears (MMPRT) induce medial meniscus extrusion (MME). However, the time-dependent extent of MME in patients suffering from the MMPRT remains unclear. This study evaluated the extent of MME after painful popping events that occurred at the onset of the MMPRT. Thirty-five patients who had an episode of posteromedial painful popping were investigated. All the patients were diagnosed as having an MMPRT by magnetic resonance imaging (MRI) within 12 months after painful popping. Medial meniscus body width (MMBW), absolute MME, and relative MME (100×absolute MME/MMBW) were assessed among three groups divided according to the time after painful popping events: early period (〈1 month), subacute period (1-3 months), and chronic period (4-12 months). In the early period, absolute and relative MMEs were 3.0 mm and 32.7%, respectively. Absolute MME increased up to 4.2 mm and 5.8 mm during the subacute and chronic periods, respectively. Relative MME also progressed to 49.2% and 60.3% in the subacute and chronic periods, respectively. This study demonstrated that absolute and relative MMEs increased progressively within the short period after the onset of symptomatic MMPRT. Our results suggest that early diagnosis of an MMPRT may be important to prevent progression of MME following the MMPRT.

The brown mussel Perna perna (L., 1758) as a sentinel species for chlorinated pesticide and dioxin-like compounds.

PubMed

Galvao, Petrus; Henkelmann, Bernhard; Longo, Renan; Torres, João Paulo Machado; Malm, Olaf; Schramm, Karl-Werner

2015-09-01

To contribute to the use of the tropical brown mussel Perna perna as a sentinel species for organochlorine pesticides (OCP) and polychlorinated biphenyls (PCB), the present study reports data on the toxicokinetics of these compounds in P. perna. Specifically, the authors present data on OCP and PCB bioaccumulation for eight sampling months from three bays (SE Brazil) and two transplant experiments (each 1 month long). Although seasonality is observed in the total lipid content of the whole soft tissue, with summer samples showing higher values, no such seasonality is observed in the OCP and PCB concentrations bioaccumulated by the mussel P. perna. Because no seasonal effect is observed in the annual OCP and PCB concentrations bioaccumulated by P. perna, the use of this species as a sentinel organism to monitor organochlorinated compounds is encouraged. One month of transplantation is not enough to allow the transplanted specimens to reach the concentrations observed in animals reared at the destination site. Nevertheless, P. perna showed a clear tendency to depurate the DDT metabolites p,p'-DDD and p,p'-DDE after 1 month of transplantation.

Implementation of an i.v.-compounding robot in a hospital-based cancer center pharmacy.

PubMed

Yaniv, Angela W; Knoer, Scott J

2013-11-15

The implementation of a robotic device for compounding patient-specific chemotherapy doses is described, including a review of data on the robot's performance over a 13-month period. The automated system prepares individualized i.v. chemotherapy doses in a variety of infusion bags and syringes; more than 50 drugs are validated for use in the machine. The robot is programmed to recognize the physical parameters of syringes and vials and uses photographic identification, barcode identification, and gravimetric measurements to ensure that the correct ingredients are compounded and the final dose is accurate. The implementation timeline, including site preparation, logistics planning, installation, calibration, staff training, development of a pharmacy information system (PIS) interface, and validation by the state board of pharmacy, was about 10 months. In its first 13 months of operation, the robot was used to prepare 7384 medication doses; 85 doses (1.2%) found to be outside the desired accuracy range (±4%) were manually modified by pharmacy staff. Ongoing system monitoring has identified mechanical and materials-related problems including vial-recognition failures (in many instances, these issues were resolved by the system operator and robotic compounding proceeded successfully), interface issues affecting robot-PIS communication, and human errors such as the loading of an incorrect vial or bag into the machine. Through staff training, information technology improvements, and workflow adjustments, the robot's throughput has been steadily improved. An i.v.-compounding robot was successfully implemented in a cancer center pharmacy. The robot performs compounding tasks safely and accurately and has been integrated into the pharmacy's workflow.

Swollen joint count in psoriatic arthritis is associated with progressive radiological damage in hands and feet.

PubMed

Simon, P; Pfoehler, C; Bergner, R; Schreiber, M; Pfreundschuh, M; Assmann, G

2012-01-01

Psoriatic arthritis (PsA) may progress to joint damage. Determining clinical predictors of joint damage assessed by radiography is important. The aim of this study was to determine clinical factors as possible predictors for radiological damage in hands and feet of PsA patients with a 12-month follow-up. We conducted a retrospective study on 53 PsA patients who were taking disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-alpha-blockers at a fixed dosage. The patients were observed in 118 follow-up visits (intervals of 12 months ± 3 months), according to a clinical and radiological protocol which included the documentation of the number of swollen and tender joints in hands and feet, the applied therapy, psoriasis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and global health assessment. Outcome was defined as radiographic damage of hands and feet (Ratingen score). For the statistical analysis the Chi-Square test for 2x2 crosstables (with Fisher's correction, as required) was used. Progressive radiological damage was more frequent among patients with an increasing swollen joint count (8 of 26 visits; 30.8%) than among those with a stable or decreased number of swollen joints (5 of 89 visits; 5.6%; p=0.001). The analysis of the patients stratified into the different treatment modalities resulted in a significant higher rate of radiological progress (20.8%) in patients on DMARD therapy compared with TNF-alpha blocking agents (0%) (p=0.009). During a 12-month follow-up of PsA patients, an increasing number of swollen joints heralds progression of radiological damage. TNF-alpha-blocker therapy appears to be superior to DMARDs in the protection from radiological progress.

Progression of diabetic retinopathy severity after treatment with dexamethasone implant: a 24-month cohort study the 'DR-Pro-DEX Study'.

PubMed

Iglicki, Matias; Zur, Dinah; Busch, Catharina; Okada, Mali; Loewenstein, Anat

2018-06-01

Intravitreal anti-vascular endothelial growth factor agents have been shown to reduce diabetic retinopathy (DR) progression; data on the effects of intravitreal corticosteroids on modifying disease severity are limited. This study evaluates the long-term effect of intravitreal dexamethasone implant (DEX) on the severity and progression of non-proliferative DR (NPDR). This was a retrospective cohort study. Sixty eyes from 60 consecutive patients with NPDR and diabetic macular edema (DME) treated with dexamethasone implant (DEX group) and 49 eyes from consecutive 49 patients without DME requiring observation only. Fundus angiography images from baseline and after 24 months were graded by two masked assessors into mild, moderate and severe NPDR and PDR, according to the ETDRS classification. Patients were followed up 1-3 and 4-6 months after each DEX implant. Re-treatment with DEX implant was on a pro re nata basis. Records were reviewed for performance of panretinal photocoagulation. Main outcome was as follows: change of DR ≥ 1 grade and progression to proliferative diabetic retinopathy (PDR). Three eyes (5%) in the DEX group and 43 (87.8%) eyes in the control group progressed to PDR (P < 0.0001). Twenty-five eyes (41.7%) in the DEX group but none in the control group demonstrated an improvement in DR severity (P < 0.0001). This study provides the first long-term evidence that DEX implant has the potential to not only delay progression of DR and PDR development, but may also improve DR severity over 24 months. Better understanding of the effects of corticosteroids will help guide its use in the treatment pathway of DR.

Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

PubMed

Dudnik, Elizabeth; Siegal, Tali; Zach, Leor; Allen, Aaron M; Flex, Dov; Yust-Katz, Shlomit; Limon, Dror; Hirsch, Fred R; Peled, Nir

2016-04-01

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred. Copyright © 2015 Elsevier Ltd. All rights reserved.

Heterogeneous Catalysis of Polyoxometalate Based Organic–Inorganic Hybrids

PubMed Central

Ren, Yuanhang; Wang, Meiyin; Chen, Xueying; Yue, Bin; He, Heyong

2015-01-01

Organic–inorganic hybrid polyoxometalate (POM) compounds are a subset of materials with unique structures and physical/chemical properties. The combination of metal-organic coordination complexes with classical POMs not only provides a powerful way to gain multifarious new compounds but also affords a new method to modify and functionalize POMs. In parallel with the many reports on the synthesis and structure of new hybrid POM compounds, the application of these compounds for heterogeneous catalysis has also attracted considerable attention. The hybrid POM compounds show noteworthy catalytic performance in acid, oxidation, and even in asymmetric catalytic reactions. This review summarizes the design and synthesis of organic–inorganic hybrid POM compounds and particularly highlights their recent progress in heterogeneous catalysis. PMID:28788017

Decontamination Systems Information and Research Program. Quarterly technical progress report, January 1--March 31, 1994

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

Not Available

1994-05-01

West Virginia University (WVU) and the US DOE Morgantown Energy Technology Center (METC) entered into a Cooperative Agreement on August 29, 1992 entitled ``Decontamination Systems Information and Research Programs.`` Stipulated within the Agreement is the requirement that WVU submit to METC a series of Technical Progress Reports on a quarterly basis. This report comprises the first Quarterly Technical Progress Report for Year 2 of the Agreement. This report reflects the progress and/or efforts performed on the sixteen (16) technical projects encompassed by the Year 2 Agreement for the period of January 1 through March 31, 1994. In situ bioremediation ofmore » chlorinated organic solvents; Microbial enrichment for enhancing in-situ biodegradation of hazardous organic wastes; Treatment of volatile organic compounds (VOCs) using biofilters; Drain-enhanced soil flushing (DESF) for organic contaminants removal; Chemical destruction of chlorinated organic compounds; Remediation of hazardous sites with steam reforming; Soil decontamination with a packed flotation column; Use of granular activated carbon columns for the simultaneous removal of organics, heavy metals, and radionuclides; Monolayer and multilayer self-assembled polyion films for gas-phase chemical sensors; Compact mercuric iodide detector technology development; Evaluation of IR and mass spectrometric techniques for on-site monitoring of volatile organic compounds; A systematic database of the state of hazardous waste clean-up technologies; Dust control methods for insitu nuclear and hazardous waste handling; Winfield Lock and Dam remediation; and Socio-economic assessment of alternative environmental restoration technologies.« less

The role of knee alignment in disease progression and functional decline in knee osteoarthritis.

PubMed

Sharma, L; Song, J; Felson, D T; Cahue, S; Shamiyeh, E; Dunlop, D D

2001-07-11

Knee osteoarthritis (OA) is a leading cause of disability in older persons. Few risk factors for disease progression or functional decline have been identified. Hip-knee-ankle alignment influences load distribution at the knee; varus and valgus alignment increase medial and lateral load, respectively. To test the hypotheses that (1) varus alignment increases risk of medial knee OA progression during the subsequent 18 months, (2) valgus alignment increases risk of subsequent lateral knee OA progression, (3) greater severity of malalignment is associated with greater subsequent loss of joint space, and (4) greater burden of malalignment is associated with greater subsequent decline in physical function. Prospective longitudinal cohort study conducted March 1997 to March 2000 at an academic medical center in Chicago, Ill. A total of 237 persons recruited from the community with primary knee OA, defined by presence of definite tibiofemoral osteophytes and at least some difficulty with knee-requiring activity; 230 (97%) completed the study. Progression of OA, defined as a 1-grade increase in severity of joint space narrowing on semiflexed, fluoroscopically confirmed knee radiographs; change in narrowest joint space width; and change in physical function between baseline and 18 months, compared by knee alignment at baseline. Varus alignment at baseline was associated with a 4-fold increase in the odds of medial progression, adjusting for age, sex, and body mass index (adjusted odds ratio [OR], 4.09; 95% confidence interval [CI], 2.20-7.62). Valgus alignment at baseline was associated with a nearly 5-fold increase in the odds of lateral progression (adjusted OR, 4.89; 95% CI, 2.13-11.20). Severity of varus correlated with greater medial joint space loss during the subsequent 18 months (R = 0.52; 95% CI, 0.40-0.62 in dominant knees), and severity of valgus correlated with greater subsequent lateral joint space loss (R = 0.35; 95% CI, 0.21-0.47 in dominant knees). Having alignment of more than 5 degrees (in either direction) in both knees at baseline was associated with significantly greater functional deterioration during the 18 months than having alignment of 5 degrees or less in both knees, after adjusting for age, sex, body mass index, and pain. This is, to our knowledge, the first demonstration that in primary knee OA varus alignment increases risk of medial OA progression, that valgus alignment increases risk of lateral OA progression, that burden of malalignment predicts decline in physical function, and that these effects can be detected after as little as 18 months of observation.

Chemical stability and in chemico reactivity of 24 fragrance ingredients of concern for skin sensitization risk assessment.

PubMed

Avonto, Cristina; Wang, Mei; Chittiboyina, Amar G; Vukmanovic, Stanislav; Khan, Ikhlas A

2018-02-01

Twenty-four pure fragrance ingredients have been identified as potential concern for skin sensitization. Several of these compounds are chemically unstable and convert into reactive species upon exposure to air or light. In the present work, a systematic investigation of the correlation between chemical stability and reactivity has been undertaken. The compounds were subjected to forced photodegradation for three months and the chemical changes were studied with GC-MS. At the end of the stability study, two-thirds of the samples were found to be unstable. The generation of chemically reactive species was investigated using the in chemico HTS-DCYA assay. Eleven and fourteen compounds were chemically reactive before and after three months, respectively. A significant increase in reactivity upon degradation was found for isoeugenol, linalool, limonene, lyral, citronellol and geraniol; in the same conditions, the reactivity of hydroxycitronellal decreased. The non-reactive compounds α-isomethyl ionone, benzyl alcohol, amyl cinnamal and farnesol became reactive after photo-oxidative degradation. Overall, forced degradation resulted in four non-reactive fragrance compounds to display in chemico thiol reactivity, while ten out of 24 compounds remained inactive. Chemical degradation does not necessarily occur with generation of reactive species. Non-chemical activation may be involved for the 10 stable unreactive compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Concurrent radiotherapy: fotemustine combination for newly diagnosed malignant glioma patients, a phase II study.

PubMed

Beauchesne, Patrick D; Taillandier, L; Bernier, V; Carnin, C

2009-06-01

Fotemustine is a nitrosourea compound used for the treatment of malignant gliomas, especially in France. Recently, an EORTC-NCIC study has shown that a concomitant combination of radiotherapy plus temozolomide (an oral cytotoxic drug) improved survival in glioblastoma patients. We set out to test a concurrent combination of radiotherapy and fotemustine for newly malignant gliomas. A prospective single-center phase II study opened for accrual in September 2004. Patients over 18 years of age able to give informed consent and with histologically proven, newly diagnosed supratentorial malignant gliomas were eligible. All patients were treated by a standard cranial irradiation (conformal irradiation, tumor bulk plus a margin of 2.5 cm) and concomitant daily administration of 10 mg/m(2) of fotemustine (5 days per week, 6 weeks, 1 h 30 min before radiation therapy). Adjuvant chemotherapy, fotemustine, was administered at tumor progression as standard and classic regimen. Twenty-two patients were enrolled, 16 men and 6 women, median age 56 years (range 32-74), median Karnofsky performance status 70 (range 60-90). Histology included 16 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 1 mixed glioma. Eight patients underwent surgery (three total resections). Fourteen patients had a stereotactic biopsy. The concurrent radiotherapy-fotemustine combination was well tolerated: toxicity was mild and three hematologic toxicities grade 3-4 were observed. Median survival from the initial diagnosis was 9.9 months, two patients are currently alive. Median survival was 11 months for surgery and 9 months for stereotactic biopsy. Concomitant radiotherapy-fotemustine combination is safe and well tolerated. Overall survival of over 10 months for the whole population compares favorably with other reports.

Chemopreventive potential of natural compounds in head and neck cancer

PubMed Central

Rahman, Mohammad Aminur; Amin, A.R.M. Ruhul; Shin, Dong M.

2013-01-01

Head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers world-wide. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development, which together underscore the importance of novel strategies for cancer prevention. Cancer chemoprevention, the use of natural or synthetic compounds to prevent, arrest, or reverse the process of carcinogenesis at its earliest stages, aims to reverse premalignancies and prevent second primary tumors. Genomics and proteomics information including initial mutation, cancer promotion, progression and susceptibility has brought molecularly targeted therapies for drug development. The development of preventive approaches using specific natural or synthetic compounds, or both, requires a depth of understanding of the cross-talk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Many natural dietary compounds have been identified as multiple molecular targets, effective in the prevention and treatment of cancer. This review describes recent advances in the understanding of the complex signaling networks driving cancer progression using head and neck cancer as a prototype, and of molecularly targeted natural compounds under preclinical and clinical investigation. PMID:20924973

Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma

PubMed Central

Iwamoto, F M.; Abrey, L E.; Beal, K; Gutin, P H.; Rosenblum, M K.; Reuter, V E.; DeAngelis, L M.; Lassman, A B.

2009-01-01

Background: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. Methods: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease. Results: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. Conclusions: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control. GLOSSARY CA9 = carbonic anhydrase 9; CI = confidence interval; FDG = [18F]fluorodeoxyglucose; FLAIR = fluid-attenuation inversion recovery; GBM = glioblastoma; HIF-1 α = hypoxia-inducible factor 1α; KPS = Karnofsky performance status; MR = magnetic resonance; OS = overall survival; PFS = progression-free survival; TMZ = temozolomide; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor. PMID:19822869

Aberrant expression of copper associated genes after copper accumulation in COMMD1-deficient dogs.

PubMed

Favier, Robert P; Spee, Bart; Fieten, Hille; van den Ingh, Ted S G A M; Schotanus, Baukje A; Brinkhof, Bas; Rothuizen, Jan; Penning, Louis C

2015-01-01

COMMD1-deficient dogs progressively develop copper-induced chronic hepatitis. Since high copper leads to oxidative damage, we measured copper metabolism and oxidative stress related gene products during development of the disease. Five COMMD1-deficient dogs were studied from 6 months of age over a period of five years. Every 6 months blood was analysed and liver biopsies were taken for routine histological evaluation (grading of hepatitis), rubeanic acid copper staining and quantitative copper analysis. Expression of genes involved in copper metabolism (COX17, CCS, ATOX1, MT1A, CP, ATP7A, ATP7B, ) and oxidative stress (SOD1, catalase, GPX1 ) was measured by qPCR. Due to a sudden death of two animals, the remaining three dogs were treated with d-penicillamine from 43 months of age till the end of the study. Presented data for time points 48, 54, and 60 months was descriptive only. A progressive trend from slight to marked hepatitis was observed at histology, which was clearly preceded by an increase in semi-quantitative copper levels starting at 12 months until 42 months of age. During the progression of hepatitis most gene products measured were transiently increased. Most prominent was the rapid increase in the copper binding gene product MT1A mRNA levels. This was followed by a transient increase in ATP7A and ATP7B mRNA levels. In the sequence of events, copper accumulation induced progressive hepatitis followed by a transient increase in gene products associated with intracellular copper trafficking and temporal activation of anti-oxidative stress mechanisms. Copyright © 2014 Elsevier GmbH. All rights reserved.

The Compound Atwood Machine Problem

ERIC Educational Resources Information Center

Coelho, R. Lopes

2017-01-01

The present paper accounts for progress in physics teaching in the sense that a problem, which has been closed to students for being too difficult, is gained for the high school curriculum. This problem is the compound Atwood machine with three bodies. Its introduction into high school classes is based on a recent study on the weighing of an…

The compound Atwood machine problem

NASA Astrophysics Data System (ADS)

Lopes Coelho, R.

2017-05-01

The present paper accounts for progress in physics teaching in the sense that a problem, which has been closed to students for being too difficult, is gained for the high school curriculum. This problem is the compound Atwood machine with three bodies. Its introduction into high school classes is based on a recent study on the weighing of an Atwood machine.

ENGAGE: A Game Based Learning and Problem Solving Framework

DTIC Science & Technology

2012-07-13

Gamification Summit 2012  Mensa Colloquium 2012.2: Social and Video Games  Seattle Science Festival  TED Salon Vancouver : http...From - To) 6/1/2012 – 6/30/2012 4. TITLE AND SUBTITLE ENGAGE: A Game Based Learning and Problem Solving Framework 5a. CONTRACT NUMBER N/A 5b...Popović ENGAGE: A Game Based Learning and Problem Solving Framework (Task 1 Month 4) Progress, Status and Management Report Monthly Progress

EphB1 as a Novel Drug Target to Combat Pain and Addiction

DTIC Science & Technology

2016-09-01

goals? Strong progress has been made since we changed directions. We have developed a very robust AlphaScreen chemiluminescent assay that probes the...hit compounds, 22, that reduced the chemiluminescent signal >10% at a concentration of 5 uM compound, with 6 of these compounds reducing over 25% (and...we have developed a very robust chemiluminescent Alpha assay that allows us to measure with a high degree of well- to-well consistency in 384 well

New Horizons in C-F Activation by Main Group Electrophiles

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

Ozerov, Oleg V.

2016-02-13

This technical report describes progress on the DOE sponsored project "New Horizons in C-F Activation by Main Group Electrophiles" during the period of 09/15/2010 – 08/31/2015. The main goal of this project was to develop improved catalysts for conversion of carbon-fluorine bonds in potentially harmful compounds. The approach involved combining of a highly reactive positively charged main-group compound with a highly unreactive negatively charged species (anions) as a way to access potent catalysts for carbon-fluorine bond activation. This report details progress made in improving synthetic pathways to a variety of new anions with improved properties and analysis of their potentialmore » in catalysis.« less

76 FR 25519 - National Foster Care Month, 2011

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-05

... Foster Care Month, 2011 By the President of the United States A Proclamation Progress in America can be... where they can feel secure and thrive. During National Foster Care Month, we renew our commitment to... possible for children when they cannot remain in their own homes. During National Foster Care Month, we...

Early MRI Detection and Closed Bone Graft Epiphysiodesis May Alter the Course of Avascular Necrosis Following Unstable Slipped Capital Femoral Epiphysis.

PubMed

Napora, Joshua K; Gilmore, Allison; Son-Hing, Jochen P; Grimberg, Dominic C; Thompson, George H; Liu, Raymond W

2018-04-01

Unstable slipped capital femoral epiphysis (SCFE) has an increased incidence of avascular necrosis (AVN). Early identification and surgical intervention for AVN may help preserve the femoral head. We retrospectively reviewed 48 patients (50 hips) with unstable SCFE managed between 2000 and 2014. AVN was diagnosed based on 2 different postoperative protocols. Seventeen patients (17 hips) had a scheduled magnetic resonance imaging (MRI) between 1 and 6 months from initial surgery, and the remaining 31 patients (33 hips) were evaluated by plain radiographs alone. If AVN was diagnosed, we offered core decompression and closed bone graft epiphysiodesis (CBGE) to mitigate its affects. At final follow-up, we assessed progression of AVN using the Steinberg classification. Overall 13 hips (26%) with unstable SCFEs developed AVN. MRI revealed AVN in 7 of 17 hips (41%) at a mean of 2.5 months postoperatively (range, 1.0 to 5.2 mo). Six hips diagnosed by MRI received surgical intervention (4 CBGE, 1 free vascularized fibula graft, and 1 repinning due to screw cutout) at a mean of 4.1 months (range, 1.3 to 7.2 mo) postoperatively. None of the 4 patients treated with CBGE within 2 months postoperatively progressed to stage IVC AVN. The 2 patients treated after 4 months postoperatively both progressed to stage VC AVN.Plain radiographs demonstrated AVN in 6 of 33 hips (18%) at a mean of 6.8 months postoperatively (range, 2.1 to 21.1 mo). One patient diagnosed with stage IVB AVN at 2.4 months had screw cutout and received CBGE at 2.5 months from initial pinning. The remaining 5 were not offered surgical intervention. Five of the 6 radiographically diagnosed AVN, including the 1 treated with CBGE, progressed to stage IVC AVN or greater. Although all patients with positive MRI scans developed radiographic AVN, none of the 4 patients treated with CBGE within 2 months after pinning developed grade IVC or greater AVN. Early MRI detection and CBGE may mitigate the effects of AVN after SCFE. Level III-retrospective comparative study.

NI-60RECURRENT PATTERNS OF BEVACIZUMAB MONOTHERAPY FOR RECURRENT PRIMARY GLIOBLASTOMA AND PERSPECTIVES ON BEVACIZUMAB-BASED THERAPIES

PubMed Central

Nagane, Motoo; Kobayashi, Keiichi; Saito, Kuniaki; Shiokawa, Yoshiaki

2014-01-01

BACKGROUND. Prognosis of patients with recurrent glioblastoma (GBM) remains dismal, their median overall survival (mOS) ranging from 7 to 10 months. Currently, bevacizumab (BEV), a monoclonal antibody against VEGF, has been widely used since it prolonged progression-free survival (PFS) accompanied with symptom relief in BEV trials. However, improvement of OS seems modest at most, and issues regarding short survival after BEV failure, invasive relapse, and difficulty in determining true progression remain unsolved. Here we examined the patterns of radiological BEV failure in relationship with survival of several post-treatment periods. METHODS. Twenty-five patients with primary GBM who were treated with BEV monotherapy at recurrence in Kyorin University hospital since August 2009 were included in this study. Mean age was 53 yo, 13 males/12 females, median KPS was 60 (30-100), and mOS from the initial surgery was 23.2 months. MRI patterns at BEV progression were determined using modified classification by Nowosielsky et al. (Neurology 2014) as follows: 1) T2-diffuse, 2) cT1-flare up, 3) Primary non-responders, 4) T2-circumscribed, and 5) Remote metastasis. RESULTS. mPFS and mOS of BEV monotherapy were 3.4 and 7.6 months, respectively, and post-BEV mOS was 4.7 months. Frequency and BEV-PFS/post-BEV OS were 1) 20%, 3.8/0.8 months; 2) 40%, 3.4/7.1 months, 3) 24%, 0.9/3.3 months, 4) 8%, 3.7/3.9 months, 5) 8%, 2.0/4.2 months. The cT1-flare up recurrent pattern was found most frequently with relatively better survivals, whereas the T2-diffuse recurrence included fatal brain stem invasion in two cases, resulting in poorer prognosis. CONCLUSIONS. BEV monotherapy showed limited survival benefit and the clinical course after BEV failure may differ by patterns of relapse. Although RANO criteria have been a standard method to determine progression, measurement of T2/FLAIR hyperintensity remains critically controversial. Efforts to improve BEV-based therapy for recurrent GBM including longitudinal and combined chemotherapy will be also discussed.

5 CFR 841.606 - Interest on survivor reduction deposits.

Code of Federal Regulations, 2010 CFR

2010-01-01

... balance will be compounded annually and accrued monthly. The additional interest due each month equals the remaining balance due times the difference between— (1) One and six tenths raised to the 1/12 power; and (2... of the monthly difference times the difference between— (1) One and six tenths raised to the power...

Haloanisole and halophenol contamination in Spanish aged red wines.

PubMed

Copete, M L; Zalacain, A; Lorenzo, C; Carot, J M; Esteve, M D; Climent, M; Salinas, M R

2009-01-01

This is the first study to be carried out on the incidence of halophenols and haloanisoles, including trichloroanisole, in aged red wines. A total of 966 red wines, aged for 6, 12 and 24 months in oak barrels and from different Spanish production areas, were analysed by stir bar sorptive extraction followed by gas chromatography/mass spectrometry (GC/MS). From the wines sampled, 155 (16.1%) were contaminated with one or several compounds, with 7.6, 6.9 and 1.5% corresponding to the 12- (aged-12), 6- (aged-6) and 24-month-aged (aged-24) wines, respectively. The most abundant compounds causing taint were 2,3,4,6-tetrachloroanisole and 2,4,6-trichloroanisol (6.8 and 5.3%, respectively). No 2,4,6-tribromophenol was found in any of the samples. Contamination with halo compounds was highest in samples from South-West Spain, followed by those from Northern Spain. The mean concentration for all compounds were always higher than their respective olfactory threshold, but none of these halo compounds represent a health hazard to humans through the consumption of commercial red aged wines.

Vitamin D levels are associated with gross motor function in amyotrophic lateral sclerosis.

PubMed

Paganoni, Sabrina; Macklin, Eric A; Karam, Chafic; Yu, Hong; Gonterman, Fernando; Fetterman, K Ashley; Cudkowicz, Merit; Berry, James; Wills, Anne-Marie

2017-10-01

The objective of this study was to determine whether serum vitamin D [25(OH)D] levels are associated with disease progression in amyotrophic lateral sclerosis (ALS). 25(OH)D was measured in subjects enrolled in a multicenter study for validation of ALS biomarkers. Baseline 25(OH)D levels were correlated with baseline ALSFRS-R scores. Average 25(OH)D levels from baseline and month 6 visits (seasonally asynchronous) were used to predict subsequent rate of change in ALSFRS-R from month 6 to month 18. Most subjects had either insufficient or deficient 25(OH)D levels. Lower 25(OH)D was associated with lower ALSFRS-R gross motor scores, but not lower ALSFRS-R total scores at baseline. Levels of 25(OH)D were not predictive of disease progression over the next 12 months. 25(OH)D was associated with baseline gross motor ALSFRS-R scores but did not predict the rate of disease progression. Vitamin D levels may reflect poor mobility in patients with ALS. Muscle Nerve, 2017 Muscle Nerve 56: 726-731, 2017. © 2017 Wiley Periodicals, Inc.

Thoracic 9 Spinal Transection-Induced Model of Muscle Spasticity in the Rat: A Systematic Electrophysiological and Histopathological Characterization

PubMed Central

Corleto, Jose A.; Bravo-Hernández, Mariana; Kamizato, Kota; Kakinohana, Osamu; Santucci, Camila; Navarro, Michael R.; Platoshyn, Oleksandr; Cizkova, Dasa; Lukacova, Nadezda; Taylor, Julian; Marsala, Martin

2015-01-01

The development of spinal hyper-reflexia as part of the spasticity syndrome represents one of the major complications associated with chronic spinal traumatic injury (SCI). The primary mechanism leading to progressive appearance of muscle spasticity is multimodal and may include loss of descending inhibitory tone, alteration of segmental interneuron-mediated inhibition and/or increased reflex activity to sensory input. Here, we characterized a chronic thoracic (Th 9) complete transection model of muscle spasticity in Sprague-Dawley (SD) rats. Isoflurane-anesthetized rats received a Th9 laminectomy and the spinal cord was transected using a scalpel blade. After the transection the presence of muscle spasticity quantified as stretch and cutaneous hyper-reflexia was identified and quantified as time-dependent changes in: i) ankle-rotation-evoked peripheral muscle resistance (PMR) and corresponding electromyography (EMG) activity, ii) Hoffmann reflex, and iii) EMG responses in gastrocnemius muscle after paw tactile stimulation for up to 8 months after injury. To validate the clinical relevance of this model, the treatment potency after systemic treatment with the clinically established anti-spastic agents baclofen (GABAB receptor agonist), tizanidine (α2-adrenergic agonist) and NGX424 (AMPA receptor antagonist) was also tested. During the first 3 months post spinal transection, a progressive increase in ankle rotation-evoked muscle resistance, Hoffmann reflex amplitude and increased EMG responses to peripherally applied tactile stimuli were consistently measured. These changes, indicative of the spasticity syndrome, then remained relatively stable for up to 8 months post injury. Systemic treatment with baclofen, tizanidine and NGX424 led to a significant but transient suppression of spinal hyper-reflexia. These data demonstrate that a chronic Th9 spinal transection model in adult SD rat represents a reliable experimental platform to be used in studying the pathophysiology of chronic spinal injury-induced spasticity. In addition a consistent anti-spastic effect measured after treatment with clinically effective anti-spastic agents indicate that this model can effectively be used in screening new anti-spasticity compounds or procedures aimed at modulating chronic spinal trauma-associated muscle spasticity. PMID:26713446

An Evaluation of Formic Acid as an Electron Donor for Palladium (PD) Catalyzed Destruction of Nitroaromatic Compounds

DTIC Science & Technology

2004-03-23

the first half of the 20th century. From WWI and WWII TNT production in Germany alone grew from 3,000 tons to over 20,000 tons per month (Urbanski...effluent. Kratz (1949) reported that in Germany , for production of 4,000 tons of TNT a month, 5,000 – 6,000 m3 of “red water” was generated daily (Urbanski...Dillert et al. (1995) report that in Germany several places are known where the water supply is endangered by nitroaromatic compounds. Recent surveys of

Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice

PubMed Central

Rogers, Justin T.; Liu, Chia-Chen; Zhao, Na; Wang, Jian; Putzke, Travis; Yang, Longyu; Shinohara, Mitsuru; Fryer, John D.; Kanekiyo, Takahisa; Bu, Guojun

2017-01-01

Aging is accompanied by increased neuroinflammation, synaptic dysfunction and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months) and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, GFAP, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation (LTP) was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation, and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging. PMID:28254590

24 CFR 968.230 - Progress reports.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Progress reports. 968.230 Section 968.230 Housing and Urban Development Regulations Relating to Housing and Urban Development (Continued... Fewer Than 250 Units) § 968.230 Progress reports. For each six-month period ending March 31 and...

40 CFR 35.1650-6 - Reports.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Reports. (a) States with Phase 1 projects shall submit semi-annual progress reports (original and one copy... in the next six months. (b) Phase 2. States with Phase 2 projects shall submit progress reports... Phase 2 project progress reports shall be determined by the size and complexity of the project, and...

40 CFR 35.1650-6 - Reports.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Reports. (a) States with Phase 1 projects shall submit semi-annual progress reports (original and one copy... in the next six months. (b) Phase 2. States with Phase 2 projects shall submit progress reports... Phase 2 project progress reports shall be determined by the size and complexity of the project, and...

Progression into Engineering. Building Bridges between Education, Training and Employment.

ERIC Educational Resources Information Center

Evans, Karen; And Others

This publication reports findings of a 12-month study of progression opportunities in engineering education and training, a study which explored ways of bridging the gap between skills and knowledge acquired through basic training and prevocational education and those required for progression to higher levels of occupational training and…

Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy.

PubMed

Krishnan, Sunil; Rana, Vishal; Janjan, Nora A; Varadhachary, Gauri R; Abbruzzese, James L; Das, Prajnan; Delclos, Marc E; Gould, Morris S; Evans, Douglas B; Wolff, Robert A; Crane, Christopher H

2007-07-01

The current study was conducted to determine whether there were differences in outcome for patients with unresectable locally advanced pancreatic cancer (LAPC) who received treatment with chemoradiation therapy (CR) versus induction chemotherapy followed by CR (CCR). Between December 1993 and July 2005, 323 consecutive patients with LAPC were treated at the authors' institution with radiotherapy and concurrent gemcitabine or fluoropyrimidine chemotherapy. Two hundred forty-seven patients received CR as initial treatment, and 76 patients received a median of 2.5 months of gemcitabine-based induction chemotherapy prior to CR. Most patients received a radiation dose of 30 grays in 10 fractions (85%) concurrently with infusional 5-fluorouracil (41%), gemcitabine (39%), or capecitabine (20%). The median follow-up was 5.5 months (range, 1-63 months). For all patients, the median overall survival (OS) and progression-free survival (PFS) were 9 months and 5 months, respectively, and the 2-year estimated OS and PFS rates were 9% and 5%, respectively. The median OS and PFS were 8.5 months and 4.2 months, respectively, in the CR group and 11.9 months and 6.4 months, respectively, in the CCR group (both P < .001). The median times to local and distant progression were 6.0 months and 5.6 months, respectively, in the CR group and 8.9 and 9.5 months, respectively, in the CCR group (P = .003 and P = .007, respectively). There was no significant difference in the patterns of failure with the use of induction chemotherapy. The results from this analysis indicated that, by excluding patients with rapid distant progression, induction chemotherapy may select patients with LAPC for optimal benefit from consolidative CR. The authors believe that this strategy of enriching the population of patients who receive a locoregional treatment modality merits prospective randomized evaluation. Copyright (c) 2007 American Cancer Society.

The impact of pre-intervention rate of kidney function change on the assessment of CKD progression.

PubMed

Fassett, Robert G; Geraghty, Dominic P; Coombes, Jeff S

2014-10-01

Without a run-in phase, chronic kidney disease (CKD) patients enrolled in clinical trials may not be identified as having progressive disease. The aim of this analysis was to quantify the effects of a run-in phase on kidney function outcome in CKD patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial. The LORD trial assessed the effects of atorvastatin on the rate of change in the estimated glomerular filtration rate (eGFR) and included patients with serum creatinine 120 μmol/l. In this post hoc analysis, we assessed eGFR change during the 12-month period prior to enrolment, the 3-month run-in phase and the first 12-month period of the trial. Eighty of the original 132 patients (where retrospective data were available) were included. The rate of eGFR change during each period was compared. Overall kidney function decreased during the 12 months prior to enrolment by (mean, SD) 0.39 ± 0.98 ml/min/1.73 m(2)/month, improved during the 3-month run-in phase by 0.48 ± 2.90 ml/min/1.73 m(2)/month and decreased during the first 12 months of the trial by 0.15 ± 0.57 ml/min/1.73 m(2)/month. However, only 39 % of patients had declining eGFR during the 12 months prior, 19 % in the 3-month run-in and 42 % during the first 12-month study phase. Most patients (>60 %) entering this clinical trial had stable or improving kidney function. Enrolment was associated with further improved kidney function, which may have been due to 'regression to the mean' or to the Hawthorne effect. Investigators should include a run-in period to establish the presence of eGFR decline to use as an inclusion criterion in clinical trials assessing this measure of CKD progression.

Plasma D-dimer as a predictor of the progression of abdominal aortic aneurysm.

PubMed

Vele, E; Kurtcehajic, A; Zerem, E; Maskovic, J; Alibegovic, E; Hujdurovic, A

2016-11-01

Essentials D-dimer could provide important information about abdominal aortic aneurysm (AAA) progression. The greatest diameter of the infrarenal aorta and the value of plasma D-dimer were determined. AAA progression is correlated with increasing plasma D-dimer levels. The increasing value of plasma D-dimer could be a predictor of aneurysm progression. Background The natural course of abdominal aortic aneurysm (AAA) is mostly asymptomatic and unpredictable. D-dimer could provide potentially important information about subsequent AAA progression. Objectives The aims of this study were to establish the relationship between the progression of an abdominal aortic aneurysm (AAA) and plasma D-dimer concentration over a 12-month period and determine the value of plasma D-dimer in patients with sub-aneurysmal aortic dilatation. Patients/Methods This was a prospective observational study that involved 33 patients with an AAA, 30 patients with sub-aneurysmal aortic dilatation and 30 control subjects. The greatest diameter of the infrarenal aorta, which was assessed by ultrasound, and the value of plasma D-dimer were determined for all subjects at baseline assessment, as well as after 12 months for those with an AAA. Results A positive correlation was found between the diameter of an AAA and plasma D-dimer concentration at the baseline and the control measurement stages. There was a strong positive correlation between AAA progression and increasing plasma D-dimer concentration over a 12-month period. Among patients with sub-aneurysmal aortic dilatation (n = 30), the value of plasma D-dimer was higher compared with matched controls (n = 30). Conclusions There is a strongly positive correlation between AAA progression and increasing plasma D-dimer concentration. The value of plasma D-dimer is higher in patients with sub-aneurysmal aortic dilatation than in control subjects. © 2016 International Society on Thrombosis and Haemostasis.

Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein.

PubMed

Fleming, Sheila M; Salcedo, Jonathan; Fernagut, Pierre-Olivier; Rockenstein, Edward; Masliah, Eliezer; Levine, Michael S; Chesselet, Marie-Françoise

2004-10-20

Accumulation of alpha-synuclein in brain is a hallmark of synucleinopathies, neurodegenerative diseases that include Parkinson's disease. Mice overexpressing alpha-synuclein under the Thy-1 promoter (ASO) show abnormal accumulation of alpha-synuclein in cortical and subcortical regions of the brain, including the substantia nigra. We examined the motor deficits in ASO mice with a battery of sensorimotor tests that are sensitive to alterations in the nigrostriatal dopaminergic system. Male wild-type and ASO mice were tested every 2 months for 8 months for motor performance and coordination on a challenging beam, inverted grid, and pole, sensorimotor deficits in an adhesive removal test, spontaneous activity in a cylinder, and gait. Fine motor skills were assessed by the ability to grasp cotton from a bin. ASO mice displayed significant impairments in motor performance and coordination and a reduction in spontaneous activity as early as 2 months of age. Motor performance and coordination impairments became progressively worse with age and sensorimotor deficits appeared at 6 months. Fine motor skills were altered at 4 months and worsened at 8 months. These data indicate that overexpression of alpha-synuclein induced an early and progressive behavioral phenotype that can be detected in multiple tests of sensorimotor function. These behavioral deficits provide a useful way to assess novel drug therapy in genetic models of synucleinopathies.

Carbon ion radiotherapy performed as re-irradiation using active beam delivery in patients with tumors of the brain, skull base and sacral region.

PubMed

Combs, Stephanie E; Kalbe, Adriana; Nikoghosyan, Anna; Ackermann, Benjamin; Jäkel, Oliver; Haberer, Thomas; Debus, Jürgen

2011-01-01

To asses carbon ion radiation therapy (RT) performed as re-irradiation in 28 patients with recurrent tumors. Twenty-eight patients were treated with carbon ion RT as re-irradiation for recurrent chordoma and chondrosarcoma of the skull base (n=16 and n=2), one chordoma and one chondrosarcoma of the os sacrum, high-risk meningioma (n=3), adenoid-cystic carcinoma (n=4) as well as one SCCHN. All patients were treated using active raster scanning, and treatment planning was performed on CT- and MRI-basis. All patients were followed prospectively during follow-up. In all patients re-irradiation could be applied safely without interruptions. For skull base tumors, local tumor control after re-irradiation was 92% at 24 months and 64% at 36 months. Survival after re-irradiation was 86% at 24 months, and 43% at 60 months. In all three meningiomas treated with C12 for re-irradiation, the tumor recurrence was located within the former RT-field. Two patients developed tumor progression at 6 months, and in one patient the tumor remained stable for 67 months. In patients with head-and-neck tumors, three patients developed local tumor progression at 12, 24 and 29 months after re-irradiation. Median local progression-free survival was 24 months. For sacral tumors, re-irradiation offered palliation with tumor control for 24 and 36 months. Due to the physical characteristics particle therapy offers a new treatment modality in cases with tumor recurrences. With carbon ions, the additional biological benefits may be exploited for long-term tumor control. Further evaluation in a larger patients' cohort will be performed in the future. Copyright © 2010. Published by Elsevier Ireland Ltd.

{sup 18}F-Fluorodeoxyglucose/Positron Emission Tomography Predicts Patterns of Failure After Definitive Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer

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

Ohri, Nitin, E-mail: ohri.nitin@gmail.com; Bodner, William R.; Halmos, Balazs

Background: We previously reported that pretreatment positron emission tomography (PET) identifies lesions at high risk for progression after concurrent chemoradiation therapy (CRT) for locally advanced non-small cell lung cancer (NSCLC). Here we validate those findings and generate tumor control probability (TCP) models. Methods: We identified patients treated with definitive, concurrent CRT for locally advanced NSCLC who underwent staging {sup 18}F-fluorodeoxyglucose/PET/computed tomography. Visible hypermetabolic lesions (primary tumors and lymph nodes) were delineated on each patient's pretreatment PET scan. Posttreatment imaging was reviewed to identify locations of disease progression. Competing risks analyses were performed to examine metabolic tumor volume (MTV) and radiation therapymore » dose as predictors of local disease progression. TCP modeling was performed to describe the likelihood of local disease control as a function of lesion size. Results: Eighty-nine patients with 259 hypermetabolic lesions (83 primary tumors and 176 regional lymph nodes) met the inclusion criteria. Twenty-eight patients were included in our previous report, and the remaining 61 constituted our validation cohort. The median follow-up time was 22.7 months for living patients. In 20 patients, the first site of progression was a primary tumor or lymph node treated with radiation therapy. The median time to progression for those patients was 11.5 months. Data from our validation cohort confirmed that lesion MTV predicts local progression, with a 30-month cumulative incidence rate of 23% for lesions above 25 cc compared with 4% for lesions below 25 cc (P=.008). We found no evidence that radiation therapy dose was associated with local progression risk. TCP modeling yielded predicted 30-month local control rates of 98% for a 1-cc lesion, 94% for a 10-cc lesion, and 74% for a 50-cc lesion. Conclusion: Pretreatment FDG-PET identifies lesions at risk for progression after CRT for locally advanced NSCLC. Strategies to improve local control should be tested on high-risk lesions, and treatment deintensification for low-risk lesions should be explored.« less

Pathological characteristics of spine metastases treated with high-dose single-fraction stereotactic radiosurgery.

PubMed

Katsoulakis, Evangelia; Laufer, Ilya; Bilsky, Mark; Agaram, Narasimhan P; Lovelock, Michael; Yamada, Yoshiya

2017-01-01

OBJECTIVE Spine radiosurgery is increasingly being used to treat spinal metastases. As patients are living longer because of the increasing efficacy of systemic agents, appropriate follow-up and posttreatment management for these patients is critical. Tumor progression after spine radiosurgery is rare; however, vertebral compression fractures are recognized as a more common posttreatment effect. The use of radiographic imaging alone posttreatment may makeit difficult to distinguish tumor progression from postradiation changes such as fibrosis. This is the largest series from a prospective database in which the authors examine histopathology of samples obtained from patients who underwent surgical intervention for presumed tumor progression or mechanical pain secondary to compression fracture. The majority of patients had tumor ablation and resulting fibrosis rather than tumor progression. The aim of this study was to evaluate tumor histopathology and characteristics of patients who underwent pathological sampling because of radiographic tumor progression, fibrosis, or collapsed vertebrae after receiving high-dose single-fraction stereotactic radiosurgery. METHODS Between January 2005 and January 2014, a total of 582 patients were treated with linear accelerator-based single-fraction (18-24 Gy) stereotactic radiosurgery. The authors retrospectively identified 30 patients (5.1%) who underwent surgical intervention for 32 lesions with vertebral cement augmentation for either mechanical pain or instability secondary to vertebral compression fracture (n = 17) or instrumentation (n = 15) for radiographic tumor progression. Radiation and surgical treatment, histopathology, and long-term outcomes were reviewed. Survival and time to recurrence were calculated using the Kaplan-Meier method. RESULTS The mean age at the time of radiosurgery was 59 years (range 36-80 years). The initial pathological diagnoses were obtained for all patients and primarily included radioresistant tumor types, including renal cell carcinoma in 7 (22%), melanoma in 6 (19%), lung carcinoma in 4 (12%), and sarcoma in 3 (9%). The median time to surgical intervention was 24.7 months (range 1.6-50.8 months). The median follow-up and overall survival for all patients were 42.5 months and 41 months (overall survival range 7-86 months), respectively. The majority of assessed lesions showed no evidence of tumor on pathological review (25 of 32, 78%), while a minority of lesions revealed residual tumor (7 of 32, 22%). The median survival for patients after tumor recurrence was 5 months (range 2-70 months). CONCLUSIONS High-dose single-fraction radiosurgery is tumor ablative in the majority of instances. In a minority of cases, tumor persists and salvage treatments should be considered.

Pathological characteristics of spine metastases treated with high-dose single-fraction stereotactic radiosurgery

PubMed Central

Katsoulakis, Evangelia; Laufer, Ilya; Bilsky, Mark; Agaram, Narasimhan P.; Lovelock, Michael; Yamada, Yoshiya

2017-01-01

OBJECTIVE Spine radiosurgery is increasingly being used to treat spinal metastases. As patients are living longer because of the increasing efficacy of systemic agents, appropriate follow-up and posttreatment management for these patients is critical. Tumor progression after spine radiosurgery is rare; however, vertebral compression fractures are recognized as a more common posttreatment effect. The use of radiographic imaging alone posttreatment may make it difficult to distinguish tumor progression from postradiation changes such as fibrosis. This is the largest series from a prospective database in which the authors examine histopathology of samples obtained from patients who underwent surgical intervention for presumed tumor progression or mechanical pain secondary to compression fracture. The majority of patients had tumor ablation and resulting fibrosis rather than tumor progression. The aim of this study was to evaluate tumor histopathology and characteristics of patients who underwent pathological sampling because of radiographic tumor progression, fibrosis, or collapsed vertebrae after receiving high-dose single-fraction stereotactic radiosurgery. METHODS Between January 2005 and January 2014, a total of 582 patients were treated with linear accelerator–based single-fraction (18–24 Gy) stereotactic radiosurgery. The authors retrospectively identified 30 patients (5.1%) who underwent surgical intervention for 32 lesions with vertebral cement augmentation for either mechanical pain or instability secondary to vertebral compression fracture (n = 17) or instrumentation (n = 15) for radiographic tumor progression. Radiation and surgical treatment, histopathology, and long-term outcomes were reviewed. Survival and time to recurrence were calculated using the Kaplan-Meier method. RESULTS The mean age at the time of radiosurgery was 59 years (range 36–80 years). The initial pathological diagnoses were obtained for all patients and primarily included radioresistant tumor types, including renal cell carcinoma in 7 (22%), melanoma in 6 (19%), lung carcinoma in 4 (12%), and sarcoma in 3 (9%). The median time to surgical intervention was 24.7 months (range 1.6–50.8 months). The median follow-up and overall survival for all patients were 42.5 months and 41 months (overall survival range 7–86 months), respectively. The majority of assessed lesions showed no evidence of tumor on pathological review (25 of 32, 78%), while a minority of lesions revealed residual tumor (7 of 32, 22%). The median survival for patients after tumor recurrence was 5 months (range 2–70 months). CONCLUSIONS High-dose single-fraction radiosurgery is tumor ablative in the majority of instances. In a minority of cases, tumor persists and salvage treatments should be considered. PMID:28041326

Reliability of chronic allograft nephropathy diagnosis in sequential protocol biopsies.

PubMed

Serón, Daniel; Moreso, Francesc; Fulladosa, Xavier; Hueso, Miguel; Carrera, Marta; Grinyó, Josep M

2002-02-01

Chronic allograft nephropathy (CAN) progresses rapidly during the first few months and slowly thereafter. Although the presence of CAN in protocol renal biopsies is a predictor of outcome, the reliability of this diagnosis according to Banff criteria has not been characterized. Renal lesions were evaluated according to the Banff criteria in sequential protocol biopsies performed at 4 and 14 months in 310 biopsies obtained from 155 patients. CAN progressed from 40 to 53% (P=0.001) while serum creatinine remained stable (146 +/- 44 vs. 147 +/- 48 micromol/L, P=NS). Graft survival in patients with and without CAN in the first biopsy was 74 versus 91% (P < 0.05), and in the second biopsy 75 versus 94% (P < 0.05). In 54 patients (35%) no CAN was present in both biopsies, 39 (25%) showed progression to CAN, 19 (12%) showed regression of CAN, and 43 (28%) showed CAN in both biopsies. Graft survival was: 100%, 81.6%, 82.6% and 69.4%, respectively (P < 0.01). Assuming that CAN does not regress and sampling error is normally distributed, we estimated that 25% of biopsies cannot be properly classified. The increase in the incidence of CAN between the 4th and 14th month is lower than the proportion of misclassified biopsies. Thus, monitoring the progression of CAN by means of two sequential biopsies at 4 and 14 months is inaccurate. We suggest that progression of scarring be monitored by means of a donor and a protocol biopsy performed during the first year evaluated with a quantitative approach.

Recent Progress in the Study of Inorganic Nanotubes and Fullerene-Like Structures

NASA Astrophysics Data System (ADS)

Tenne, R.; Seifert, G.

2009-08-01

The synthesis of WS2 inorganic nanotubes (INT) and inorganic fullerene-like (IF) structures in 1992 signified the opening of a fertile and challenging field of scientific endeavor. These structures were the first of a long and ever-expanding series of INT and IF structures. Although initially much of the effort concentrated on the synthesis of INT and IF from compounds with layered structures, recently there has been a surge of efforts to synthesize crystalline and polycrystalline nanotubular structures from compounds with quasi-isotropic structures, like spinels, BaTiO3, SiO2, TiO2, and many others. The present review summarizes some of the progress in this field in recent years. Much of the progress in this field was achieved through strong interaction between theoretical and experimental work. This article has four themes: (a) new synthetic approaches leading to new kinds of IF and INT; (b) study of the molecular structure of such nanoparticles with new tools, such as aberration-corrected transmission electron microscopy (TEM) and high-angle annular dark field (HAADF); (c) recent progress in the investigation of the properties of such nanostructures; and (d) examples of applications for which clear progress has been accomplished, in particular in solid lubrication and high-strength nanocomposites.

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors

PubMed Central

Hobday, Timothy J.; Qin, Rui; Reidy-Lagunes, Diane; Moore, Malcolm J.; Strosberg, Jonathan; Kaubisch, Andreas; Shah, Manisha; Kindler, Hedy Lee; Lenz, Heinz-Josef; Chen, Helen; Erlichman, Charles

2015-01-01

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted. PMID:25488966

Crack-cocaine use accelerates HIV disease progression in a cohort of HIV-positive drug users.

PubMed

Baum, Marianna K; Rafie, Carlin; Lai, Shenghan; Sales, Sabrina; Page, Bryan; Campa, Adriana

2009-01-01

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. We evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to

Continued EGFR-TKI with concurrent radiotherapy to improve time to progression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment.

PubMed

Wang, Y; Li, Y; Xia, L; Niu, K; Chen, X; Lu, D; Kong, R; Chen, Z; Sun, J

2018-03-01

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.

A phase 2 study of vatalanib in metastatic melanoma patients.

PubMed

Cook, Natalie; Basu, Bristi; Biswas, Swethajit; Kareclas, Paula; Mann, Colette; Palmer, Cheryl; Thomas, Anne; Nicholson, Steve; Morgan, Bruno; Lomas, David; Sirohi, Bhawna; Mander, Adrian P; Middleton, Mark; Corrie, Pippa G

2010-10-01

A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma. Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0-2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming's single stage design. Tumour control rate (CR+PR+SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8-3.7 months) and median overall survival was 6.5 months (95% CI 3.9-10.2 months). Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing. Copyright © 2010 Elsevier Ltd. All rights reserved.

Menogaril in the treatment of relapsed multiple myeloma. A phase II trial of the Cancer Center of Wake Forest University.

PubMed

Cruz, J M; Case, L D; Dalton, H B; Ramseur, W L; Richards, F; Jackson, D V; Muss, H B; Zekan, P J; Brodkin, R A; Brown, R C

1992-04-01

Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m2 intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.

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

Janssens, Geert O.R.J.; Gidding, Corrie E.M.; Lindert, Erik J. van

Purpose: Most children with a diffuse intrinsic brainstem glioma will die within 1 year after diagnosis. To reduce patient burden, we investigated the feasibility of a radical hypofractionation radiotherapy schedule, given over 3 weeks, as an alternative to the standard regimen (30 fractions over 6 weeks). Methods and Materials: Nine children, ages 3-13, were treated by 13 fractions of 3 Gy (n = 8) or 6 fractions of 5.5 Gy (n = 1) given over 3 weeks. All patients had symptoms for {<=}3 months and {>=}2 signs of the neurologic triad (long tract signs, ataxia, cranial nerve deficit). Bilateral involvementmore » of the pons (n = 8), encasement of the basilar artery (n = 7) and extension into the cerebellar peduncle (n = 6) was visible on magnetic resonance imaging. Results: Symptom improvement occurred in all patients within 2 weeks after start of radiotherapy. At a mean follow-up time of 15 months, 7 patients have died. Median time to progression and overall survival was 4.9 and 8.6 months, respectively. Median time to death after progression was 3.6 months. No Grade 3 or 4 toxicity was observed. In a recently published review of clinical trials, median time to progression, overall survival, and time between progression and death ranged from 5.0-8.8, 7.0-16, and 1.0-4.5 months, respectively, with more aggressive regimens. Conclusion: This radical hypofractionation radiotherapy regimen for children with diffuse intrinsic brainstem glioma is feasible and associated with no Grade 3 or 4 toxicities. With a minimal overall treatment time, it offers quick symptom relief and outcome results within the range of published data.« less

Glioblastoma Recurrence Patterns After Radiation Therapy With Regard to the Subventricular Zone

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

Adeberg, Sebastian, E-mail: Sebastian.adeberg@med.uni-heidelberg; König, Laila; Bostel, Tilman

Purpose: We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). Methods and Materials: 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. Results: The medianmore » PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. Conclusion: GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates.« less

Metforminium Decavanadate as a Potential Metallopharmaceutical Drug for the Treatment of Diabetes Mellitus.

PubMed

Treviño, Samuel; Velázquez-Vázquez, Denisse; Sánchez-Lara, Eduardo; Diaz-Fonseca, Alfonso; Flores-Hernandez, José Ángel; Pérez-Benítez, Aarón; Brambila-Colombres, Eduardo; González-Vergara, Enrique

2016-01-01

New potential drugs based on vanadium are being developed as possible treatments for diabetes mellitus (DM) and its complications. In this regard, our working group developed metforminium decavanadate (MetfDeca), a compound with hypoglycemic and hypolipidemic properties. MetfDeca was evaluated in models of type 1 and type 2 diabetes mellitus, on male Wistar rats. Alloxan-induction was employed to produce DM1 model, while a hypercaloric-diet was employed to generate DM2 model. Two-month treatments with 3.7 μg (2.5 μM)/300 g/twice a week for DM2 and 7.18 μg (4.8 μM)/300 g/twice a week for DM1 of MetfDeca, respectively, were administered. The resulting pharmacological data showed nontoxicological effects on liver and kidney. At the same time, MetfDeca showed an improvement of carbohydrates and lipids in tissues and serum. MetfDeca treatment was better than the monotherapies with metformin for DM2 and insulin for DM1. Additionally, MetfDeca showed a protective effect on pancreatic beta cells of DM1 rats, suggesting a possible regeneration of these cells, since they recovered their insulin levels. Therefore, MetfDeca could be considered not only as an insulin-mimetic agent, but also as an insulin-enhancing agent. Efforts to elucidate the mechanism of action of this compound are now in progress.

Metforminium Decavanadate as a Potential Metallopharmaceutical Drug for the Treatment of Diabetes Mellitus

PubMed Central

Treviño, Samuel; Velázquez-Vázquez, Denisse; Sánchez-Lara, Eduardo; Diaz-Fonseca, Alfonso; Flores-Hernandez, José Ángel; Pérez-Benítez, Aarón; Brambila-Colombres, Eduardo; González-Vergara, Enrique

2016-01-01

New potential drugs based on vanadium are being developed as possible treatments for diabetes mellitus (DM) and its complications. In this regard, our working group developed metforminium decavanadate (MetfDeca), a compound with hypoglycemic and hypolipidemic properties. MetfDeca was evaluated in models of type 1 and type 2 diabetes mellitus, on male Wistar rats. Alloxan-induction was employed to produce DM1 model, while a hypercaloric-diet was employed to generate DM2 model. Two-month treatments with 3.7 μg (2.5 μM)/300 g/twice a week for DM2 and 7.18 μg (4.8 μM)/300 g/twice a week for DM1 of MetfDeca, respectively, were administered. The resulting pharmacological data showed nontoxicological effects on liver and kidney. At the same time, MetfDeca showed an improvement of carbohydrates and lipids in tissues and serum. MetfDeca treatment was better than the monotherapies with metformin for DM2 and insulin for DM1. Additionally, MetfDeca showed a protective effect on pancreatic beta cells of DM1 rats, suggesting a possible regeneration of these cells, since they recovered their insulin levels. Therefore, MetfDeca could be considered not only as an insulin-mimetic agent, but also as an insulin-enhancing agent. Efforts to elucidate the mechanism of action of this compound are now in progress. PMID:27119007

Still a role for surgery as first-line therapy of splenic marginal zone lymphoma? Results of a prospective observational study.

PubMed

Pata, Giacomo; Bartoli, Michele; Damiani, Enrico; Solari, Stefano; Anastasia, Antonella; Pagani, Chiara; Tucci, Alessandra

2017-05-01

Assessment of hematologic improvement, survival and peri-operative morbidity after first-line splenectomy for splenic marginal zone lymphoma (SMZL). Forty-three patients undergoing open splenectomy were prospectively analyzed. Perioperative clinical course, overall and progression-free survival (OS-PFS) were evaluated. Risk factors analyzed were gender, age, ASA-grade, ECOG performance status, presence of B-symptoms, body mass index, steroidal treatment, serum albumin concentration, IIL-score, operative time, spleen size and weight. The median follow-up was 31 months (IQR 15-76; range 24-154). Anemia and thrombocytopenia resolved in 80% of patients at 6 months; in 60% at 2 years. The 5-year and 10-year PFS were 35% and 13% respectively, with a median of 35 months (shorter in patients with ECOG performance status ≥2 and B-symptoms). Nineteen cases (44.2%) had a progression of disease within 2 years. Of these, 14 (32.6%) received adjuvant chemotherapy (mainly R-FC or R-CVP). Progression was attributed to high-grade B lymphoma in 7 (16.3%) patients. The median time between diagnosis and progression to aggressive lymphoma was 25.5 months (range 18.8-81.8). The median time to next treatment was 83.5 months (95% CI 49-118). The 5-year and 10-year OS were 75% and 53% respectively. Mortality was due to disease progression and histological transformation in high-grade B lymphoma in 50% of cases, myelodisplastic syndrome in 15%, recurrence of hemolytic anemia in 15%, Hodgkin lymphoma in 7% and to infections (mainly pulmonary) in the remaining 13% of cases. Post-operative morbidity was 2.3% (1 patient with grade-3 complication). Overall grade ≥2 complication rate was 32.5% (mainly hemorrhagic and pulmonary complications). Spleen weight was the only independent risk factor for morbidity. Mortality was nil. Splenectomy is safe and effective as regards cytopenia resolution and OS, although disease progression is frequently observed at follow-up. Such results are strictly linked to accurate pre- and post-operative clinical management and optimal anesthesiologic approach. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

LIPT1 deficiency presenting as early infantile epileptic encephalopathy, Leigh disease, and secondary pyruvate dehydrogenase complex deficiency.

PubMed

Stowe, Robert C; Sun, Qin; Elsea, Sarah H; Scaglia, Fernando

2018-05-01

Lipoic acid is an essential cofactor for the mitochondrial 2-ketoacid dehydrogenase complexes and the glycine cleavage system. Lipoyltransferase 1 catalyzes the covalent attachment of lipoate to these enzyme systems. Pathogenic variants in LIPT1 gene have recently been described in four patients from three families, commonly presenting with severe lactic acidosis resulting in neonatal death and/or poor neurocognitive outcomes. We report a 2-month-old male with severe lactic acidosis, refractory status epilepticus, and brain imaging suggestive of Leigh disease. Exome sequencing implicated compound heterozygous LIPT1 pathogenic variants. We describe the fifth case of LIPT1 deficiency, whose phenotype progressed to that of an early infantile epileptic encephalopathy, which is novel compared to previously described patients whom we will review. Due to the significant biochemical and phenotypic overlap that LIPT1 deficiency and mitochondrial energy cofactor disorders have with pyruvate dehydrogenase deficiency and/or nonketotic hyperglycinemia, they are and have been presumptively under-diagnosed without exome sequencing. © 2018 Wiley Periodicals, Inc.

Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study.

PubMed

Traboulsee, Anthony; Li, David K B; Cascione, Mark; Fang, Juanzhi; Dangond, Fernando; Miller, Aaron

2018-05-11

On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial. Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS. Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3-4 in the IFN β-1a SC 22 μg group only (p < 0.05), whereas the presence of ≥2 versus 0-1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2-4; p < 0.05) and IFN β-1a SC 22 μg groups (Years 3-4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1-4; ≥2 vs. 0-1, Years 2-4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN β-1a SC 44 μg group only (Year 1; p < 0.05). The presence of ≥2 versus 0-1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN β-1a SC 44 μg group. Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a SC 22 μg, but not in those receiving IFN β-1a SC 44 μg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN β-1a SC 44 μg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.

A PHARMACOKINETIC MODEL FOR ESTIMATING EXPOSURE OF AMERICANS TO DIOXIN-LIKE COMPOUNDS IN THE PAST, PRESENT, AND FUTURE

EPA Science Inventory

Empirical evidence suggests that exposure of Americans to dioxin-like compounds was low during the early decades of the 20th century, then increased during the 1940s and 1950s reaching a peak in the 1960s and 1970s, and progressively decreased to lower levels in the 1980s and 199...

Changes in Retinal Nonperfusion Associated with Suppression of Vascular Endothelial Growth Factor in Retinal Vein Occlusion

PubMed Central

Mir, Tahreem A.; Kherani, Saleema; Hafiz, Gulnar; Scott, Adrienne W.; Zimmer-Galler, Ingrid; Wenick, Adam S.; Solomon, Sharon; Han, Ian; Poon, David; He, Lingmin; Shah, Syed Mahmood; Brady, Christopher J.; Meyerle, Catherine; Sodhi, Akrit; Linz, Marguerite O.; Sophie, Raafay; Campochiaro, Peter A.

2017-01-01

Purpose To assess changes in retinal nonperfusion (RNP) in patients with retinal vein occlusion (RVO) treated with ranibizumab (RBZ) Design Secondary outcome measure in randomized double-masked controlled clinical trial Subjects Thirty-nine patients with central RVO (CRVO) and 42 with branch RVO (BRVO) Methods Subjects were randomized to 0.5mg or 2.0mg RBZ every month for 6 months and then re-randomized to pro re nata (prn) groups RBZ+scatter photocoagulation (laser) or RBZ alone for an additional 30 months. Main Outcome Measures Comparison of percentage of patients with increased or decreased area of RNP in patients with RVO treated with 0.5mg versus 2.0mg RBZ, during monthly injections versus prn RBZ, and in patients treated with prn RBZ versus prn RBZ+laser. Results In RVO patients given monthly injections of 0.5mg or 2.0mg RBZ for 6 months there was no significant difference in the percentage who showed reduction or increase in area of RNP. However, regardless of dose, during the 6 month period of monthly injections, a higher percentage of patients showed a reduction in area of RNP and a lower percentage showed an increase in area of RNP compared to subsequent time periods of prn RBZ treatment. After the 6 month period of monthly injections, BRVO, but not CRVO patients randomized to prn RBZ+laser showed significantly less progression of RNP compared to patients treated with prn RBZ. Conclusions Regardless of dose of ranibizumab (0.5mg or 2.0mg), monthly injections promote improvement and reduce progression of RNP compared to prn injections. Addition of scatter photocoagulation to prn RBZ may reduce progression of RNP in patients with BRVO, but a statistically significant reduction was not seen in patients with CRVO. PMID:26712560

Efficacy of fulvestrant in the treatment of postmenopausal women with endocrine-resistant advanced breast cancer in routine clinical practice.

PubMed

Blancas, I; Fontanillas, M; Conde, V; Lao, J; Martínez, E; Sotelo, M J; Jaen, A; Bayo, J L; Carabantes, F; Illarramendi, J J; Gordon, M M; Cruz, J; García-Palomo, A; Mendiola, C; Pérez-Ruiz, E; Bofill, J S; Baena-Cañada, J M; Jáñez, N M; Esquerdo, G; Ruiz-Borrego, M

2018-07-01

This study aimed to describe the efficacy of fulvestrant 500 mg in postmenopausal women with estrogen receptor (ER)-positive advanced/metastatic breast cancer who had disease progression after receiving anti-estrogen therapy in clinical practice, getting real-world data. Multicenter, retrospective, observational study conducted in Spain. Postmenopausal women with locally advanced/metastatic ER-positive breast cancer who received treatment with fulvestrant 500 mg after progression with a previous anti-estrogen therapy were eligible. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), clinical benefit rate (CBR), duration of clinical benefit (DoCB), and safety profile. A total of 263 women were evaluated (median age, 65.8 years). At a median follow-up of 21.5 months, median PFS and OS were 10.6 and 43.2 months, respectively. PFS according to 1st, 2nd, 3rd, and ≥ 4th lines were 11.5, 10.6, 9.9, and 8.5 months, respectively (p = 0.0245). PFS in patients with visceral involvement was 10 months vs 10.6 months in patients without visceral involvement (p = 0.6604), 9.6 months in patients with high Ki67 vs 10 months in patients with low Ki67 (p = 0.7224), and 10.2 months in HER2+ patients vs 10.3 months in HER2- patients (p = 0.6809). The CBR was 56.5% and the DoCB was 18.4 months. The most frequently adverse events were injection site pain (10.3%) and musculoskeletal disorders (7.6%). Fulvestrant 500 mg administered in clinical practice was shown to be effective (PFS, 10.6 months; CBR, 56.5%) and well tolerated, in accordance with previous trials.

Antifungal Compounds against Candida Infections from Traditional Chinese Medicine

PubMed Central

2017-01-01

Infections caused by Candida albicans, often refractory and with high morbidity and mortality, cause a heavy burden on the public health while the current antifungal drugs are limited and are associated with toxicity and resistance. Many plant-derived molecules including compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through different targets such as cell membrane, cell wall, mitochondria, and virulence factors. Here, we review the recent progress in the anti-Candida compounds from TCM, as well as their antifungal mechanisms. Considering the diverse targets and structures, compounds from TCM might be a potential library for antifungal drug development. PMID:29445739

Etiology of Ibrutinib Discontinuation and Outcomes in Chronic Lymphocytic Leukemia Patients

PubMed Central

Maddocks, Kami J.; Ruppert, Amy S.; Lozanski, Gerard; Heerema, Nyla A.; Zhao, Weiqiang; Abruzzo, Lynne; Lozanski, Arletta; Davis, Melanie; Gordon, Amber; Smith, Lisa L.; Mantel, Rose; Jones, Jeffrey A.; Flynn, Joseph M.; Jaglowski, Samantha M.; Andritsos, Leslie A.; Awan, Farrukh; Blum, Kristie A.; Grever, Michael R.; Johnson, Amy J.; Byrd, John C.; Woyach, Jennifer A.

2015-01-01

Importance The Bruton’s Tyrosine Kinase inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuation from this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. Objective To determine features associated with discontinuation of ibrutinib and outcomes. Design 308 patients participating in four sequential trials of ibrutinib were included. These trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. Setting The Ohio State University Comprehensive Cancer Center Participants Patients with CLL enrolled on 4 sequential clinical trials. Main Outcome Measure Patients were evaluated for time to discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued due to progression, targeted deep sequencing was performed in samples at baseline and relapse. Results With a median follow-up of 20 months, 232 patients remain on therapy, 31 have discontinued because of progression, and 45 have discontinued for other reasons. Disease progression includes Richter’s transformation or progressive CLL. Richter’s appeared to occur early and CLL progressions later (cumulative incidence at 12 months: 4.5% (95% CI: 2.0% to 7.0%) and 0.3% (95% CI: 0% to 1.0%), respectively). Median survival following Richter’s transformation was 3.5 months (95% CI: 0.3–6.0), and 17.6 months (95% CI: 4.7-not reached) following CLL progression. Sequencing on peripheral blood from 8 patients with Richter’s transformation revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCγ2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCγ2 mutations in all. These mutations were not identified pre-treatment in any patient. Conclusions and Relevance This single institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with Richter’s transformation. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCγ2 with progression and clearly show that CLL progressions are associated with these mutations, while Richter’s transformation is likely not. PMID:26182309

Efficacy of icotinib in lung squamous-cell cancer: A real-world experience from single institution.

PubMed

Xu, Jianping; Liu, Xiaoyan; Yang, Sheng; Zhang, Xiangru; Shi, Yuankai

2017-12-01

Squamous cell carcinoma is a less common type of nonsmall cell lung cancer (NSCLC) which associates with a poor clinical prognosis and lacks specific therapy. This study aimed to evaluate the efficacy and safety of icotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has proven to be effective in EGFR-mutated NSCLC, in patients with lung squamous-cell cancer. Retrospective analysis was conducted in patients who had advanced lung squamous-cell cancer confirmed by cytology or histology. Patients were treated orally with icotinib (125 mg, three times daily) until event of unacceptable toxicity, disease progression or death. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, overall response rate and disease control rate. Between January 2014 and May 2016, 20 patients were enrolled and evaluated for the efficacy and safety of icotinib. Overall, the median overall survival and progression-free survival were 9.93 months (95% confidence interval (CI): 3.46-16.40) and 3.0 months (95% CI: 0.00-8.35), respectively. The overall response rate and disease control rate were 20% and 70%, respectively. For treatment-naive patients (n = 11), the overall survival and progression-free survival were 9.93 months (95% CI: 0.00-23.49) and 6.27 months (95% CI: 0.00-12.61); the response rate and disease control rate were 27.3% and 54.5%, respectively. The overall survival and progression-free survival of patients treated with second- or multiple-line icotinib treatment (n = 9) were 6.5 months (95% CI: 0.80-12.20) and 1.2 months (95% CI: 1.10-1.30). A total of 11 patients experienced at least one treatment-related adverse event, most of which were mild to moderate. The most common manifestations were rash (n = 6, 30%) followed by diarrhea (n = 2, 10%). Icotinib has demonstrated a favorable efficacy and safety profile in patients with advanced lung squamous-cell cancer. © 2017 John Wiley & Sons Australia, Ltd.

Hanford Works monthly report, December 1950

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

Prout, G.R.

1951-01-22

This is a progress report of the production reactors on the Hanford Reservation for the month of December 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, April 1952

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

Prout, G.R.

1952-05-20

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, August 1950

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

Prout, G.R.

1950-09-18

This is a progress report of the production reactors on the Hanford Reservation for the month of August 1950. This report takes each division (e.g. manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, May 1951

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

Prout, G.R.

1951-06-21

This is a progress report of the production reactors on the Hanford Reservation for the month of May 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, December 1951

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

Prout, G.R.

1952-01-22

This is a progress report of the production reactors on the Hanford Reservation for the month of December 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, March 1951

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

Prout, G.R.

1951-04-20

This is a progress report of the production reactors on the Hanford Reservation for the month of March 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1951

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, March 1952

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

Prout, G.R.

1952-04-18

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1952

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

Prout, G.R.

1952-08-15

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford works monthly report, September 1951

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of September 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, January 1952

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

Prout, G.R.

This is a progress report of the production reactors on the Hanford Reservation for the month of January 1952. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, August 1951

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

Not Available

1951-09-24

This is a progress report of the production reactors on the Hanford Reservation for the month of August 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, July 1950

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

Prout, G.R.

1950-08-18

This is a progress report of the production reactors on the Hanford Reservation for the month of July 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, November 1951

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

Prout, G.R.

1951-12-21

This is a progress report of the production reactors on the Hanford Reservation for the month of November 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, October 1950

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

Prout, G.R.

1950-11-20

This is a progress report of the production reactors on the Hanford Reservation for the month of October 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, September 1950

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

Prout, G.R.

1950-10-20

This is a progress report of the production reactors on the Hanford Reservation for the month of September 1950. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Works monthly report, November 1950

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

Prout, G.R.

1950-12-20

This is a progress report of the production reactors on the Hanford Reservation for the month of November 1950. This report takes each division (e.g. manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Common Progress Monitoring Omissions: Planning and Practice. Progress Monitoring Brief #1

ERIC Educational Resources Information Center

National Center on Response to Intervention, 2013

2013-01-01

Progress monitoring, one of the essential components of Response to Intervention (RTI), is characterized by repeated measurement of academic performance that is conducted at least monthly. The process may be used to assess students' academic performance over time, to quantify student rates of improvement or responsiveness to instruction, and to…

Common Progress Monitoring Omissions: Reporting Information to Parents. Progress Monitoring Brief #4

ERIC Educational Resources Information Center

National Center on Response to Intervention, 2013

2013-01-01

Progress monitoring, one of the essential components of Response to Intervention (RTI), is characterized by repeated measurement of academic performance that is conducted at least monthly. The process may be used to assess students' academic performance over time, to quantify student rates of improvement or responsiveness to instruction, and to…

Gas chromatography-mass spectrometry and high-performance liquid chromatography-diode array detection for dating of paper ink.

PubMed

Díaz-Santana, Oscar; Vega-Moreno, Daura; Conde-Hardisson, Francisco

2017-09-15

An extraction and determination method is shown for the analysis of dyes and solvents present in two types of ballpoint pen inks that are deposited onto paper. Ink extracts are analysed using a combination of gas chromatography with mass spectrometry (GC-MS), and high-pressure liquid chromatography with photodiode array detection (HPLC-DAD), within a single sample extraction procedure. Seventeen solvents and thirteen dyes contained in two Montblanc ® inks (black and blue) were monitored for 45 months at monthly intervals, in order to determine variations in the concentrations of the compounds over time. We also studied the relative variations between different compounds and the generation of degradation products such as phenol. The concentration data obtained from these compounds during their exposure have been analysed and a multiple regression model is developed for each ink type that allows an estimate of the exposure time of the ink on paper with a maximum error of between 4 and 7 months. Copyright © 2017 Elsevier B.V. All rights reserved.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

PubMed

Herrick, Ariane L; Peytrignet, Sebastien; Lunt, Mark; Pan, Xiaoyan; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan J; Dinsdale, Graham; Brown, Edith; Czirják, László; Distler, Jörg H W; Distler, Oliver; Fligelstone, Kim; Gregory, William J; Ochiel, Rachel; Vonk, Madelon C; Ancuţa, Codrina; Ong, Voon H; Farge, Dominique; Hudson, Marie; Matucci-Cerinic, Marco; Balbir-Gurman, Alexandra; Midtvedt, Øyvind; Jobanputra, Paresh; Jordan, Alison C; Stevens, Wendy; Moinzadeh, Pia; Hall, Frances C; Agard, Christian; Anderson, Marina E; Diot, Elisabeth; Madhok, Rajan; Akil, Mohammed; Buch, Maya H; Chung, Lorinda; Damjanov, Nemanja S; Gunawardena, Harsha; Lanyon, Peter; Ahmad, Yasmeen; Chakravarty, Kuntal; Jacobsen, Søren; MacGregor, Alexander J; McHugh, Neil; Müller-Ladner, Ulf; Riemekasten, Gabriela; Becker, Michael; Roddy, Janet; Carreira, Patricia E; Fauchais, Anne Laure; Hachulla, Eric; Hamilton, Jennifer; İnanç, Murat; McLaren, John S; van Laar, Jacob M; Pathare, Sanjay; Proudman, Susanna M; Rudin, Anna; Sahhar, Joanne; Coppere, Brigitte; Serratrice, Christine; Sheeran, Tom; Veale, Douglas J; Grange, Claire; Trad, Georges-Selim; Denton, Christopher P

2018-04-01

Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy

PubMed Central

Drappatz, Jan; de Groot, John; Prados, Michael D; Reardon, David A; Schiff, David; Chamberlain, Marc; Mikkelsen, Tom; Desjardins, Annick; Holland, Jaymes; Ping, Jerry; Weitzman, Ron; Cloughesy, Timothy F

2018-01-01

Abstract Background Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM). Methods Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety. Results Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome. Conclusions Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions. Clinical Trials Registration Number NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288) PMID:29016998

Antioxidant effect of Morus nigra on Chagas disease progression.

PubMed

Montenote, Michelly Cristina; Wajsman, Vithor Zuccaro; Konno, Yoichi Takaki; Ferreira, Paulo César; Silva, Regildo Márcio Gonçalves; Therezo, Altino Luiz Silva; Silva, Luciana Pereira; Martins, Luciamáre Perinetti Alves

2017-11-06

Considering the widespread popular use of Morus nigra and the amount of scientific information on its antioxidant and anti-inflammatory activity, the effectiveness of this phytotherapeutic compound in the parasitemia progression during the acute phase of Chagas disease and its role in the development of the inflammatory process as well as its effects on the oxidative damage in the chronic phase of infection were evaluated. Thus, 96 male Swiss mice were randomly divided into eight groups, four groups were uninfected controls, and four groups were intraperitoneally infected with 5.0 x 104 blood trypomastigotes forms of T. cruzi QM2 strain. Four batches composed of one uninfected and one infected group were respectively treated with 70% alcohol solution and 25 μL, 50 μL and 75 μL of the phytotherapeutic compound. Levels of antioxidant elements (TBARS, FRAP, GSH and Sulfhydryl groups) were measured in plasma samples. The phytotherapeutic compound's antioxidant activity was measured by polyphenol and total flavonoid quantification, DPPH, NO, and FRAP method. Our results showed that the vehicle influenced some of the results that may have physiological relevance in Chagas disease. However, an important action of M. nigra tincture was observed in the progression of Chagas disease, since our results demonstrated a reduction in parasitemia of treated groups when compared to controls, especially in the group receiving 25 µL. However, in the chronic phase, the 50-µL dosage presented a better activity on some antioxidant defenses and minimized the tissue inflammatory process. Results indicated an important action of M. nigra tincture on the Chagas disease progression.

Investigation of innovative synthesis of biologically active compounds on the basis of newly developed reactions.

PubMed

Honda, Toshio

2012-01-01

Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets. Newly developed reactions should also be used for efficient synthesis of desired compounds. Thus, recent progress in the synthesis of biologically active compounds by focusing on the development of new reactions is summarized in this review article.

Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease

PubMed Central

Venigalla, Madhuri; Gyengesi, Erika; Münch, Gerald

2015-01-01

Alzheimer's disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer's disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer's disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer's disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer's disease or slow down its progression, and they should enter clinical trials as soon as possible. PMID:26487830

Approach towards an integrative drug treatment of Alzheimer's disease.

PubMed

Windisch, M

2000-01-01

At present pharmacotherapy of Alzheimer's disease (AD) is limited to acetylcholinesterase inhibitors. These drugs produce small, but consistent improvements of memory and global function, some are also positively influencing activities of daily living. This therapeutic approach neglects the complexity of AD and the fact that most of the degenerating neurons are not cholinergic. Acetylcholinesterase inhibitors are symptomatic drugs, with no influence on disease progression. There is a need for disease modifying compounds, or preventive drugs. Data are indicating that vitamin E has some ability to influence the disease progression. The potency of non-steroidal anti-inflammatory drugs (NSAIDs) or estrogen as preventive agents has to be explored further in prospective clinical studies. The initial hope in the use of naturally occurring neurotrophic factors, like nerve growth factor, to rescue cholinergic neurons from degeneration and to restore cognitive function has been disappointed in first, small clinical studies. The peptidergic drug Cerebrolysin exhibiting neurotrophic stimulation, neuroimmunotrophic regulation and induction of BBB glucose transporter expression, might be able to address the pathological changes of AD at different levels simultaneously. In addition to an impressive preclinical database, results from 3 placebo-controlled, double-blind studies demonstrate significant improvements of cognitive performance, global function and activities of daily living in AD patients. In all studies persisting improvements, up to 6 months after drug withdrawal, indicate a powerful disease modifying activity.

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma.

PubMed

Kil, P J M; Goldschmidt, H M J; Wieggers, B J A; Kariakine, O B; Studer, U E; Whelan, P; Hetherington, J; de Reijke, Th M; Hoekstra, J W; Collette, L

2003-01-01

To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to clinical progression. Finally to compare TPS with prostate-specific antigen (PSA) measurements in terms of prognostic impact in patients with metastatic prostatic carcinoma. TPS and PSA measurements were performed before start of and monthly during intermittent MAB in 68 patients participating in EORTC protocol 30954. Both TPS and PSA were measured in serum. Fifty-six patients from eight centers were included in the final analysis because at least three TPS values were available. TPS and PSA values were correlated with clinical course of the disease. Median follow-up was 21.3 months. Three patient groups were defined on clinical grounds: (a) clinically progressive disease (n=18); (b) clinically stable disease (n=33); and (c) patients who did not reach a predefined nadir PSA value following 9 months of treatment (n=5). Pretreatment TPS was significantly higher in the clinically progressive patients than in the other patient groups (p=0.0041). When grouping patients according to their pretreatment TPS values (cut-off value of 100 U/l) the pretreatment TPS value (>100 U/l) proved to be a statistically significant prognostic factor with respect to time to progression: elevated TPS was associated with a 3.8 increased risk for progressive disease (p=0.0055). Pretreatment PSA (>100 ng/ml) was of no prognostic value for time to progression. In five patients increase of TPS coincided with or preceded clinical progression during treatment, whereas PSA remained normal. Additional value of pretreatment TPS measurements in metastatic prostate cancer patients is found in defining the patients with rapid clinical progression. Following MAB an increase in TPS signifies clinical progression even if PSA is found to remain normal.

Evaluation of longitudinal 12 and 24 month cognitive outcomes in premanifest and early Huntington's disease.

PubMed

Stout, Julie C; Jones, Rebecca; Labuschagne, Izelle; O'Regan, Alison M; Say, Miranda J; Dumas, Eve M; Queller, Sarah; Justo, Damian; Santos, Rachelle Dar; Coleman, Allison; Hart, Ellen P; Dürr, Alexandra; Leavitt, Blair R; Roos, Raymund A; Langbehn, Doug R; Tabrizi, Sarah J; Frost, Chris

2012-07-01

Deterioration of cognitive functioning is a debilitating symptom in many neurodegenerative diseases, such as Huntington's disease (HD). To date, there are no effective treatments for the cognitive problems associated with HD. Cognitive assessment outcomes will have a central role in the efforts to develop treatments to delay onset or slow the progression of the disease. The TRACK-HD study was designed to build a rational basis for the selection of cognitive outcomes for HD clinical trials. There were a total of 349 participants, including controls (n=116), premanifest HD (n=117) and early HD (n=116). A standardised cognitive assessment battery (including nine cognitive tests comprising 12 outcome measures) was administered at baseline, and at 12 and 24 months, and consisted of a combination of paper and pencil and computerised tasks selected to be sensitive to cortical-striatal damage or HD. Each cognitive outcome was analysed separately using a generalised least squares regression model. Results are expressed as effect sizes to permit comparisons between tasks. 10 of the 12 cognitive outcomes showed evidence of deterioration in the early HD group, relative to controls, over 24 months, with greatest sensitivity in Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading. In contrast, there was very little evidence of deterioration in the premanifest HD group relative to controls. The findings describe tests that are sensitive to longitudinal cognitive change in HD and elucidate important considerations for selecting cognitive outcomes for clinical trials of compounds aimed at ameliorating cognitive decline in HD.

Gas-turbine critical research and advanced technology support project

NASA Technical Reports Server (NTRS)

Clark, J. S.; Lowell, C. E.; Niedzwiecki, R. W.; Nainiger, J. J.

1979-01-01

The technical progress made during the first 15 months of a planned 40-month project to provide a critical-technology data base for utility gas-turbine systems capable of burning coal-derived fuels is summarized. Tasks were included in the following areas: (1) combustion, to study the combustion of coal-derived fuels and conversion of fuel-bound nitrogen to NOx; (2) materials, to understand and prevent hot corrosion; and (3) system studies, to integrate and guide the other technologies. Significant progress was made.

Proceedings of the first international symposium on neutron capture therapy

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

Fairchild, R.G.; Brownell, G.L.

This meeting was arranged jointly by MIT and BNL in order to illuminate progress in the synthesis and targeting of boron compounds and to evaluate and document progress in radiobiological and dosimetric aspects of neutron capture therapy. It is hoped that this meeting will facilitate transfer of information between groups working in these fields, and encourage synergistic collaboration.

Nuclear medicine technology progress report for quarter ending June 30, 1978. ABELLED COMPOUNDS; PATIENTS; POSITRON SOURCES; CARBON 11; ISOMERIC NUCLEI; LABELLED COMPOUNDS; BIOLOGICAL LOCALIZATION; CHEMICAL PREPARATION; ISOMERIC NUCLEI; LABELLED COMPOUNDS; RATS; CHEMICAL PREPARATION; LABELLED COMPOUNDS; RATS; TISSUE DISTRIBUTION

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

Knapp, Jr., F. F.

Progress is reported for the applications of /sup 11/C, /sup 195m/Pt, /sup 75/Se, and /sup 123m/Te. Additional human clinical trials with /sup 11/C-DL-tryptophan and /sup 11/C-l-aminocyclobutane carboxylic acid have been completed. The modified Buecherer-Strecker amino acid synthesis has been used to prepare /sup 11/C-DL-phenylglycine and /sup 11/C-DL-phenylalanine. These two new /sup 11/C-labeled amino acids will be studied as potential tumor localizing agents. Preliminary studies concerning the comparative organ and subcellular distribution of /sup 195m/Pt-labeled cis- and trans- dichlorodiamineplatinum(II) have been completed. The results of in vivo studies have shown the cis isomer to bind to nuclear DNA to a significantlymore » greater extent than the trans isomer. A series of /sup 123m/Te-labeled long-chain fatty acid analogs have been prepared as isosteres of unsaturated fatty acids. Several of these compounds show pronounced heart uptake in rats and may represent a new class of potential myocardial imaging agents. Studies on the preparation and tissue distribution of /sup 75/Se-..beta..-aminoethyl selenosulfate continue.« less

[Lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement].

PubMed

Caliez, J; Monnet, I; Pujals, A; Rousseau-Bussac, G; Jabot, L; Boudjemaa, A; Leroy, K; Chouaid, C

2017-05-01

Among patients with non-small-cell lung cancer, coexistence of EGFR mutation and ALK rearrangement is rare. We describe the clinical features of two patients with this double anomaly. A 62-year-old Caucasian non-smoking woman was diagnosed with cT4N0M0 lung adenocarcinoma. Initial biopsy showed EGFR mutation and ALK rearrangement. She received cisplatin-gemcitabine, followed by 17 months of gemcitabine. Owing to progression, she received erlotinib for 14 months, then paclitaxel for 6 months and finally crizotinib. A partial response was achieved and maintained for 24 months. A 45-year-old Caucasian woman, light smoker, was diagnosed with cT2N3M0 lung adenocarcinoma. Only EGFR mutation was found on initial analysis. She underwent treatment with cisplatin-gemcitabine and thoracic radiotherapy. Progression occurred after 8 months and afatinbib was started. Eight months later, progression was observed with a neoplasic pleural effusion in which tumor cells expressing ALK rearrangement were found. A new FISH analysis was performed on the initial tumor but did not find this rearrangement. Despite a third line of crizotinib, the patient died one month later. The literature shows 45 other cases of these two abnormalities, observed either from the start or during follow-up. EGFR's TKI were almost always given before ALK's TKI. Therapeutic strategy needs to be clarified in cases of double alteration. With regard to the second patient, appearance of ALK rearrangement may constitute a resistance mechanism to EGFR's TKI. Copyright © 2016 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Composition and Integrity of PAHs, Nitro-PAHs, Hopanes and Steranes In Diesel Exhaust Particulate Matter.

PubMed

Huang, Lei; Bohac, Stanislav V; Chernyak, Sergei M; Batterman, Stuart A

2013-08-01

Diesel exhaust particulate matter contains many semivolatile organic compounds (SVOCs) of environmental and health significance. This study investigates the composition, emission rates, and integrity of 25 SVOCs, including polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), and diesel biomarkers hopanes and steranes. Diesel engine particulate matter (PM), generated using an engine test bench, three engine conditions, and ultra-low sulfur diesel (ULSD), was collected on borosilicate glass fiber filters. Under high engine load, the PM emission rate was 0.102 g/kWh, and emission rate of ΣPAHs (10 compounds), ΣNPAHs (6 compounds), Σhopanes (2 compounds), and Σsteranes (2 compounds) were 2.52, 0.351, 0.02 ~ 2 and 1μg/kWh, respectively. Storage losses were evaluated for three cases: conditioning filters in clean air at 25 °C and 33% relative humidity (RH) for 24 h; storing filter samples (without extraction) wrapped in aluminum foil at 4 °C for up to one month; and storing filter extracts in glass vials capped with Teflon crimp seals at 4 °C for up to six months. After conditioning filters for 24 h, 30% of the more volatile PAHs were lost, but lower volatility NPAHs, hopanes and steranes showed negligible changes. Storing wrapped filters and extracts at 4 °C for up to one month did not lead to significant losses, but storing extracts for five months led to significant losses of PAHs and NPAHs; hopanes and steranes demonstrated greater integrity. These results suggest that even relatively brief filter conditioning periods, needed for gravimetric measurements of PM mass, and extended storage of filter extracts can lead to underestimates of SVOC concentrations. Thus, SVOC sampling and analysis protocols should utilize stringent criteria and performance checks to identify and limit possible biases occurring during filter and extract processing.

Composition and Integrity of PAHs, Nitro-PAHs, Hopanes and Steranes In Diesel Exhaust Particulate Matter

PubMed Central

Huang, Lei; Bohac, Stanislav V.; Chernyak, Sergei M.; Batterman, Stuart A.

2013-01-01

Diesel exhaust particulate matter contains many semivolatile organic compounds (SVOCs) of environmental and health significance. This study investigates the composition, emission rates, and integrity of 25 SVOCs, including polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), and diesel biomarkers hopanes and steranes. Diesel engine particulate matter (PM), generated using an engine test bench, three engine conditions, and ultra-low sulfur diesel (ULSD), was collected on borosilicate glass fiber filters. Under high engine load, the PM emission rate was 0.102 g/kWh, and emission rate of ΣPAHs (10 compounds), ΣNPAHs (6 compounds), Σhopanes (2 compounds), and Σsteranes (2 compounds) were 2.52, 0.351, 0.02 ~ 2 and 1μg/kWh, respectively. Storage losses were evaluated for three cases: conditioning filters in clean air at 25 °C and 33% relative humidity (RH) for 24 h; storing filter samples (without extraction) wrapped in aluminum foil at 4 °C for up to one month; and storing filter extracts in glass vials capped with Teflon crimp seals at 4 °C for up to six months. After conditioning filters for 24 h, 30% of the more volatile PAHs were lost, but lower volatility NPAHs, hopanes and steranes showed negligible changes. Storing wrapped filters and extracts at 4 °C for up to one month did not lead to significant losses, but storing extracts for five months led to significant losses of PAHs and NPAHs; hopanes and steranes demonstrated greater integrity. These results suggest that even relatively brief filter conditioning periods, needed for gravimetric measurements of PM mass, and extended storage of filter extracts can lead to underestimates of SVOC concentrations. Thus, SVOC sampling and analysis protocols should utilize stringent criteria and performance checks to identify and limit possible biases occurring during filter and extract processing. PMID:24363468

Hanford Atomic Products Operation monthly report, April 1954

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

McCune, F.K.

1954-05-21

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1954. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Atomic Products Operation monthly report, March 1953

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

McCune, F.K.

1953-04-22

This is a progress report of the production reactors on the Hanford Reservation for the month of March 1953. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

78 FR 26223 - National Physical Fitness and Sports Month, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-03

... Physical Fitness and Sports Month, 2013 By the President of the United States of America A Proclamation... life. During National Physical Fitness and Sports Month, we celebrate that progress and keep striving... at work. Through Let's Move! and the President's Council on Fitness, Sports, and Nutrition, we...

Hanford Atomic Products Operation monthly report, April 1953

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

McCune, F.K.

1953-05-20

This is a progress report of the production reactors on the Hanford Reservation for the month of April 1951. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes its accomplishments and employee relations for that month.

Hanford Atomic Products Operation monthly report, January 1954

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

McCune, F.K.

1954-02-25

This is a progress report of the production reactors on the Hanford Reservation for the month of January 1954. This report takes each division (e.g., manufacturing, medical, accounting, occupational safety, security, reactor operations, etc.) of the site and summarizes the accomplishments and employee relations for that month.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.

PubMed

Byrne, Susan; Jansen, Lara; U-King-Im, Jean-Marie; Siddiqui, Ata; Lidov, Hart G W; Bodi, Istvan; Smith, Luke; Mein, Rachael; Cullup, Thomas; Dionisi-Vici, Carlo; Al-Gazali, Lihadh; Al-Owain, Mohammed; Bruwer, Zandre; Al Thihli, Khalid; El-Garhy, Rana; Flanigan, Kevin M; Manickam, Kandamurugu; Zmuda, Erik; Banks, Wesley; Gershoni-Baruch, Ruth; Mandel, Hanna; Dagan, Efrat; Raas-Rothschild, Annick; Barash, Hila; Filloux, Francis; Creel, Donnell; Harris, Michael; Hamosh, Ada; Kölker, Stefan; Ebrahimi-Fakhari, Darius; Hoffmann, Georg F; Manchester, David; Boyer, Philip J; Manzur, Adnan Y; Lourenco, Charles Marques; Pilz, Daniela T; Kamath, Arveen; Prabhakar, Prab; Rao, Vamshi K; Rogers, R Curtis; Ryan, Monique M; Brown, Natasha J; McLean, Catriona A; Said, Edith; Schara, Ulrike; Stein, Anja; Sewry, Caroline; Travan, Laura; Wijburg, Frits A; Zenker, Martin; Mohammed, Shehla; Fanto, Manolis; Gautel, Mathias; Jungbluth, Heinz

2016-03-01

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

PubMed Central

Byrne, Susan; Jansen, Lara; U-King-Im, Jean-Marie; Siddiqui, Ata; Lidov, Hart G. W.; Bodi, Istvan; Smith, Luke; Mein, Rachael; Cullup, Thomas; Dionisi-Vici, Carlo; Al-Gazali, Lihadh; Al-Owain, Mohammed; Bruwer, Zandre; Al Thihli, Khalid; El-Garhy, Rana; Flanigan, Kevin M.; Manickam, Kandamurugu; Zmuda, Erik; Banks, Wesley; Gershoni-Baruch, Ruth; Mandel, Hanna; Dagan, Efrat; Raas-Rothschild, Annick; Barash, Hila; Filloux, Francis; Creel, Donnell; Harris, Michael; Hamosh, Ada; Kölker, Stefan; Ebrahimi-Fakhari, Darius; Hoffmann, Georg F.; Manchester, David; Boyer, Philip J.; Manzur, Adnan Y.; Lourenco, Charles Marques; Pilz, Daniela T.; Kamath, Arveen; Prabhakar, Prab; Rao, Vamshi K.; Rogers, R. Curtis; Ryan, Monique M.; Brown, Natasha J.; McLean, Catriona A.; Said, Edith; Schara, Ulrike; Stein, Anja; Sewry, Caroline; Travan, Laura; Wijburg, Frits A.; Zenker, Martin; Mohammed, Shehla; Fanto, Manolis; Gautel, Mathias

2016-01-01

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease. PMID:26917586

Association between volatile sulfur compounds and periodontal disease progression in elderly non-smokers.

PubMed

Makino, Yuka; Yamaga, Takayuki; Yoshihara, Akihiro; Nohno, Kaname; Miyazaki, Hideo

2012-05-01

Periodontal pathogenic microorganisms produce volatile sulfur compounds (VSCs), such as hydrogen sulfide, methyl mercaptan, and dimethyl sulfide. VSCs are toxic to periodontal tissue. Therefore, there is a relationship between periodontitis and the VSC level of mouth air. However, the association between VSC and periodontal disease progression has not been investigated in a longitudinal study. The purpose of this study is to evaluate the association between VSCs in mouth air and periodontal disease progression among elderly dentulous non-smokers. Two hundred forty-one dentulous non-smokers (103 males and 138 females; all 70 years old) had their VSC levels examined with a portable sulfide monitor, and their periodontal status was assessed. Periodontal examinations were performed at baseline and once a year for 3 years to investigate the clinical attachment levels of all teeth. Participants were classified by membership in tertile groups (lowest, middle, and highest) according to the value of baseline VSC measurements. In negative binomial regression analysis, the number of teeth with periodontal disease progression for participants in the highest tertile of VSC measurement was greater (incidence rate ratio of 1.33, P = 0.011) than for the reference group (lowest tertile of VSC measurement) after simultaneously adjusting for sex, number of remaining teeth, and maximum clinical attachment level. VSC measurements were significantly associated with periodontal disease progression in a non-smoking dentulous elderly population. This suggests that VSC measurements are useful for the diagnosis of periodontal disease progression.

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models

PubMed Central

Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-01-01

Aim To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Material and Methods Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. Results In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87–97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4–5 months and sites recovered with a high probability (96–98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Conclusion Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. PMID:24888705

Prognostic Value of [18F]-Fluoromethylcholine Positron Emission Tomography/Computed Tomography Before Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer.

PubMed

Cysouw, Matthijs; Bouman-Wammes, Esther; Hoekstra, Otto; van den Eertwegh, Alfons; Piet, Maartje; van Moorselaar, Jeroen; Boellaard, Ronald; Dahele, Max; Oprea-Lager, Daniela

2018-06-01

To investigate the predictive value of [ 18 F]-fluoromethylcholine positron emission tomography/computed tomography (PET/CT)-derived parameters on progression-free survival (PFS) in oligometastatic prostate cancer patients treated with stereotactic body radiation therapy (SBRT). In [ 18 F]-fluoromethylcholine PET/CT scans of 40 consecutive patients with ≤4 metachronous metastases treated with SBRT we retrospectively measured the number of metastases, standardized uptake values (SUV mean , SUV max , SUV peak ), metabolically active tumor volume (MATV), and total lesion choline uptake. Partial-volume correction was applied using the iterative deconvolution Lucy-Richardson algorithm. Thirty-seven lymph node and 13 bone metastases were treated with SBRT. Thirty-three patients (82.5%) had 1 lesion, 4 (10%) had 2 lesions, and 3 (7.5%) had 3 lesions. After a median follow-up of 32.6 months (interquartile range, 35.5 months), the median PFS was 11.5 months (95% confidence interval 8.4-14.6 months). Having more than a single metastasis was a significant prognostic factor (hazard ratio 2.74; P = .03), and there was a trend in risk of progression for large MATV (hazard ratio 1.86; P = .10). No SUV or total lesion choline uptake was significantly predictive for PFS, regardless of partial-volume correction. All PET semiquantitative parameters were significantly correlated with each other (P ≤ .013). The number of choline-avid metastases was a significant prognostic factor for progression after [ 18 F]-fluormethylcholine PET/CT-guided SBRT for recurrent oligometastatic prostate cancer, and there seemed to be a trend in risk of progression for patients with large MATVs. The lesional level of [ 18 F]-fluoromethylcholine uptake was not prognostic for progression. Copyright © 2018 Elsevier Inc. All rights reserved.

Dacarbazine in combination with bevacizumab for the treatment of unresectable/metastatic melanoma: a phase II study.

PubMed

Ferrucci, Pier F; Minchella, Ida; Mosconi, Massimo; Gandini, Sara; Verrecchia, Francesco; Cocorocchio, Emilia; Passoni, Claudia; Pari, Chiara; Testori, Alessandro; Coco, Paola; Munzone, Elisabetta

2015-06-01

The combined treatment of dacarbazine with an antiangiogenic drug such as bevacizumab may potentiate the therapeutic effects of dacarbazine in metastatic melanoma (MM). Preliminary antitumour activity of dacarbazine plus bevacizumab is evaluated, together with the toxicity and safety profile, in MM patients. This prospective, open-label, phase II study included patients with previously untreated MM or unresectable melanoma. Patients received dacarbazine and bevacizumab until progressive disease or unacceptable toxicity. The primary efficacy variable was the overall response rate. The secondary efficacy parameters included duration of response, duration of stable disease, time to progression/progression-free survival, time to treatment failure and overall survival. The safety analysis included recordings of adverse events and exposure to study treatment. The intention-to-treat population included 37 patients (24 men and 13 women, mean age 54.2±13.1 years). Overall response rate was 18.9% (seven patients achieved a response) and clinical benefit was 48.6%. In patients who achieved a response, the median duration of response was 16.9 months and the median duration of stable disease was 12.5 months. The median time to progression/progression-free survival and time to treatment failure were 5.5 and 3.1 months, respectively. The median overall survival was 11.4 months. Almost all patients (94.6%) experienced at least one adverse event; however, no new area of toxicity of bevacizumab emerged. The dacarbazine/bevacizumab combination provides benefits compared with dacarbazine monotherapy in historical controls, with an acceptable safety profile. This combination appears to be a valid option in specific subgroups of patients, namely, those triple negative (BRAF, C-KIT and NRAS wild type) or with a BRAF mutation who have already received, or are not eligible for, immunomodulating or targeted agents.

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

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

Mizumoto, Masashi; Okumura, Toshiyuki; Hashimoto, Takayuki

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function. Methods and Materials: The subjects were 259 patients treated with PBT at University of Tsukuba between January 2001 and December 2007. We evaluated the Child-Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effectmore » of tumor progression. An increase in the Child-Pugh score of 1 or more was defined as an adverse event. Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child-Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child-Pugh score, 15 had a 1-point increase, and 10 had an increase of {>=}2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively. Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.« less

Long-term outcome in BRAF(V600E) melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression.

PubMed

Puzanov, Igor; Amaravadi, Ravi K; McArthur, Grant A; Flaherty, Keith T; Chapman, Paul B; Sosman, Jeffrey A; Ribas, Antoni; Shackleton, Mark; Hwu, Patrick; Chmielowski, Bartosz; Nolop, Keith B; Lin, Paul S; Kim, Kevin B

2015-07-01

Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported. Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded. Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy. Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.

A PHASE II TRIAL OF THALIDOMIDE IN PATIENTS WITH REFRACTORY ENDOMETRIAL CANCER AND CORRELATION WITH ANGIOGENESIS BIOMARKERS: A GYNECOLOGIC ONCOLOGY GROUP STUDY

PubMed Central

McMeekin, D. Scott; Sill, Michael W.; Benbrook, Doris; Darcy, Kathleen M.; Stearns-Kurosawa, Deborah J.; Eaton, Lynne; Yamada, S. Diane

2007-01-01

Objectives A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of thalidomide in persistent or recurrent endometrial cancer refractory to cytotoxic chemotherapy, and to correlate angiogenesis biomarker expression with clinical outcome. Methods Consenting patients were treated until progression or intolerable toxicity with an oral starting dose of 200 mg thalidomide/day that was to increase by 200 mg every 2 weeks to a target dose of 1000 mg/day. Vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), and soluble endothelial protein C receptor (sEPCR) were analyzed by ELISA in pre and post-treatment specimens. Results Twenty-four of 27 patients enrolled in the study were eligible, of whom 2 reached the target dose, 8 progressed before achieving the target dose and 14 refused or had toxicity that prohibited escalation. Two patients (8.3%) remained progression-free ≥ 6 months. There were 3 (12.5%) with partial responses, 2 (8.3%) with stable disease, 15 (62.5%) with increasing disease, and 4 (16.7%) who were inevaluable for response. Median progression-free survival and overall survival were 1.7 months and 6.3 months, respectively. No grade 4 toxicities were observed. Common grade 3 toxicities included hematologic (n=3), cardiovascular (n=3), constitutional (n=3), and neurologic (n=4). Thalidomide did not decrease VEGF or bFGF levels but reduced sEPCR levels in serum. Elevated plasma vascular endothelial growth factor levels were associated with increased risk of progression and death. Conclusions Thalidomide demonstrated limited ability to delay progression (as measured by PFS at 6 months), produce objective responses or reduce angiogenic marker levels in chemotherapy refractory endometrial cancer. VEGF level appears to be prognostically significant in such patients, independent of thalidomide treatment. PMID:17306350

Vegetarian low-protein diets supplemented with keto analogues: a niche for the few or an option for many?

PubMed

Piccoli, Giorgina B; Ferraresi, Martina; Deagostini, Maria C; Vigotti, Federica Neve; Consiglio, Valentina; Scognamiglio, Stefania; Moro, Irene; Clari, Roberta; Fassio, Federica; Biolcati, Marilisa; Porpiglia, Francesco

2013-09-01

Low-protein diets are often mentioned but seldom used to slow chronic kidney disease (CKD) progression. The aim of the study was to investigate the potential for implementation of a simplified low-protein diet supplemented with alpha-keto analogues (LPD-KA) as part of the routine work-up in CKD patients. In an implementation study (December 2007-November 2011), all patients with CKD Stages IV-V not on dialysis, rapidly progressive Stage III and/or refractory proteinuria, were offered either a simplified LPD-KA, or commercially available low-protein food. LPD-KA consisted of proteins 0.6 g/kg/day, supplementation with Ketosteril 1 pill/10 Kg, 1-3 free-choice meals/week and a simplified schema based on 'allowed' and 'forbidden' foods. 'Success' was defined as at least 6 months on LPD-KA. Progression was defined as reduction in glomerular filtration rate (GFR)[(Chronic Kidney Disease Epidemiology Collaboration) formula CKD-EPI] in patients with at least 6 months of follow-up. Of about 2500 patients referred (8% CKD Stages IV-V), 139 started LPD-KA; median age (70 years) and prevalence of comorbidity (79%) were in line with the dialysis population. Start of dialysis was the main reason for discontinuation (40 cases, unplanned in 7); clinical reasons were recorded in 7, personal preference in 14 and improvement and death in 8 each. The low gross mortality (4% per year) and the progression rate (from -8 to 0 mL/min/year at 6 months) are reassuring concerning safety. None of the baseline conditions, including age, educational level, comorbidity or kidney function, discriminated the patients who followed the diet for at least 6 months. Our data suggest a wider offer of LPD-KA to patients with severe and progressive CKD. The promising results in terms of mortality and progression need confirmation with different study designs.

Prognostic Significance of Carbohydrate Antigen 19-9 in Unresectable Locally Advanced Pancreatic Cancer Treated With Dose-Escalated Intensity Modulated Radiation Therapy and Concurrent Full-Dose Gemcitabine: Analysis of a Prospective Phase 1/2 Dose Escalation Study

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

Vainshtein, Jeffrey M., E-mail: jvainsh@med.umich.edu; Schipper, Matthew; Zalupski, Mark M.

2013-05-01

Purpose: Although established in the postresection setting, the prognostic value of carbohydrate antigen 19-9 (CA19-9) in unresectable locally advanced pancreatic cancer (LAPC) is less clear. We examined the prognostic utility of CA19-9 in patients with unresectable LAPC treated on a prospective trial of intensity modulated radiation therapy (IMRT) dose escalation with concurrent gemcitabine. Methods and Materials: Forty-six patients with unresectable LAPC were treated at the University of Michigan on a phase 1/2 trial of IMRT dose escalation with concurrent gemcitabine. CA19-9 was obtained at baseline and during routine follow-up. Cox models were used to assess the effect of baseline factorsmore » on freedom from local progression (FFLP), distant progression (FFDP), progression-free survival (PFS), and overall survival (OS). Stepwise forward regression was used to build multivariate predictive models for each endpoint. Results: Thirty-eight patients were eligible for the present analysis. On univariate analysis, baseline CA19-9 and age predicted OS, CA19-9 at baseline and 3 months predicted PFS, gross tumor volume (GTV) and black race predicted FFLP, and CA19-9 at 3 months predicted FFDP. On stepwise multivariate regression modeling, baseline CA19-9, age, and female sex predicted OS; baseline CA19-9 and female sex predicted both PFS and FFDP; and GTV predicted FFLP. Patients with baseline CA19-9 ≤90 U/mL had improved OS (median 23.0 vs 11.1 months, HR 2.88, P<.01) and PFS (14.4 vs 7.0 months, HR 3.61, P=.001). CA19-9 progression over 90 U/mL was prognostic for both OS (HR 3.65, P=.001) and PFS (HR 3.04, P=.001), and it was a stronger predictor of death than either local progression (HR 1.46, P=.42) or distant progression (HR 3.31, P=.004). Conclusions: In patients with unresectable LAPC undergoing definitive chemoradiation therapy, baseline CA19-9 was independently prognostic even after established prognostic factors were controlled for, whereas CA19-9 progression strongly predicted disease progression and death. Future trials should stratify by baseline CA19-9 and incorporate CA19-9 progression as a criterion for progressive disease.« less

Characterization of Retinal Disease Progression in a 1-Year Longitudinal Study of Eyes With Mild Nonproliferative Retinopathy in Diabetes Type 2.

PubMed

Ribeiro, Luisa; Bandello, Francesco; Tejerina, Amparo Navea; Vujosevic, Stela; Varano, Monica; Egan, Catherine; Sivaprasad, Sobha; Menon, Geeta; Massin, Pascale; Verbraak, Frank D; Lund-Andersen, Henrik; Martinez, Jose P; Jürgens, Ignasi; Smets, Erica; Coriat, Caroline; Wiedemann, Peter; Ágoas, Victor; Querques, Giuseppe; Holz, Frank G; Nunes, Sandrina; Neves, Catarina; Cunha-Vaz, José

2015-08-01

To identify eyes of patients with diabetes type 2 that show progression of retinal disease within a 1-year period using noninvasive techniques. Three hundred seventy-four type 2 diabetic patients with mild nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study [ETDRS] level 20 or 35) were included in a 12-month prospective observational study to identify retinopathy progression. Four visits were scheduled at 0, 3, 6, and 12 months. Microaneurysm (MA) activity using the RetmarkerDR and retinal thickness using spectral-domain optical coherence tomography (SD-OCT) were assessed by a central reading center at all visits and ETDRS severity level in the first and last visits. Three hundred thirty-one eyes/patients completed the study. Microaneurysm formation rate greater than or equal to 2 was present in 68.1% of the eyes and MA turnover greater than or equal to 6 in 54.0% at month 6. Higher MA turnover values were registered in eyes that showed progression in ETDRS severity level (P < 0.03). There were also significant correlations between increased microaneurysm activity and increases in retinal thickness. Spectral-domain OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Progression of retinal thickening was registered in eyes that had either subclinical or clinical macular edema at baseline. Changes in MA activity measured with RetmarkerDR and in central retinal thickness in eyes with mild nonproliferative diabetic retinopathy and diabetes type 2 are able to identify eyes at risk of progression. These eyes/patients should be selected for inclusion in future clinical trials of drugs targeted to prevent diabetic retinopathy progression to vision-threatening complications. (ClinicalTrials.gov number, NCT01145599.)

The role of early magnetic resonance imaging in predicting survival on bevacizumab for recurrent glioblastoma: Results from a prospective clinical trial (CABARET).

PubMed

Field, Kathryn M; Phal, Pramit M; Fitt, Greg; Goh, Christine; Nowak, Anna K; Rosenthal, Mark A; Simes, John; Barnes, Elizabeth H; Sawkins, Kate; Cher, Lawrence M; Hovey, Elizabeth J; Wheeler, Helen

2017-09-15

Bevacizumab has been associated with prolonged progression-free survival for patients with recurrent glioblastoma; however, not all derive a benefit. An early indicator of efficacy or futility may allow early discontinuation for nonresponders. This study prospectively assessed the role of early magnetic resonance imaging (eMRI) and its correlation with subsequent routine magnetic resonance imaging (MRI) results and survival. Patients were part of a randomized phase 2 clinical trial (CABARET) comparing bevacizumab with bevacizumab plus carboplatin for recurrent glioblastoma. eMRI was conducted after 4 weeks in the trial (after 2 treatments with bevacizumab [10 mg/kg every 2 weeks]). The results were compared with the results of the subsequent 8-week MRI standard. For 119 of 122 patients, eMRI was available, and 111 had subsequent MRI for comparison. Thirty-six (30%) had an early radiological response, and 17 (14%) had progressive disease. The concordance between eMRI and 8-week MRI was moderate (κ = 0.56), with most providing the same result (n = 79 [71%]). There was strong evidence that progression-free survival and overall survival were predicted by the eMRI response (both P values < .001). The median survival was 8.6 months for an eMRI response, 6.6 months for stable disease, and 3.7 months for progressive disease; the hazard ratio (progressive disease vs stable disease) was 3.4 (95% confidence interval, 1.9-6.0). Landmark analyses showed that eMRI progression was a strong predictor of mortality independent of other potential baseline predictors. In this study, early progression on MRI appears to be a robust marker of a poor prognosis for patients on bevacizumab. Cancer 2017;123:3576-82. © 2017 American Cancer Society. © 2017 American Cancer Society.

Biodegradation studies of selected hydrocarbons from diesel oil.

PubMed

Sepic, E; Trier, C; Leskovsek, H

1996-10-01

In-vitro biodegradation of aliphatic and aromatic hydrocarbons present in diesel oil by Pseudomonas fluorescens, Texaco was studied in an aqueous medium. Small aliquots of diesel oil and its aromatic fraction were incubated aerobically for periods of up to seven months and analysed by GC-MS. Biotic losses proved to be greater for aliphatic than aromatic compounds. Most biodegradation occurred within the first 20 d of incubation. The most rapid biodegradation, up to 65% in 8 d, was observed for n-alkanes (C14-C18). The same compounds were also shown to be less affected by abiotic losses. Biodegradation of n-alkanes from diesel oil and diesel oil itself showed first order kinetics for the initial incubation period. Aromatic compounds proved to be resistant to biodegradation and only phenanthrene had been degraded (30%) within 6 months.

Targeting TMPRSS2 ERG in Prostate Cancer

DTIC Science & Technology

2016-09-01

Assay development for surface Plasmon resonance with purified ERG protein (months 31-36, completed July 2016) 7c. Perform thermal shift and...surface Plasmon resonance on compounds and determine binding constants (months 37-42, completed July 2016) Task 8. Identify FDA approved drugs that

Research Progress of Natural Product Gentiopicroside - a Secoiridoid Compound.

PubMed

Wu, Shaoping; Ning, Yaoyao; Zhao, Yingyong; Sun, Wenji; Thorimbert, Serge; Dechoux, Luc; Sollogoub, Matthieu; Zhang, Yongmin

2017-01-01

Gentiopicroside is a secoiridoid compound isolated from Gentiana lutea which is called Qin Jiao in Chinese. It is one of the most common herbal medicines used in China. In this article, we review the pharmacological and biological activity (antiviral, anti-inflammatory, analgesia, antihepatotoxic and choleretic), as well as biotransformation of the gentiopicroside. In addition, attempt towards the total synthesis of gentiopicroside is also presented.

Vision Integrating Strategies in Ophthalmology and Neurochemistry (VISION)

DTIC Science & Technology

2012-02-01

23, PPT and DPN (Table 1). The most potent of these compounds, ZYC-3, ZYC-26 and G1 are non- feminizing compared to the inactive compounds; PPT, an...induced cytotoxicity. Although these agents are estrogen analogs, they lack feminizing activity. • Discovered progressive quantitative changes in...Abstract #4619 Nixon ES, Simpkins JW. Neuroprotective effects of non- feminizing estrogen analogues in retinal neurons. 2011 Society for Neuroscience

Systems integration of marketable subsystems: A collection of progress reports

NASA Technical Reports Server (NTRS)

1978-01-01

Monthly progress reports are given in the areas of marketable subsystems integration; development, design, and building of site data acquisition subsystems and data processing systems; operation of the solar test facility and a systems analysis.

Stabilization of a progressive hemangioblastoma under treatment with thalidomide.

PubMed

Piribauer, Maria; Czech, Thomas; Dieckmann, Karin; Birner, Peter; Hainfellner, Johannes A; Prayer, Daniela; Fazeny-Dörner, Barbara; Weinländer, Georg; Marosi, Christine

2004-02-01

After the second recurrence of spinal seeding in hemangioblastoma not associated to von-Hippel-Lindau disease, we treated an adult female patient with thalidomide 200 mg orally/day at night for longer than 1 year. The patient reported subjective relief of symptoms after 1 month. Magnetic resonance imaging (MRI) controls 1,6 and 11 months after begin of thalidomide treatment did not show further tumor progression. She remained wheelchair-bound, but mobility of her arms continuously improved. There was no thalidomide associated side-effect in this patient until her death from pneumonia due to legionnaire's disease. Antiangiogenic treatment with interferon (IFN) alpha-2a and IFN alpha-2b and with SU 5416 has been reported to be effective and well tolerated in several patients with previously progressive angioblastomas and hemangioblastomas. This case adds further evidence of the efficacy of an antiangiogenic treatment concept in a progressive hemangioblastoma.

Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study.

PubMed

Necchi, A; Joseph, R W; Loriot, Y; Hoffman-Censits, J; Perez-Gracia, J L; Petrylak, D P; Derleth, C L; Tayama, D; Zhu, Q; Ding, B; Kaiser, C; Rosenberg, J E

2017-12-01

Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator's discretion: this analysis assessed post-progression outcomes in these patients. Patients were treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. In total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for ≥ 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma. NCT02108652. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Comparison of the Decomposition VOC Profile during Winter and Summer in a Moist, Mid-Latitude (Cfb) Climate

PubMed Central

Forbes, Shari L.; Perrault, Katelynn A.; Stefanuto, Pierre-Hugues; Nizio, Katie D.; Focant, Jean-François

2014-01-01

The investigation of volatile organic compounds (VOCs) associated with decomposition is an emerging field in forensic taphonomy due to their importance in locating human remains using biological detectors such as insects and canines. A consistent decomposition VOC profile has not yet been elucidated due to the intrinsic impact of the environment on the decomposition process in different climatic zones. The study of decomposition VOCs has typically occurred during the warmer months to enable chemical profiling of all decomposition stages. The present study investigated the decomposition VOC profile in air during both warmer and cooler months in a moist, mid-latitude (Cfb) climate as decomposition occurs year-round in this environment. Pig carcasses (Sus scrofa domesticus L.) were placed on a soil surface to decompose naturally and their VOC profile was monitored during the winter and summer months. Corresponding control sites were also monitored to determine the natural VOC profile of the surrounding soil and vegetation. VOC samples were collected onto sorbent tubes and analyzed using comprehensive two-dimensional gas chromatography – time-of-flight mass spectrometry (GC×GC-TOFMS). The summer months were characterized by higher temperatures and solar radiation, greater rainfall accumulation, and comparable humidity when compared to the winter months. The rate of decomposition was faster and the number and abundance of VOCs was proportionally higher in summer. However, a similar trend was observed in winter and summer demonstrating a rapid increase in VOC abundance during active decay with a second increase in abundance occurring later in the decomposition process. Sulfur-containing compounds, alcohols and ketones represented the most abundant classes of compounds in both seasons, although almost all 10 compound classes identified contributed to discriminating the stages of decomposition throughout both seasons. The advantages of GC×GC-TOFMS were demonstrated for detecting and identifying trace levels of VOCs, particularly ethers, which are rarely reported as decomposition VOCs. PMID:25412504

Comparison of the decomposition VOC profile during winter and summer in a moist, mid-latitude (Cfb) climate.

PubMed

Forbes, Shari L; Perrault, Katelynn A; Stefanuto, Pierre-Hugues; Nizio, Katie D; Focant, Jean-François

2014-01-01

The investigation of volatile organic compounds (VOCs) associated with decomposition is an emerging field in forensic taphonomy due to their importance in locating human remains using biological detectors such as insects and canines. A consistent decomposition VOC profile has not yet been elucidated due to the intrinsic impact of the environment on the decomposition process in different climatic zones. The study of decomposition VOCs has typically occurred during the warmer months to enable chemical profiling of all decomposition stages. The present study investigated the decomposition VOC profile in air during both warmer and cooler months in a moist, mid-latitude (Cfb) climate as decomposition occurs year-round in this environment. Pig carcasses (Sus scrofa domesticus L.) were placed on a soil surface to decompose naturally and their VOC profile was monitored during the winter and summer months. Corresponding control sites were also monitored to determine the natural VOC profile of the surrounding soil and vegetation. VOC samples were collected onto sorbent tubes and analyzed using comprehensive two-dimensional gas chromatography--time-of-flight mass spectrometry (GC × GC-TOFMS). The summer months were characterized by higher temperatures and solar radiation, greater rainfall accumulation, and comparable humidity when compared to the winter months. The rate of decomposition was faster and the number and abundance of VOCs was proportionally higher in summer. However, a similar trend was observed in winter and summer demonstrating a rapid increase in VOC abundance during active decay with a second increase in abundance occurring later in the decomposition process. Sulfur-containing compounds, alcohols and ketones represented the most abundant classes of compounds in both seasons, although almost all 10 compound classes identified contributed to discriminating the stages of decomposition throughout both seasons. The advantages of GC × GC-TOFMS were demonstrated for detecting and identifying trace levels of VOCs, particularly ethers, which are rarely reported as decomposition VOCs.

Phase III, randomised, multicentre trial of maintenance immunotherapy with low-dose interleukin-2 and interferon-alpha for metastatic renal cell cancer.

PubMed

Passalacqua, Rodolfo; Buzio, Carlo; Buti, Sebastiano; Porta, Camillo; Labianca, Roberto; Pezzuolo, Debora; Camisa, Roberta; Sabbatini, Roberto; Benecchi, Luigi; Messina, Caterina; Cengarle, Rita; Vaglio, Augusto; Dalla Chiesa, Matteo; Tomasello, Gianluca; Caminiti, Caterina

2010-04-01

This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD.

Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design.

PubMed

Peeters, Frederique E C M; van Mourik, Manouk J W; Meex, Steven J R; Bucerius, Jan; Schalla, Simon M; Gerretsen, Suzanne C; Mihl, Casper; Dweck, Marc R; Schurgers, Leon J; Wildberger, Joachim E; Crijns, Harry J G M; Kietselaer, Bas L J H

2018-03-21

BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild-moderate CAVS will be included in the study, and baseline 18 F-sodiumfluoride ( 18 F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18 F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18 F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT).

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed.

PubMed

Smith, Nicholas J; Winstone, Anne Marie; Stellitano, Lesley; Cox, Timothy M; Verity, Christopher M

2012-02-01

To report the demographic, phenotypic, and time-to-diagnosis characteristics of children with GM2 gangliosidosis referred to the UK study of Progressive Intellectual and Neurological Deterioration. Case notification is made via monthly surveillance card, administered by the British Paediatric Surveillance Unit to all UK-based paediatricians; children with GM2 gangliosidosis were identified from cases satisfying inclusion in the UK study of Progressive Intellectual and Neurological Deterioration and analysed according to phenotypic and biochemical categories. Between May 1997 and January 2010, 73 individuals with GM2 gangliosidoses were reported: 40 with Tay-Sachs disease, 31 with Sandhoff disease, and two with GM2 activator protein deficiency. Together they account for 6% (73/1164) of all diagnosed cases of progressive intellectual and neurological deterioration. The majority (62/73) were sporadic index cases with no family history. Children of Pakistani ancestry were overrepresented in all subtypes, particularly juvenile Sandhoff disease, accounting for 10 of 11 notified cases. Infantile-onset variants predominated (55/73); the mean age at onset of symptoms was 6.2 and 4.7 months for infantile-onset Tay-Sachs and Sandhoff disease respectively, and 26.2 and 34.7 months for the corresponding juvenile-onset variants. Time to diagnosis averaged 7.4 months and 28.0 months in infantile- and juvenile-onset disease respectively. GM2 gangliosidosis is a significant cause of childhood neurodegenerative disease; timely diagnosis relies upon improved clinical recognition, which may be increasingly important as specific therapies become available. There is a potential benefit from the introduction of screening programmes for high-risk ethnic groups. © The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.

Vascular calcification on plain radiographs is associated with carotid intima media thickness, malnutrition and cardiovascular events in dialysis patients: a prospective observational study

PubMed Central

2013-01-01

Background Vascular calcification (VC) and carotid intima media thickness (CIMT) are strongly associated with cardiovascular (CV) disease. We hypothesized that significant VC on plain radiographs is associated with CIMT and CV events in dialysis patients. In addition, we evaluated risk factors for VC progression on plain radiographs in dialysis patients. Methods In this 2-year observational, prospective study, 67 dialysis patients were included. We checked plain radiographs at baseline and after 2 years. Laboratory tests and malnutrition score were obtained at baseline, after 12 months, and after 24 months. Results The mean age of patients was 56.3 ± 10.3 years and duration of dialysis was 41.3 ± 34.5 months. The prevalence of significant VC was 61.2% and the prevalence of carotid artery atheromatous plaques was 55.6%. Mean CIMT, malnutrition scores, CRP level and prevalence of carotid atheromatous plaques were significantly higher in patients with significant VC. Serum albumin and total iron binding capacity were significantly lower in patients with significant VC compared to patients without significant VC. During a mean observational period of 22 months, patients without significant VC showed lower CV events by the Kaplan-Meyer method (p = 0.010). Progression of VC was found in 35.7% among 56 patients followed up. Hemoglobin after 24 months was an independent factor for progression of VC (Exp(B) = 0.344, 95% Confidence Interval = 0.13 – 0.96, p = 0.034). Conclusions Significant VC on plain radiograph was associated with CIMT, malnutrition, inflammation, and CV events in dialysis patients. Conditions which increase hemoglobin level may retard progression of VC in dialysis patients. PMID:23360132

A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer.

PubMed

Cai, Ling; Zhu, Jian-fei; Zhang, Xue-wen; Lin, Su-xia; Su, Xiao-dong; Lin, Peng; Chen, Kai; Zhang, Lan-jun

2014-11-01

We proposed to identify the efficacy of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) using whole brain radiotherapy (WBRT)/stereotactic radiosurgery (SRS)/surgery in brain metastases from patients with non-small cell lung cancer (NSCLC) and clarify the association between treatment outcome and EGFR gene mutation status. A total of 282 patients with NSCLC brain metastases who underwent WBRT/SRS/surgery alone or in combination with TKI were enrolled in our study from 2003-2013. Amplification mutation refractory system technology was used to determine the EGFR mutation status in 109 tissue samples. EGFR mutation detection was performed in 109 patients with tumor tissues. The EGFR positive rate was 50 % (55/109), including 26 exon 19 deletions and 24 L858R mutations. The median follow-up time was 28 months. The median overall survival, median progression-free survival of intracranial disease, and median progression-free survival of extracranial disease was significantly longer for patients with TKI treatment (31.9 vs 17.0 months, P < 0.0001; 19.8 vs 12.0 months, P < 0.0001; and 19.6 vs 12.3 months, P < 0.0001; respectively). In subgroup analysis within the TKI group, patients harboring EGFR mutations had better extracranial disease control (20.4 vs 14.1 months, P = 0.032). Administration of TKI agents with conventional therapy compared with conventional therapy alone might be beneficial for overall survival, progression-free survival of intracranial disease and progression-free survival of extracranial disease in patients with brain metastases from NSCLC independent of EGFR mutations.

A Pilot Study of Hypofractionated Stereotactic Radiation Therapy and Sunitinib in Previously Irradiated Patients With Recurrent High-Grade Glioma

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

Wuthrick, Evan J., E-mail: evan.wuthrick@osumc.edu; Curran, Walter J.; Camphausen, Kevin

Purpose/Objective(s): Angiogenic blockade with irradiation may enhance the therapeutic ratio of radiation therapy (RT) through vascular normalization. We sought to determine the safety and toxicity profile of continuous daily-dosed sunitinib when combined with hypofractionated stereotactic RT (fSRT) for recurrent high-grade gliomas (rHGG). Methods and Materials: Eligible patients had malignant high-grade glioma that recurred or progressed after primary surgery and RT. All patients received a minimum of a 10-day course of fSRT, had World Health Organization performance status of 0 to 1, and a life expectancy of >3 months. During fSRT, sunitinib was administered at 37.5 mg daily. The primary endpoint was acutemore » toxicity, and response was assessed via serial magnetic resonance imaging. Results: Eleven patients with rHGG were enrolled. The fSRT doses delivered ranged from 30 to 42 Gy in 2.5- to 3.75-Gy fractions. The median follow-up time was 40 months. Common acute toxicities included hematologic disorders, fatigue, hypertension, and elevated liver transaminases. Sunitinib and fSRT were well tolerated. One grade 4 mucositis toxicity occurred, and no grade 4 or 5 hypertensive events or intracerebral hemorrhages occurred. One patient had a nearly complete response, and 4 patients had stable disease for >9 months. Two patients (18%) remain alive and progression-free >3 years from enrollment. The 6-month progression-free survival was 45%. Conclusions: Sunitinib at a daily dose of 37.5 mg given concurrently with hypofractionated stereotactic reirradiation for rHGG yields acceptable toxicities and an encouraging 6-month progression-free survival.« less

Mycophenolate mofetil combined with systemic corticosteroids prevents progression to chronic recurrent inflammation and development of 'sunset glow fundus' in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada disease.

PubMed

Abu El-Asrar, Ahmed M; Dosari, Mona; Hemachandran, Suhail; Gikandi, Priscilla W; Al-Muammar, Abdulrahman

2017-02-01

To evaluate the effectiveness and safety of mycophenolate mofetil (MMF) as first-line therapy combined with systemic corticosteroids in initial-onset acute uveitis associated with Vogt-Koyanagi-Harada (VKH) disease. This prospective study included 38 patients (76 eyes). The main outcome measures were final visual acuity, corticosteroid-sparing effect, progression to chronic recurrent granulomatous uveitis and development of complications, particularly 'sunset glow fundus'. The mean follow-up period was 37.0 ± 29.3 (range 9-120 months). Visual acuity of 20/20 was achieved by 93.4% of the eyes. Corticosteroid-sparing effect was achieved in all patients. The mean interval between starting treatment and tapering to 10 mg or less daily was 3.8 ± 1.3 months (range 3-7 months). Twenty-two patients (57.9%) discontinued treatment without relapse of inflammation. The mean time observed off of treatment was 28.1 ± 19.6 months (range 1-60 months). None of the eyes progressed to chronic recurrent granulomatous uveitis. The ocular complications encountered were glaucoma in two eyes (2.6%) and cataract in five eyes (6.6%). None of the eyes developed 'sunset glow fundus', and none of the patients developed any systemic adverse events associated with the treatment. Use of MMF as first-line therapy combined with systemic corticosteroids in patients with initial-onset acute VKH disease prevents progression to chronic recurrent granulomatous inflammation and development of 'sunset glow fundus'. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Chemosaturation with Percutaneous Hepatic Perfusion for Unresectable Isolated Hepatic Metastases from Sarcoma

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

Deneve, Jeremiah L., E-mail: Jeremiah.Deneve@Moffitt.org; Choi, Junsung; Gonzalez, Ricardo J.

Purpose: Treatment of patients with unresectable liver metastases is challenging. Regional therapies to the liver have been developed that maximize treatment of the localized disease process without systemic toxic adverse effects. We discuss the procedural aspects of liver chemosaturation with percutaneous hepatic perfusion (CS-PHP). Methods: We present as an illustration of this technique a case report of the treatment of unresectable metastatic leiomyosarcoma of the liver. Results: A randomized phase III trial for unresectable liver metastases from melanoma was recently completed comparing CS-PHP with melphalan vs. best alternative care (BAC). When compared with BAC, CS-PHP was associated with a significantmore » improvement in hepatic progression-free survival (8.0 months CS-PHP vs. 1.6 months BAC, p < 0.0001) and overall progression-free survival (6.7 months CS-PHP vs. 1.6 months BAC, p < 0.0001), respectively. On the basis of these results, and given our experience as one of the treating institutions for this phase III trial, we appealed for compassionate use of CS-PHP in a patient with isolated bilobar unresectable hepatic metastases from leiomyosarcoma. Four target lesions were identified and monitored to assess treatment response. A total of 4 CS-PHP procedures were performed, with a 25 % reduction in size of the largest lesion observed and 16 month hepatic progression-free survival. Toxicity was mild (neutropenia) and manageable on an outpatient basis. Conclusion: CS-PHP offers several advantages for unresectable hepatic sarcoma metastases. CS-PHP is minimally invasive and repeatable, and it has a predictable and manageable systemic toxicity profile. For appropriately selected patients, CS-PHP can delay tumor progression and could potentially improve survival.« less

Clinical and biomechanical changes following a 4-month toe-out gait modification program for people with medial knee osteoarthritis: a randomized controlled trial.

PubMed

Hunt, M A; Charlton, J M; Krowchuk, N M; Tse, C T F; Hatfield, G L

2018-04-27

To compare changes in knee pain, function, and loading following a 4-month progressive walking program with or without toe-out gait modification in people with medial tibiofemoral knee osteoarthritis. Individuals with medial knee osteoarthritis were randomized to a 4-month program to increase walking activity with (toe-out) or without (progressive walking) concomitant toe-out gait modification. The walking program was similar between the two groups, except that the gait modification group was trained to walk with 15° more toe-out. Primary outcomes included: knee joint pain (WOMAC), foot progression angles and knee joint loading during gait (knee adduction moment (KAM)). Secondary outcomes included WOMAC function, timed stair climb, and knee flexion moments during gait. Seventy-nine participants (40 in toe-out group, 39 in progressive walking group) were recruited. Intention-to-treat analysis showed no between-group differences in knee pain, function, or timed stair climb. However, the toe-out group exhibited significantly greater changes in foot progression angle (mean difference = -9.04° (indicating more toe-out), 95% CI: -11.22°, -6.86°; P < 0.001), late stance KAM (mean difference = -0.26 %BW*ht, 95% CI: -0.39 %BW*ht, -0.12 %BW*ht, P < 0.001) and KAM impulse (-0.06 %BW*ht*s, 95% CI: -0.11 %BW*ht*s, -0.01 %BW*ht*s; P = 0.031) compared to the progressive walking group at follow-up. The only between-group difference that remained at a 1-month retention assessment was foot progression angle, with greater changes in the toe-out group (mean difference = -6.78°, 95% CI: -8.82°, -4.75°; P < 0.001). Though both groups experienced improvements in self-reported pain and function, only the toe-out group experienced biomechanical improvements. NCT02019108. Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

[Research and development on efficacy of Chinese herbal compound].

PubMed

Liu, Jian-Xun; Ren, Jian-Xun; Lin, Cheng-Ren

2016-03-01

The efficacy not only is summarized by clinical effect of Chinese herbal compound on theory of traditional Chinese medicine, but also is manifested to clinical effect by interaction of many intricate chemical substances. The efficacy of Chinese herbal compound is current research focus in field of traditional Chinese medicine. By currently knowing in different aspects which included the progression in efficacy of Chinese herbal compound, symptomatic efficacy of Chinese herbal compound, the relationship between the efficacy and pharmacologic effect of Chinese herbal compound, the efficacy related pharmacodynamic substance and the evaluation of efficacy, it had been summarized mainly problems and methods in research and development process of the efficacy of Chinese herbal compound in this paper. Paper also elucidated problems that need to pay attention in research of efficacy in order to provide references for clinical and experimental studies of efficacy in Chinese herbal compound, boost research and development level of new traditional Chinese drug and facilitate modernization of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology).

PubMed

Soffietti, Riccardo; Trevisan, Elisa; Bertero, Luca; Cassoni, Paola; Morra, Isabella; Fabrini, Maria Grazia; Pasqualetti, Francesco; Lolli, Ivan; Castiglione, Anna; Ciccone, Giovannino; Rudà, Roberta

2014-02-01

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

Stereotactic Ablative Radiation Therapy as First Local Therapy for Lung Oligometastases From Colorectal Cancer: A Single-Institution Cohort Study

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

Filippi, Andrea Riccardo, E-mail: andreariccardo.filippi@unito.it; Badellino, Serena; Ceccarelli, Manuela

2015-03-01

Purpose: To estimate stereotactic ablative radiation therapy (SABR) efficacy and its potential role as an alternative to surgery for the treatment of lung metastases from colorectal cancer. Methods and Materials: Forty consecutive patients who received SABR as first local therapy at the time of lung progression were included, from 2004 to 2014. The primary study endpoint was overall survival. Secondary endpoints were progression-free survival and safety. Results: A single nodule was treated in 26 patients (65%), 2 nodules in 10 patients (25%), 3 in 3 patients (7.5%), and 4 in 1 patient (2.5%), for a total of 59 lesions. The medianmore » delivered biological effective dose was 96 Gy, in 1 to 8 daily fractions. Median follow-up time was 20 months (range, 3-72 months). Overall survival rates at 1, 2, and 5 years were, respectively, 84%, 73%, and 39%, with 14 patients (35%) dead. Median overall survival was 46 months. Progression occurred in 25 patients (62.5%), at a median interval of 8 months; failure at SABR site was observed in 3 patients (7.5%). Progression-free survival rates were 49% and 27% at 1 and 2 years, respectively. Discussion: The results of this retrospective exploratory analysis suggest safety and efficacy of SABR in patients affected with colorectal cancer lung oligometastases and urge inclusion of SABR in prospective clinical trials.« less

Urothelial papilloma of the bladder: a review of 34 de novo cases.

PubMed

Magi-Galluzzi, Cristina; Epstein, Jonathan I

2004-12-01

Urothelial papilloma of the bladder is an uncommon entity when using restrictive diagnostic criteria. We retrospectively studied 34 patients who were diagnosed with urothelial papilloma of the bladder using the criteria of the 1998 WHO/ISUP classification system. Six cases were in-house and the remaining 28 were referred from other institutions as consults to one of the authors. In all cases, the diagnosis of papilloma was the first manifestation of urothelial neoplasia. The mean age of the patients at diagnosis was 57.8 years (range, 23-87 years). The male-to-female ratio was 2.4:1 (24 males and 10 females). The tumor size averaged 3.3 mm (range, 1-20 mm; median, 2 mm). Simple papillary fronds were seen in all cases; in 5 cases the additional finding of secondary budding off of small fronds from larger ones was also seen. In all cases, the fronds had a round morphology; yet in 4 cases elongated fronds were also noted. In 5 cases, dilated lymphatics within the fibrovascular fronds were apparent. One case had foamy histiocytes within the fibrovascular stalks. In all cases, the lining consisted of normal-appearing urothelium without hyperplasia, dysplasia, and/or mitotic figures. Some of the distinctive histologic features seen were changes in the umbrella cells: vacuolization (n = 4), prominence with cytologic atypia (n = 2), eosinophilic syncytial morphology (n = 1), apocrine-like morphology (n = 1), and mucinous metaplasia (n = 1). Follow-up was available in 26 cases with a mean follow-up for those without evidence of progression of 28.9 months (range, 3-127 months). Three patients (8.8%) developed recurrent papilloma 4, 15, and 18 months after the initial diagnosis of papilloma; 1 of these patients also showed progression to noninvasive low-grade urothelial carcinoma at the time of recurrence (15 months). Three patients (8.8%) progressed to higher-grade disease: 2 to noninvasive low grade urothelial carcinoma (11 and 15 months after the original diagnosis) and 1 to a papillary urothelial neoplasm of low malignant potential at 104 months and a noninvasive low-grade urothelial carcinoma at 141 months from the initial diagnosis of papilloma. None of the patients demonstrated progression to either lamina propria (T1) or muscularis propria (T2) invasion. Two patients died of unrelated causes. None of the patients died of bladder cancer. Patients with urothelial papillomas have a low incidence of recurrence and rarely progress to develop urothelial carcinoma. It seems reasonable to avoid labeling these patients as having cancer. It remains to be studied whether and when patients with papillomas who have no evidence of recurrence or progression no longer need to be followed.

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension

PubMed Central

Galiè, Nazzareno; Jansa, Pavel; Pulido, Tomás; Channick, Richard N.; Delcroix, Marion; Ghofrani, Hossein-Ardeschir; Le Brun, Franck-Olivier; Mehta, Sanjay; Perchenet, Loïc; Rubin, Lewis J.; Sastry, B.K.S.; Simonneau, Gérald; Sitbon, Olivier; Souza, Rogério; Torbicki, Adam

2017-01-01

Aims The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. Methods and results Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28–0.86; HR 0.72, 95% CL 0.42–1.22; and HR 0.22, 95% CL 0.15–0.33, respectively). Conclusions For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality. PMID:28329315

Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer.

PubMed

Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng

2017-10-10

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 -15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer.

Cryoablation combined with allogenic natural killer cell immunotherapy improves the curative effect in patients with advanced hepatocellular cancer

PubMed Central

Lin, Mao; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, Lizhi; Xu, Kecheng

2017-01-01

In this study, the clinical efficacy of cryosurgery combined with allogenic natural killer cell immunotherapy for advanced hepatocellular cancer was evaluated. From October 2015 to March 2017, we enrolled 61 patients who met the enrollment criteria and divided them into two groups: 1) the simple cryoablation group (Cryo group, n = 26); and 2) the cryoablation combined with allogenic natural killer cells group (Cryo-NK group, n = 35), the safety and short-term effects were evaluated firstly, then the median progression-free survival, response rate and disease control rate were assessed. All adverse events experienced by the patients were recorded, and included local (e.g., pain, pleural effusion, and ascites) and systemic (e.g., chills, fatigue, and fever) reactions, fever was more frequent. Other possible seriously side effects (e.g., blood or bone marrow changes) were not detected. Combining allogeneic natural killer cells with cryoablation had a synergistic effect, not only enhancing the immune function, improving the quality of life of the patients, but also reducing the expression of AFP and significantly exhibiting good clinical efficacy of the patients. After a median follow-up of 8.7 months (3.9 –15.1months), median progression-free survival was higher in Cryo-NK (9.1 months) than in Cryo (7.6 months, P = 0.0107), median progression-free survival who received multiple natural killer was higher than who just received single natural killer (9.7 months vs.8.4 months, P = 0.0011, respectively), the response rate in Cryo-NK (60.0%) was higher than in Cryo (46.1%, P < 0.05), the disease control rate in Cryo-NK (85.7%) was higher than in Cryo group (69.2%, P < 0.01). Percutaneous cryoablation combined with allogeneic natural killer cell immunotherapy significantly increased median progression-free survival of advanced hepatocellular cancer patients. Multiple allogeneic natural killer cells infusion was associated with better prognosis to advanced hepatocellular cancer. PMID:29137237

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.

PubMed

Galiè, Nazzareno; Jansa, Pavel; Pulido, Tomás; Channick, Richard N; Delcroix, Marion; Ghofrani, Hossein-Ardeschir; Le Brun, Franck-Olivier; Mehta, Sanjay; Perchenet, Loïc; Rubin, Lewis J; Sastry, B K S; Simonneau, Gérald; Sitbon, Olivier; Souza, Rogério; Torbicki, Adam

2017-04-14

The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored. Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively). For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality. © The Author 2017. Published on behalf of the European Society of Cardiology

Doxorubicin-Loaded 70–150 μm Microspheres for Liver-Dominant Metastatic Breast Cancer: Results and Outcomes of a Pilot Study

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

Lin, Yen-Ting, E-mail: ymerically@gmail.com; Médioni, Jacques, E-mail: jacques.medioni@aphp.fr; Amouyal, Grégory, E-mail: gregory.amouyal@aphp.fr

PurposePatients with breast cancer liver metastasis have a poor prognosis. Local therapy for liver metastasis increases survival. The purpose of this pilot prospective study was to evaluate the efficacy and safety of doxorubicin drug-eluting beads chemoembolization for liver-dominant breast cancer metastasis (LdBM) refractory to chemotherapy.Materials and MethodsAll patients with LdBM refractory to of two or more lines of systemic chemotherapy were screened. Two chemoembolizations at 1-month intervals were scheduled for each patient. Tumor responses were evaluated by MRI every 3 months until progression or death. Adverse events were recorded according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.02)more » 1 month after each chemoembolization. All patients were free from systemic treatment until progression. Patients with hormone-positive receptors and/or HER-positive disease status continued their targeted therapy.ResultsOut of 23 patients enrolled (mean age: 57.5 ± 11.5 years), 17 completed two chemoembolizations and six underwent only one because of severe adverse events. At 3-month follow-up, the disease control rate was 83 %. The median progression-free survival from the first chemoembolization was 8 months, and the median overall survival was 17 months. Nineteen patients remained free from any systemic chemotherapy for a mean of 209 ± 92 days until progression. Eight grade 3 (asthenia n = 3, anemia n = 2, thrombocythemia n = 2, liver toxicity n = 1) (Rev 1 Comment 1) occurred after the first procedure. No patient died directly due to the procedure.ConclusionWhile chemoembolization with doxorubicin eluding beads for refractory LdBM leads to an 83 % disease control rate, it also causes severe side effects that need to be adequately managed.« less

Effectiveness study of atropine for progressive myopia in Europeans.

PubMed

Polling, J R; Kok, R G W; Tideman, J W L; Meskat, B; Klaver, C C W

2016-07-01

PurposeRandomized controlled trials have shown the efficacy of atropine for progressive myopia, and this treatment has become the preferred pattern for this condition in Taiwan. This study explores the effectiveness of atropine 0.5% treatment for progressive high myopia and adherence to therapy in a non-Asian country.MethodsAn effectiveness study was performed in Rotterdam, the Netherlands. Overall 77 children (mean age 10.3 years±2.3), of European (n=53), Asian (n=18), and African (n=6) descent with progressive myopia were prescribed atropine 0.5% eye drops daily. Both parents and children filled in a questionnaire regarding adverse events and adherence to therapy. A standardized eye examination including cycloplegic refraction and axial length was performed at baseline and 1, 4, and 12 months after initiation of therapy.ResultsMean spherical equivalent at baseline was -6.6D (±3.3). The majority (60/77, 78%) of children adhered to atropine treatment for 12 months; 11 of the 17 children who discontinued therapy did so within 1 month after the start of therapy. The most prominent reported adverse events were photophobia (72%), followed by reading problems (38%), and headaches (22%). The progression rate of spherical equivalent before treatment (-1.0D/year±0.7) diminished substantially during treatment (-0.1D/year±0.7) compared to those who ceased therapy (-0.5D/year±0.6; P=0.03).ConclusionsDespite the relatively high occurrence of adverse events, our study shows that atropine can be an effective and sustainable treatment for progressive high myopia in Europeans.

Seasonal changes of concentrations of inorganic and organic nitrogen in coastal marine sediments

NASA Astrophysics Data System (ADS)

Yamada, Hisashi; Kayama, Mitsu; Fujisawa, Kuniyasu

1987-05-01

The seasonal fluctuations of the concentration of nitrogenous compounds in sediments was investigated for three regions of the Seto Inland Sea in Japan; the variation of nitrogenous compounds in sediments was also studied in a laboratory experiment. The amounts of ammonium, dissolved organic nitrogen, nitrite and nitrate, as percentages of the dissolved total nitrogen of the interstitial water, were in the ranges of 47-99%, 10-50%, 0·1-0·6% and 0·3-4·1%, respectively. Ammonium was the major component and organic nitrogen was the next most important. The concentrations of these nitrogenous compounds changed seasonally: dissolved total nitrogen was higher in the warm month of September than in May; ammonium increased in warm months and decreased in cold months, but nitrite and nitrate increased in cold months. It was possible to explain the seasonal fluctuation of nitrogenous compounds in terms of the rates of the metabolic pathways of nitrogen in the sediments. Ammonium was not necessarily correlated with dissolved organic nitrogen. From this, it was considered that ammonium did not occur from solubilization of particulate organic nitrogen followed by mineralization, but from direct mineralization of particulate organic nitrogen in sediments. For the sediments of Suho Nada, Hiuchi Nada and station B-47 in Beppu Bay, the ratio of dissolved ammonium to adsorbed ammonium in the sediments was in the range 10-25%, but the ratio was 60-70% of adsorbed ammonium in the considerably anaerobic sediments at station B-45 in Beppu Bay. The ratio of dissolved ammonium to adsorbed ammonium increased with the increase of the concentration of sulfide in sediments. It was recognized that the anaerobic conditions of the sediments led to the dissolution of adsorbed ammonium.

Design of a fragment library that maximally represents available chemical space.

PubMed

Schulz, M N; Landström, J; Bright, K; Hubbard, R E

2011-07-01

Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resulting Fragment Sets have been characterised on the basis of computed physico-chemical properties and their similarity to the Input Libraries. A method that iteratively identifies fragments with the maximum number of similar compounds in the Input Library (Nearest Neighbours) produces the most diverse library. This approach could increase the success of experimental ligand discovery projects, by providing fragments that can be progressed rapidly to larger compounds through access to available similar compounds (known as SAR by Catalog).

Hydraulic Fracturing Fluid Analysis for Regulatory Parameters - A Progress Report

EPA Pesticide Factsheets

This presentation is a progress report on the analysis of Hydraulic Fracturing Fluids for regulatory compounds outlined in the various US EPA methodologies. Fracturing fluids vary significantly in consistency and viscosity prior to fracturing. Due to the nature of the fluids the analytical challenges will have to be addressed. This presentation also outlines the sampling issues associated with the collection of dissolved gas samples.

Progression-free survival as primary endpoint in randomized clinical trials of targeted agents for advanced renal cell carcinoma. Correlation with overall survival, benchmarking and power analysis.

PubMed

Bria, Emilio; Massari, Francesco; Maines, Francesca; Pilotto, Sara; Bonomi, Maria; Porta, Camillo; Bracarda, Sergio; Heng, Daniel; Santini, Daniele; Sperduti, Isabella; Giannarelli, Diana; Cognetti, Francesco; Tortora, Giampaolo; Milella, Michele

2015-01-01

A correlation, power and benchmarking analysis between progression-free and overall survival (PFS, OS) of randomized trials with targeted agents or immunotherapy for advanced renal cell carcinoma (RCC) was performed to provide a practical tool for clinical trial design. For 1st-line of treatment, a significant correlation was observed between 6-month PFS and 12-month OS, between 3-month PFS and 9-month OS and between the distributions of the cumulative PFS and OS estimates. According to the regression equation derived for 1st-line targeted agents, 7859, 2873, 712, and 190 patients would be required to determine a 3%, 5%, 10% and 20% PFS advantage at 6 months, corresponding to an absolute increase in 12-month OS rates of 2%, 3%, 6% and 11%, respectively. These data support PFS as a reliable endpoint for advanced RCC receiving up-front therapies. Benchmarking and power analyses, on the basis of the updated survival expectations, may represent practical tools for future trial' design. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Prototype solar heating and cooling systems

NASA Technical Reports Server (NTRS)

1979-01-01

A combination of monthly progress reports are presented. It contains a summary of activities and progress made from November 1, 1978, to February 28, 1979. The effort calls for the development, manufacture, test, system installation, maintenance, problem resolution, and performance evaluation.

Mass Transportation in Massachusetts : demonstration project progress report no. 4

DOT National Transportation Integrated Search

1963-09-01

This fourth Progress Report presents the results of the first eight months of the program of demonstration experiments which the MTC is conducting in cooperation wit the Office of Transportation of the Housing and Home Finance Agency.

99m-Technetium phosphate compound joint scintigraphy in the management of juvenile osteochondritis dissecans of the femoral condyles

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

Cahill, B.R.; Berg, B.C.

The known sensitivity of joint scintigraphy in following the course of fracture healing caused the authors to believe that this radiologic technique might be valuable in the management of osteochondritis dissecans (OCD). Accordingly, 99mTc-diphosphonate joint scintigraphy was used on 18 patients with OCD of the knee. The average age was 13 1/2 years. The scintigrams were repeated at 6-week intervals until healing had occurred. When the diagnosis of OCD was established by standard roentgenograms and joint scintigraphy, the patients were placed on an activity restriction program, attempting to reach a symptom-free level. The patients were followed for an average ofmore » 18 months. Ninety-five scans were categorized according to their level of scintigraphic activity. This led to a discrete four-part scintigraphic classification that is indicative of the extent of healing or progression of this condition, and precedes changes seen on standard x-rays by months. Joint scintigraphy also rules out anomalies of ossification in the diagnosis of OCD since an anomaly should have a normal scintigraphic appearance. We have concluded that joint scintigraphy is valuable in the management of OCD because of its superior sensitivity to changes in the activity of the lesion. As experience is gained with this technique, those cases that should be prophylactically surgically stabilized may be indicated.« less

Selected approaches for rational drug design and high throughput screening to identify anti-cancer molecules.

PubMed

Hedvat, Michael; Emdad, Luni; Das, Swadesh K; Kim, Keetae; Dasgupta, Santanu; Thomas, Shibu; Hu, Bin; Zhu, Shan; Dash, Rupesh; Quinn, Bridget A; Oyesanya, Regina A; Kegelman, Timothy P; Sokhi, Upneet K; Sarkar, Siddik; Erdogan, Eda; Menezes, Mitchell E; Bhoopathi, Praveen; Wang, Xiang-Yang; Pomper, Martin G; Wei, Jun; Wu, Bainan; Stebbins, John L; Diaz, Paul W; Reed, John C; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

2012-11-01

Structure-based modeling combined with rational drug design, and high throughput screening approaches offer significant potential for identifying and developing lead compounds with therapeutic potential. The present review focuses on these two approaches using explicit examples based on specific derivatives of Gossypol generated through rational design and applications of a cancer-specificpromoter derived from Progression Elevated Gene-3. The Gossypol derivative Sabutoclax (BI-97C1) displays potent anti-tumor activity against a diverse spectrum of human tumors. The model of the docked structure of Gossypol bound to Bcl-XL provided a virtual structure-activity-relationship where appropriate modifications were predicted on a rational basis. These structure-based studies led to the isolation of Sabutoclax, an optically pure isomer of Apogossypol displaying superior efficacy and reduced toxicity. These studies illustrate the power of combining structure-based modeling with rational design to predict appropriate derivatives of lead compounds to be empirically tested and evaluated for bioactivity. Another approach to cancer drug discovery utilizes a cancer-specific promoter as readouts of the transformed state. The promoter region of Progression Elevated Gene-3 is such a promoter with cancer-specific activity. The specificity of this promoter has been exploited as a means of constructing cancer terminator viruses that selectively kill cancer cells and as a systemic imaging modality that specifically visualizes in vivo cancer growth with no background from normal tissues. Screening of small molecule inhibitors that suppress the Progression Elevated Gene-3-promoter may provide relevant lead compounds for cancer therapy that can be combined with further structure-based approaches leading to the development of novel compounds for cancer therapy.

Progress of research in treatment of hyperlipidemia by monomer or compound recipe of Chinese herbal medicine.

PubMed

Dou, Xiao-bing; Wo, Xing-de; Fan, Chun-lei

2008-03-01

Hyperlipidemia (HLP) is the No.1 risk factor for patients with atherosclerosis (AS) and is directly related to the occurrence of coronary artery disease (CAD) and cerebrovascular disease. Therefore, prevention and treatment of AS is of great importance and of practical significance in controlling the incidence and mortality of CAD. With its peculiar syndrome-dependent therapy, traditional Chinese medicine (TCM) has accumulated abundant practical experiences in this field and good clinical effects have been achieved. Chinese herbal medicine, with its particularly unique advantages and high potentials yet to be tapped, displays its huge strength in HLP prevention and treatment. The progress of studies concerning prevention and treatment of HLP by Chinese herbal medicines, in the form of monomers or compound recipes, is reviewed in this paper.

Recent progress in the synthesis of thiazolo[3,2-a]pyrimidine compounds

NASA Astrophysics Data System (ADS)

Wu, F. Y.; Luo, Y.; Hu, C. B.

2018-01-01

In this paper, the progress in the synthesis of thiazole[3,2-a]pyrimidine compounds in the field of medicine and pesticide were reviewed. The main synthetic routes include: (i) synthesis of thiazolo[3,2-a]pyrimidines, spiro thiazolo[3,2-a]pyrimidines and pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidines by multicomponent reactions (MCRs). (ii) synthesis of thiazolo[3,2-a]pyrimidines by condensation of pyrimidine-2-thiones, which were obtained by Biginelli reaction between aromatic aldehydes and thiourea, with substituted 2-bromo-1-phenylethanone or chloroacetic acid. (iii) synthesis of pyridothieno-fused thiazolo[3,2-a]pyrimidinones via Pictet-Spengler reaction. (iv) synthesis of pyrido[4,3-d]thiazolo[3,2-a]pyrimidine by reacting 2-aminothiazole with the α, β-unsaturated ketones.

CYP2C19 progress curve analysis and mechanism-based inactivation by three methylenedioxyphenyl compounds.

PubMed

Salminen, Kaisa A; Meyer, Achim; Imming, Peter; Raunio, Hannu

2011-12-01

Several in vitro criteria were used to assess whether three methylenedioxyphenyl (MDP) compounds, the isoquinoline alkaloids bulbocapnine, canadine, and protopine, are mechanism-based inactivators of CYP2C19. The recently reported fluorometric CYP2C19 progress curve analysis approach was applied first to determine whether these alkaloids demonstrate time-dependent inhibition. In this experiment, bulbocapnine, canadine, and protopine displayed time dependence and saturation in their inactivation kinetics with K(I) and k(inact) values of 72.4 ± 14.7 μM and 0.38 ± 0.036 min(-1), 2.1 ± 0.63 μM and 0.18 ± 0.015 min(-1), and 7.1 ± 2.3 μM and 0.24 ± 0.021 min(-1), respectively. Additional studies were performed to determine whether other specific criteria for mechanism-based inactivation were fulfilled: NADPH dependence, irreversibility, and involvement of a catalytic step in the enzyme inactivation. CYP2C19 activity was not significantly restored by dialysis when it had been inactivated by the alkaloids in the presence of a NADPH-regenerating system, and a metabolic-intermediate complex-associated increase in absorbance at approximately 455 nm was observed. In conclusion, the CYP2C19 progress curve analysis method revealed time-dependent inhibition by these alkaloids, and additional experiments confirmed its quasi-irreversible nature. This study revealed that the CYP2C19 progress curve analysis method is useful for identifying novel mechanism-based inactivators and yields a wealth of information in one run. The alkaloids bulbocapnine, canadine, and protopine, present in herbal medicines, are new mechanism-based inactivators and the first MDP compounds exhibiting quasi-irreversible inactivation of CYP2C19.

Association between Smoking and the Progression of Computed Tomography Findings in Chronic Pancreatitis.

PubMed

Lee, Jeong Woo; Kim, Ho Gak; Lee, Dong Wook; Han, Jimin; Kwon, Hyuk Yong; Seo, Chang Jin; Oh, Ji Hye; Lee, Joo Hyoung; Jung, Jin Tae; Kwon, Joong Goo; Kim, Eun Young

2016-05-23

Smoking and alcohol intake are two wellknown risk factors for chronic pancreatitis. However, there are few studies examining the association between smoking and changes in computed tomography (CT) findings in chronic pancreatitis. The authors evaluated associations between smoking, drinking and the progression of calcification on CT in chronic pancreatitis. In this retrospective study, 59 patients with chronic pancreatitis who had undergone initial and follow-up CT between January 2002 and September 2010 were included. Progression of calcification among CT findings was compared according to the amount of alcohol intake and smoking. The median duration of followup was 51.6 months (range, 17.1 to 112.7 months). At initial CT findings, there was pancreatic calcification in 35 patients (59.3%). In the follow-up CT, progression of calcification was observed in 37 patients (62.7%). Progression of calcification was more common in smokers according to the multivariate analysis (odds ratio [OR], 9.987; p=0.006). The amount of smoking was a significant predictor for progression of calcification in the multivariate analysis (OR, 6.051 in less than 1 pack per day smokers; OR, 36.562 in more than 1 pack per day smokers; p=0.008). Continued smoking accelerates pancreatic calcification, and the amount of smoking is associated with the progression of calcification in chronic pancreatitis.

Incidence of infection in 39-month-old ewes with TMEM154 diplotypes "1 1," "1 3," and "3 3" after natural exposure to ovine progressive pneumonia virus

USDA-ARS?s Scientific Manuscript database

Production and well-being of sheep and goats in many countries are harmfully impacted by small ruminant lentiviruses (SRLV) that cause incurable, progressive diseases. Susceptibility to ovine progressive pneumonia virus (OPPV), the North American form of SRLV, is influenced by variants of the ovine...

Applied technology section. Monthly report, December 1993

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

Buckner, M.R.

1994-01-28

This monthly report contains abstracts of the progress made in various projects from the applied technology section at the Savannah River Plant. Research areas include engineering modeling and simulation, applied physics, experimental thermal hydraulics, and packaging and transportation.

Field Evaluation of Anti-Biofouling Compounds on Optical Instrumentation

NASA Technical Reports Server (NTRS)

McLean, Scott; Schofield, Bryan; Zibordi, Giuseppe; Lewis, Marlon; Hooker, Stanford; Weidemann, Alan

1997-01-01

Biofouling has been a serious question in the stability of optical measurements in the ocean, particularly in moored and drifting buoy applications. Many investigators coat optical surfaces with various compounds to reduce the amount of fouling; to our knowledge, however, there are no objective, in-situ comparative testing of these compounds to evaluate their effectiveness with respect to optical stability relative to untreated controls. We have tested a wide range of compounds at in-situ locations in Halifax Harbour and in the Adriatic Sea on passive optical sensors. Compounds tested include a variety of TBT formulations, antifungal agents, and low-friction silicone-based compounds; time-scales of up to four months were evaluated. The results of these experiments are discussed.

Phase II study of Gleevec® plus hydroxyurea in adults with progressive or recurrent low-grade glioma1

PubMed Central

Reardon, David A.; Desjardins, Annick; Vredenburgh, James J.; Herndon, James E.; Coan, April; Gururangan, Sridharan; Peters, Katherine B.; McLendon, Roger; Sathornsumetee, Sith; Rich, Jeremy N.; Lipp, Eric S.; Janney, Dorothea; Friedman, Henry S.

2013-01-01

Background We evaluated the efficacy of imatinib plus hydroxyurea in patients with progressive/recurrent low-grade glioma. Methods A total of 64 patients with recurrent/progressive low-grade glioma were enrolled in this single-center study that stratified patients into astrocytoma and oligodendroglioma cohorts. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary endpoint was progression-free survival at 12 months (PFS-12) and secondary endpoints were safety, median progression-free survival and radiographic response rate. Results Thirty-two patients were enrolled into each cohort. Eleven patients (17%) had prior radiotherapy and 24 (38%) had received prior chemotherapy. The median PFS and PFS-12 were 11 months and 39%, respectively. Outcome did not differ between the histologic cohorts. No patient achieved a radiographic response. The most common grade 3 or greater adverse events were neutropenia (11%), thrombocytopenia (3%) and diarrhea (3%). Conclusions Imatinib plus hydroxyurea was well tolerated among recurrent/progressive LGG patients but this regimen demonstrated negligible anti-tumor activity. PMID:22371319

Progressive outer retinal necrosis associated with occlusive vasculitis in acquired immunodeficiency syndrome.

PubMed

Tseng, Chien-Chi; Chen, San-Ni; Hwang, Jiunn-Feng; Lin, Chun-Ju; Chen, Huan-Sheng

2015-05-01

A 45-year-old man, a case of acquired immunodeficiency syndrome, received a highly active antiretroviral therapy at the outpatient service for 4 years without regular follow-up. He experienced progressively blurred vision for 6 months and a cutaneous zoster on his back 3 months ago. He was diagnosed with progressive outer retinal necrosis by polymerase chain reaction-restriction fragment length polymorphism using an aqueous humor sample, which revealed an existence of varicella zoster virus. He was given a combination of systemic, intravitreal antiviral and a highly active antiretroviral therapy. Occlusive vasculitis, an unusual finding for progressive outer retinal necrosis, developed in both eyes 1 week after the secondary intravitreal injection. Unfortunately, his vision deteriorated to no light perception in both eyes within 2 weeks. Progressive outer retinal necrosis is characterized clinically as showing minimal or no inflammation in the aqueous and vitreous humors, absence of retinal vasculitis, and patches of yellowish spots located deep in the retina. Physicians should pay attention to this rare case of progressive outer retinal necrosis associated occlusive vasculitis with very poor prognosis in spite of aggressive treatment. Copyright © 2015. Published by Elsevier B.V.

Standardized Treatment of Neonatal Status Epilepticus Improves Outcome.

PubMed

Harris, Mandy L; Malloy, Katherine M; Lawson, Sheena N; Rose, Rebecca S; Buss, William F; Mietzsch, Ulrike

2016-12-01

We aimed to decrease practice variation in treatment of neonatal status epilepticus by implementing a standardized protocol. Our primary goal was to achieve 80% adherence to the algorithm within 12 months. Secondary outcome measures included serum phenobarbital concentrations, number of patients progressing from seizures to status epilepticus, and length of hospital stay. Data collection occurred for 6 months prior and 12 months following protocol implementation. Adherence of 80% within 12 months was partially achieved in patients diagnosed in our hospital; in pretreated patients, adherence was not achieved. Maximum phenobarbital concentrations were decreased (56.8 vs 41.0 µg/mL), fewer patients progressed from seizures to status epilepticus (46% vs 36%), and hospital length of stay decreased by 9.7 days in survivors. In conclusion, standardized, protocol-driven treatment of neonatal status epilepticus improves consistency and short-term outcome. © The Author(s) 2016.

[Nutrition and attention deficit hyperactivity disorder: developmental follow-up of the anthropometric variables of a group of patients receiving treatment with osmotic controlled-release methylphenidate].

PubMed

Dura-Trave, T; Yoldi-Petri, M E; Zardoya-Santos, P

2011-09-01

To perform a developmental analysis of the anthropometric variables of a group of patients diagnosed with attention deficit hyperactivity disorder (ADHD) in order to determine the repercussions of treatment with osmotic controlled-release methylphenidate (MTF-OROS). The medical records of 187 patients with ADHD under treatment with MTF-OROS over a period of 30 months were reviewed. Data collected included weight, height and body mass index at diagnosis (baseline) and at 6, 12, 18, 24 and 30 months' follow-up. The mean age at diagnosis was 8.14 ± 1.6 years. The dose of MTF-OROS was progressively increased until 36.9 ± 12.1 mg/day (1.05 mg/kg/day) at day 30 of the follow-up. At diagnosis, 34.9% of patients had a deficient nutritional situation (subnutrition or malnutrition), which affected 50.3% of the patients at 30 months. The baseline value for weight (Z-score) progressively decreased during treatment until values that were significantly lower than the baseline value at 12 months were reached (p < 0.05); these values remained significantly lower until 30 months. The baseline value for height (Z-score) also progressively decreased during treatment until values that were significantly lower than the baseline value at 24 and 30 months were reached (p < 0.05). At the time they were diagnosed with ADHD, one out of every three patients was in a deficient nutritional situation (subnutrition or malnutrition). Continued treatment with MTF-OROS for 30 months had a negative influence on height, which could perhaps be attenuated by improving the patients' nutrition.

Initiation and progression of physical activity after laparoscopic and open gastric bypass surgery.

PubMed

Evans, Ronald K; Bond, Dale S; Demaria, Eric J; Wolfe, Luke G; Meador, Jill G; Kellum, John M

2004-12-01

This study compared postoperative physical activity participation among patients who underwent laparoscopic (LGBS) or open gastric bypass surgery (OGBS). Postoperative physical activity participation is considered important for achieving optimal weight loss and maintenance after gastric bypass surgery. However, no study has examined the relationship between surgery type and postoperative physical activity. Minimal invasiveness and reduced recovery time associated with LGBS compared with OGBS may permit earlier initiation and faster progression of postsurgical physical activity and potentially contribute to greater long-term adherence rates. Self-reported physical activity participation and aerobic physical activity hours per week at 2-weeks, 3-months, and 6-months postsurgery were assessed among LGBS and OGBS patients (presurgical body mass index of 35 to 70 kg/m(2)) at a university hospital from 1988-2002. Of the 2,235 patients, 531 (24%) and 1704 (76%) underwent LGBS and OGBS, respectively. A greater proportion of LGBS patients reported physical activity participation at each time point compared with OGBS patients (2 week, 76% vs 62%; 3 months, 84% vs 74%; 6 months, 85% vs 76%). Furthermore, LGBS patients reported a significantly greater physical activity duration at 2-weeks postsurgery compared with OGBS patients. A nonsignificant trend toward greater physical activity duration was observed in the LGBS patients at 3 months, whereas 6-month physical activity duration was similar between groups. LGBS, compared with OGBS, may promote earlier onset, progression, and maintenance of physical activity until 6 months postsurgery. Future studies need to prospectively determine whether LGBS, via facilitation of greater engagement in postsurgical physical activity, contributes to more successful weight loss and weight maintenance compared with OGBS.

Progression of Pro23His Retinopathy in a Miniature Swine Model of Retinitis Pigmentosa

PubMed Central

Scott, Patrick A.; de Castro, Juan P. Fernandez; DeMarco, Paul J.; Ross, Jason W.; Njoka, Josephat; Walters, Eric; Prather, Randall S.; McCall, Maureen A.; Kaplan, Henry J.

2017-01-01

Purpose We characterize the progression of retinopathy in Filial 1 (F1) progeny of a transgenic (Tg) founder miniswine exhibiting severe Pro23His (P23H) retinopathy. Methods The F1 TgP23H miniswine progeny were created by crossing TgP23H founder miniswine 53-1 with wild type (WT) inbred miniature swine. Scotopic (rod-driven) and photopic (cone-driven) retinal functions were evaluated in F1 TgP23H and WT littermates using full field electroretinograms (ffERGs) at 1, 2, 3, 6, 9, 12, and 18 months of age, as well as the Tg founder miniswine at 6 years of age. Miniswine were euthanized and their retinas processed for morphologic evaluation at the light and electron microscopic level. Retinal morphology of a 36-month-old Tg miniswine also was examined. Results Wild type littermates reached mature scotopic and photopic retinal function by 3 months, while TgP23H miniswine showed abnormal scotopic ffERGs at the earliest time point, 1 month, and depressed photopic ffERGs after 2 months. Rod and cone photoreceptors (PR) exhibited morphologic abnormalities and dropout from the outer nuclear layer at 1 month, with only a monolayer of cone PR somata remaining after 2 months. The retinas showed progressive neural remodeling of the outer retina that included dendritic retraction of rod bipolar cells and glial seal formation by Müller cells. The TgP23H founder miniswine showed cone PR with relatively intact morphology exclusive to the area centralis. Conclusions The F1 Tg miniswine and the TgP23H founder miniswine exhibit similar retinopathy. Translational Relevance TgP23H miniswine are a useful large-eye model to study pathogenesis and preservation cone PRs in humans with retinitis pigmentosa. PMID:28316877

[Liver and lung metastases of colorectal cancer. Long-term survival and prognostic factors].

PubMed

Sponholz, S; Bölükbas, S; Schirren, M; Oguzhan, S; Kudelin, N; Schirren, J

2016-02-01

The resection of liver and lung metastases from colorectal cancer has not yet been completely investigated. The aim of this study was to investigate the overall survival and prognostic factors for patients with liver and lung metastases from colorectal cancer. A retrospective review of a prospective database of 52 patients with liver and lung metastases from colorectal cancer, undergoing metastasectomy with curative intent from 1999-2009 at a single institution was carried out. The mean overall survival (OS) was 64 months. For synchronous liver and lung metastases the mean overall survival was 63 months (5-year survival 54 %) and for metachronous liver and lung metastases 74 months (5-year survival 58 %, p = 0.451). A poor prognostic outcome was observed in cases of localization of the primary tumor in the rectum (OS 81 vs. 38 months, p = 0.004), with multiple lung metastases (≥ 2 metastases, OS 74 vs. 59 months, p = 0.032) and with disease progression after premetastasectomy chemotherapy (OS 74 vs. 63 vs. 15 months, p < 0.001). No influence on overall survival was detected for bilateral lung metastases, thoracic lymph node metastases, disease recurrence and disease-free interval < 36 months. Metastasectomy for liver and lung metastases of colorectal cancer is associated with a good overall survival in selected cases. Patients with liver and lung metastases should not be routinely excluded from metastasectomy and patients with thoracic lymph node metastases should also not be routinely excluded. Negative prognostic factors for survival are localization of the tumor in the rectum, multiple metastases and disease progression after premetastasectomy chemotherapy. Patients with disease progression after premetastasectomy chemotherapy should be excluded from metastasectomy.

Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome.

PubMed

Madsen, Andreas Nygaard; Hansen, Gitte; Paulsen, Sarah Juel; Lykkegaard, Kirsten; Tang-Christensen, Mads; Hansen, Harald S; Levin, Barry E; Larsen, Philip Just; Knudsen, Lotte Bjerre; Fosgerau, Keld; Vrang, Niels

2010-09-01

The availability of useful animal models reflecting the human obesity syndrome is crucial in the search for novel compounds for the pharmacological treatment of obesity. In the current study, we have performed an extensive characterization of the obesity syndrome in a polygenetic animal model, namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization including blood biochemistry and glucose homeostasis was examined at 2, 3, 6, and 9 months of age. Furthermore, in 6-month-old HE-fed DIO rats, the anti-obesity effects of liraglutide and sibutramine were examined in a 28-day study. Only HE-fed DIO rats developed visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia, and showed a worsening of glucose tolerance over time. In line with the hyperlipidemic profile, a severe hepatic fat infiltration was observed in DIO rats at 6 months of age. The effects of liraglutide and sibutramine were tested in 6-month-old DIO rats. Both compounds effectively reduced food intake and body weight in DIO rats. Liraglutide furthermore improved glucose tolerance when compared with sibutramine. Our data highlights the usefulness of a polygenetic animal model for screening of compounds affecting food intake, body weight, and glucose homeostasis. Furthermore, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents.

Compound 49b Reduces Inflammatory Markers and Apoptosis after Ocular Blast Injury

DTIC Science & Technology

2013-09-01

retinal endothelial cells and in a diabetic retinopathy model [7, 10]. Compound 49b was based on the chemical structure of isoproterenol with chemical...Iraq and Afghanistan wars. N Engl J Med, 2011; 364: 2172-3. 7. Zhang Q, Guy K, Pagadala J, et al., Compound 49b Prevents Diabetes -Induced Apoptosis...is effective in reducing TNF and apoptotic 9 proteins in diabetic animals up to 6 months, when applied daily [7]. Isoproterenol was

Tissue distribution comparison between healthy and fatty liver rats after oral administration of hawthorn leaf extract.

PubMed

Yin, Jingjing; Qu, Jianguo; Zhang, Wenjie; Lu, Dongrui; Gao, Yucong; Ying, Xixiang; Kang, Tingguo

2014-05-01

Hawthorn leaves, a well-known traditional Chinese medicine, have been widely used for treating cardiovascular and fatty liver diseases. The present study aimed to investigate the therapeutic basis treating fatty liver disease by comparing the tissue distribution of six compounds of hawthorn leaf extract (HLE) in fatty liver rats and healthy rats after oral administration at first day, half month and one month, separately. Therefore, a sensitive and specific HPLC method with internal standard was developed and validated to determine chlorogenic acid, vitexin-4''-O-glucoside, vitexin-2''-O-rhamnoside, vitexin, rutin and hyperoside in the tissues including heart, liver, spleen, kidney, stomach and intestine. The results indicated that the six compounds in HLE presented some bioactivity in treating rat fatty liver as the concentrations of the six compounds varied significantly in inter- and intragroup comparisons (healthy and/or fatty liver group). Copyright © 2013 John Wiley & Sons, Ltd.

Xylella fastidiosa infection of grapevines affects xylem levels of phenolic compounds and pathogenesis-related proteins

USDA-ARS?s Scientific Manuscript database

Pierce’s disease (PD), caused by the xylem-dwelling pathogen Xylella fastidiosa (X.f.), is a serious threat to grape production. The effects of X.f. infection six months post-inoculation on defense-associated proteins and phenolic compounds found in xylem sap and tissue were evaluated. Defense-assoc...

Emission characteristics of volatile organic compounds from semiconductor manufacturing.

PubMed

Chein, HungMin; Chen, Tzu Ming

2003-08-01

A huge amount of volatile organic compounds (VOCs) is produced and emitted with waste gases from semiconductor manufacturing processes, such as cleaning, etching, and developing. VOC emissions from semiconductor factories located at Science-Based Industrial Park, Hsin-chu, Taiwan, were measured and characterized in this study. A total of nine typical semiconductor fabricators (fabs) were monitored over a 12-month period (October 2000-September 2001). A flame ionization analyzer was employed to measure the VOC emission rate continuously in a real-time fashion. The amount of chemical use was adopted from the data that were reported to the Environmental Protection Bureau in Hsin-chu County as per the regulation of the Taiwan Environmental Protection Administration. The VOC emission factor, defined as the emission rate (kg/month) divided by the amount of chemical use (L/month), was determined to be 0.038 +/- 0.016 kg/L. A linear regression equation is proposed to fit the data with the correlation coefficient (R2)=0.863. The emission profiles of VOCs, which were drawn using the gas chromatograph/mass spectrometer analysis method, show that isopropyl alcohol is the dominant compound in most of the fabs.

Detection of decomposition volatile organic compounds in soil following removal of remains from a surface deposition site.

PubMed

Perrault, Katelynn A; Stefanuto, Pierre-Hugues; Stuart, Barbara H; Rai, Tapan; Focant, Jean-François; Forbes, Shari L

2015-09-01

Cadaver-detection dogs use volatile organic compounds (VOCs) to search for human remains including those deposited on or beneath soil. Soil can act as a sink for VOCs, causing loading of decomposition VOCs in the soil following soft tissue decomposition. The objective of this study was to chemically profile decomposition VOCs from surface decomposition sites after remains were removed from their primary location. Pig carcasses were used as human analogues and were deposited on a soil surface to decompose for 3 months. The remains were then removed from each site and VOCs were collected from the soil for 7 months thereafter and analyzed by comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS). Decomposition VOCs diminished within 6 weeks and hydrocarbons were the most persistent compound class. Decomposition VOCs could still be detected in the soil after 7 months using Principal Component Analysis. This study demonstrated that the decomposition VOC profile, while detectable by GC×GC-TOFMS in the soil, was considerably reduced and altered in composition upon removal of remains. Chemical reference data is provided by this study for future investigations of canine alert behavior in scenarios involving scattered or scavenged remains.

Conversion of Azides into Diazo Compounds in Water

PubMed Central

Chou, Ho-Hsuan; Raines, Ronald T.

2013-01-01

Diazo compounds are in widespread use in synthetic organic chemistry, but have untapped potential in chemical biology. We report on the design and optimization of a phosphinoester that mediates the efficient conversion of azides into diazo compounds in phosphate buffer at neutral pH and room temperature. High yields are maintained in the presence of common nucleophilic or electrophilic functional groups, and reaction progress can be monitored by colorimetry. As azido groups are easy to install and maintain in biopolymers or their ligands, this new mode of azide reactivity could have substantial utility in chemical biology. PMID:24053717

Early-onset, slow progression of cone photoreceptor dysfunction and degeneration in CNG channel subunit CNGB3 deficiency.

PubMed

Xu, Jianhua; Morris, Lynsie; Fliesler, Steven J; Sherry, David M; Ding, Xi-Qin

2011-06-01

To investigate the progression of cone dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. Retinal structure and function in CNGB3(-/-) and wild-type (WT) mice were evaluated by electroretinography (ERG), lectin cytochemistry, and correlative Western blot analysis of cone-specific proteins. Cone and rod terminal integrity was assessed by electron microscopy and synaptic protein immunohistochemical distribution. Cone ERG amplitudes (photopic b-wave) in CNGB3(-/-) mice were reduced to approximately 50% of WT levels by postnatal day 15, decreasing further to approximately 30% of WT levels by 1 month and to approximately 20% by 12 months of age. Rod ERG responses (scotopic a-wave) were not affected in CNGB3(-/-) mice. Average CNGB3(-/-) cone densities were approximately 80% of WT levels at 1 month and declined slowly thereafter to only approximately 50% of WT levels by 12 months. Expression levels of M-opsin, cone transducin α-subunit, and cone arrestin in CNGB3(-/-) mice were reduced by 50% to 60% by 1 month and declined to 35% to 45% of WT levels by 9 months. In addition, cone opsin mislocalized to the outer nuclear layer and the outer plexiform layer in the CNGB3(-/-) retina. Cone and rod synaptic marker expression and terminal ultrastructure were normal in the CNGB3(-/-) retina. These findings are consistent with an early-onset, slow progression of cone functional defects and cone loss in CNGB3(-/-) mice, with the cone signaling deficits arising from disrupted phototransduction and cone loss rather than from synaptic defects.

Longitudinal patterns of youth access to cigarettes and smoking progression: Minnesota Adolescent Community Cohort (MACC) study (2000 – 2003)

PubMed Central

Widome, Rachel; Forster, Jean L.; Hannan, Peter J.; Perry, Cheryl L.

2008-01-01

OBJECTIVES To measure community-level changes in the methods youth use to obtain cigarettes over time and to relate these methods to the progression of smoking. METHODS We analyzed 2000-2003 data from the Minnesota Adolescent Community Cohort study, where youth (beginning at age 12), who were living in Minnesota at baseline, were surveyed every six months via telephone. We conducted mixed model repeated measures logistic regression to obtain probabilities of cigarette access methods among past 30-day smokers (n = 340 at baseline). RESULTS The probability of obtaining cigarettes from a commercial source in the past month declined from 0.36 at baseline to 0.22 at the sixth survey point while the probability of obtaining cigarettes from a social source during the previous month increased from 0.54 to 0.76 (p for both trends = 0.0001). At the community level, the likelihood of adolescents obtaining cigarettes from social sources was inversely related to the likelihood of progressing to heavy smoking (p < 0.001). CONCLUSIONS During this time, youth shifted to greater reliance on social sources and less on commercial sources. A trend toward less commercial access to cigarettes accompanied by an increase in social access may translate to youth being less likely to progress to heavier smoking. PMID:17719080

Withaferin A and sulforaphane regulate breast cancer cell cycle progression through epigenetic mechanisms.

PubMed

Royston, Kendra J; Paul, Bidisha; Nozell, Susan; Rajbhandari, Rajani; Tollefsbol, Trygve O

2018-07-01

Little is known about the effects of combinatorial dietary compounds on the regulation of epigenetic mechanisms involved in breast cancer prevention. The human diet consists of a multitude of components, and there is a need to elucidate how certain compounds interact in collaboration. Withaferin A (WA), found in the Indian winter cherry and documented as a DNA methyltransferase (DNMT) inhibitor, and sulforaphane (SFN), a well-known histone deacetylase (HDAC) inhibitor found in cruciferous vegetables, are two epigenetic modifying compounds that have only recently been studied in conjunction. The use of DNMT and HDAC inhibitors to reverse the malignant expression of certain genes in breast cancer has shown considerable promise. Previously, we found that SFN + WA synergistically promote breast cancer cell death. Herein, we determined that these compounds inhibit cell cycle progression from S to G2 phase in MDA-MB-231 and MCF-7 breast cancer. Furthermore, we demonstrate that this unique combination of epigenetic modifying compounds down-regulates the levels of Cyclin D1 and CDK4, and pRB; conversely, the levels of E2F mRNA and tumor suppressor p21 are increased independently of p53. We find these events coincide with an increase in unrestricted histone methylation. We propose SFN + WA-induced breast cancer cell death is attributed, in part, to epigenetic modifications that result in the modulated expression of key genes responsible for the regulation of cancer cell senescence. Copyright © 2018 Elsevier Inc. All rights reserved.

Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function.

PubMed

Ferro, Austin; Carbone, Emily; Marzouk, Evan; Siegel, Asher; Nguyen, Donna; Polley, Kailen; Hartman, Jessilyn; Frederick, Kimberley; Ives, Stephen; Lagalwar, Sarita

2017-01-22

Mitochondrial dysfunction plays a significant role in the aging process and in neurodegenerative diseases including several hereditary spinocerebellar ataxias and other movement disorders marked by progressive degeneration of the cerebellum. The goal of this protocol is to assess mitochondrial dysfunction in Spinocerebellar ataxia type 1 (SCA1) and assess the efficacy of pharmacological targeting of metabolic respiration via the water-soluble compound succinic acid to slow disease progression. This approach is applicable to other cerebellar diseases and can be adapted to a host of water-soluble therapies. Ex vivo analysis of mitochondrial respiration is used to detect and quantify disease-related changes in mitochondrial function. With genetic evidence (unpublished data) and proteomic evidence of mitochondrial dysfunction in the SCA1 mouse model, we evaluate the efficacy of treatment with the water-soluble metabolic booster succinic acid by dissolving this compound directly into the home cage drinking water. The ability of the drug to pass the blood brain barrier can be deduced using high performance liquid chromatography (HPLC). The efficacy of these compounds can then be tested using multiple behavioral paradigms including the accelerating rotarod, balance beam test and footprint analysis. Cytoarchitectural integrity of the cerebellum can be assessed using immunofluorescence assays that detect Purkinje cell nuclei and Purkinje cell dendrites and soma. These methods are robust techniques for determining mitochondrial dysfunction and the efficacy of treatment with water-soluble compounds in cerebellar neurodegenerative disease.

Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior

PubMed Central

Morin, Emilie; Cheng, Sonia; Mete, Ozgur; Serra, Stefano; Araujo, Paula B; Temple, Sara; Cleary, Sean; Gallinger, Steven; Greig, Paul D; McGilvray, Ian; Wei, Alice; Asa, Sylvia L; Ezzat, Shereen

2013-01-01

Pancreatic neuroendocrine tumors (pNETs) are the second most common pancreatic neoplasms, exhibiting a complex spectrum of clinical behaviors. To examine the clinico-pathological characteristics associated with long-term prognosis we reviewed 119 patients with pNETs treated in a tertiary referral center using the WHO 2010 grading and the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems, with a median follow-up of 38 months. Tumor size, immunohistochemistry (IHC) profiling and patient characteristics-determining stage were analyzed. Primary clinical outcomes were disease progression or death. The mean age at presentation was 52 years; 55% were female patients, 11% were associated with MEN1 (multiple endocrine neoplasia 1) or VHL (Von Hippel–Lindau); mean tumor diameter was 3.3 cm (standard deviation, SD) (2.92). The clinical presentation was incidental in 39% with endocrine hypersecretion syndromes in only 24% of cases. Nevertheless, endocrine hormone tissue immunoreactivity was identified in 67 (56.3%) cases. According to WHO 2010 grading, 50 (42%), 38 (31.9%), and 3 (2.5%) of tumors were low grade (G1), intermediate grade (G2), and high grade (G3), respectively. Disease progression occurred more frequently in higher WHO grades (G1: 6%, G2: 10.5%, G3: 67%, P = 0.026) and in more advanced AJCC stages (I: 2%, IV: 63%, P = 0.033). Shorter progression free survival (PFS) was noted in higher grades (G3 vs. G2; 21 vs. 144 months; P = 0.015) and in more advanced AJCC stages (stage I: 218 months, IV: 24 months, P < 0.001). Liver involvement (20 vs. 173 months, P < 0.001) or histologically positive lymph nodes (33 vs. 208 months, P < 0.001) were independently associated with shorter PFS. Conversely, tissue endocrine hormone immunoreactivity, independent of circulating levels was significantly associated with less aggressive disease. Age, gender, number of primary tumors, and heredity were not significantly associated with prognosis. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value. Although the AJCC staging and WHO 2010 grading systems are useful in predicting disease progression, tissue endocrine hormone profiling provides additional information of potentially important prognostic value. PMID:24403235

Comparing clinical attachment level and pocket depth for predicting periodontal disease progression in healthy sites of patients with chronic periodontitis using multi-state Markov models.

PubMed

Mdala, Ibrahimu; Olsen, Ingar; Haffajee, Anne D; Socransky, Sigmund S; Thoresen, Magne; de Blasio, Birgitte Freiesleben

2014-09-01

To understand degeneration of healthy sites and identify factors associated with disease progression in patients with chronic periodontitis. Data on healthy sites from 163 American and Swedish subjects were analysed using two-three-state (health, gingivitis, chronic periodontitis) Markov models based on bleeding on probing (BOP), and either clinical attachment level (CAL) + BOP or pocket depth (PD) + BOP. In 2 years, 10% (CAL + BOP) and 3% (PD + BOP) of healthy sites developed chronic periodontitis. On average, healthy sites remained healthy for 32 months before transiting in both models. Most transitions (87-97%) from health were to the gingivitis state. The expected duration of the gingivitis lesion was 4-5 months and sites recovered with a high probability (96-98%). Disease severity as measured by number of sites with CAL/PD > 4 mm at baseline and smoking, were associated with fast progression from health to chronic periodontitis within 6 months as were gingival redness in the PD + BOP model only. With age, the rate of disease progression to gingivitis decreased. Transition probabilities for gingivitis and chronic periodontitis were higher with CAL + BOP than with PD + BOP. Smoking and disease severity were significant predictors for fast progression. © 2014 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

A method to detect progression of glaucoma using the multifocal visual evoked potential technique

PubMed Central

Wangsupadilok, Boonchai; Kanadani, Fabio N.; Grippo, Tomas M.; Liebmann, Jeffrey M.; Ritch, Robert; Hood, Donald C.

2010-01-01

Purpose To describe a method for monitoring progression of glaucoma using the multifocal visual evoked potential (mfVEP) technique. Methods Eighty-seven patients diagnosed with open-angle glaucoma were divided into two groups. Group I, comprised 43 patients who had a repeat mfVEP test within 50 days (mean 0.9 ± 0.5 months), and group II, 44 patients who had a repeat test after at least 6 months (mean 20.7 ± 9.7 months). Monocular mfVEPs were obtained using a 60-sector pattern reversal dartboard display. Monocular and interocular analyses were performed. Data from the two visits were compared. The total number of abnormal test points with P < 5% within the visual field (total scores) and number of abnormal test points within a cluster (cluster size) were calculated. Data for group I provided a measure of test–retest variability independent of disease progression. Data for group II provided a possible measure of progression. Results The difference in the total scores for group II between visit 1 and visit 2 for the interocular and monocular comparison was significant (P < 0.05) as was the difference in cluster size for the interocular comparison (P < 0.05). Group I did not show a significant change in either total score or cluster size. Conclusion The change in the total score and cluster size over time provides a possible method for assessing progression of glaucoma with the mfVEP technique. PMID:18830654

Illness in breastfeeding infants relates to concentration of lactoferrin and secretory Immunoglobulin A in mother’s milk

PubMed Central

Breakey, Alicia A.; Hinde, Katie; Valeggia, Claudia R.; Sinofsky, Allison; Ellison, Peter T.

2015-01-01

Background and objectives: This study aims to better understand the relationship between immune compounds in human milk and infant health. We hypothesized that the concentration of immune compounds in milk would relate to infant illness symptoms according to two possible theoretical paradigms. In the ‘protective’ paradigm, high concentrations of immune compounds prevent infant illness. The converse, the ‘responsive’ framework, posits that concentrations of immune compounds are elevated in response to infection. Methodology: Milk samples (n = 110) and illness data were collected among the Toba of Argentina from 30 mother–infant dyads. Samples were assayed for two immune proteins, lactoferrin and secretory immunoglobulin A (sIgA). Generalized estimating equations were used to assess the relationship between immune composition of milk and symptoms of illness in infants. Results: Lactoferrin was positively associated with symptoms of illness in infants (odds ratios >1), both in the month preceding the sample collection and the subsequent month. sIgA was negatively associated with symptoms (odds ratios <1) in the preceding and subsequent months, an association which was particularly strong for gastrointestinal symptoms. Conclusions and implications: The two compounds investigated in our study had opposite relationships with symptoms of illness; the positive relationship between lactoferrin and illness lends support to our ‘responsive’ paradigm, and the negative relationship between sIgA and symptoms of illness was consistent with our ‘protective’ framework. That elevated lactoferrin is restricted to periods of illness suggests that there may be a cost to mother or infant associated with persistently elevated lactoferrin that is not incurred with elevated sIgA. PMID:25608691

Seeking new anti-cancer agents from autophagy-regulating natural products.

PubMed

Hua, Fang; Shang, Shuang; Hu, Zhuo-Wei

2017-04-01

Natural products are an important original source of many widely used drugs, including anti-cancer drugs. Early research efforts for seeking anti-cancer therapy from the natural products are mainly focused on the compounds with cytotoxicity capability. The good examples include vinblastine, vincristine, the camptothecin derivatives; topotecan, irinotecan, epipodophyllotoxin derivatives and paclitaxel. In a recent decade, the fundamental progression has been made in the understanding of molecular and cellular mechanisms regarding tumor initiation, metastasis, therapeutic resistance, immune escape, and relapse, which provide a great opportunity for the development of new mechanism-based anticancer drugs, especially drugs against new molecular and cellular targets. Autophagy, a critical cell homeostasis mechanism and promising drug target involved in a verity of human diseases including cancer, can be modulated by many compounds derived from natural products. In this review, we'll give a short introduction of autophagy and discuss the roles of autophagy in the tumorigenesis and progression. And then, we summarize the accumulated evidences to show the anti-tumor effects of several compounds derived from natural products through modulation of autophagy activity.

Frequency doubling technology perimetry for detection of visual field progression in glaucoma: a pointwise linear regression analysis.

PubMed

Liu, Shu; Yu, Marco; Weinreb, Robert N; Lai, Gilda; Lam, Dennis Shun-Chiu; Leung, Christopher Kai-Shun

2014-05-02

We compared the detection of visual field progression and its rate of change between standard automated perimetry (SAP) and Matrix frequency doubling technology perimetry (FDTP) in glaucoma. We followed prospectively 217 eyes (179 glaucoma and 38 normal eyes) for SAP and FDTP testing at 4-month intervals for ≥36 months. Pointwise linear regression analysis was performed. A test location was considered progressing when the rate of change of visual sensitivity was ≤-1 dB/y for nonedge and ≤-2 dB/y for edge locations. Three criteria were used to define progression in an eye: ≥3 adjacent nonedge test locations (conservative), any three locations (moderate), and any two locations (liberal) progressed. The rate of change of visual sensitivity was calculated with linear mixed models. Of the 217 eyes, 6.1% and 3.9% progressed with the conservative criteria, 14.5% and 5.6% of eyes progressed with the moderate criteria, and 20.1% and 11.7% of eyes progressed with the liberal criteria by FDTP and SAP, respectively. Taking all test locations into consideration (total, 54 × 179 locations), FDTP detected more progressing locations (176) than SAP (103, P < 0.001). The rate of change of visual field mean deviation (MD) was significantly faster for FDTP (all with P < 0.001). No eyes showed progression in the normal group using the conservative and the moderate criteria. With a faster rate of change of visual sensitivity, FDTP detected more progressing eyes than SAP at a comparable level of specificity. Frequency doubling technology perimetry can provide a useful alternative to monitor glaucoma progression.

The Chronopsychological Aspects of College Students' Academic Progress

ERIC Educational Resources Information Center

Barbarash, N.; Chichilenko, M.; Tarasenko, N.; Dvurechenskaia, G.; Kuvshinov, D.

2006-01-01

The idea of the human "individual year" (IY) refers to the span of time from one birthday to the next and provisionally divided into trimesters: the first trimester consisting of months one through three from the date of birth, the second consisting of months four through six, the third consisting of months seven through nine, and the…

Identification of a prospective early motor progression cluster of Parkinson's disease: Data from the PPMI study.

PubMed

Vavougios, George D; Doskas, Triantafyllos; Kormas, Constantinos; Krogfelt, Karen A; Zarogiannis, Sotirios G; Stefanis, Leonidas

2018-04-15

The aim of our study is to phenotype PD motor progression, and to detect whether serum, cerebrospinal fluid (CSF), neuroimaging biomarkers and neuropsychological measures characterize PD motor progression phenotypes. We defined motor progression as a difference of at least one point in the Hoehn & Yahr (H&Y) scale between the baseline (Visit 0, V0), 12 months (Visit 04, V04) and 36 months (Visit 08, V08) milestones of the Progression Markers Initiative (PPMI) study. H&Y progression events were recorded at each milestone in order to be used as cluster analysis variables, in order to produce progression phenotypes. Subsequently, cross-cluster comparisons prior to and following (pairwise) propensity score matching were performed in order to assess phenotype - defining characteristics. Four progression clusters where identified: SPPD: Secondarily Progressive PD, H&Y progression between V04 and V08; EPPD: Early Progressive PD. H&Y progression between V0 and V04; NPPD: Non Progressive PD, no H&Y progression; MIPD: Minimally Improving PD, i.e. Minimal H&Y improvement H&Y progression between V04 and V08;. Independent Samples Mann Whitney U tests determined CSF aSyn (p = 0.006, adj p-value = 0.036. I) and Semantic Animal fluency T-score (SFT, p = 0.003, adjusted p-value = 0.016.) as statistically significant cross-cluster characteristics. Following Propensity Score Matching, SFT, Hopkins Verbal Learning Test (Retention/Recall), Serum IGF1, CSF aSyn, DaT-SPECT binding ratios (SBRs) and the Benton Judgement of Line Orientation Test (BJLOT) were determined as statistically significant predictors of cluster differentiation (p < 0.05). SFT, Serum IGF1, CSF aSyn and DaT-SPECT-derived, basal ganglia Striatal Binding Ratios warrant further investigation as possible motor progression biomarkers. Copyright © 2018 Elsevier B.V. All rights reserved.

Mass transportation in Massachusetts : demonstration project progress report no. 3

DOT National Transportation Integrated Search

1963-06-25

The Third Progress Report marks the completion of six months experiments in the program conducted by the Mass Transportation Commission, with the cooperation of the Office of Transportation of the Housing and Home Finance Agency. As of mid-June, expe...

Outcomes After Whole Brain Reirradiation in Patients With Brain Metastases

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

Son, Christina H.; Jimenez, Rachel; Niemierko, Andrzej

Purpose: Patients with brain metastases are often treated with whole brain radiation therapy (WBRT) for purposes of palliation. The treatment of those who experience subsequent intracranial disease progression can include a second course of WBRT, although there is controversy surrounding its safety and efficacy. This study examines the outcomes in patients at Massachusetts General Hospital who underwent reirradiation. Patients and Methods: We examined the medical records of 17 patients at Massachusetts General Hospital with brain metastases who were initially treated with WBRT between 2002 and 2008 and were subsequently retreated with a second course of WBRT. The median dose formore » the first course of WBRT was 35 Gy (range, 28-40 Gy), with a fraction size of 2 to 3 Gy (median, 2.5 Gy). The median dose at reirradiation was 21.6 Gy (range, 14-30 Gy), with a fraction size of 1.5 to 2 Gy (median, 1.8 Gy). Results: The second course of WBRT was administered upon radiographic disease progression in all patients. Of 10 patients with complete follow-up data, 8 patients experienced complete or partial symptom resolution, and 2 did not show clinical improvement. The time to radiographic progression was 5.2 months. The median overall survival for all patients after diagnosis of metastases was 24.7 months. The median survival time after initiation of reirradiation was 5.2 months (95% CI, 1.3-8.7). In 6 patients with stable extracranial disease, the median survival time after retreatment was 19.8 months (95% CI, 2.7-{infinity}), compared with 2.5 months (95% CI, 0.8-5.5) for those with extracranial disease progression (p = 0.05). Acute adverse reactions occurred in 70.5% of patients but were mild to moderate in severity. Conclusion: In select patients and especially those with stable extracranial disease, reirradiation may be an appropriate and effective intervention to provide symptomatic relief and slow intracranial disease progression. Side effects were minimal and did not cause substantial changes in quality of life.« less

Rapidly Progressive Maxillary Atelectasis.

PubMed

Elkhatib, Ahmad; McMullen, Kyle; Hachem, Ralph Abi; Carrau, Ricardo L; Mastros, Nicholas

2017-07-01

Report of a patient with rapidly progressive maxillary atelectasis documented by sequential imaging. A 51-year-old man, presented with left periorbital and retro-orbital pain associated with left nasal obstruction. An initial computed tomographic (CT) scan of the paranasal sinuses failed to reveal any significant abnormality. A subsequent CT scan, indicated for recurrence of symptoms 11 months later, showed significant maxillary atelectasis. An uncinectomy, maxillary antrostomy, and anterior ethmoidectomy resulted in a complete resolution of the symptoms. Chronic maxillary atelectasis is most commonly a consequence of chronic rhinosinusitis. All previous reports have indicated a chronic process but lacked documentation of the course of the disease. This report documents a patient of rapidly progressive chronic maxillary atelectasis with CT scans that demonstrate changes in the maxillary sinus (from normal to atelectatic) within 11 months.

Case Report: Diabetic Foot Ulcer Infection Treated with Topical Compounded Medications.

PubMed

Agbi, Kelechi E; Carvalho, Maria; Phan, Ha; Tuma, Cristiane

2017-01-01

An adult diabetic male with three toes amputated on his right foot presented with an ulcer infection on his left foot, unresponsive to conventional antifungal oral medication for over two months. The ulcerated foot wound had a large impairment on the patient's quality of life, as determined by the Wound-QoL questionnaire. The compounding pharmacist recommended and the physician prescribed two topical compounded medicines, which were applied twice a day, free of charge at the compounding pharmacy. The foot ulcer infection was completely resolved following 13 days of treatment, with no longer any impairment on the patient's quality of life. This scientific case study highlights the value of pharmaceutical compounding in current therapeutics, the importance of the triad relationship, and the key role of the compounding pharmacist in diabetes care. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Flashback phenomenon and residual neurological deficits after the use of "bath salt" 3, 4- methylenedioxypyrovalerone.

PubMed

Mangold, Aaron R; Bravo, Thomas P; Traub, Stephen J; Maher, Steven A; Lipinski, Christopher A

2014-01-01

The use and abuse of designer drugs has been recognized for decades; however there are many derivatives of compounds that make their way into the community. Abuse of compound(s) known on the street as "bath salt" is on the rise. We report the case of a 33-year-old man who complained of "flashbacks" and right arm shaking that followed a night of "bath salt" snorting. The active compound methylenedioxypyrovalerone methamphetamine (MDPV) was confirmed; however, analysis of three different "bath salt" products showed difference in their active components. The patient's symptoms remained stable and he was discharged home after observation in the emergency department with instructions to return for any symptom progression. Practitioners should be aware of the abuse of the compounds and that not all "bath salt" products contain MDPV.

Comparative analysis of machine learning methods in ligand-based virtual screening of large compound libraries.

PubMed

Ma, Xiao H; Jia, Jia; Zhu, Feng; Xue, Ying; Li, Ze R; Chen, Yu Z

2009-05-01

Machine learning methods have been explored as ligand-based virtual screening tools for facilitating drug lead discovery. These methods predict compounds of specific pharmacodynamic, pharmacokinetic or toxicological properties based on their structure-derived structural and physicochemical properties. Increasing attention has been directed at these methods because of their capability in predicting compounds of diverse structures and complex structure-activity relationships without requiring the knowledge of target 3D structure. This article reviews current progresses in using machine learning methods for virtual screening of pharmacodynamically active compounds from large compound libraries, and analyzes and compares the reported performances of machine learning tools with those of structure-based and other ligand-based (such as pharmacophore and clustering) virtual screening methods. The feasibility to improve the performance of machine learning methods in screening large libraries is discussed.

Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

PubMed Central

2009-01-01

CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

Bioremediation of PAH-contamined soils: Consequences on formation and degradation of polar-polycyclic aromatic compounds and microbial community abundance.

PubMed

Biache, Coralie; Ouali, Salma; Cébron, Aurélie; Lorgeoux, Catherine; Colombano, Stéfan; Faure, Pierre

2017-05-05

A bioslurry batch experiment was carried out over five months on three polycyclic aromatic compound (PAC) contaminated soils to study the PAC (PAH and polar-PAC) behavior during soil incubation and to evaluate the impact of PAC contamination on the abundance of microbial communities and functional PAH-degrading populations. Organic matter characteristics and reactivity, assessed through solvent extractable organic matter and PAC contents, and soil organic matter mineralization were monitored during 5 months. Total bacteria and fungi, and PAH-ring hydroxylating dioxygenase genes were quantified. Results showed that PAHs and polar-PACs were degraded with different degradation dynamics. Differences in degradation rates were observed among the three soils depending on PAH distribution and availability. Overall, low molecular weight compounds were preferentially degraded. Degradation selectivity between isomers and structurally similar compounds was observed which could be used to check the efficiency of bioremediation processes. Bacterial communities were dominant over fungi and were most likely responsible for PAC degradation. Abundance of PAH-degrading bacteria increased during incubations, but their proportion in the bacterial communities tended to decrease. The accumulation of some oxygenated-PACs during the bioslurry experiment underlines the necessity to monitor these compounds during application of remediation treatment on PAH contaminated soils. Copyright © 2017 Elsevier B.V. All rights reserved.

Progressive ataxia in a Charolais bull.

PubMed

Zicker, S C; Kasari, T R; Scruggs, D W; Read, W K; Edwards, J F

1988-06-01

A 20-month-old Charolais bull was referred for evaluation of progressive hind limb ataxia. Clinical findings suggested a neuroanatomic lesion caudal to T2. Postmortem histologic examination revealed multifocal, acellular, pale, eosinophilic plaques throughout the cerebellum, which were diagnostic for the disease progressive ataxia of Charolais cattle. This disease is presumed to have a hereditary transmission and is not commonly recognized in the United States.

[Study on early intervention of compound nutrition for cognitive dysfunction in Alzheimer's disease].

PubMed

Wang, Chao; Xie, Wei; Zhu, Jinfeng; Dang, Rui; Wang, Decai

2014-01-01

To observe the early prevention effect of the compound nutrients recipe for cognitive dysfunction of Alzheimer' s disease model-APP-PSN transgenic mouse. 36 APP-PSN transgenic mice aged two months randomly were divided into the intervention group supplied with compound recipe in the diet and the control group fed based feed, the former had high dose and low dose, 12 APP-PSN transgenic negative mice aged two months as the negative control were fed based feed. After 3 months' intervention, four groups' cognitive functions were evaluated using the Morris water maze, active avoidance experiment and jumping stair experiment. There was not statistically different between all the four groups for the weight and food intake. Compared with the control group, Morris water maze's incubation period of the intervention group was lower obviously, and jumping stair experiment's incubation period of the intervention group was higher obviously. In the active avoidance experiment, the high and low dose intervention group' s conditioned response accounted about 46.67% and 45.00% respectively, and the control group's conditioned response accounted about 20.83%. The differences of the three behavioral experiments between control group and intervention group had the statistical significance (P < 0.05), so the same as between control group and negative control group (P < 0.05). And there was no difference between intervention group and negative control group for the three behavioral experiments. The early supplementation with compound nutrition could postpone the occurrence and development of Alzheimer' s disease mice model's cognitive dysfunction.

Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial.

PubMed

O'Leary, Daniel H; Reuwer, Anne Q; Nissen, Steven E; Després, Jean-Pierre; Deanfield, John E; Brown, Michael W; Zhou, Rong; Zabbatino, Salvatore M; Job, Bernard; Kastelein, John J P; Visseren, Frank L J

2011-07-01

The aim of this trial was to determine whether obese patients benefit from treatment with rimonabant in terms of progression of carotid atherosclerosis. Rimonabant, a selective cannabinoid-1 receptor blocker, reduces body weight and improves cardiometabolic risk factors in patients who are obese. A prospective, double-blind, placebo-controlled trial (Atherosclerosis Underlying Development assessed by Intima-media Thickness in patients On Rimonabant (AUDITOR)) randomised 661 patients with abdominal obesity and metabolic syndrome to rimonabant or placebo for 30 months of treatment. The absolute change in the average value for six segments of far wall carotid intima-media thickness from baseline to month 30 was 0.010 ± 0.095 mm in the rimonabant group and 0.012 ± 0.091 mm in the placebo group (p=0.67). The annualised change was an increase of 0.005 ± 0.042 mm for the rimonabant-treated group and 0.007 ± 0.043 mm for the placebo-treated group (p=0.45). There was no difference in atherosclerosis progression between patients receiving rimonabant for 30 months and those receiving placebo for the primary efficacy measure (absolute change in carotid intima-media thickness). These findings are consistent with a similar study using coronary intravascular ultrasound and another study evaluating the occurrence of cardiovascular events. Our findings suggest that a 5% loss of body weight over a 30-month period with rimonabant is insufficient to modify atherosclerosis progression in the carotid artery in obese patients with metabolic syndrome. Clinical trial registration information clinicaltrials.gov Identifier: NCT00228176.

Spiral ganglion degeneration and hearing loss as a consequence of satellite cell death in saposin B-deficient mice.

PubMed

Akil, Omar; Sun, Ying; Vijayakumar, Sarath; Zhang, Wujuan; Ku, Tiffany; Lee, Chi-Kyou; Jones, Sherri; Grabowski, Gregory A; Lustig, Lawrence R

2015-02-18

Saposin B (Sap B) is an essential activator protein for arylsulfatase A in the hydrolysis of sulfatide, a lipid component of myelin. To study Sap B's role in hearing and balance, a Sap B-deficient (B(-/-)) mouse was evaluated. At both light and electron microscopy (EM) levels, inclusion body accumulation was seen in satellite cells surrounding spiral ganglion (SG) neurons from postnatal month 1 onward, progressing into large vacuoles preceding satellite cell degeneration, and followed by SG degeneration. EM also revealed reduced or absent myelin sheaths in SG neurons from postnatal month 8 onwards. Hearing loss was initially seen at postnatal month 6 and progressed thereafter for frequency-specific stimuli, whereas click responses became abnormal from postnatal month 13 onward. The progressive hearing loss correlated with the accumulation of inclusion bodies in the satellite cells and their subsequent degeneration. Outer hair cell numbers and efferent function measures (distortion product otoacoustic emissions and contralateral suppression) were normal in the B(-/-) mice throughout this period. Alcian blue staining of SGs demonstrated that these inclusion bodies corresponded to sulfatide accumulation. In contrast, changes in the vestibular system were much milder, but caused severe physiologic deficits. These results demonstrate that loss of Sap B function leads to progressive sulfatide accumulation in satellite cells surrounding the SG neurons, leading to satellite cell degeneration and subsequent SG degeneration with a resultant loss of hearing. Relative sparing of the efferent auditory and vestibular neurons suggests that alternate glycosphingolipid metabolic pathways predominate in these other systems. Copyright © 2015 the authors 0270-6474/15/353263-13$15.00/0.

Restrictive allograft syndrome after lung transplantation: new radiological insights.

PubMed

Dubbeldam, Adriana; Barthels, Caroline; Coolen, Johan; Verschakelen, Johny A; Verleden, Stijn E; Vos, Robin; Verleden, Geert M; De Wever, Walter

2017-07-01

To describe the CT changes in patients with restrictive allograft syndrome (RAS) after lung transplantation, before and after clinical diagnosis. This retrospective study included 22 patients with clinical diagnosis of RAS. Diagnosis was based on a combination of forced expiratory volume (FEV1) decline (≥20 %) and total lung capacity (TLC) decline (≥10 %). All available CT scans after transplantation were analyzed for the appearance and evolution of lung abnormalities. In 14 patients, non-regressing nodules and reticulations predominantly affecting the upper lobes developed an average of 13.9 months prior to the diagnosis of RAS. Median graft survival after onset of non-regressing abnormalities was 33.5 months, with most patients in follow-up (9/14). In eight patients, a sudden appearance of diffuse consolidations mainly affecting both upper and lower lobes was seen an average of 2.8 months prior to the diagnosis of RAS. Median graft survival was 6.4 months after first onset of non-regressing abnormalities, with graft loss in most patients (6/8). RAS has been previously described as a homogenous group. However, our study shows two different groups of RAS-patients: one with slow progression and one with fast progression. The two groups show different onset and progression patterns of CT abnormalities. • RAS is the newest discovered form of chronic lung allograft dysfunction (CLAD). • RAS is not a homogenous group, as survival varies greatly between patients. • In this study, we see two different CT onset and progression patterns. • These two different CT patterns also correlate with a different survival rate.

Sunitinib-induced hypothyroidism predicts progression-free survival in metastatic renal cell carcinoma patients.

PubMed

Buda-Nowak, Anna; Kucharz, Jakub; Dumnicka, Paulina; Kuzniewski, Marek; Herman, Roman Maria; Zygulska, Aneta L; Kusnierz-Cabala, Beata

2017-04-01

Sunitinib is a tyrosine kinase inhibitor (TKI) used in treatment of metastatic renal cell carcinoma (mRCC), gastrointestinal stromal tumors and pancreatic neuroendocrine tumors. One of the most common side effects related to sunitinib is hypothyroidism. Recent trials suggest correlation between the incidence of hypothyroidism and treatment outcome in patients treated with TKI. This study evaluates whether development of hypothyroidism is a predictive marker of progression-free survival (PFS) in patients with mRCC treated with sunitinib. Twenty-seven patients diagnosed with clear cell mRCC, after nephrectomy and in 'good' or 'intermediate' MSKCC risk prognostic group, were included in the study. All patients received sunitinib as a first-line treatment on a standard schedule (initial dose 50 mg/day, 4 weeks on, 2 weeks off). The thyroid-stimulating hormone serum levels were obtained at the baseline and every 12 weeks of treatment. In statistic analyses, we used Kaplan-Meier method for assessment of progression-free survival; for comparison of survival, we used log-rank test. In our study, the incidence of hypothyroidism was 44%. The patients who had developed hypothyroidism had better median PFS to patients with normal thyroid function 28,3 months [95% (CI) 20.4-36.2 months] versus 9.8 months (6.4-13.1 months). In survival analysis, we perceive that thyroid dysfunction is a predictive factor of a progression-free survival (PFS). In the unified group of patients, the development of hypothyroidism during treatment with sunitinib is a positive marker for PFS. During that treatment, thyroid function should be evaluated regularly.

Long-term patterns of urinary pyroglutamic acid in healthy humans.

PubMed

Lord, Richard S

2016-02-01

An investigation of human biological variation in urinary organic acids, including pyroglutamic acid along with 39 other compounds, was previously reported in which levels were determined for 8 weeks in healthy adult subjects. Here, unique, 4-week-long physiological trends for one of those compounds, pyroglutamic acid (PGA), are reported. When PGA levels for an individual rose above 40 μg/mg creatinine, 4-week downward progressions occurred until levels reached values near 15 μg/mg creatinine and the pattern was reversed when levels for an individual were below that level in the early weeks of the study. The pattern was especially prominent among 8 of the 13 menstruating female subjects suggesting a possible association with metabolic stress of the menstrual cycle. However, it also appeared in 3 of the 8 male subjects where other sources of metabolic stress may be present. The menstrual association is consistent with estrogen-mediated increase in oxidative stress. Since PGA is linked to glutathione turnover, the consistency of extreme values across all individuals displaying the pattern indicates that 15 and 40 μg/mg creatinine may represent limits that trigger shifts in sulfur amino acid metabolism. This is the first observation of approximate month-long cyclic responses in a glutathione-related urinary marker in humans. © 2016 The Author. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Effectiveness study of atropine for progressive myopia in Europeans

PubMed Central

Polling, J R; Kok, R G W; Tideman, J W L; Meskat, B; Klaver, C C W

2016-01-01

Purpose Randomized controlled trials have shown the efficacy of atropine for progressive myopia, and this treatment has become the preferred pattern for this condition in Taiwan. This study explores the effectiveness of atropine 0.5% treatment for progressive high myopia and adherence to therapy in a non-Asian country. Methods An effectiveness study was performed in Rotterdam, the Netherlands. Overall 77 children (mean age 10.3 years±2.3), of European (n=53), Asian (n=18), and African (n=6) descent with progressive myopia were prescribed atropine 0.5% eye drops daily. Both parents and children filled in a questionnaire regarding adverse events and adherence to therapy. A standardized eye examination including cycloplegic refraction and axial length was performed at baseline and 1, 4, and 12 months after initiation of therapy. Results Mean spherical equivalent at baseline was −6.6D (±3.3). The majority (60/77, 78%) of children adhered to atropine treatment for 12 months; 11 of the 17 children who discontinued therapy did so within 1 month after the start of therapy. The most prominent reported adverse events were photophobia (72%), followed by reading problems (38%), and headaches (22%). The progression rate of spherical equivalent before treatment (−1.0D/year±0.7) diminished substantially during treatment (−0.1D/year±0.7) compared to those who ceased therapy (−0.5D/year±0.6; P=0.03). Conclusions Despite the relatively high occurrence of adverse events, our study shows that atropine can be an effective and sustainable treatment for progressive high myopia in Europeans. PMID:27101751

Recovery of polyclonal immunoglobulins one year after autologous stem cell transplantation as a long-term predictor marker of progression and survival in multiple myeloma.

PubMed

González-Calle, Verónica; Cerdá, Seila; Labrador, Jorge; Sobejano, Eduardo; González-Mena, Beatriz; Aguilera, Carmen; Ocio, Enrique María; Vidriales, María Belén; Puig, Noemí; Gutiérrez, Norma Carmen; García-Sanz, Ramón; Alonso, José María; López, Rosa; Aguilar, Carlos; de Coca, Alfonso García; Hernández, Roberto; Hernández, José Mariano; Escalante, Fernando; Mateos, María-Victoria

2017-05-01

Immunoparesis or suppression of polyclonal immunoglobulins is a very common condition in newly diagnosed myeloma patients. However, the recovery of polyclonal immunoglobulins in the setting of immune reconstitution after autologous stem cell transplantation and its effect on outcome has not yet been explored. We conducted this study in a cohort of 295 patients who had undergone autologous transplantation. In order to explore the potential role of immunoglubulin recovery as a dynamic predictor of progression or survival after transplantation, conditional probabilities of progression-free survival and overall survival were estimated according to immunoglobulin recovery at different time points using a landmark approach. One year after transplant, when B-cell reconstitution is expected to be completed, among 169 patients alive and progression free, 88 patients (52%) showed immunoglobulin recovery and 81 (48%) did not. Interestingly, the group with immunoglobulin recovery had a significantly longer median progression-free survival than the group with persistent immunoparesis (median 60.4 vs. 27.9 months, respectively; Hazard Ratio: 0.45, 95%Confidence Interval: 0.31-0.66; P <0.001), and improved overall survival (11.3 vs. 7.3 years; Hazard Ratio: 0.45, 95%Confidence Interval: 0.27-0.74; P =0.002). Furthermore, the percentage of normal plasma cells detected by flow cytometry in the bone marrow assessed at day 100 after transplantation was associated with the immunoglobulin recovery at that time and may predict immunoglobulin recovery in the subsequent months: nine months and one year. In conclusion, the recovery of polyclonal immunoglobulins one year after autologous transplantation in myeloma patients is an independent long-term predictor marker for progression and survival. Copyright© Ferrata Storti Foundation.

Routine Computer Tomography Imaging for the Detection of Recurrences in High-Risk Melanoma Patients.

PubMed

Park, Tristen S; Phan, Giao Q; Yang, James C; Kammula, Udai; Hughes, Marybeth S; Trebska-McGowan, Kasia; Morton, Kathleen E; White, Donald E; Rosenberg, Steven A; Sherry, Richard M

2017-04-01

The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.

Anti-inflammatory use may not negatively impact oncologic outcomes following intravesical BCG for high-grade non-muscle-invasive bladder cancer.

PubMed

Singla, Nirmish; Haddad, Ahmed Q; Passoni, Niccolo M; Meissner, Matthew; Lotan, Yair

2017-01-01

To evaluate whether anti-inflammatory agents affect outcomes in patients receiving intravesical BCG therapy for high-grade (HG) non-muscle-invasive bladder cancer (NMIBC). We reviewed the records of 203 patients in a prospective database of HG NMIBC from 2006 to 2012 at a single institution. Patients who had muscle-invasive disease (n = 32), low-grade pathology (n = 4), underwent early cystectomy within 3 months (n = 25), had <3 months of follow-up (n = 11), or did not receive an induction course of intravesical BCG (n = 32) were excluded. Clinicopathologic data were tabulated including demographics, comorbidities, pathologic stage and grades, intravesical therapy, and concomitant use of aspirin, NSAIDs, COX inhibitors, and statins. Multivariate Cox regression analysis explored predictive factors for recurrence, progression (stage progression or progression to cystectomy), cancer-specific survival (CSS), and overall survival (OS). Ninety-nine patients with HG NMIBC who received at least one induction course of intravesical BCG were identified, with median follow-up of 31.4 months. There were 20 (20.2 %) deaths, including 6 (6.1 %) patients with bladder cancer-related mortality. 13 % patients experienced tumor progression and 27 % underwent cystectomy following failure of intravesical therapy. Anti-inflammatory use included statins (65 %), aspirin (63 %), or non-aspirin NSAIDs/COX inhibitors (26 %). Anti-inflammatory use was not significantly predictive of recurrence, progression, or mortality outcomes on Cox regression. CIS stage was associated with higher progression, while age, BMI, and Charlson score were independent predictors of overall mortality. Despite speculation of inhibitory effects on BCG immunomodulation there was no evidence that anti-inflammatory agents impacted oncologic outcomes in patients receiving BCG for HG NMIBC.

Treatment with Sunitinib for Patients with Progressive Metastatic Pheochromocytomas and Sympathetic Paragangliomas

PubMed Central

Ayala-Ramirez, Montserrat; Chougnet, Cecile N.; Habra, Mouhammed Amir; Palmer, J. Lynn; Leboulleux, Sophie; Cabanillas, Maria E.; Caramella, Caroline; Anderson, Pete; Al Ghuzlan, Abir; Waguespack, Steven G.; Deandreis, Desirée

2012-01-01

Context: Patients with progressive metastatic pheochromocytomas (PHEOs) or sympathetic paragangliomas (SPGLs) face a dismal prognosis. Current systemic therapies are limited. Objectives: The primary end point was progression-free survival determined by RECIST 1.1 criteria or positron emission tomography with [18F]fluorodeoxyglucose/computed tomography ([18F]FDG-PET/CT), in the absence of measurable soft tissue targets. Secondary endpoints were tumor response according to RECIST criteria version 1.1 or FDG uptake, blood pressure control, and safety. Design: We conducted a retrospective review of medical records of patients with metastatic PHEO/SPGL treated with sunitinib from December 2007 through December 2011. An intention-to-treat analysis was performed. Patients and Setting: Seventeen patients with progressive metastatic PHEO/SPGLs treated at the Institut Gustave-Roussy and MD Anderson Cancer Center. Interventions: Patients treated with sunitinib. Results: According to RECIST 1.1, eight patients experienced clinical benefit; three experienced partial response, and five had stable disease, including four with predominant skeletal metastases that showed a 30% or greater reduction in glucose uptake on [18F]FDG-PET/CT. Of 14 patients who had hypertension, six became normotensive and two discontinued antihypertensives. One patient treated with sunitinib and rapamycin experienced a durable benefit beyond 36 months. The median overall survival from the time sunitinib was initiated was 26.7 months with a progression-free survival of 4.1 months (95% confidence interval = 1.4–11.0). Most patients who experienced a clinical benefit were carriers of SDHB mutations. Conclusion: Sunitinib is associated with tumor size reduction, decreased [18F]FDG-PET/CT uptake, disease stabilization, and hypertension improvement in some patients with progressive metastatic PHEO/PGL. Prospective multi-institutional clinical trials are needed to determine the true benefits of sunitinib. PMID:22965939

Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.

PubMed

Lonial, Sagar; Dimopoulos, Meletios; Palumbo, Antonio; White, Darrell; Grosicki, Sebastian; Spicka, Ivan; Walter-Croneck, Adam; Moreau, Philippe; Mateos, Maria-Victoria; Magen, Hila; Belch, Andrew; Reece, Donna; Beksac, Meral; Spencer, Andrew; Oakervee, Heather; Orlowski, Robert Z; Taniwaki, Masafumi; Röllig, Christoph; Einsele, Hermann; Wu, Ka Lung; Singhal, Anil; San-Miguel, Jesus; Matsumoto, Morio; Katz, Jessica; Bleickardt, Eric; Poulart, Valerie; Anderson, Kenneth C; Richardson, Paul

2015-08-13

Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

Hydroxyurea with or without imatinib in the treatment of recurrent or progressive meningiomas: a randomized phase II trial by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).

PubMed

Mazza, Elena; Brandes, Alba; Zanon, Silvia; Eoli, Marika; Lombardi, Giuseppe; Faedi, Marina; Franceschi, Enrico; Reni, Michele

2016-01-01

Hydroxyurea (HU) is among the most widely used salvage therapies in progressive meningiomas. Platelet-derived growth factor receptors are expressed in virtually all meningiomas. Imatinib sensitizes transformed cells to the cytotoxic effects of chemotherapeutic agents that interfere with DNA metabolism. The combination of HU with imatinib yielded intriguing results in recurrent malignant glioma. The current trial addressed the activity of this association against meningioma. Patients with recurrent or progressive WHO grade I-III meningioma, without therapeutic indication for surgery, radiotherapy, or stereotactic radiosurgery, aged 18-75 years, ECOG performance status 0-2, and not on enzyme-inducing anti-epileptic drugs were randomized to receive HU 500 mg BID ± imatinib 400 mg QD until progression, unacceptable toxicity, or patient's refusal. The primary endpoint was progression-free survival rate at 9 months (PFS-9). Between September 2009 and February 2012, 15 patients were randomized to receive HU + imatinib (N = 7; Arm A) or HU alone (N = 8; Arm B). Afterward the trial was prematurely closed due to slow enrollment rate. PFS-9 (A/B) was 0/75%, and median PFS was 4/19.5 months. Median and 2-year overall survival (A/B) rates were: 6/27.5 months; 28.5/75%, respectively. Main G3-4 toxicities were: G3 neutropenia in 1/0, G4 headache in 1/1, and G3 vomiting in 1/0. The conduction of a study in recurrent or progressive meningioma remains a challenge. Given the limited number of patients enrolled, no firm conclusions can be drawn about the combination of imatinib and HU. The optimal systemic therapy for meningioma failing surgery and radiation has yet to be identified.

Statistical research on the bioactivity of new marine natural products discovered during the 28 years from 1985 to 2012.

PubMed

Hu, Yiwen; Chen, Jiahui; Hu, Guping; Yu, Jianchen; Zhu, Xun; Lin, Yongcheng; Chen, Shengping; Yuan, Jie

2015-01-07

Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development.

Structure-Based Virtual Screening of Commercially Available Compound Libraries.

PubMed

Kireev, Dmitri

2016-01-01

Virtual screening (VS) is an efficient hit-finding tool. Its distinctive strength is that it allows one to screen compound libraries that are not available in the lab. Moreover, structure-based (SB) VS also enables an understanding of how the hit compounds bind the protein target, thus laying ground work for the rational hit-to-lead progression. SBVS requires a very limited experimental effort and is particularly well suited for academic labs and small biotech companies that, unlike pharmaceutical companies, do not have physical access to quality small-molecule libraries. Here, we describe SBVS of commercial compound libraries for Mer kinase inhibitors. The screening protocol relies on the docking algorithm Glide complemented by a post-docking filter based on structural protein-ligand interaction fingerprints (SPLIF).

A METHOD FOR AUTOMATED ANALYSIS OF 10 ML WATER SAMPLES CONTAINING ACIDIC, BASIC, AND NEUTRAL SEMIVOLATILE COMPOUNDS LISTED IN USEPA METHOD 8270 BY SOLID PHASE EXTRACTION COUPLED IN-LINE TO LARGE VOLUME INJECTION GAS CHROMATOGRAPHY/MASS SPECTROMETRY

EPA Science Inventory

Data is presented showing the progress made towards the development of a new automated system combining solid phase extraction (SPE) with gas chromatography/mass spectrometry for the single run analysis of water samples containing a broad range of acid, base and neutral compounds...

Recent advances in H-phosphonate chemistry. Part 1. H-phosphonate esters: synthesis and basic reactions.

PubMed

Sobkowski, Michal; Kraszewski, Adam; Stawinski, Jacek

2015-01-01

This review covers recent progress in the preparation of H-phosphonate mono- and diesters, basic studies on mechanistic and stereochemical aspects of this class of phosphorus compounds, and their fundamental chemistry in terms of transformation of P-H bonds into P-heteroatom bonds. Selected recent applications of H-phosphonate derivatives in basic organic phosphorus chemistry and in the synthesis of biologically important phosphorus compounds are also discussed.

RLE (Research Laboratory of Electronics) Progress Report Number 129.

DTIC Science & Technology

1987-01-01

8217," ’,/’.’t MICROCOP ,"Y RESOLUTION TEST C-’HA"-/’%’.’."."% "-’- -" "."o -- - -" " OI FILE COPYAJ MASSACHUSETTS INSTITUTE OF EHOGYD The RESEARCH LABORATORY of...Intercalation Compound Structures and Transitions .................................. 59 10.0 Semiconductor Surface Studies...understanding of the HEMT, which is the basic block in building surface superlattices on III-V compound materials, our device structure has been simu

Effect of pasteurisation and freezing method on bioactive compounds and antioxidant activity of strawberry pulp.

PubMed

Gonçalves, Gilma Auxiliadora Santos; Resende, Nathane Silva; Carvalho, Elisângela Elena Nunes; Resende, Jaime Vilela de; Vilas Boas, Eduardo Valério de Barros

2017-09-01

This study evaluated the stability of strawberry pulp subjected to three factors, pasteurisation (pasteurised and unpasteurised), freezing method (static air and forced air) and storage time (0, 2, 4 and 6 months). Pasteurisation favoured vitamin C retention during storage but enhanced the total loss of phenolics without affecting anthocyanin levels. Freezing by forced air was more effective in retaining phenolics during the first 4 months of storage, although the freezing method did not affect the anthocyanin levels. Processing and storage reduced the levels of individual phenolics. Freezing by forced air was more effective than static air in retaining antioxidant activity of the pulp. Polyphenol oxidase and peroxidase enzyme levels were relatively stable and independent of pasteurisation, freezing and storage time. Even after 6 months of frozen storage, strawberry pulp is a significant source of nutrients and bioactive compounds and retains high antioxidant capacity independent of pasteurisation and freezing method.

Results of a Phase II Study to Evaluate the Efficacy of Docetaxel and Carboplatin in Metastatic Malignant Melanoma Patients Who Failed First-Line Therapy Containing Dacarbazine.

PubMed

Lee, Choong-kun; Jung, Minkyu; Choi, Hye Jin; Kim, Hye Ryun; Kim, Hyo Song; Roh, Mi Ryung; Ahn, Joong Bae; Chung, Hyun Cheol; Heo, Su Jin; Rha, Sun Young; Shin, Sang Joon

2015-10-01

There is no standard second-line regimen for malignant melanoma patients with disease progression after first-line chemotherapy, and platinum-alkylating agents combined with paclitaxel have shown modest efficacy. We conducted a phase II, open-label, single-arm study to test the efficacy of docetaxel combined with carboplatin for malignant melanoma patients who failed previous treatment with dacarbazine. Intravenous docetaxel (35 mg/m(2) on days 1 and 8 of each cycle) and carboplatin (area under the curve 3 on days 1 and 8 of each cycle) was administered every 21 days. Primary end point was objective response rate (ORR). Thirty patients were enrolled in the study, and the median follow-up duration was 19.8 months. Among 25 per-protocol patients, there were three responders (1 with complete response and 2 with partial response) and 17 stable disease patients (ORR, 12.0%). Among the per-protocol population, the median progression-free survival (PFS) was 4.3 months and the median overall survival (OS) was 9.6 months. Uveal melanoma patients (n=9) showed the best prognosis compared to other subtypes (median PFS, 7.6 months; OS, 9.9 months). The most common grade 3 or 4 adverse event was neutropenia (n=15, 50.0%). Docetaxel combined with carboplatin showed association with an acceptable safety profile and overall efficacy for patients with malignant melanoma who had progressed on chemotherapy containing dacarbazine.

Irradiation of Pediatric High-Grade Spinal Cord Tumors

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

Tendulkar, Rahul D.; Pai Panandiker, Atmaram S., E-mail: atmaram.pai-panandiker@stjude.or; Wu Shengjie

2010-12-01

Purpose: To report the outcome using radiation therapy (RT) for pediatric patients with high-grade spinal cord tumors. Methods and Materials: A retrospective chart review was conducted that included 17 children with high-grade spinal cord tumors treated with RT at St. Jude Children's Research Hospital between 1981 and 2007. Three patients had gross total resection, 11 had subtotal resection, and 3 underwent biopsy. The tumor diagnosis was glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 8), or anaplastic oligodendroglioma (n = 2). Seven patients received craniospinal irradiation (34.2-48.6 Gy). The median dose to the primary site was 52.2 Gy (range,more » 38-66 Gy). Results: The median progression-free and overall survivals were 10.8 and 13.8 months, respectively. Local tumor progression at 12 months (79% vs. 30%, p = 0.02) and median survival (13.1 vs. 27.2 months, p = 0.09) were worse for patients with glioblastoma multiforme compared with anaplastic astrocytoma or oligodendroglioma. The median overall survival was shorter for patients when failure included neuraxis dissemination (n = 8) compared with local failure alone (n = 5), 9.6 vs. 13.8 months, p = 0.08. Three long-term survivors with World Health Organization Grade III tumors were alive with follow-up, ranging from 88-239 months. Conclusions: High-grade spinal cord primary tumors in children have a poor prognosis. The propensity for neuraxis metastases as a component of progression after RT suggests the need for more aggressive therapy.« less

Indolent anti-Hu-associated paraneoplastic sensory neuropathy.

PubMed

Graus, F; Bonaventura, I; Uchuya, M; Valls-Solé, J; Reñé, R; Leger, J M; Tolosa, E; Delattre, J Y

1994-12-01

Paraneoplastic sensory neuropathy (PSN) usually runs a subacute progressive course, leaving the patient with severe sensory dysfunction in weeks to months. We describe five patients with PSN, high titers of anti-Hu antibodies (type 1 antineuronal nuclear autoantibodies), and an indolent clinical course. The patients had a median age of 55 years (range, 41 to 72). Four had small-cell (3) or undifferentiated large-cell (1) lung cancer. Patients presented with mild, asymmetric sensory symptoms; in two, the neuropathy was predominant in the arms. Two patients also had a visceral neuropathy causing gastrointestinal dysfunction. The PSN was stable or progressed very slowly without treatment for a median of 18 months (range, 5 to 32) and remained so after treatment with immunoglobulins (1 patient), chemotherapy (3), or both therapies (1). All patients were ambulatory, leading an independent life up until the time of the last visit or until death from the tumor (2 patients). The median follow-up was 36 months (range, 22 to 52). A paraneoplastic origin should be considered in patients with mild, very slowly progressive sensory neuropathies.

A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial.

PubMed

Drooger, Jan C; van Tinteren, Harm; de Groot, Steffen M; Ten Tije, Albert J; de Graaf, Hiltje; Portielje, Johanneke E A; Jager, Agnes; Honkoop, Aafke; Linn, Sabine C; Kroep, Judith R; Erdkamp, Frans L G; Hamberg, Paul; Imholz, Alex L T; van Rossum-Schornagel, Quirine C; Heijns, Joan B; van Leeuwen-Stok, A Elise; Sleijfer, Stefan

2016-10-01

To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016;122:2961-2970. © 2016 American Cancer Society. © 2016 American Cancer Society.

Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program.

PubMed

Papazoglou, Dimitrios; Wannesson, Luciano; Berthold, Dominik; Cathomas, Richard; Gillessen, Silke; Rothermundt, Christian; Hasler, Loretta; Winterhalder, Ralph; Barth, Andreas; Mingrone, Walter; Nussbaum, Catrina Uhlmann; von Rohr, Lukas; von Burg, Philippe; Schmid, Mathias; Richner, Jürg; Baumann, Sylvia; Kühne, Reto; Stenner, Frank; Rothschild, Sacha I

2017-06-01

Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone. Copyright © 2016 Elsevier Inc. All rights reserved.

Conserved mechanisms of tumorigenesis in the Drosophila adult midgut.

PubMed

Martorell, Òscar; Merlos-Suárez, Anna; Campbell, Kyra; Barriga, Francisco M; Christov, Christo P; Miguel-Aliaga, Irene; Batlle, Eduard; Casanova, Jordi; Casali, Andreu

2014-01-01

Whereas the series of genetic events leading to colorectal cancer (CRC) have been well established, the precise functions that these alterations play in tumor progression and how they disrupt intestinal homeostasis remain poorly characterized. Activation of the Wnt/Wg signaling pathway by a mutation in the gene APC is the most common trigger for CRC, inducing benign lesions that progress to carcinomas due to the accumulation of other genetic alterations. Among those, Ras mutations drive tumour progression in CRC, as well as in most epithelial cancers. As mammalian and Drosophila's intestines share many similarities, we decided to explore the alterations induced in the Drosophila midgut by the combined activation of the Wnt signaling pathway with gain of function of Ras signaling in the intestinal stem cells. Here we show that compound Apc-Ras clones, but not clones bearing the individual mutations, expand as aggressive intestinal tumor-like outgrowths. These lesions reproduce many of the human CRC hallmarks such as increased proliferation, blockade of cell differentiation and cell polarity and disrupted organ architecture. This process is followed by expression of tumoral markers present in human lesions. Finally, a metabolic behavioral assay shows that these flies suffer a progressive deterioration in intestinal homeostasis, providing a simple readout that could be used in screens for tumor modifiers or therapeutic compounds. Taken together, our results illustrate the conservation of the mechanisms of CRC tumorigenesis in Drosophila, providing an excellent model system to unravel the events that, upon mutation in Apc and Ras, lead to CRC initiation and progression.

Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial

PubMed Central

Martín-Martorell, P; Roselló, S; Rodríguez-Braun, E; Chirivella, I; Bosch, A; Cervantes, A

2008-01-01

This is a phase II institutional exploratory trial of biweekly irinotecan and cetuximab administration regimen in metastatic colorectal cancer patients progressing to at least one previous chemotherapy line. A total of 40 patients were treated between November 2005 and November 2007 with irinotecan 180 mg m−2 and cetuximab 500 mg m−2 q2w (every 2 weeks), in every 21-day cycles, until unacceptable toxicity or progressive disease. An overall response rate of 22.5% was obtained (two complete and seven partial responses). The disease control rate was 60%. The time to progression was 3.4 months and the overall survival was 8 months. The toxicity compared very favourably to weekly cetuximab combination schedules. Grade 3/4 adverse effects were observed in 12 patients. Overall, our results turn up very similar both in terms of toxicity and efficacy to those obtained by weekly and biweekly administration regimens. PMID:18665167

Aversive and non-aversive memory impairment in the mucopolysaccharidosis II mouse model.

PubMed

Azambuja, Amanda Stapenhorst; Correa, Lilian; Gabiatti, Bernardo Pappi; Martins, Giselle Renata; de Oliveira Franco, Álvaro; Ribeiro, Maria Flávia Marques; Baldo, Guilherme

2018-02-01

Hunter syndrome (MPS II, OMIM 309900) is a lysosomal storage disorder due to deficient iduronate sulphatase activity. Patients present multiple cognitive alterations, and the aim of this work was to verify if MPS II mice also present some progressive cognitive alterations. For that, MPS II mice from 2 to 6 months of age were submitted to repeated open field and inhibitory avoidance tests to evaluate memory parameters. MPS II mice presented impaired memory at 6 months evaluated by open field test. They also performed poorly in the inhibitory avoidance test from 4 months. We conclude that MPS II mice develop cognitive alterations as the disease progresses. These tests can be used in the future to study the efficacy of therapeutic approaches in the central nervous system.

Lymphocyte-conditioned medium in combination with interleukin-2 effectively induces antitumour autoimmunity by adoptive transfer of short activated killer (SHAK) cells.

PubMed

Buer, J; Hilse, R; Dallmann, I; Grosse, J; Kirchner, H; Zorn, U; Hänninen, E L; Franzke, A; Duensing, S; Poliwoda, H

1995-03-01

In this study, effective antitumour immunity was transferred by autologous short activated killer (SHAK) cells induced over four hours with lymphocyte conditioned medium (LCM) and recombinant interleukin-2 (rIL-2). Among eight patients with progressive metastatic renal cell carcinoma refractory to standard therapy, there were six objective tumour responses to SHAKs. Progression-free survival ranged from 0 to 8+ months, and overall survival ranged from 2 to 14+ months, with a median of 9+ months. Systemic toxicity of SHAKs was limited to flulike symptoms. Patient SHAKs provided a tumour-specific immunity, both cellular and humoral (expression and secretion of secondary cytokines, including IL-2, GM-CSF, INF-gamma and TNF-alpha), far superior to rIL-2 activated killer cells.

Recent Progress and Development of Crystal Structure Analysis of Enzymes and Other Proteins

NASA Astrophysics Data System (ADS)

Tanokura, Masaru; Nagata, Koji; Miyazono, Ken-Ichi; Miyakawa, Takuya; Okai, Masahiko

Structural biology has made tremendous progress in this decade. Here we briefly introduce the Target Proteins Research Program, a national project promoted by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. The program aims to reveal the structure and function of proteins that are of great importance in both academic research and industrial application. We also summarize the results of structure-function analyses of (i) transcriptional regulatory proteins useful for the breading of drought and heat stress tolerant crops, (ii) useful enzymes for the production of chiral compounds, and (iii) useful enzymes for the degradation of environmental pollution substances. These results can be utilized in various areas of industries, to enhance food production, to improve the efficiency of pharmaceutical compound production, and to promote the bioremediation of contaminated soil and water.

Sequencing of Local Therapy Affects the Pattern of Treatment Failure and Survival in Children With Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

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

Pai Panandiker, Atmaram S., E-mail: atmaram.pai-panandiker@stjude.org; Merchant, Thomas E.; Beltran, Chris

Purpose: To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). Methods and Materials: Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. Results: Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolledmore » into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% {+-} 9%; progression-free survival was 33.2% {+-} 10%; and OS was 53.5% {+-} 10%. Children receiving delayed RT ({>=}1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. Conclusions: Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.« less

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

PubMed

Fizazi, Karim; Tran, NamPhuong; Fein, Luis; Matsubara, Nobuaki; Rodriguez-Antolin, Alfredo; Alekseev, Boris Y; Özgüroğlu, Mustafa; Ye, Dingwei; Feyerabend, Susan; Protheroe, Andrew; De Porre, Peter; Kheoh, Thian; Park, Youn C; Todd, Mary B; Chi, Kim N

2017-07-27

Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone acetate and prednisone to androgen-deprivation therapy significantly increased overall survival and radiographic progression-free survival in men with newly diagnosed, metastatic, castration-sensitive prostate cancer. (Funded by Janssen Research and Development; LATITUDE ClinicalTrials.gov number, NCT01715285 .).

Developmental Progression of Looking and Reaching Performance on the A-not-B Task

PubMed Central

Cuevas, Kimberly; Bell, Martha Ann

2013-01-01

From a neuropsychological perspective, the cognitive skills of working memory, inhibition, and attention and the maturation of the frontal lobe are requisites for successful A-not-B performance on both the looking and reaching versions of the task. This study used a longitudinal design to examine the developmental progression of infants’ performance on the looking and reaching versions of the A-not-B task. Twenty infants were tested on both versions of the task once a month from 5 to 10 months of age. Infants had higher object permanence scores on the looking version of the task from 5 to 8 months, with comparable performance across response modalities at 9 and 10 months. The same pattern of performance was found on nonreversal (A) trials: Infants performed better on looking trials from 5 to 7 months and they performed equally on both response trials from 8 to 10 months. Overall, infants performed better on looking reversal (B) trials than reaching reversal trials. These data suggest that performance differences between response modalities early in development can be attributed to major differences in the maturation of brain circuitry associated with the actual task response. PMID:20822245

A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE).

PubMed

Radwan, Noura; Phillips, Ryan; Ross, Ashley; Rowe, Steven P; Gorin, Michael A; Antonarakis, Emmanuel S; Deville, Curtiland; Greco, Stephen; Denmeade, Samuel; Paller, Channing; Song, Daniel Y; Diehn, Maximilian; Wang, Hao; Carducci, Michael; Pienta, Kenneth J; Pomper, Martin G; DeWeese, Theodore L; Dicker, Adam; Eisenberger, Mario; Tran, Phuoc T

2017-06-29

We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18 F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease. Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory. The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state. ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://clinicaltrials.gov/show/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

Bevacizumab salvage therapy following progression in high-grade glioma patients treated with VEGF receptor tyrosine kinase inhibitors

PubMed Central

Scott, Brian J.; Quant, Eudocia C.; McNamara, Margaret B.; Ryg, Peter A.; Batchelor, Tracy T.; Wen, Patrick Y.

2010-01-01

Agents targeting the vascular endothelial growth factor (VEGF) pathway are being used with increasing frequency in patients with recurrent high-grade glioma. The effect of more than one antiangiogenic therapy given in succession has not been established. We reviewed the efficacy of bevacizumab, a VEGF-A monoclonal antibody, in patients who progressed following prior therapy with VEGF receptor tyrosine kinase inhibitors (R-TKi). Seventy-three patients with recurrent high-grade gliomas received VEGF R-TKi (cediranib, sorafenib, pazopanib, or sunitinib) as part of phase I or II clinical trials. Twenty-four of these patients with glioblastoma progressed and received bevacizumab-containing regimens immediately after R-TKi. Those who stopped R-TKi therapy for reasons other than disease progression, or received a treatment that did not include bevacizumab, were excluded from the analysis. The efficacy of bevacizumab-containing regimens in these 24 patients was evaluated. During R-TKi therapy, 6 of 24 patients (25%) had a partial response (PR) to treatment. The 6-month progression-free survival (APF6) was 16.7% and median time-to-progression (TTP) was 14.3 weeks. Grade III/IV toxicities were seen in 13 of 24 patients (54%). Subsequently with bevacizumab salvage therapy, 5 of 24 patients (21%) had a PR, the APF6 was 12.5%, and the median TTP was 8 weeks. Five of 24 patients had grade III/IV toxicities (21%). The median overall survival (OS) from the start of R-TKi therapy was 9.2 months (range: 2.8–34.1+), whereas the median OS after bevacizumab was 5.2 months (range: 1.3–28.9+). Bevacizumab retains modest activity in high-grade glioma patients who progress on R-TKi. However, the APF6 of 12.5% in this cohort of patients indicates that durable tumor control is not achieved for most patients. PMID:20156808

Aortic elasticity indices by magnetic resonance predict progression of ascending aorta dilation.

PubMed

Aquaro, Giovanni Donato; Briatico Vangosa, Alessandra; Toia, Patrizia; Barison, Andrea; Ait-Ali, Lamia; Midiri, Massimo; Cotroneo, Antonio Raffaele; Emdin, Michele; Festa, Pierluigi

2017-04-01

Aortic distensibility and pulse-wave velocity (PWV) are under investigation as parameters by which to evaluate the indication for ascending aorta (AA) replacement. The maximum rate of systolic distension (MRSD) was proposed as a new index of aortic elasticity. The aim of this study was to assess the role of aortic elasticity parameters to predict AA growth rates in patients with AA dilation (AAD). Magnetic resonance imaging (MRI) was performed annually in 65 patients with AA dilation (median follow-up 17 months; 25-75th percentile; range 12-30 months). A significant increase in AA diameter was defined as a ≥2-mm increase. An increase in AA diameter was found in 42 (68 %) patients (AAD+ group) and absent in 20. Median increase was 0.16 (25-75th percentile; range 0.32-0.7) mm/month. The AAD+ group had a lower MRSD (4.6 ± 2.2 vs 7.4 ± 2.0, p < 0.001) but the same PWV and distensibility. MRSD showed 93.7 % specificity and 75.6 % sensitivity for prediction of increase. Patients with MRSD ≤ 6 had lower progression-free survival times (p < 0.002). After a follow-up of 4.1 years, patients who underwent surgical therapy had lower MRSD and distensibility than others. MRSD is an index of aorta elastic properties and is a valuable predictor for progression in AAD. • MRI-derived parameters of aortic wall elasticity predict progression of ascending aorta dilation. • Maximal rate of systolic distension (MRSD) was the best predictor of progression. • Patients with MRSD ≤ 6 had lower progression-free survival (PFS) times. • Patients who underwent surgical therapy had lower MRSD and distensibility. • MRI-derived parameters identify patients with fast progression of Ascending Aorta Dilation.

Association between Smoking and the Progression of Computed Tomography Findings in Chronic Pancreatitis

PubMed Central

Lee, Jeong Woo; Kim, Ho Gak; Lee, Dong Wook; Han, Jimin; Kwon, Hyuk Yong; Seo, Chang Jin; Oh, Ji Hye; Lee, Joo Hyoung; Jung, Jin Tae; Kwon, Joong Goo; Kim, Eun Young

2016-01-01

Background/Aims Smoking and alcohol intake are two well-known risk factors for chronic pancreatitis. However, there are few studies examining the association between smoking and changes in computed tomography (CT) findings in chronic pancreatitis. The authors evaluated associations between smoking, drinking and the progression of calcification on CT in chronic pancreatitis. Methods In this retrospective study, 59 patients with chronic pancreatitis who had undergone initial and follow-up CT between January 2002 and September 2010 were included. Progression of calcification among CT findings was compared according to the amount of alcohol intake and smoking. Results The median duration of follow-up was 51.6 months (range, 17.1 to 112.7 months). At initial CT findings, there was pancreatic calcification in 35 patients (59.3%). In the follow-up CT, progression of calcification was observed in 37 patients (62.7%). Progression of calcification was more common in smokers according to the multivariate analysis (odds ratio [OR], 9.987; p=0.006). The amount of smoking was a significant predictor for progression of calcification in the multivariate analysis (OR, 6.051 in less than 1 pack per day smokers; OR, 36.562 in more than 1 pack per day smokers; p=0.008). Conclusions Continued smoking accelerates pancreatic calcification, and the amount of smoking is associated with the progression of calcification in chronic pancreatitis. PMID:26601825

Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia.

PubMed

Byrd, John C; Brown, Jennifer R; O'Brien, Susan; Barrientos, Jacqueline C; Kay, Neil E; Reddy, Nishitha M; Coutre, Steven; Tam, Constantine S; Mulligan, Stephen P; Jaeger, Ulrich; Devereux, Steve; Barr, Paul M; Furman, Richard R; Kipps, Thomas J; Cymbalista, Florence; Pocock, Christopher; Thornton, Patrick; Caligaris-Cappio, Federico; Robak, Tadeusz; Delgado, Julio; Schuster, Stephen J; Montillo, Marco; Schuh, Anna; de Vos, Sven; Gill, Devinder; Bloor, Adrian; Dearden, Claire; Moreno, Carol; Jones, Jeffrey J; Chu, Alvina D; Fardis, Maria; McGreivy, Jesse; Clow, Fong; James, Danelle F; Hillmen, Peter

2014-07-17

In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome. In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia

PubMed Central

Byrd, J.C.; Brown, J.R.; O’Brien, S.; Barrientos, J.C.; Kay, N.E.; Reddy, N.M.; Coutre, S.; Tam, C.S.; Mulligan, S.P.; Jaeger, U.; Devereux, S.; Barr, P.M.; Furman, R.R.; Kipps, T.J.; Cymbalista, F.; Pocock, C.; Thornton, P.; Caligaris-Cappio, F.; Robak, T.; Delgado, J.; Schuster, S.J.; Montillo, M.; Schuh, A.; de Vos, S.; Gill, D.; Bloor, A.; Dearden, C.; Moreno, C.; Jones, J.J.; Chu, A.D.; Fardis, M.; McGreivy, J.; Clow, F.; James, D.F.; Hillmen, P.

2014-01-01

Background In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, in patients at risk for a poor outcome. Methods In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points. Results At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P = 0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group. Conclusions Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.) PMID:24881631

Recent progress in tidal modeling

NASA Technical Reports Server (NTRS)

Vial, F.; Forbes, J. M.

1989-01-01

Recent contributions to tidal theory during the last five years are reviewed. Specific areas where recent progress has occurred include: the action of mean wind and dissipation on tides, interactions of other waves with tides, the use of TGCM in tidal studies. Furthermore, attention is put on the nonlinear interaction between semidiurnal and diurnal tides. Finally, more realistic thermal excitation and background wind and temperature models have been developed in the past few years. This has led to new month-to-month numerical simulations of the semidiurnal tide. Some results using these models are presented and compared with ATMAP tidal climatologies.

Progressive trichodysplasia spinulosa in a patient with chronic lymphocytic leukaemia in remission.

PubMed

Lee, Joyce S-S; Frederiksen, Peter; Kossard, Steven

2008-02-01

A 70-year old Caucasian man with chronic lymphocytic leukaemia developed trichodysplasia spinulosa 2 months after ceasing chemotherapy. Histological features characteristic to this condition include dilated and enlarged hair follicles, hyperplastic hair bulbs, hyperplasia of inner root sheath cells with numerous large, eosinophilic, trichohyaline granules, and hypercornification. Although he was in remission for chronic lymphocytic leukaemia, lesions were slowly progressive 15 months after cessation of chemotherapy. We also describe a painless pull-test where spicules can be easily plucked and assessed microscopically for inner root sheath keratinization, or observed with surface microscopy in a clinic setting.

Progressive solitary sclerosis

PubMed Central

Kaufmann, Timothy J.; Weinshenker, Brian G.; Kantarci, Orhun H.; Schmalstieg, William F.; Paz Soldan, M. Mateo; Flanagan, Eoin P.

2016-01-01

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. Results: The patients' median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. PMID:27638926

An Examination of an Early Intervention Reading Program Focusing on the Progress Monitoring of Literacy Skills and the Reading Self-Concepts of Struggling Readers

ERIC Educational Resources Information Center

Samuelson, Teresa C.

2010-01-01

The purpose of this study was to examine progress monitoring, reading self-concept, and the literacy skills of first and second grade struggling readers. Progress monitoring is an instructional process used by teachers to assess students' academic performance on a regular basis, typically weekly or monthly. When based on the skill level of the…

Clinically relevant enhancement of human sperm motility using compounds with reported phosphodiesterase inhibitor activity

PubMed Central

Tardif, Steve; Madamidola, Oladipo A.; Brown, Sean G.; Frame, Lorna; Lefièvre, Linda; Wyatt, Paul G.; Barratt, Christopher L.R.; Martins Da Silva, Sarah J.

2014-01-01

STUDY QUESTION Can we identify compound(s) with reported phosphodiesterase inhibitor (PDEI) activity that could be added to human spermatozoa in vitro to enhance their motility without compromising other sperm functions? SUMMARY ANSWER We have identified several compounds that produce robust and effective stimulation of sperm motility and, importantly, have a positive response on patient samples. WHAT IS KNOWN ALREADY For >20 years, the use of non-selective PDEIs, such as pentoxifylline, has been known to influence the motility of human spermatozoa; however, conflicting results have been obtained. It is now clear that human sperm express several different phosphodiesterases and these are compartmentalized at different regions of the cells. By using type-specific PDEIs, differential modulation of sperm motility may be achieved without adversely affecting other functions such as the acrosome reaction (AR). STUDY DESIGN, SIZE, DURATION This was a basic medical research study examining sperm samples from normozoospermic donors and subfertile patients attending the Assisted Conception Unit (ACU), Ninewells Hospital Dundee for diagnostic semen analysis, IVF and ICSI. Phase 1 screened 43 commercially available compounds with reported PDEI activity to identify lead compounds that stimulate sperm motility. Samples were exposed (20 min) to three concentrations (1, 10 and 100 µM) of compound, and selected candidates (n = 6) progressed to Phase 2, which provided a more comprehensive assessment using a battery of in vitro sperm function tests. PARTICIPANTS/MATERIALS, SETTING, METHODS All healthy donors and subfertile patients were recruited at the Medical Research Institute, University of Dundee and ACU, Ninewells Hospital Dundee (ethical approval 08/S1402/6). In Phase 1, poor motility cells recovered from the 40% interface of the discontinuous density gradient were used as surrogates for patient samples. Pooled samples from three to four different donors were utilized in order to reduce variability and increase the number of cells available for simultaneous examination of multiple compounds. During Phase 2 testing, semen samples from 23 patients attending for either routine diagnostic andrology assessment or IVF/ICSI were prepared and exposed to selected compounds. Additionally, 48 aliquots of prepared samples, surplus to clinical use, were examined from IVF (n = 32) and ICSI (n = 16) patients to further determine the effects of selected compounds under clinical conditions of treatment. Effects of compounds on sperm motility were assessed by computer-assisted sperm analysis. A modified Kremer test using methyl cellulose was used to assess sperm functional ability to penetrate into viscous media. Sperm acrosome integrity and induction of apoptosis were assessed using the acrosomal content marker PSA-FITC and annexin V kit, respectively. MAIN RESULTS AND THE ROLE OF CHANCE In Phase 1, six compounds were found to have a strong effect on poor motility samples with a magnitude of response of ≥60% increase in percentage total motility. Under capacitating and non-capacitating conditions, these compounds significantly (P ≤ 0.05) increased the percentage of total and progressive motility. Furthermore, these compounds enhanced penetration into a cervical mucus substitute (P ≤ 0.05). Finally, the AR was not significantly induced and these compounds did not significantly increase the externalization of phosphatidylserine (P = 0.6, respectively). In general, the six compounds maintained the stimulation of motility over long periods of time (180 min) and their effects were still observed after their removal. In examinations of clinical samples, there was a general observation of a more significant stimulation of sperm motility in samples with lower baseline motility. In ICSI samples, compounds #26, #37 and #38 were the most effective at significantly increasing total motility (88, 81 and 79% of samples, respectively) and progressive motility (94, 93 and 81% of samples, respectively). In conclusion, using a two-phased drug discovery screening approach including the examination of clinical samples, 3/43 compounds were identified as promising candidates for further study. LIMITATIONS, REASONS FOR CAUTION This is an in vitro study and caution must be taken when extrapolating the results. Data for patients were from one assessment and thus the robustness of responses needs to be established. The n values for ICSI samples were relatively small. WIDER IMPLICATIONS OF THE FINDINGS We have systematically screened and identified several compounds that have robust and effective stimulation (i.e. functional significance with longevity and no toxicity) of total and progressive motility under clinical conditions of treatment. These compounds could be clinical candidates with possibilities in terms of assisted reproductive technology options for current or future patients affected by asthenozoospermia or oligoasthenozoospermia. STUDY FUNDING/COMPETING INTEREST(S) This study was funded primarily by the MRC (DPFS) but with additional funding from the Wellcome Trust, Tenovus (Scotland), University of Dundee, NHS Tayside and Scottish Enterprise. The authors have no competing interests. A patent (#WO2013054111A1) has been published containing some of the information presented in this manuscript. PMID:25124668

Long-term Follow-up of Treatment with Ibrutinib and Rituximab in Patients with High-Risk Chronic Lymphocytic Leukemia.

PubMed

Jain, Preetesh; Keating, Michael J; Wierda, William G; Sivina, Mariela; Thompson, Philip A; Ferrajoli, Alessandra; Estrov, Zeev; Kantarjian, Hagop; O'Brien, Susan; Burger, Jan A

2017-05-01

Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial. Experimental Design: We report the long-term outcome [median follow-up of 47 months (range, 36-51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated. Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2-51 months), and median number of treatment cycles was 42 (range, 2-49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p ( n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached. Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 23(9); 2154-8. ©2016 AACR . ©2016 American Association for Cancer Research.

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

Massimino, Maura; Gandola, Lorenza; Spreafico, Filippo

Purpose: Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation. Methods and Materials: In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa ({+-} carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible. Results: Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapymore » in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months. Conclusions: Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.« less

Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study.

PubMed

García-Del-Muro, Xavier; López-Pousa, Antonio; Maurel, Joan; Martín, Javier; Martínez-Trufero, Javier; Casado, Antonio; Gómez-España, Auxiliadora; Fra, Joaquín; Cruz, Josefina; Poveda, Andrés; Meana, Andrés; Pericay, Carlos; Cubedo, Ricardo; Rubió, Jordi; De Juan, Ana; Laínez, Nuria; Carrasco, Juan Antonio; de Andrés, Raquel; Buesa, José M

2011-06-20

To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

Oxaliplatin rechallenge in metastatic colorectal cancer patients after prior oxaliplatin treatment.

PubMed

Kim, Jae-Joon; Kang, Jihoon; Hong, Yong Sang; Kim, Kyu-Pyo; Kim, Sun Young; Kim, Tae Won; Kim, Jeong Eun

2018-04-05

Because the number of cytotoxic agents available for the treatment of metastatic colorectal cancer (mCRC) is limited, rechallenge with the same chemotherapy agents can provide a continuum of treatment. This study investigated the efficacy and feasibility of oxaliplatin rechallenge in mCRC patients who had been previously exposed to oxaliplatin-based chemotherapy. Patients were included if they had mCRC and evaluable disease, had remained disease-free or progression-free for at least 6 months after the last dose of prior oxaliplatin-based therapy, and were retreated with oxaliplatin therapy. Between January 2009 and May 2014, 110 patients were retreated with oxaliplatin-based regimens; of these, 42 (38.2%) had received prior oxaliplatin as adjuvant chemotherapy and 68 (61.8%) as palliative chemotherapy. The overall response rate to oxaliplatin rechallenge was 30.9% (34/110), and the disease control rate was 68.2% (75/110), with one patient achieving complete response, 33 achieving partial response, and 41 having stable disease. Median progression-free survival and overall survival following oxaliplatin rechallenge were 5.9 months (95% confidence interval [CI], 4.4-7.4 months) and 18.5 months (95% CI, 14.0-23.0 months), respectively. Sixteen patients experienced grade 2 or 3 neuropathy. Ten patients experienced any grade hypersensitivity reaction within four cycles of treatment, including six who stopped treatment due to grade 3 or 4 hypersensitivity reactions. Rechallenge with oxaliplatin-based therapy may be an option for patients who achieve at least 6 months of disease-free or progression-free survival with prior oxaliplatin-based chemotherapy. However, neurotoxicity and hypersensitivity reactions should be carefully monitored in this setting.

Early-Onset, Slow Progression of Cone Photoreceptor Dysfunction and Degeneration in CNG Channel Subunit CNGB3 Deficiency

PubMed Central

Xu, Jianhua; Morris, Lynsie; Fliesler, Steven J.; Sherry, David M.

2011-01-01

Purpose. To investigate the progression of cone dysfunction and degeneration in CNG channel subunit CNGB3 deficiency. Methods. Retinal structure and function in CNGB3−/− and wild-type (WT) mice were evaluated by electroretinography (ERG), lectin cytochemistry, and correlative Western blot analysis of cone-specific proteins. Cone and rod terminal integrity was assessed by electron microscopy and synaptic protein immunohistochemical distribution. Results. Cone ERG amplitudes (photopic b-wave) in CNGB3−/− mice were reduced to approximately 50% of WT levels by postnatal day 15, decreasing further to approximately 30% of WT levels by 1 month and to approximately 20% by 12 months of age. Rod ERG responses (scotopic a-wave) were not affected in CNGB3−/− mice. Average CNGB3−/− cone densities were approximately 80% of WT levels at 1 month and declined slowly thereafter to only approximately 50% of WT levels by 12 months. Expression levels of M-opsin, cone transducin α-subunit, and cone arrestin in CNGB3−/− mice were reduced by 50% to 60% by 1 month and declined to 35% to 45% of WT levels by 9 months. In addition, cone opsin mislocalized to the outer nuclear layer and the outer plexiform layer in the CNGB3−/− retina. Cone and rod synaptic marker expression and terminal ultrastructure were normal in the CNGB3−/− retina. Conclusions. These findings are consistent with an early-onset, slow progression of cone functional defects and cone loss in CNGB3−/− mice, with the cone signaling deficits arising from disrupted phototransduction and cone loss rather than from synaptic defects. PMID:21273547

Discovery of Rigidified α,β-Unsaturated Imines as New Resistance-breaking Insecticides for Malaria Vector Control.

PubMed

Arlt, Alexander; Böhnke, Niels; Horstmann, Sebastian; Vermeer, Arnoldus W P; Werner, Stefan; Velten, Robert

2016-10-01

During our continuous search for new resistance-breaking insecticides applicable to malaria vector control, a new class of α,β-unsaturated imines was identified by applying the principle of conformational rigidification as a powerful tool for compound optimisation. Herein we describe the successful synthesis of these compounds and their biological test results. Our lead compound 16 from this insecticidal class outperforms market standards, notably for the control of mosquito strains that exhibit either metabolic or target-site resistance to these established insecticides. In our model system for insecticide-treated mosquito nets the compound reveals long-lasting efficacy for up to several months.

Towards optimizing the sequence of bevacizumab and nitrosoureas in recurrent malignant glioma.

PubMed

Wiestler, Benedikt; Radbruch, Alexander; Osswald, Matthias; Combs, Stephanie E; Jungk, Christine; Winkler, Frank; Bendszus, Martin; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Wick, Antje

2014-03-01

Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III (n = 9) and grade IV (n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.

Progression of chronic periodontitis can be predicted by the levels of Porphyromonas gingivalis and Treponema denticola in subgingival plaque.

PubMed

Byrne, S J; Dashper, S G; Darby, I B; Adams, G G; Hoffmann, B; Reynolds, E C

2009-12-01

Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth associated with bacteria. Diagnosis is achieved retrospectively by clinical observation of attachment loss. Predicting disease progression would allow for targeted preventive therapy. The aim of this study was to monitor disease progression in patients on a maintenance program and determine the levels of specific bacteria in subgingival plaque samples and then examine the ability of the clinical parameters of disease and levels of specific bacteria in the plaque samples to predict disease progression. During a 12-month longitudinal study of 41 subjects, 25 sites in 21 subjects experienced disease progression indicated by at least 2 mm of clinical attachment loss. Real-time polymerase chain reaction was used to determine the levels of Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum, and Prevotella intermedia in subgingival plaque samples. No clinical parameters were able to predict periodontal disease progression. In sites undergoing imminent periodontal disease progression within the next 3 months, significant partial correlations were found between P. gingivalis and T. forsythia (r = 0.55, P < 0.001) and T. denticola and T. forsythia (r = 0.43, P = 0.04). The odds of a site undergoing imminent periodontal disease progression increased with increasing levels of P. gingivalis and T. denticola. Monitoring the proportions of P. gingivalis and T. denticola in subgingival plaque has the potential to help identify sites at significant risk for progression of periodontitis, which would assist in the targeted treatment of disease.

Central corneal thickness and progression of the visual field and optic disc in glaucoma

PubMed Central

Chauhan, B C; Hutchison, D M; LeBlanc, R P; Artes, P H; Nicolela, M T

2005-01-01

Aims: To determine whether central corneal thickness (CCT) is a significant predictor of visual field and optic disc progression in open angle glaucoma. Methods: Data were obtained from a prospective study of glaucoma patients tested with static automated perimetry and confocal scanning laser tomography every 6 months. Progression was determined using a trend based approach called evidence of change (EOC) analysis in which sectoral ordinal scores based on the significance of regression coefficients of visual field pattern deviation and neuroretinal rim area over time are summed. Visual field progression was also determined using the event based glaucoma change probability (GCP) analysis using both total and pattern deviation. Results: The sample contained 101 eyes of 54 patients (mean (SD) age 56.5 (9.8) years) with a mean follow up of 9.2 (0.7) years and 20.7 (2.3) sets of examinations every 6 months. Lower CCT was associated with worse baseline visual fields and lower mean IOP in the follow up. In the longitudinal analysis CCT was not correlated with the EOC scores for visual field or optic disc change. In the GCP analyses, there was a tendency for groups classified as progressing to have lower CCT compared to non-progressing groups. In a multivariate analyses accounting for IOP, the opposite was found, whereby higher CCT was associated with visual field progression. None of the independent factors were predictive of optic disc progression. Conclusions: In this cohort of patients with established glaucoma, CCT was not a useful index in the risk assessment of visual field and optic disc progression. PMID:16024855

Reversibility of Vasalgel™ male contraceptive in a rabbit model.

PubMed

Waller, Donald; Bolick, David; Lissner, Elaine; Premanandan, Christopher; Gamerman, Gary

2017-01-01

Development of a non-hormonal long-acting reversible contraceptive for men could have a significant impact on reducing unintended pregnancies. Vasalgel™ is a high molecular weight polymer consisting of styrene-alt-maleic acid (SMA) dissolved in dimethyl sulfoxide being developed as a reversible male contraceptive device. It forms a hydrogel when implanted into the vasa deferentia, which prevents the passage of sperm. Previous studies in the rabbit have proven its efficacy, durability and rapid onset. This study evaluates the capacity to restore sperm concentrations in ejaculates after a reversal procedure. Sodium bicarbonate was injected into the vasa deferentia after fourteen months of azoospermia following the injection of two device variations (Vasalgel 100 and Vasalgel 80). Semen samples were then collected for six months and sperm characteristics were compared to baseline levels. Samples of vasa deferentia were obtained for histological examination. Spermatozoa were present in all subject ejaculates after the reversal procedure. Sperm concentration and sperm motility were similar to baseline levels after reversal, while sperm forward progression was significantly lower and normal acrosomes were not observed. Forward progression percentages increased linearly during six months of semen collection, however, normal acrosomes were not observed at the conclusion of the study. Histologically, several vasa deferentia were clear of the device and contained an intact epithelial lining. A smaller proportion of tissues contained residual test material. A secondary intraluminal inflammatory response was seen occasionally in the tissues containing residual material. There was no difference between the two device variations for studied parameters. Vasalgel's prevention of sperm transport for 14 months was reversed through an intravasal injection of sodium bicarbonate. Post-reversal sperm concentrations and motility returned to baseline levels during the six-month follow up. Residual material in the vas lumen or compromised epididymal and vas deferens function may be resulting in reduced forward progression and loss of acrosomes during transit through the vas. Reduced forward progression and the lack of normal acrosomes strongly suggest impaired sperm function.

125I Brachytherapy in Locally Advanced Nonsmall Cell Lung Cancer After Progression of Concurrent Radiochemotherapy

PubMed Central

Xiang, Zhanwang; Li, Guohong; Liu, Zhenyin; Huang, Jinhua; Zhong, Zhihui; Sun, Lin; Li, Chuanxing; Zhang, Funjun

2015-01-01

Abstract To investigate the safety and effectiveness of computed tomography (CT)-guided 125I seed implantation for locally advanced nonsmall cell lung cancer (NSCLC) after progression of concurrent radiochemotherapy (CCRT). We reviewed 78 locally advanced NSCLC patients who had each one cycle of first-line CCRT but had progressive disease identified from January 2006 to February 2015 at our institution. A total of 37 patients with 44 lesions received CT-guided percutaneous 125I seed implantation and second-line chemotherapy (group A), while 41 with 41 lesions received second-line chemotherapy (group B). Patients in group A and B received a total of 37 and 41 first cycle of CCRT treatment. The median follow-up was 19 (range 3–36) months. After the second treatment, the total response rate (RR) in tumor response accounted for 63.6% in group A, which was significantly higher than that of group B (41.5%) (P = 0.033). The median progression-free survival time (PFST) was 8.00 ± 1.09 months and 5.00 ± 0.64 months in groups A and B (P = 0.011). The 1-, 2-, and 3-year overall survival (OS) rates for group A were 56.8%, 16.2%, and 2.7%, respectively. For group B, OS rates were 36.6%, 9.8%, and 2.4%, respectively. The median OS time was 14.00 ± 1.82 months and 10.00 ± 1.37 months for groups A and B, respectively (P = 0.059). Similar toxicity reactions were found in both groups. Tumor-related clinical symptoms were significantly reduced and the patients’ quality of life was obviously improved. CT-guided 125I seed implantation proved to be potentially beneficial in treating localized advanced NSCLC; it achieved good local control rates and relieved clinical symptoms without increasing side effects. PMID:26656370

Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation.

PubMed

Carrión, José A; Torres, Ferran; Crespo, Gonzalo; Miquel, Rosa; García-Valdecasas, Juan-Carlos; Navasa, Miquel; Forns, Xavier

2010-01-01

Significant liver fibrosis (F >or= 2) and portal hypertension (hepatic venous pressure gradient [HVPG] >or= 6 mmHg) at 1 year after liver transplantation (LT) identify patients with severe hepatitis C recurrence. We evaluated whether repeated liver stiffness measurements (LSM) following LT can discriminate between slow and rapid "fibrosers" (fibrosis stage F2-F4 at 1 year after LT). Eighty-four patients who had undergone LT and who were infected with hepatitis C virus (HCV) and 19 LT controls who were not infected with HCV underwent LSM at 3, 6, 9, and 12 months after LT. All HCV-infected patients underwent liver biopsy 12 months after LT (paired HVPG measurements in 74); 31 (37%) were rapid fibrosers. Median LSM (in kilopascal) at months 6, 9, and 12 were significantly higher in rapid fibrosers (9.9, 9.5, 12.1) than in slow fibrosers (6.9, 7.5, 6.6) (P < 0.01 all time points). The slope of liver stiffness progression (kPa x month) in rapid fibrosers (0.42) was significantly greater than in slow fibrosers (0.05) (P < 0.001), suggesting two different speeds of liver fibrosis progression. Figures were almost identical for patients with HVPG >or= 6 mmHg or HVPG < 6 mmHg at 1 year after LT. Multivariate analysis identified donor age, bilirubin level, and LSM as independent predictors of fibrosis progression and portal hypertension in the estimation group (n = 50) and were validated in a second group of 34 patients. The areas under the receiver operating characteristic curve that could identify rapid fibrosers and patients with portal hypertension as early as 6 months after LT were 0.83 and 0.87, respectively, in the estimation group and 0.75 and 0.80, respectively, in the validation group. Early and repeated LSM following hepatitis C recurrence in combination with clinical variables discriminates between rapid and slow fibrosers after LT.

E4206: AMG 706 and Octreotide in Patients with Low-Grade Neuroendocrine Tumors.

PubMed

Lubner, Sam; Feng, Yang; Mulcahy, Mary; O'Dwyer, Peter; Giang, Guang-Yu; Louis Hinshaw, J; Deming, Dustin; Klein, Leonard; Teitelbaum, Ursina; Payne, Jennifer; Engstrom, Paul; Stella, Philip; Meropol, Neal; Benson, Al

2018-05-31

Rate of progression-free survival at a particular point in time, i.e., a landmark analysis, is a difficult endpoint for a heterogenous malignancy such as neuroendocrine cancer.Landmark analyses can also be complicated by evolution in the standard of care during the conduct of a clinical trial.Improvements in biomarker development would be useful in developing future clinical trials in NET to better tailor individualized therapies and assess for possible efficacy endpoints. Neuroendocrine tumors (NETs) are rare malignancies of the gastrointestinal (GI) tract that are highly vascularized and overexpress vascular-endothelial growth factor (VEGF). Sunitinib has demonstrated efficacy in the pancreatic subset of NET. This study explored the activity of another oral VEGF inhibitor, AMG 706 or motesanib, a multikinase inhibitor that targets receptor tyrosine kinases, including VEGFR1, VEGFR2, VEGFR3, KIT, RET, and PDGFR (IC50s = 2, 3, 6, 8, 59, and 84 nM, respectively). This was a single-arm, first-line, phase II study run through the Eastern Cooperative Oncology Group. Patients with low-grade NET (as defined by central confirmation of Ki-67 of 0%-2%) were administered a flat dose of 125 mg per day orally combined with octreotide long acting-repeatable (LAR) for patients who had been on a stable dose. The primary objective was to determine the 4-month progression-free survival (PFS). Forty-four patients were evaluated per protocol. The 4-month PFS was 78.5%. The partial response rate was 13.6% (6/44), stable disease was 54.5% (24/44), 9.1% (4/44) had progressive disease, and 10/44 were not evaluable for response. Common toxicities included fatigue, hypertension, nausea, and headache, and most were grade 1-2. Median PFS was 8.7 months, and overall survival was 27.5 months. Motesanib (AMG 706) demonstrated a 4-month PFS that met the per-protocol definition of efficacy. Fatigue and hypertension were the most common toxicities, and few grade 3-4 toxicities were encountered. The progression-free survival of 8.7 months in all NETs merits further study. The Oncologist 2018. © AlphaMed Press 2018.

[Chronic inflammatory demyelinating polyradiculoneuropathy in childhood: outcomes after methylprednisolone pulse therapy].

PubMed

Rafai, M A; Moutaouakil, F; El Otmani, H; Fadel, H; Boulaajaj, F Z; El Moutawakil, B; Gam, I; Slassi, I

2006-06-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) in children is relatively rare and treatment is based primarily on intravenous immunoglobulins or oral corticosteroids. Boluses of methylprednisolone (MP) are a seldom used alternative. We report the case of an 8-year-old child, first presented at the age of 3 years, with recurring episodes of functional impotence of both lower limbs and walking impairment, partially reversible without treatment. Clinical, progressive, and electrophysiological data and the analysis of the cerebrospinal fluid were compatible with CIDP. MP boluses were administered: after a total eight monthly boluses, very satisfactory progression on the clinical and electrophysiological fronts was noted after 24 months. Childhood CIDP presents clinical, electrophysiological, progressive, and prognostic particularities, they recur readily and the outcome is good. Boluses of methylprednisolone are an alternative to the treatment of these neuropathies in childhood.

Progression of osteoarthritis following TPLO surgery: a prospective radiographic study of 40 dogs.

PubMed

Rayward, R M; Thomson, D G; Davies, J V; Innes, J F; Whitelock, R G

2004-02-01

The aim of this prospective study was to assess the progression of osteoarthritis following tibial plateau levelling osteotomy (TPLO) surgery. Osteoarthritis was monitored radiographically by means of an osteophyte scale on entry to the study, and at six weeks and six months following surgical intervention. Forty dogs were recruited to the study. At each visit, animals were assessed clinically, radiographically, by force platform analysis and by synovial fluid sampling. The radiographic data is the subject of this report. A significant increase in mean osteophyte score was noted between the entry and six-month examination time point. This increase in the mean osteophyte score was due to the increased score recorded in 16 dogs. However, in the majority of dogs, there was no progression of osteophytosis during the course of this study.

Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study.

PubMed

Martín-Richard, Marta; Massutí, Bartomeu; Pineda, Eva; Alonso, Vicente; Marmol, Maribel; Castellano, Daniel; Fonseca, Emilio; Galán, Antonio; Llanos, Marta; Sala, Maria Angeles; Pericay, Carlos; Rivera, Fernando; Sastre, Javier; Segura, Angel; Quindós, Maria; Maisonobe, Pascal

2013-09-20

Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.

The time course of neurolinguistic and neuropsychological symptoms in three cases of logopenic primary progressive aphasia.

PubMed

Etcheverry, Louise; Seidel, Barbara; Grande, Marion; Schulte, Stephanie; Pieperhoff, Peter; Südmeyer, Martin; Minnerop, Martina; Binkofski, Ferdinand; Huber, Walter; Grodzinsky, Yosef; Amunts, Katrin; Heim, Stefan

2012-06-01

Primary progressive aphasia (PPA) is a rare clinical dementia syndrome affecting predominantly language abilities. Word-finding difficulties and comprehension deficits despite relatively preserved cognitive functions are characteristic symptoms during the first two years, and distinguish PPA from other dementia types like Alzheimer's disease. However, the dynamics of changes in language and non-linguistic abilities are not well understood. Most studies on progression used cross-sectional designs, which provide only limited insight into the course of the disease. Here we report the results of a longitudinal study in three cases of logopenic PPA over a period of 18 months, with exemplary longitudinal data from one patient even over 46 months. A comprehensive battery of neurolinguistic and neuropsychological tests was applied four times at intervals of six months. Over this period, deterioration of verbal abilities such as picture naming, story retelling, and semantic word recall was found, and the individual decline was quantified and compared between the three patients. Furthermore, decrease in non-verbal skills such as divided attention and increasing apraxia was observed in all three patients. In addition, inter-subject variability in the progression with different focuses was observed, with one patient developing a non-fluent PPA variant. The longitudinal, multivariate investigation of logopenic PPA thus provides novel insights into the progressive deterioration of verbal as well as non-verbal abilities. These deficits may further interact and thus form a multi-causal basis for the patients' problems in every-day life which need to be considered when planning individually targeted intervention in PPA. Copyright © 2012 Elsevier Ltd. All rights reserved.

Predicting progress in Picture Exchange Communication System (PECS) use by children with autism.

PubMed

Pasco, Greg; Tohill, Christina

2011-01-01

The Picture Exchange Communication System (PECS) is a widely used communication intervention for non-verbal children with autism spectrum disorder. Findings for the benefits of PECS have almost universally been positive, although there is very limited information about the characteristics of PECS users that determine the amount of progress that they are likely to make. To explore the utility of using children's developmental age to predict the subsequent degree of progress using PECS. In a retrospective study, 23 non-verbal 5- and 6-year-old children with autism spectrum disorder attending a special school were assessed to determine their highest level of PECS ability. They were then allocated to one of two groups depending on whether or not they had mastered PECS phase III. All participants had been assessed using the Psycho-Educational Profile-Revised (PEP-R) on entry to the school and before being introduced to PECS. Total developmental age scores were examined to determine whether they accurately predicted membership of the two PECS ability groups. All the 16 children who had mastered PECS phase III had total developmental age scores of 16 months or above, whilst six of the seven children who had not progressed beyond phase III scored below 16 months--the other child had a score of 16 months. The assessment of the developmental level of potential PECS users may provide valuable predictive information for speech-and-language therapists and other professionals in relation to the likely degree of progress and in setting realistic and achievable targets. © 2010 Royal College of Speech & Language Therapists.

Representation of the equatorial stratospheric quasi-biennial oscillation in EOF phase space. [EOF (empirical orthogonal function)

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

Wallace, J.M.; Panetta, R.L.; Estberg, J.

1993-06-15

A 35-year record of monthly mean zonal wind data for the equatorial stratosphere is represented in terms of a vector (radius and phase angle) in a two-dimensional phase space defined by the normalized expansion coefficients of the two leading empirical orthogonal functions (EOFs) of the vertical structure. The tip of the vector completes one nearly circular loop during each cycle of the quasi-biennial oscillation (QBO). Hence, its position and rate of progress along the orbit of the point provide a measure of the instantaneous amplitude and rate of phase progression of the QBO. Although the phase of the QBO bearsmore » little if any relation to calendar month, the rate of phase progression is strongly modulated by the first and second harmonics of the annual cycle, with a primary maximum in April/May, in agreement with previous studies based on the descent rates of easterly and westerly regimes. A simple linear prediction model is developed for the rate of phase progression, based on the phase of the QBO and the phase of the annual cycle. The model is capable of hindcasting the phase of the QBO to within a specified degree of accuracy approximately 50% longer than a default scheme based on the mean observed rate of phase progression of the QBO (1 cycle per 28.1 months). If the seasonal dependence is ignored, the prediction equation corresponds to the [open quotes]circle map,[close quotes] for which an extensive literature exists in dynamical systems theory. 17 refs., 14 figs., 2 tabs.« less

Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study

PubMed Central

2013-01-01

Background Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. Methods This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Results Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Conclusion Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. Trial registration ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18. PMID:24053191

Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.

PubMed

Weiss, Brian; Widemann, Brigitte C; Wolters, Pamela; Dombi, Eva; Vinks, Alexander; Cantor, Alan; Perentesis, John; Schorry, Elizabeth; Ullrich, Nicole; Gutmann, David H; Tonsgard, James; Viskochil, David; Korf, Bruce; Packer, Roger J; Fisher, Michael J

2015-04-01

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients. © The Author(s) 2014. 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.

Feasibility of Active Machine Learning for Multiclass Compound Classification.

PubMed

Lang, Tobias; Flachsenberg, Florian; von Luxburg, Ulrike; Rarey, Matthias

2016-01-25

A common task in the hit-to-lead process is classifying sets of compounds into multiple, usually structural classes, which build the groundwork for subsequent SAR studies. Machine learning techniques can be used to automate this process by learning classification models from training compounds of each class. Gathering class information for compounds can be cost-intensive as the required data needs to be provided by human experts or experiments. This paper studies whether active machine learning can be used to reduce the required number of training compounds. Active learning is a machine learning method which processes class label data in an iterative fashion. It has gained much attention in a broad range of application areas. In this paper, an active learning method for multiclass compound classification is proposed. This method selects informative training compounds so as to optimally support the learning progress. The combination with human feedback leads to a semiautomated interactive multiclass classification procedure. This method was investigated empirically on 15 compound classification tasks containing 86-2870 compounds in 3-38 classes. The empirical results show that active learning can solve these classification tasks using 10-80% of the data which would be necessary for standard learning techniques.

[Carbonyl compounds emission and uptake by plant: Research progress].

PubMed

Li, Jian; Cai, Jing; Yan, Liu-Shui; Li, Ling-Na; Tao, Min

2013-02-01

This paper reviewed the researches on the carbonyl compounds emission and uptake by plants, and discussed the compensation point of the bidirectional exchange of carbonyl compounds between plants and atmosphere. The uptake by leaf stomata and stratum corneum is the principal way for the purification of air aldehydes by plants. After entering into plant leaves, most parts of carbonyl compounds can be metabolized into organic acid, glucide, amino acid, and carbon dioxide, etc. , by the endoenzymes in leaves. The exchange direction of the carbonyl compounds between plants and atmosphere can be preliminarily predicted by the compensation point and the concentrations of ambient carbonyl compounds. This paper summarized the analytical methods such as DNPH/HPLC/UV and PFPH/GC/MS used for the determination of carbonyl compounds emitted from plants or in plant leaves. The main research interests in the future were pointed out, e. g. , to improve and optimize the analytical methods for the determination of carbonyl compounds emitted from plants and the researches on systems (e. g. , plant-soil system), to enlarge the detection species of carbonyl compounds emitted from plants, to screen the plant species which can effectively metabolize the pollutants, and to popularize the phytoremediation techniques for atmospheric

Microwave-assisted one-pot synthesis of new phenanthrene fused-tetrahydrodibenzo-acridinones as potential cytotoxic and apoptosis inducing agents.

PubMed

Kumar, Niggula Praveen; Sharma, Pankaj; Reddy, T Srinivasa; Shankaraiah, Nagula; Bhargava, Suresh K; Kamal, Ahmed

2018-05-10

An expeditious microwave-assisted one-pot synthesis of new cytotoxic phenanthrene fused-tetrahydrodibenzo-acridinones has been successfully accomplished. This protocol offers wide substrate scope, catalyst-free synthesis, atom-economy, simple recrystallization, high yields, and ethanol was used as green solvent. These new compounds were tested for their in vitro cytotoxicity against cervical (HeLa), prostate (PC-3), fibrosarcoma (HT-1080), ovarian (SKOV-3) cancer cells, and were safer to normal (Hek-293T) kidney cell line. All the compounds have displayed significant cytotoxicity profile, among them 8m being the most potent compound with an IC 50 0.24 ± 0.05 μM against SKOV-3 ovarian cancer cells. Flow cytometry analysis revealed that cells were blocked at the G2/M phase of the cell cycle. The effect of 8m on F-actin polymerisation was also studied. Hoechst staining clearly showed the decreased number of viable cells and indicated apoptosis progression. Compound 8m caused the collapse of mitochondrial membrane potential as observed via JC-1 staining and also enhanced the generation of reactive oxygen species. The increase of caspase-3 activation by 3.7 folds supported the strong apoptosis induction. In addition, an in vitro 3D-spheroid progression assay was performed with 8m that significantly suppressed the tumor cells. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Bioactives in Chinese Proprietary Medicine Modulates 5α-Reductase Activity and Gene Expression Associated with Androgenetic Alopecia

PubMed Central

Tan, Justin J. Y.; Pan, Jing; Sun, Lihan; Zhang, Junying; Wu, Chunyong; Kang, Lifeng

2017-01-01

Androgenetic alopecia (AGA) is characterized by a progressive and patterned transformation of thick, pigmented terminal scalp hairs into short, hypo-pigmented vellus-like hairs. The use of Minoxidil and Finasteride to treat AGA are often associated with complications in safety and efficacy. However, herbal remedies are deemed to have lesser side effects in many societies. This study aims to identify potential hair growth properties of individual compounds from a Chinese proprietary medicine known as Yangxue Shengfa capsule (YSC), used in China for many years for improving AGA. Six marker compounds, including 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), Chlorogenic acid, Emodin, Ferulic acid, Isoimperatorin, and Paeoniflorin were used for simultaneous HPLC quantification and anti-AGA in-vitro screening. Simultaneous quantification of these components was performed on 75% (v/v) methanol extracts of YSC, using a Welch Ultimate XB-C18 column and gradient elution. Five compounds significantly promoted cell proliferation in cultured immortalized human Dermal Papilla Cells (DPC). Multiple genes associated with the progression of AGA, including IGF-1, DKK-1, and TGF-β1, were found to be regulated by some of these compounds. Interestingly, Ferulic acid and Emodin demonstrated good pharmacological properties against AGA, thereby concluding the potential of these bioactives to be used in the treatment against AGA. PMID:28450835

Microcomputer-Assisted Mathematics: From Simple Interest to e.

ERIC Educational Resources Information Center

Kimberling, Clark

1985-01-01

The progression from simple interest to compound interest leads naturally and quickly to the number e, involving mathematical discovery learning through writing programs. Several programs are given, with suggestions for a teaching sequence. (MNS)

Evaluation of non-invasive treatment applied to occlusal surfaces.

PubMed

Flório, F M; Pereira, A C; Meneghim, M de C; Ramacciato, J C

2001-01-01

The purpose of this study was to evaluate the efficacy of non-invasive methods of treatment for active incipent occlusal caries. Anamnesis, professional prophylaxis, and visual inspection were used to classify 250 Brazilian pre-school-children. First permanent decayed molars (n=98) from thirty-one subjects (6 years+ 6 months) were selected and divided into three groups. Group 1: fissure sealants with resin-modified glass ionomer - Vitremer (n=29); Group 2: fluoride varnish -Duraphat (n=36) and control group: tooth brushing and 0.2 percent NaF weekly mouthwashes (n=33). Four clinical evaluations were carried out over three, six, nine, and twelve months. Caries activity and progression were observed through clinical and radiographic evaluation. The results were analyzed by Fisher=s Exact test. After twelve months, the results showed 100 percent of arrestment of caries activity for Group 1, 83.3 percent for group 2, and 72.7 percent for control group. At the same time, the results showed 0 percent of caries progression for group 1, 5.5 percent for Group 2, and 6.1 percent for control group. Group 1 showed a better inactivation property than the other groups (p<0.05). There were no statistically significant differences in caries progression among these groups (p>0.05). It was concluded that this non-invasive methods were able to arrest the progression of occlusal caries, but fissure sealant showed better results in controlling caries activity.

PREVENTION OF COLITIS-ASSOCIATED CANCER: NATURAL COMPOUNDS THAT TARGET THE IL-6 SOLUBLE RECEPTOR

PubMed Central

Moriasi, Cate; Subramaniam, Dharmalingam; Awasthi, Shanjana; Anant, Shrikant; Ramalingam, Satish

2014-01-01

The risk of developing colorectal cancer increases in patients with inflammatory bowel disease (IBD) and a growing body of evidence shows the critical role of interleukin (IL-6) in this process. IL-6 is both a pro- and anti-inflammatory cytokine whose effects are mediated through activation of STAT3. Recent studies have also demonstrated that IL-6 trans-signaling through its soluble receptor occurs in IBD and cancer. IL-6 trans-signaling therefore is emerging as an attractive approach to diminish the inflammatory signals in conditions of chronic inflammation. The purpose of cancer chemoprevention is to either delay the onset or progression from precancerous lesions. Natural compounds because of their low toxicity render themselves excellent candidates that can be administered over the lifetime of an individual. With the focus of managing IBD over a long time and preventing onset of colitis-associated cancer, we believe that there should be increased research focus on identifying chemopreventive compounds that can render themselves to long term use possibly for the lifetime of predisposed individuals. Here, we review the role of IL-6 signaling in IBD and colitis-associated cancer and underscore the importance of searching for natural compounds that would target the IL-6 trans-signaling pathway as a way to diminish chronic inflammatory conditions in the gastrointestinal tract and possibly hamper the progression to colon cancer. We propose that effective screening and identification of natural chemopreventive compounds that target IL-6 trans-signaling has important implications for the development of optimal strategies against cancer development triggered by inflammation. PMID:22583410

Progress in the pharmacological treatment of human cystic and alveolar echinococcosis: Compounds and therapeutic targets

PubMed Central

Siles-Lucas, Mar; Casulli, Adriano; Cirilli, Roberto

2018-01-01

Human cystic and alveolar echinococcosis are helmintic zoonotic diseases caused by infections with the larval stages of the cestode parasites Echinococcus granulosus and E. multilocularis, respectively. Both diseases are progressive and chronic, and often fatal if left unattended for E. multilocularis. As a treatment approach, chemotherapy against these orphan and neglected diseases has been available for more than 40 years. However, drug options were limited to the benzimidazoles albendazole and mebendazole, the only chemical compounds currently licensed for treatment in humans. To compensate this therapeutic shortfall, new treatment alternatives are urgently needed, including the identification, development, and assessment of novel compound classes and drug targets. Here is presented a thorough overview of the range of compounds that have been tested against E. granulosus and E. multilocularis in recent years, including in vitro and in vivo data on their mode of action, dosage, administration regimen, therapeutic outcomes, and associated clinical symptoms. Drugs covered included albendazole, mebendazole, and other members of the benzimidazole family and their derivatives, including improved formulations and combined therapies with other biocidal agents. Chemically synthetized molecules previously known to be effective against other infectious and non-infectious conditions such as anti-virals, antibiotics, anti-parasites, anti-mycotics, and anti-neoplastics are addressed. In view of their increasing relevance, natural occurring compounds derived from plant and fungal extracts are also discussed. Special attention has been paid to the recent application of genomic science on drug discovery and clinical medicine, particularly through the identification of small inhibitor molecules tackling key metabolic enzymes or signalling pathways. PMID:29677189

Residential solar-heating/cooling system

NASA Technical Reports Server (NTRS)

1980-01-01

Report documents progress of residential solar-heating and cooling system development program at 5-month mark of anticipated 17-month program. System design has been completed, and development and component testing has been initiated. Report includes diagrams, operation overview, optimization studies of subcomponents, and marketing plans for system.

Bulk Viscoelastic Contribution to the Wet Sliding Friction of Rubber Compounds

NASA Astrophysics Data System (ADS)

Pan, Xiao-Dong

2002-03-01

An efficient stopping of an automobile on a wet highway in a rainy day is of obvious importance to the safety of the driving public. Here tire tread made of filled rubber compounds plays an essential role in detremining the wet traction performance. Even though significant progress has been made in improving this tire performance character and much knowledge has been accumulated, there still lacks a coherent fundamental understanding on this dynamic process. Consequently there currently exist no accurate guidelines for designing rubber compounds for better wet traction, and for predicting the wet traction performance of a rubber compound. In this experimental study, a portable British Pendulum Skid Tester has been employed to examine in the laboratory how the rubber compound material properties affect its wet sliding friction on a concrete surface. A dramatic dispaly of the impacts from the compound bulk viscoelastic properties has been observed for the first time. This observation will be discussed in relation to previous results discussed in the literature.

[Everolimus plus exemestane in postmenopausal patients with estrogen-receptor-positive advanced breast cancer - Japanese subgroup analysis of BOLERO -2].

PubMed

Ito, Yoshinori; Masuda, Norikazu; Iwata, Hiroji; Mukai, Hirofumi; Horiguchi, Jun; Tokuda, Yutaka; Kuroi, Katsumasa; Mori, Asuka; Ohno, Nobutsugu; Noguchi, Shinzaburo

2015-01-01

In a phase 3, double-blind, randomized, international study (the BOLERO-2), the addition of mTOR inhibitor everolimus to exemestane was evaluated in postmenopausal women with estrogen-receptor-positive (ER⁺) advanced/recurrent breast cancer that was refractory to any nonsteroidal aromatase inhibitor (NSAI). This report presents the safety and updated (18- month) efficacy results from the Japanese subset (n=106) of BOLERO-2. After a median follow-up of 18 months, the median progression-free survival time was 8.5 months with everolimus plus exemestane compared to 4.2 months with placebo plus exemestane. The most common adverse events (AEs) with everolimus plus exemestane were stomatitis, rash, dysgeusia, and non-infectious lung disease. The AEs reported with the combination therapy were mostly of grade 1 or 2 and manageable with appropriate intervention. In conclusion, this combination could be a useful addition to the armamentarium of treatments for Japanese postmenopausal women with ER⁺ advanced/recurrent breast cancer progressing on NSAIs.

Split-course, high-dose palliative pelvic radiotherapy for locally progressive hormone-refractory prostate cancer.

PubMed

Gogna, Nirdosh Kumar; Baxi, Siddhartha; Hickey, Brigid; Baumann, Kathryn; Burmeister, Elizabeth; Holt, Tanya

2012-06-01

Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients. A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45-60 Gy in 18-24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity. The median age was 71 years (range, 53-88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported. The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported. Copyright © 2012 Elsevier Inc. All rights reserved.

Comprehensive atmospheric modeling of reactive cyclic siloxanes and their oxidation products

NASA Astrophysics Data System (ADS)

Janechek, Nathan J.; Hansen, Kaj M.; Stanier, Charles O.

2017-07-01

Cyclic volatile methyl siloxanes (cVMSs) are important components in personal care products that transport and react in the atmosphere. Octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), dodecamethylcyclohexasiloxane (D6), and their gas-phase oxidation products have been incorporated into the Community Multiscale Air Quality (CMAQ) model. Gas-phase oxidation products, as the precursor to secondary organic aerosol from this compound class, were included to quantify the maximum potential for aerosol formation from gas-phase reactions with OH. Four 1-month periods were modeled to quantify typical concentrations, seasonal variability, spatial patterns, and vertical profiles. Typical model concentrations showed parent compounds were highly dependent on population density as cities had monthly averaged peak D5 concentrations up to 432 ng m-3. Peak oxidized D5 concentrations were significantly less, up to 9 ng m-3, and were located downwind of major urban areas. Model results were compared to available measurements and previous simulation results. Seasonal variation was analyzed and differences in seasonal influences were observed between urban and rural locations. Parent compound concentrations in urban and peri-urban locations were sensitive to transport factors, while parent compounds in rural areas and oxidized product concentrations were influenced by large-scale seasonal variability in OH.

Factors Contributing to Patient Satisfaction with Rehabilitation Following Stroke.

ERIC Educational Resources Information Center

Clark, M. S.; Smith, D. S.

1998-01-01

A study that investigated the satisfaction of 60 Australian stroke survivors with their rehabilitative progress over 12 months found satisfaction with progress improved with time and was influenced by the return to previous lifestyle activities, depression, family functioning, understanding of stroke, and clarity of expectations on admission to…

Statistical Research on the Bioactivity of New Marine Natural Products Discovered during the 28 Years from 1985 to 2012

PubMed Central

Hu, Yiwen; Chen, Jiahui; Hu, Guping; Yu, Jianchen; Zhu, Xun; Lin, Yongcheng; Chen, Shengping; Yuan, Jie

2015-01-01

Every year, hundreds of new compounds are discovered from the metabolites of marine organisms. Finding new and useful compounds is one of the crucial drivers for this field of research. Here we describe the statistics of bioactive compounds discovered from marine organisms from 1985 to 2012. This work is based on our database, which contains information on more than 15,000 chemical substances including 4196 bioactive marine natural products. We performed a comprehensive statistical analysis to understand the characteristics of the novel bioactive compounds and detail temporal trends, chemical structures, species distribution, and research progress. We hope this meta-analysis will provide useful information for research into the bioactivity of marine natural products and drug development. PMID:25574736

Anticancer effects of different seaweeds on human colon and breast cancers.

PubMed

Moussavou, Ghislain; Kwak, Dong Hoon; Obiang-Obonou, Brice Wilfried; Maranguy, Cyr Abel Ogandaga; Dinzouna-Boutamba, Sylvatrie-Danne; Lee, Dae Hoon; Pissibanganga, Ordelia Gwenaelle Manvoudou; Ko, Kisung; Seo, Jae In; Choo, Young Kug

2014-09-24

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents.

The Progressive BSSG Rat Model of Parkinson's: Recapitulating Multiple Key Features of the Human Disease

PubMed Central

Van Kampen, Jackalina M.; Baranowski, David C.; Robertson, Harold A.; Shaw, Christopher A.; Kay, Denis G.

2015-01-01

The development of effective neuroprotective therapies for Parkinson's disease (PD) has been severely hindered by the notable lack of an appropriate animal model for preclinical screening. Indeed, most models currently available are either acute in nature or fail to recapitulate all characteristic features of the disease. Here, we present a novel progressive model of PD, with behavioural and cellular features that closely approximate those observed in patients. Chronic exposure to dietary phytosterol glucosides has been found to be neurotoxic. When fed to rats, β-sitosterol β-d-glucoside (BSSG) triggers the progressive development of parkinsonism, with clinical signs and histopathology beginning to appear following cessation of exposure to the neurotoxic insult and continuing to develop over several months. Here, we characterize the progressive nature of this model, its non-motor features, the anatomical spread of synucleinopathy, and response to levodopa administration. In Sprague Dawley rats, chronic BSSG feeding for 4 months triggered the progressive development of a parkinsonian phenotype and pathological events that evolved slowly over time, with neuronal loss beginning only after toxin exposure was terminated. At approximately 3 months following initiation of BSSG exposure, animals displayed the early emergence of an olfactory deficit, in the absence of significant dopaminergic nigral cell loss or locomotor deficits. Locomotor deficits developed gradually over time, initially appearing as locomotor asymmetry and developing into akinesia/bradykinesia, which was reversed by levodopa treatment. Late-stage cognitive impairment was observed in the form of spatial working memory deficits, as assessed by the radial arm maze. In addition to the progressive loss of TH+ cells in the substantia nigra, the appearance of proteinase K-resistant intracellular α-synuclein aggregates was also observed to develop progressively, appearing first in the olfactory bulb, then the striatum, the substantia nigra and, finally, hippocampal and cortical regions. The slowly progressive nature of this model, together with its construct, face and predictive validity, make it ideal for the screening of potential neuroprotective therapies for the treatment of PD. PMID:26439489

Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.

PubMed

Campone, Mario; Bachelot, Thomas; Gnant, Michael; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Noguchi, Shinzaburo; Shtivelband, Mikhail; Pritchard, Kathleen I; Provencher, Louise; Burris, Howard A; Hart, Lowell; Melichar, Bohuslav; Hortobagyi, Gabriel N; Arena, Francis; Baselga, José; Panneerselvam, Ashok; Héniquez, Aurelia; El-Hashimyt, Mona; Taran, Tetiana; Sahmoud, Tarek; Piccart, Martine

2013-08-01

Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Induction Gemcitabine and Stereotactic Body Radiotherapy for Locally Advanced Nonmetastatic Pancreas Cancer

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

Mahadevan, Anand, E-mail: amahadev@bidmc.harvard.edu; Miksad, Rebecca; Goldstein, Michael

2011-11-15

Purpose: Stereotactic body radiotherapy (SBRT) has been used successfully to treat patients with locally advanced pancreas cancer. However, many patients develop metastatic disease soon after diagnosis and may receive little benefit from such therapy. We therefore retrospectively analyzed a planned strategy of initial chemotherapy with restaging and then treatment for those patients with no evidence of metastatic progression with SBRT. Methods and Materials: Forty-seven patients received gemcitabine (1,000 mg/m{sup 2} per week for 3 weeks then 1 week off) until tolerance, at least six cycles, or progression. Patients without metastases after two cycles were treated with SBRT (tolerance-based dose ofmore » 24-36 Gy in 3 fractions) between the third and fourth cycles without interrupting the chemotherapy cycles. Results: Eight of the 47 patients (17%) were found to have metastatic disease after two cycles of gemcitabine; the remaining 39 patients received SBRT. The median follow-up for survivors was 21 months (range, 6-36 months). The median overall survival for all patients who received SBRT was 20 months, and the median progression-free survival was 15 months. The local control rate was 85% (33 of 39 patients); and 54% of patients (21 of 39) developed metastases. Late Grade III toxicities such as GI bleeding and obstruction were observed in 9% (3/39) of patients. Conclusion: For patients with locally advanced pancreas cancer, this strategy uses local therapy for those who are most likely to benefit from it and spares those patients with early metastatic progression from treatment. SBRT delivers such local therapy safely with minimal interruption to systemic chemotherapy, thereby potentially improving the outcome in these patients.« less

Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease.

PubMed

Hacker, Mallory L; DeLong, Mahlon R; Turchan, Maxim; Heusinkveld, Lauren E; Ostrem, Jill L; Molinari, Anna L; Currie, Amanda D; Konrad, Peter E; Davis, Thomas L; Phibbs, Fenna T; Hedera, Peter; Cannard, Kevin R; Drye, Lea T; Sternberg, Alice L; Shade, David M; Tonascia, James; Charles, David

2018-06-29

To evaluate whether the progression of individual motor features was influenced by early deep brain stimulation (DBS), a post hoc analysis of Unified Parkinson's Disease Rating Scale-III (UPDRS-III) score (after a 7-day washout) was conducted from the 2-year DBS in early Parkinson disease (PD) pilot trial dataset. The prospective pilot trial enrolled patients with PD aged 50-75 years, treated with PD medications for 6 months-4 years, and no history of dyskinesia or other motor fluctuations, who were randomized to receive optimal drug therapy (ODT) or DBS plus ODT (DBS + ODT). At baseline and 6, 12, 18, and 24 months, all patients stopped all PD therapy for 1 week (medication and stimulation, if applicable). UPDRS-III "off" item scores were compared between the ODT and DBS + ODT groups (n = 28); items with significant between-group differences were analyzed further. UPDRS-III "off" rest tremor score change from baseline to 24 months was worse in patients receiving ODT vs DBS + ODT ( p = 0.002). Rest tremor slopes from baseline to 24 months favored DBS + ODT both "off" and "on" therapy ( p < 0.001, p = 0.003, respectively). More ODT patients developed new rest tremor in previously unaffected limbs than those receiving DBS + ODT ( p = 0.001). These results suggest the possibility that DBS in early PD may slow rest tremor progression. Future investigation in a larger cohort is needed, and these findings will be tested in the Food and Drug Administration-approved, phase III, pivotal, multicenter clinical trial evaluating DBS in early PD. This study provides Class II evidence that for patients with early PD, DBS may slow the progression of rest tremor. © 2018 American Academy of Neurology.

Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.

PubMed

Pujade-Lauraine, Eric; Hilpert, Felix; Weber, Béatrice; Reuss, Alexander; Poveda, Andres; Kristensen, Gunnar; Sorio, Roberto; Vergote, Ignace; Witteveen, Petronella; Bamias, Aristotelis; Pereira, Deolinda; Wimberger, Pauline; Oaknin, Ana; Mirza, Mansoor Raza; Follana, Philippe; Bollag, David; Ray-Coquard, Isabelle

2014-05-01

In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC. Eligible patients had measurable/assessable OC that had progressed < 6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

Everolimus for Previously Treated Advanced Gastric Cancer: Results of the Randomized, Double-Blind, Phase III GRANITE-1 Study

PubMed Central

Ohtsu, Atsushi; Ajani, Jaffer A.; Bai, Yu-Xian; Bang, Yung-Jue; Chung, Hyun-Cheol; Pan, Hong-Ming; Sahmoud, Tarek; Shen, Lin; Yeh, Kun-Huei; Chin, Keisho; Muro, Kei; Kim, Yeul Hong; Ferry, David; Tebbutt, Niall C.; Al-Batran, Salah-Eddin; Smith, Heind; Costantini, Chiara; Rizvi, Syed; Lebwohl, David; Van Cutsem, Eric

2013-01-01

Purpose The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer. Patients and Methods Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety. Results Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW. Conclusion Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers. PMID:24043745

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey].

PubMed

Lorcet, Marianne; Lortholary, Alain; Kurtz, Jean Emmanuel; Berton-Rigaud, Dominique; Fabbro, Michel; De La Motte Rouge, Thibault; Kaminsky-Forrett, Marie Christine; Floquet, Anne; Freyer, Gilles; Combe, Pierre; Dohollou, Nadine; Kalbacher, Elsa; Despax, Raymond; Largillier, Remy; Hardy Bessard, Anne Claire; Gane, Nicolas; Sehouli, Jalid; Oskay-Oezcelik, Guelten; Licaj, Idlir; Ray-Coquard, Isabelle; Joly Lobbedez, Florence

2018-05-01

Expression IV survey evaluated the patients' expectations to a maintenance therapy. From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines. Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission. This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

SAFETY AND ACTIVITY OF TEMSIROLIMUS AND BEVACIZUMAB IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA PREVIOUSLY TREATED WITH TYROSINE KINASE INHIBITORS: A PHASE 2 CONSORTIUM STUDY

PubMed Central

Merchan, Jaime R.; Qin, Rui; Pitot, Henry; Picus, Joel; Liu, Glenn; Fitch, Tom; Maples, William J.; Flynn, Patrick J.; Fruth, Briant F.; Erlichman, Charles

2015-01-01

Purpose Bevacizumab or Temsirolimus regimens have clinical activity in the first line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent. Methods In the phase I portion, eligible patients were treated with Temsirolimus (25 mg IV weekly) and escalating doses of IV Bevacizumab (level 1=5mg/kg; level 2=10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression free rate. Secondary endpoints were response rate, toxicity evaluation, PFS and OS. Results MTD was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (Temsirolimus 25 mg IV weekly and Bevacizumab 10 mg/kg IV every two weeks). The 6-month progression free rate was 40% (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response/stable/progressive disease were seen in 23%/63%/14% of patients. Most common grade 3-4 AEs included fatigue (17.8%), hypertriglyceridemia (11.1%), stomatitis (8.9%), proteinuria (8.9%), abdominal pain (6.7%), and anemia (6.7%). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively. Conclusions Temsirolimus and Bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population. PMID:25556030

An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe.

PubMed

Takei, Koji; Tsuda, Kikumi; Takahashi, Fumihiro; Hirai, Manabu; Palumbo, Joseph

2017-10-01

There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.

Semi-Quantitative Imaging Biomarkers of Knee Osteoarthritis Progression: Data from the FNIH OA Biomarkers Consortium

PubMed Central

Collins, Jamie E.; Losina, Elena; Nevitt, Michael C.; Roemer, Frank W.; Guermazi, Ali; Lynch, John A.; Katz, Jeffrey N.; Kwoh, C. Kent; Kraus, Virginia B.; Hunter, David J.

2017-01-01

Objective To determine the association between changes in semi-quantitative knee MRI biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild to moderate osteoarthritis. Methods We undertook a nested case-control study as part of the Osteoarthritis Biomarkers Consortium Project. We built multivariable logistic regression models to examine the association between change over 24 months in semi-quantitative MR imaging markers and knee OA radiographic and pain progression. MRIs were read according to the MRI Osteoarthritis Knee Score (MOAKS) scoring system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and synovitis-effusion. Results The most parsimonious model included changes in cartilage thickness and surface area, synovitis-effusion, Hoffa-synovitis, and meniscal morphology (C-statistic =0.740). Subjects with worsening cartilage thickness in 3+ subregions vs. no worsening had 2.8-fold (95% CI: 1.3 – 5.9) greater odds of being a case while subjects with worsening in cartilage surface area in 3+ subregions vs. no worsening had 2.4-fold (95% CI: 1.3 – 4.4) greater odds of being a case. Having worsening in any region in meniscal morphology was associated with a 2.2-fold (95%CI: 1.3 – 3.8) greater odds of being a case. Worsening synovitis-effusion (OR=2.7) and Hoffa-synovitis (OR=2.0) were also associated with greater odds of being a case. Conclusion Twenty-four-month change in cartilage thickness, cartilage surface area, synovitis-effusion, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that they may serve as efficacy biomarkers in clinical trials of disease modifying interventions for knee OA. PMID:27111771

Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study.

PubMed

Nakajima, Sonomi; Saijo, Yasuaki; Miyashita, Chihiro; Ikeno, Tamiko; Sasaki, Seiko; Kajiwara, Junboku; Kishi, Reiko

2017-11-01

Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known. We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects. The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121). In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index. These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children. Copyright © 2017 Elsevier Inc. All rights reserved.

Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study.

PubMed

Jones, Simon A; Rojas-Caro, Sandra; Quinn, Anthony G; Friedman, Mark; Marulkar, Sachin; Ezgu, Fatih; Zaki, Osama; Gargus, J Jay; Hughes, Joanne; Plantaz, Dominique; Vara, Roshni; Eckert, Stephen; Arnoux, Jean-Baptiste; Brassier, Anais; Le Quan Sang, Kim-Hanh; Valayannopoulos, Vassili

2017-02-08

Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months.

PubMed

Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Boulware, David; Mahon, Jeffrey L; Krischer, Jeffrey P; Greenbaum, Carla J; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

2015-05-01

We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Patterns of recontracture after surgical correction of Dupuytren disease.

PubMed

Dias, Joseph J; Singh, Harvinder Pal; Ullah, Aamer; Bhowal, Bhaskar; Thompson, John R

2013-10-01

To study the evolution of deformity of the proximal interphalangeal joint over 5 years after good surgical correction of Dupuytren-induced contracture. We assessed 63 patients (72 fingers; 69 hands) with Dupuytren disease for the degree of contracture, its correction after surgery, and the range of movement at the proximal interphalangeal joints at 3 and 6 months, and 1, 3, and 5 years after fasciectomy with or without the use of a firebreak graft. We investigated associations between the recurrence of contracture and preoperative patient and surgical factors. There were 4 patterns of evolution of contracture after surgical correction. A total of 31 patients (33 hands) showed good improvement that was maintained for 5 years (minimal recontracture group). Twenty patients (23 hands) showed good initial improvement, which mildly worsened (< 20°) but was then maintained over 5 years (mild early recontracture group). Four patients (5 hands) worsened in first 3 months after surgery (> 20°) but there was no further worsening (severe early recontracture group). Eight patients (8 hands) worsened progressively over 5 years (progressive recontracture group). Worsening of contracture more than 6° between 3 and 6 months after surgery predicted progressive recontracture at 5 years. Recurrence of contracture (not disease recurrence) could be predicted as early as 6 months after surgery for Dupuytren disease. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Incident and prevalent cohorts with pulmonary arterial hypertension: insight from SERAPHIN.

PubMed

Simonneau, Gérald; Channick, Richard N; Delcroix, Marion; Galiè, Nazzareno; Ghofrani, Hossein-Ardeschir; Jansa, Pavel; Le Brun, Franck-Olivier; Mehta, Sanjay; Perchenet, Loic; Pulido, Tomás; Sastry, B K S; Sitbon, Olivier; Souza, Rogério; Torbicki, Adam; Rubin, Lewis J

2015-12-01

In SERAPHIN, a long-term, randomised, controlled trial (NCT00660179) in pulmonary arterial hypertension (PAH), macitentan significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation. We evaluated disease progression and the effect of macitentan in treatment-naïve incident and prevalent cohorts.Patients allocated to placebo, or macitentan 3 mg or 10 mg were classified by time from diagnosis to enrolment as incident (≤6 months; n=110) or prevalent (>6 months; n=157). The risk of morbidity/mortality and PAH-related death/hospitalisation was determined using Cox regression.The risk of morbidity/mortality (Kaplan-Meier estimates at month 12: 54.4% versus 26.7%; p=0.006) and PAH-related death/hospitalisation (Kaplan-Meier estimates at month 12: 47.3% versus 19.9%; p=0.006) were significantly higher for incident versus prevalent patients receiving placebo, respectively. There was no significant difference in the risk of all-cause death between incident and prevalent cohorts (p=0.587). Macitentan 10 mg significantly reduced the risk of morbidity/mortality and PAH-related death/hospitalisation versus placebo in incident and prevalent cohorts.Incident patients had a higher risk for PAH progression compared with prevalent patients but not a higher risk of death. Macitentan delayed disease progression in both incident and prevalent PAH patients. Copyright ©ERS 2015.

CD30 As a Target for the Treatment of Cutaneous T-Cell Lymphoma.

PubMed

Prince, H Miles

2015-11-10

A 72-year-man presented with a 7-month history of progressive patches and plaques over the trunk and limbs. A skin biopsy confirmed mycosis fungoides (MF). After staging investigations, he was considered to have T2N0M0B0 (stage Ib) disease and began ultraviolet (UV) B phototherapy. Despite initial response, his disease progressed after 4 months, with enlarging patches and plaques but without nodal involvement. As second-line therapy, he received interferon alfa-2b (IFN--2b) 2.7 MU daily, which he tolerated well. He again experienced initial partial response (PR), but by 18 months, he had experienced tumor progression, with patches, plaques, and multiple tumors over the body (up to 3 cm; Fig 1). Biopsy of a neck tumor demonstrated tumor-stage MF,with no evidence of large-cell transformation. Approximately 30% of lymphocytes strongly expressed CD30. CD25 was negative. He began treatment with oral methotrexate 20mg per week, which he tolerated well, and achieved a PR lasting 7 months before multiple plaque and tumor lesions recurred, along with the development of inguinal lymphadenopthy. Biopsy of the skin lesions confirmed the same disease, and [18F]fluorodeoxyglucose–positron emission tomography demonstrated avidity in inguinal and internal iliac nodes, with lymphadenopathy measuring up to 3.5 cm. He has been referred for consideration of further systemic therapy.

PubMed Central

BENSON, R.; BHASKER, S.; MOHANTI, B.K.

2015-01-01

SUMMARY Juvenile nasopharyngeal angiofibroma (JNA) is a disease of adolescent males characterised by high vascularity with local aggressiveness. This analysis was intended to see the effectiveness of radiation in locally advanced JNA. We included patients treated from 1990-2012. A total of 31 patients met study criteria. Median age was 16 years (range: 12-33 years). Radiation was used for refractory, residual or unresectable locally advanced disease. The median radiation dose was 30 Gy (range: 30-45 Gy). Median follow-up was 36 months (Range: 1-271 months). The median progression-free survival [PFS] was not reached. PFS at 3, 5 and 10 years was 91.7, 70.7 and 70.7% respectively. Three patients progressed at 38, 43 and 58 months after completion of treatment and opted for alternative therapy. One patient developed squamous cell carcinoma of the nasal ale 15 years after radiation. PMID:26019389

Afatinib for an EGFR exon 20 insertion mutation: A case report of progressive stage IV metastatic lung adenocarcinoma with 54 months' survival.

PubMed

Chan, Raymond Tsz-Tong

2018-03-01

Non-small cell lung cancers (NSCLC) harboring the uncommon epidermal growth factor receptor (EGFR) exon 20 insertion mutations are generally thought to be unresponsive to EGFR-tyrosine kinase inhibitor (TKI) therapy. Presented here is a case of stage IV NSCLC harboring an uncommon EGFR exon 20 insertion mutation that was maintained at minimal progressive disease for 54 months, with 36 months on the second-generation TKI afatinib. Contrary to the existing literature, the patient in this case demonstrated a long, durable response to the EGFR-TKI, which was exhibited by a long survival endpoint. This suggests that stability in clinical symptoms might be sufficient to warrant continuation of therapy. © 2018 The Authors. Asia-Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.

Age-dependent changes from allylphenol to prenylated benzoic acid production in Piper gaudichaudianum Kunth.

PubMed

Gaia, Anderson M; Yamaguchi, Lydia F; Jeffrey, Christopher S; Kato, Massuo J

2014-10-01

HPLC-DAD and principal component analysis (PCA) of the (1)H NMR spectrum of crude plant extracts showed high chemical variability among seedlings and adult organs of Piper gaudichaudianum. While gaudichaudianic acid was the major compound in the adult leaves, apiole and dillapiole were the major compounds in their seedling leaves. By the 15th month of seedling growth, the levels of apiole and dillapiole decreased and gaudichaudianic acid appeared along with two compounds, biosynthetically related to gaudichaudianic acid. Copyright © 2014 Elsevier Ltd. All rights reserved.

Genistein versus ICI 182, 780: an ally or enemy in metastatic progression of prostate cancer.

PubMed

Nakamura, Hisae; Wang, Yuwei; Xue, Hui; Romanish, Mark T; Mager, Dixie L; Helgason, Cheryl D; Wang, Yuzhuo

2013-12-01

Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen in synergy with androgen is essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen and the estrogen receptor play in prostate carcinogenesis remains unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor beta (ERβ) agonist (genistein) in a patient-derived PCa xenograft model mimicking localized and metastatic disease. To test the hypothesis that the tumor-promoting activity of genistein was due to its estrogenic properties, we treated the xenograft-bearing mice with genistein and an anti-estrogen compound (ICI 182, 780) and compared the differential gene expression using microarrays. Using a second xenograft model which was derived from another patient, we showed that genistein promoted disease progression in vivo and ICI 182, 780 inhibited metastatic spread. The microarray analysis revealed that the metallothionein (MT) gene family was differentially expressed in tumors treated by these compounds. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumor lines, both of which were originally derived from the same PCa patient. Together our data provide evidence that genistein stimulates and ICI 182, 780 inhibits metastatic progression, suggesting that these effects may be mediated by ERβ signalling. © 2013 Wiley Periodicals, Inc.

Transient corneal endothelial changes following accelerated collagen cross-linking for the treatment of progressive keratoconus.

PubMed

Cingü, Abdullah Kürşat; Sogutlu-Sari, Esin; Cınar, Yasin; Sahin, Muhammed; Türkçü, Fatih Mehmet; Yüksel, Harun; Sahin, Alparslan; Caça, Ihsan

2014-06-01

To evaluate the corneal endothelial changes following accelerated collagen cross-linking (CXL) for the treatment of progressive keratoconus. Thirty-six consecutive progressive keratoconus patients who received accelerated CXL treatment were enrolled in the study. Following de-epithelization, isoosmolar 0.1% riboflavin solution without dextran was instilled every 3 min throughout the 30 min of soaking time before the 5 min of 18 mW/cm(2) UVA irradiation and every 2 min during the UVA irradiation. Corneal specular microscopy was performed on both treated and fellow eyes of each patient preoperatively, in the first week, and in the first, third and sixth month postoperatively. There were significant differences in endothelial cell density (ECD), percentages of hexagonality (6A) and coefficient of variation of endothelial cell area (CV) in the first week and first month postoperatively in the treated eyes when compared to their preoperative values and also to the first week and first month ECD, 6A and CV values of the non-operative eyes. ECD returned to the preoperative values at sixth month whereas 6A and CV returned to the preoperative values at third month. Our results suggested that there may be transient changes in human corneal endothelium following accelerated UVA/riboflavin CXL. Resolution of these changes during the follow-up may indicate a safe recovery. However, the treatment guidelines for accelerated CXL including irradiance level and soaking time should be clearly established to minimize the toxic effects of the treatment.

Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

PubMed

Katroditou, Eirini; Kyrtsonis, Marie-Christine; Delimpasi, Sosana; Kyriakou, Despoina; Symeonidis, Argiris; Spanoudakis, Emmanouil; Vasilopoulos, Georgios; Anagnostopoulos, Achilles; Kioumi, Anna; Zikos, Panagiotis; Aktypi, Anthi; Briasoulis, Evangelos; Megalakaki, Aikaterini; Repousis, Panayiotis; Adamopoulos, Ioannis; Gogos, Dimitrios; Kotsopoulou, Maria; Pappa, Vassiliki; Papadaki, Eleni; Fotiou, Despoina; Nikolaou, Eftychia; Giannopoulou, Evlambia; Hatzimichael, Eleftheria; Giannakoulas, Nikolaos; Douka, Vassiliki; Kokoviadou, Kyriaki; Timotheatou, Despoina; Terpos, Evangelos

2018-05-13

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

Perspective, March 2010

ERIC Educational Resources Information Center

Achieve, Inc., 2010

2010-01-01

"Perspective" is a monthly e-newsletter presenting news and views from Achieve. This month's issue commences with a report stating how over the past five years, since the National Governors Association (NGA) and Achieve co-sponsored the National Education Summit on High Schools, states have made impressive progress in aligning their high…

Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4.

PubMed

Buzzoni, Roberto; Carnaghi, Carlo; Strosberg, Jonathan; Fazio, Nicola; Singh, Simron; Herbst, Fabian; Ridolfi, Antonia; Pavel, Marianne E; Wolin, Edward M; Valle, Juan W; Oh, Do-Youn; Yao, James C; Pommier, Rodney

2017-01-01

Recently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35-0.67; P <0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity. ClinicalTrials.gov identifier: NCT01524783. Patients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported. A total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37-0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36-0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19-0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42-0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24-0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42-0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%-65%), fatigue (27%-35%), and diarrhea (24%-34%) among the subgroups. These results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.

Epirubicin, Cisplatin, and Capecitabine for Primary Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer

PubMed Central

Sayal, Karen; Gounaris, Ioannis; Basu, Bristi; Freeman, Sue; Moyle, Penny; Hosking, Karen; Iddawela, Mahesh; Jimenez-Linan, Mercedes; Abraham, Jean; Brenton, James; Hatcher, Helen; Earl, Helena; Parkinson, Christine

2015-01-01

Objective Primary platinum-resistant epithelial ovarian cancer (EOC) is an area of unmet medical need. There is limited evidence from small studies that platinum-based combinations can overcome “resistance” in a proportion of patients. We investigated the efficacy and toxicity of platinum-based combination chemotherapy in the platinum-resistant and platinum-refractory setting. Methods Epirubicin, cisplatin, and capecitabine (ECX) combination chemotherapy was used at our institution for the treatment of relapsed EOC. From the institutional database, we identified all patients with primary platinum-refractory or platinum-resistant relapse treated with ECX as second-line therapy between 2001 and 2012. We extracted demographic, clinical, treatment, and toxicity data and outcomes. We used logistic and Cox regression models to identify predictors of response and survival respectively. Results Thirty-four 34 patients (8 refractory, 26 resistant) were treated with ECX. Response Evaluation Criteria In Solid Tumors (RECIST) response rate was 45%, median progression-free survival (PFS) was 6.4 months, and overall survival (OS) was 10.6 months. Platinum-resistant patients had better outcomes than did platinum-refractory patients (response rate, 54% vs 0%, P = 0.047; PFS 7.2 vs 1.8 months, P < 0.0001; OS 14.4 vs 3 months, P < 0.001). In regression models, time to progression after first-line treatment and platinum-refractory status were the strongest predictors of response and PFS or OS, respectively. Patients with time to progression after first-line treatment longer than 3 months showed PFS and OS of 7.9 and 14.7 months, respectively. Toxicity was manageable, with only 13% of cycles administered at reduced doses. Conclusions Epirubicin, cisplatin, and capecitabine seems to be active in platinum-resistant relapsed EOC with manageable toxicity. Further prospective investigation of platinum-anthracycline combinations is warranted in patients who relapse 3 to 6 months after first-line platinum-taxane treatment. PMID:25962114

A Prospective Study of Proton Beam Reirradiation for Esophageal Cancer.

PubMed

Fernandes, Annemarie; Berman, Abigail T; Mick, Rosemarie; Both, Stefan; Lelionis, Kristi; Lukens, John N; Ben-Josef, Edgar; Metz, James M; Plastaras, John P

2016-05-01

Reirradiation to the esophagus carries a significant risk of complications. Proton therapy may offer an advantage in the reirradiation setting due to the lack of exit dose and potential sparing of previously radiated normal tissues. Between June 2010 and February 2014, 14 patients with a history of thoracic radiation and newly diagnosed or locally recurrent esophageal cancer began proton beam reirradiation on a prospective trial. Primary endpoints were feasibility and acute toxicity. Toxicity was graded according Common Toxicity Criteria version 4.0. The median follow-up was 10 months (2-25 months) from the start of reirradiation. Eleven patients received concurrent chemotherapy. The median interval between radiation courses was 32 months (10-307 months). The median reirradiation prescription dose was 54.0 Gy (relative biological effectiveness [RBE]) (50.4-61.2 Gy[RBE]), and the median cumulative prescription dose was 109.8 Gy (76-129.4 Gy). Of the 10 patients who presented with symptomatic disease, 4 patients had complete resolution of symptoms, and 4 had diminished or stable symptoms. Two patients had progressive symptoms. The median time to symptom recurrence was 10 months. Maximum acute nonhematologic toxicity attributable to radiation was grade 2 (64%, N=9), 3 (29%, N=4), 4 (0%), and 5 (7%, N=1). The acute grade 5 toxicity was an esophagopleural fistula more likely related to tumor progression than radiation. Grade 3 nonhematologic acute toxicities included dysphagia, dehydration, and pneumonia. There was 1 late grade 5 esophageal ulcer more likely related to tumor progression than radiation. There were 4 late grade 3 toxicities: heart failure, esophageal stenosis requiring dilation, esophageal ulceration from tumor, and percutaneous endoscopic gastrostomy tube dependence. The median time to local failure was 10 months, and the median overall survival was 14 months. Our data demonstrate that proton reirradiation is feasible, with an encouraging symptom control rate, modest radiation-related toxicity, and favorable survival in this high-risk population. Copyright © 2016 Elsevier Inc. All rights reserved.

Material aid for vaccines

NASA Astrophysics Data System (ADS)

Irvine, Darrell

2018-06-01

Darrell Irvine provides an overview of the recent advances in materials science that have enabled the use of innovative natural and synthetic compounds in vaccine development capable of regulating the potency and safety of new vaccines progressing towards the clinic.

PATHOPHYSIOLOGICAL PROGRESSION AND RELATIONSHIPS FOR SELECTED ENDPOINTS

EPA Science Inventory

The Environmental Protection Agency (EPA), Office of Research and Development (ORD), National Center for Environmental Assessment (NCEA) is currently developing methodologies and information sources to use as guidelines for acute exposure to various compounds, including air toxic...

A clue to unprecedented strategy to HIV eradication: “Lock-in and apoptosis”

DOE PAGES

Tateishi, Hiroshi; Monde, Kazuaki; Anraku, Kensaku; ...

2017-08-21

Despite the development of antiretroviral therapy against HIV, eradication of the virus from the body, as a means to a cure, remains in progress. A “kick and kill” strategy proposes “kick” of the latent HIV to an active HIV to eventually be “killed”. Latency-reverting agents that can perform the “kick” function are under development and have shown promise. Management of the infected cells not to produce virions after the “kick” step is important to this strategy. Here we show that a newly synthesized compound, L-HIPPO, captures the HIV-1 protein Pr55Gag and intercepts its function to translocate the virus from themore » cytoplasm to the plasma membrane leading to virion budding. The infecting virus thus “locked-in” subsequently induces apoptosis of the host cells. This “lock-in and apoptosis” approach performed by our novel compound in HIV-infected cells provides a means to bridge the gap between the “kick” and “kill” steps of this eradication strategy. By building upon previous progress in latency reverting agents, our compound appears to provide a promising step toward the goal of HIV eradication from the body« less

Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII).

PubMed

Bialer, Meir; Johannessen, Svein I; Levy, René H; Perucca, Emilio; Tomson, Torbjörn; White, H Steve

2017-02-01

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Novel Compound Heterozygous Mutations Expand the Recognized Phenotypes of FARS2-Linked Disease.

PubMed

Walker, Melissa A; Mohler, Kyle P; Hopkins, Kyle W; Oakley, Derek H; Sweetser, David A; Ibba, Michael; Frosch, Matthew P; Thibert, Ronald L

2016-08-01

Mutations in mitochondrial aminoacyl-tRNA synthetases are an increasingly recognized cause of human diseases, often arising in individuals with compound heterozygous mutations and presenting with system-specific phenotypes, frequently neurologic. FARS2 encodes mitochondrial phenylalanyl transfer ribonucleic acid (RNA) synthetase (mtPheRS), perturbations of which have been reported in 6 cases of an infantile, lethal disease with refractory epilepsy and progressive myoclonus. Here the authors report the case of juvenile onset refractory epilepsy and progressive myoclonus with compound heterozygous FARS2 mutations. The authors describe the clinical course over 6 years of care at their institution and diagnostic studies including electroencephalogram (EEG), brain magnetic resonance imaging (MRI), serum and cerebrospinal fluid analyses, skeletal muscle biopsy histology, and autopsy gross and histologic findings, which include features shared with Alpers-Huttenlocher syndrome, Leigh syndrome, and a previously published case of FARS2 mutation associated infantile onset disease. The authors also present structure-guided analysis of the relevant mutations based on published mitochondrial phenylalanyl transfer RNA synthetase and related protein crystal structures as well as biochemical analysis of the corresponding recombinant mutant proteins. © The Author(s) 2016.

A clue to unprecedented strategy to HIV eradication: “Lock-in and apoptosis”

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

Tateishi, Hiroshi; Monde, Kazuaki; Anraku, Kensaku

Despite the development of antiretroviral therapy against HIV, eradication of the virus from the body, as a means to a cure, remains in progress. A “kick and kill” strategy proposes “kick” of the latent HIV to an active HIV to eventually be “killed”. Latency-reverting agents that can perform the “kick” function are under development and have shown promise. Management of the infected cells not to produce virions after the “kick” step is important to this strategy. Here we show that a newly synthesized compound, L-HIPPO, captures the HIV-1 protein Pr55Gag and intercepts its function to translocate the virus from themore » cytoplasm to the plasma membrane leading to virion budding. The infecting virus thus “locked-in” subsequently induces apoptosis of the host cells. This “lock-in and apoptosis” approach performed by our novel compound in HIV-infected cells provides a means to bridge the gap between the “kick” and “kill” steps of this eradication strategy. By building upon previous progress in latency reverting agents, our compound appears to provide a promising step toward the goal of HIV eradication from the body« less

Adhesives, fillers and potting compounds. Second progress report, December 1, 1967--April 1, 1968

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

Lichte, H.W.; Akst, I.B.

1968-12-31

Progress in the development program whose immediate purpose is to reduce set time of a silicone compound is described. Data are presented showing that a formulation of a current RTV silicone rubber with dibutyltin diacetate has a profitably lower set time than the same rubber in the present formulation which uses dibutyltin dilaurate, without increase in probability of either reversion or penalty to other weapons components. Time to set sufficiently to allow the next assembly step is 2 to 4 hours, compared to the 16 to 24 hours presently allowed or the 8 to 12 hours minimum attainable with themore » present formulation. The reduction is of the magnitude set as a goal, the attainment of which would increase production capacity enough to reduce the amount of new construction planned to accommodate weapons assembly programs.« less

Enhancing the Health-Promoting Effects of Tomato Fruit for Biofortified Food

PubMed Central

Rigano, Maria Manuela; Frusciante, Luigi; Barone, Amalia

2014-01-01

Consumption of tomato fruits, like those of many other plant species that are part of the human diet, is considered to be associated with several positive effects on health. Indeed, tomato fruits are an important source of bioactive compounds with known beneficial effects including vitamins, antioxidants, and anticancer substances. In particular, antioxidant metabolites are a group of vitamins, carotenoids, phenolic compounds, and phenolic acid that can provide effective protection by neutralizing free radicals, which are unstable molecules linked to the development of a number of degenerative diseases and conditions. In this review, we will summarize the recent progress on tomatoes nutritional importance and mechanisms of action of different phytochemicals against inflammation processes and prevention of chronic noncommunicable diseases (e.g., obesity, diabetes, coronary heart disease, and hypertension). In addition, we will summarize the significant progress recently made to improve the nutritional quality of tomato fruits through metabolic engineering and/or breeding. PMID:24744504

Anti-inflammatory agents from plants: progress and potential.

PubMed

Recio, M C; Andujar, I; Rios, J L

2012-01-01

The identification of substances that can promote the resolution of inflammation in a way that is homeostatic, modulatory, efficient, and well-tolerated by the body is of fundamental importance. Traditional medicines have long provided front-line pharmacotherapy for many millions of people worldwide. Medicinal extracts are a rich source of therapeutic leads for the pharmaceutical industry. The use of medicinal plant therapies to treat chronic illness, including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), is thus widespread and on the rise.The aim of this review is to present recent progress in clinical anti-inflammatory studies of plant extracts and compound leads such as green tea polyphenols, curcumin, resveratrol, boswellic acid, and cucurbitacins, among others, against chronic inflammatory diseases, mainly RA and IBD. In this context, the present paper also highlights the most promising experimental data on those plant extracts and pure compounds active in animal models of the aforementioned diseases.

Mechanisms for radiation damage in DNA. Progress report, January 1, 1980-December 31, 1980

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

Sevilla, M D

1980-09-01

In this project several mechanisms are proposed for radiation damage to DNA constituents and DNA, and a series of experiments detailed utilizing electron spin resonance spectrometry to test the proposed mechanisms. Under current investigation are irradiated systems of DNA constituents which may shed light on indirect effects. In addition, studies of radiation effects on lipids have been undertaken which will shed light on the only other proposed site for cell kill, the membrane. Studies completed during the past year are: (1) ..pi.. cations produced in DNA bases by attack of oxidizing radicals; (2) INDO studies of radicals produced in peptidesmore » and carboxylic acid model compounds; (3) electron reactions with carboxylic acids, ketones and aldehydes; and (4) ..gamma..-irradiation of esters and triglycerides. Progress has been made this year in a study of radicals generated in model compounds for the sugar-phosphate backbone.« less

Preventive Effects of Cocoa and Cocoa Antioxidants in Colon Cancer

PubMed Central

Martín, María Angeles; Goya, Luis; Ramos, Sonia

2016-01-01

Colorectal cancer is one of the main causes of cancer-related mortality in the developed world. Carcinogenesis is a multistage process conventionally defined by the initiation, promotion and progression stages. Natural polyphenolic compounds can act as highly effective antioxidant and chemo-preventive agents able to interfere at the three stages of cancer. Cocoa has been demonstrated to counteract oxidative stress and to have a potential capacity to interact with multiple carcinogenic pathways involved in inflammation, proliferation and apoptosis of initiated and malignant cells. Therefore, restriction of oxidative stress and/or prevention or delayed progression of cancer stages by cocoa antioxidant compounds has gained interest as an effective approach in colorectal cancer prevention. In this review, we look over different in vitro and in vivo studies that have identified potential targets and mechanisms whereby cocoa and their flavonoids could interfere with colonic cancer. In addition, evidence from human studies is also illustrated. PMID:28933386

Recent progress on biomass co-pyrolysis conversion into high-quality bio-oil.

PubMed

Hassan, H; Lim, J K; Hameed, B H

2016-12-01

Co-pyrolysis of biomass with abundantly available materials could be an economical method for production of bio-fuels. However, elimination of oxygenated compounds poses a considerable challenge. Catalytic co-pyrolysis is another potential technique for upgrading bio-oils for application as liquid fuels in standard engines. This technique promotes the production of high-quality bio-oil through acid catalyzed reduction of oxygenated compounds and mutagenic polyaromatic hydrocarbons. This work aims to review and summarize research progress on co-pyrolysis and catalytic co-pyrolysis, as well as their benefits on enhancement of bio-oils derived from biomass. This review focuses on the potential of plastic wastes and coal materials as co-feed in co-pyrolysis to produce valuable liquid fuel. This paper also proposes future directions for using this technique to obtain high yields of bio-oils. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lenalidomide at the dose of 25 mg every other day in patients affected by multiple myeloma and renal failure: a real-life experience.

PubMed

Cerchione, Claudio; Nappi, Davide; Pareto, Anna E; Romano, Alessandra; Martinelli, Vincenzo; Picardi, Marco; Pane, Fabrizio; Catalano, Lucio

2018-04-01

Renal impairment (RI) is a relevant complication of patients affected by multiple myeloma (MM); it can be present in up to 30-35% of newly diagnosed MM and is linked to a poor outcome. However, early recognition and early treatment with novel agents can overcome the negative impact of RI and even reverse kidney damage in most cases. Lenalidomide, available as an oral compound, is an immunomodulatory drug with both antiproliferative and immunomodulatory activity that is largely used in the management of MM. Dose reduction is mandatory in RI; however, there is no theoretical assumption against the possibility that protracting the time of full standard doses can be equally effective and tolerated by patients requiring reduced doses. In this report, we describe our retrospective experience, in 18 patients, with the administration of lenalidomide 25 mg every other day for patients with MM and RI. The overall response ratio was 66.5%. More than half (61.1%) of the patients had a renal response. The median progression-free survival was 8 months (range: 3-18 months). No serious adverse event occurred during treatment, and it was never necessary to disrupt or delay treatment for toxicity. These preliminary observations point to a significant therapeutic effect of lenalidomide, at the dose of 25 mg every other day for 21 days, with logistic and economic advantages. However, these results should be validated by controlled studies involving larger numbers of patients.

Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

PubMed Central

Antonello, ZA; Nucera, C

2015-01-01

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research. PMID:24362526