Kishikawa, Takahiro; Otsuka, Motoyuki; Suzuki, Tatsunori; Seimiya, Takahiro; Sekiba, Kazuma; Ishibashi, Rei; Tanaka, Eri; Ohno, Motoko; Yamagami, Mari; Koike, Kazuhiko
2018-05-10
Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis in vivo , we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase. Implications: Aberrant expression of satellite RNAs accelerates oncogenesis through a mechanism involving increased DNA damage. Mol Cancer Res; 1-8. ©2018 AACR. ©2018 American Association for Cancer Research.
Vibration acceleration promotes bone formation in rodent models
Uchida, Ryohei; Nakata, Ken; Kawano, Fuminori; Yonetani, Yasukazu; Ogasawara, Issei; Nakai, Naoya; Mae, Tatsuo; Matsuo, Tomohiko; Tachibana, Yuta; Yokoi, Hiroyuki; Yoshikawa, Hideki
2017-01-01
All living tissues and cells on Earth are subject to gravitational acceleration, but no reports have verified whether acceleration mode influences bone formation and healing. Therefore, this study was to compare the effects of two acceleration modes, vibration and constant (centrifugal) accelerations, on bone formation and healing in the trunk using BMP 2-induced ectopic bone formation (EBF) mouse model and a rib fracture healing (RFH) rat model. Additionally, we tried to verify the difference in mechanism of effect on bone formation by accelerations between these two models. Three groups (low- and high-magnitude vibration and control-VA groups) were evaluated in the vibration acceleration study, and two groups (centrifuge acceleration and control-CA groups) were used in the constant acceleration study. In each model, the intervention was applied for ten minutes per day from three days after surgery for eleven days (EBF model) or nine days (RFH model). All animals were sacrificed the day after the intervention ended. In the EBF model, ectopic bone was evaluated by macroscopic and histological observations, wet weight, radiography and microfocus computed tomography (micro-CT). In the RFH model, whole fracture-repaired ribs were excised with removal of soft tissue, and evaluated radiologically and histologically. Ectopic bones in the low-magnitude group (EBF model) had significantly greater wet weight and were significantly larger (macroscopically and radiographically) than those in the other two groups, whereas the size and wet weight of ectopic bones in the centrifuge acceleration group showed no significant difference compared those in control-CA group. All ectopic bones showed calcified trabeculae and maturated bone marrow. Micro-CT showed that bone volume (BV) in the low-magnitude group of EBF model was significantly higher than those in the other two groups (3.1±1.2mm3 v.s. 1.8±1.2mm3 in high-magnitude group and 1.3±0.9mm3 in control-VA group), but BV in the
Vibration acceleration promotes bone formation in rodent models.
Uchida, Ryohei; Nakata, Ken; Kawano, Fuminori; Yonetani, Yasukazu; Ogasawara, Issei; Nakai, Naoya; Mae, Tatsuo; Matsuo, Tomohiko; Tachibana, Yuta; Yokoi, Hiroyuki; Yoshikawa, Hideki
2017-01-01
All living tissues and cells on Earth are subject to gravitational acceleration, but no reports have verified whether acceleration mode influences bone formation and healing. Therefore, this study was to compare the effects of two acceleration modes, vibration and constant (centrifugal) accelerations, on bone formation and healing in the trunk using BMP 2-induced ectopic bone formation (EBF) mouse model and a rib fracture healing (RFH) rat model. Additionally, we tried to verify the difference in mechanism of effect on bone formation by accelerations between these two models. Three groups (low- and high-magnitude vibration and control-VA groups) were evaluated in the vibration acceleration study, and two groups (centrifuge acceleration and control-CA groups) were used in the constant acceleration study. In each model, the intervention was applied for ten minutes per day from three days after surgery for eleven days (EBF model) or nine days (RFH model). All animals were sacrificed the day after the intervention ended. In the EBF model, ectopic bone was evaluated by macroscopic and histological observations, wet weight, radiography and microfocus computed tomography (micro-CT). In the RFH model, whole fracture-repaired ribs were excised with removal of soft tissue, and evaluated radiologically and histologically. Ectopic bones in the low-magnitude group (EBF model) had significantly greater wet weight and were significantly larger (macroscopically and radiographically) than those in the other two groups, whereas the size and wet weight of ectopic bones in the centrifuge acceleration group showed no significant difference compared those in control-CA group. All ectopic bones showed calcified trabeculae and maturated bone marrow. Micro-CT showed that bone volume (BV) in the low-magnitude group of EBF model was significantly higher than those in the other two groups (3.1±1.2mm3 v.s. 1.8±1.2mm3 in high-magnitude group and 1.3±0.9mm3 in control-VA group), but BV in the
Garcia, I; Crowther, A J; Gama, V; Miller, C R; Miller, C Ryan; Deshmukh, M; Gershon, T R
2013-05-02
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
Hanin, Leonid; Rose, Jason
2018-03-01
We study metastatic cancer progression through an extremely general individual-patient mathematical model that is rooted in the contemporary understanding of the underlying biomedical processes yet is essentially free of specific biological assumptions of mechanistic nature. The model accounts for primary tumor growth and resection, shedding of metastases off the primary tumor and their selection, dormancy and growth in a given secondary site. However, functional parameters descriptive of these processes are assumed to be essentially arbitrary. In spite of such generality, the model allows for computing the distribution of site-specific sizes of detectable metastases in closed form. Under the assumption of exponential growth of metastases before and after primary tumor resection, we showed that, regardless of other model parameters and for every set of site-specific volumes of detected metastases, the model-based likelihood-maximizing scenario is always the same: complete suppression of metastatic growth before primary tumor resection followed by an abrupt growth acceleration after surgery. This scenario is commonly observed in clinical practice and is supported by a wealth of experimental and clinical studies conducted over the last 110 years. Furthermore, several biological mechanisms have been identified that could bring about suppression of metastasis by the primary tumor and accelerated vascularization and growth of metastases after primary tumor resection. To the best of our knowledge, the methodology for uncovering general biomedical principles developed in this work is new.
ERIC Educational Resources Information Center
Deichert, Nathan T.; Maxwell, Shannon J.; Klotz, Joseph
2016-01-01
The current study is a quasi-experimental examination of the effects of traditional and accelerated course formats on learning retention. The study analyzed data on an end-of-course exam collected from 132 students enrolled in introductory psychology courses across 3 course formats: a traditional 16-week format, a 5-week accelerated format, and an…
Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone.
Roca, Hernan; Jones, Jacqueline D; Purica, Marta C; Weidner, Savannah; Koh, Amy J; Kuo, Robert; Wilkinson, John E; Wang, Yugang; Daignault-Newton, Stephanie; Pienta, Kenneth J; Morgan, Todd M; Keller, Evan T; Nör, Jacques E; Shea, Lonnie D; McCauley, Laurie K
2018-01-02
During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.
Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.
Easter, Stephanie L; Mitchell, Elizabeth H; Baxley, Sarah E; Desmond, Renee; Frost, Andra R; Serra, Rosa
2014-01-01
Wnt5a is a non-canonical signaling Wnt that has been implicated in tumor suppression. We previously showed that loss of Wnt5a in MMTV-PyVmT tumors resulted in a switch in tumor phenotype resulting in tumors with increased basal phenotype and high Wnt/β-catenin signaling. The object of this study was to test the hypothesis that Wnt5a can act to inhibit tumors formed by activation of Wnt/β-catenin signaling. To this end, we characterized tumor and non-tumor mammary tissue from MMTV-Wnt1 and double transgenic MMTV-Wnt1;MMTV-Wnt5a mice. Wnt5a containing mice demonstrated fewer tumors with increased latency when compared to MMTV-Wnt1 controls. Expression of markers for basal-like tumors was down-regulated in the tumors that formed in the presence of Wnt5a indicating a phenotypic switch. Reduced canonical Wnt signaling was detected in double transgenic tumors as a decrease in active β-catenin protein and a decrease in Axin2 mRNA transcript levels. In non-tumor tissues, over-expression of Wnt5a in MMTV-Wnt1 mammary glands resulted in attenuation of phenotypes normally observed in MMTV-Wnt1 glands including hyperbranching and increased progenitor and basal cell populations. Even though Wnt5a could antagonize Wnt/β-catenin signaling in primary mammary epithelial cells in culture, reduced Wnt/β-catenin signaling was not detected in non-tumor MMTV-Wnt1;Wnt5a tissue in vivo. The data demonstrate that Wnt5a suppresses tumor formation and promotes a phenotypic shift in MMTV-Wnt1 tumors.
Carboxylic acid accelerated formation of diesters
Tustin, G.C.; Dickson, T.J.
1998-04-28
This invention pertains to accelerating the rate of formation of 1,1-dicarboxylic esters from the reaction of an aldehyde with a carboxylic acid anhydride or a ketene in the presence of a non-iodide containing a strong Bronsted acid catalyst by the addition of a carboxylic acid at about one bar pressure and between about 0 and 80 C in the substantial absence of a hydrogenation or carbonylation catalyst.
Carboxylic acid accelerated formation of diesters
Tustin, Gerald Charles; Dickson, Todd Jay
1998-01-01
This invention pertains to accelerating the rate of formation of 1,1-dicarboxylic esters from the reaction of an aldehyde with a carboxylic acid anhydride or a ketene in the presence of a non-iodide containing a strong Bronsted acid catalyst by the addition of a carboxylic acid at about one bar pressure and between about 0.degree. and 80.degree. C. in the substantial absence of a hydrogenation or carbonylation catalyst.
Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.
Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G
2003-01-01
Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.
Chronic skin inflammation accelerates macrophage cholesterol crystal formation and atherosclerosis
Ng, Qimin; Sanda, Gregory E.; Dey, Amit K.; Teague, Heather L.; Sorokin, Alexander V.; Dagur, Pradeep K.; Silverman, Joanna I.; Harrington, Charlotte L.; Rodante, Justin A.; Rose, Shawn M.; Varghese, Nevin J.; Belur, Agastya D.; Goyal, Aditya; Gelfand, Joel M.; Springer, Danielle A.; Bleck, Christopher K.E.; Thomas, Crystal L.; Yu, Zu-Xi; Winge, Mårten C.G.; Kruth, Howard S.; Marinkovich, M. Peter; Joshi, Aditya A.; Playford, Martin P.; Mehta, Nehal N.
2018-01-01
Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis. PMID:29321372
An accelerated technique for irradiation of malignant canine nasal and paranasal sinus tumors.
Adams, W M; Miller, P E; Vail, D M; Forrest, L J; MacEwen, E G
1998-01-01
Tumor and normal tissue response was assessed in 21 dogs with malignant nasal tumors given 42 Gy cobalt radiation in 9 or 10 fractions over 11 to 13 days. Local tumor/clinical relapse recurred in 68% of dogs, with a median relapse free interval (RFI) of 270 days. Median survival was 428 days. One year survival for all dogs was 60%. RFI and survival times are better than, or similar to, previous reports of dogs treated with radiotherapy only. Acute radiation effects were severe in one dog. Late effects were severe in six of 15 dogs (40%) with durable tumor control. Late effects included bilateral blindness (3), osteoradionecrosis (3), and seizures (1). These six dogs had a median survival of 705 days. Loss of vision occurred in at least one eye in nine dogs (47%). Tumor staging based on CT findings was predictive for survival duration. Tumor histology was not predictive of outcome. Labrador Retrievers were significantly over-represented. Despite comparable or improved tumor control and survival times provided by this accelerated protocol, relative to other radiotherapy reports, local failure remains the major cause of death, and late radiation effects can be severe in dogs with durable tumor control.
Stabilization of beta-catenin induces pancreas tumor formation.
Heiser, Patrick W; Cano, David A; Landsman, Limor; Kim, Grace E; Kench, James G; Klimstra, David S; Taketo, Maketo M; Biankin, Andrew V; Hebrok, Matthias
2008-10-01
beta-Catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of beta-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is among the leading causes of cancer death. Whereas activating mutations within beta-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of beta-catenin signaling in pancreas tumorigenesis. Using Cre/lox technology, we conditionally activated beta-catenin in a subset of murine pancreatic cells in vivo. Activation of beta-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based on morphologic and immunohistochemical comparisons. Interestingly, stabilization of beta-catenin blocks the formation of pancreatic intraepithelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to PDA. Instead, mice in which beta-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. These results demonstrate that activation of beta-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor.
Stabilization of β-catenin induces pancreas tumor formation
Heiser, Patrick W.; Cano, David A.; Landsman, Limor; Kim, Grace E.; Kench, James G.; Klimstra, David S.; Taketo, Maketo M.; Biankin, Andrew V.; Hebrok, Matthias
2008-01-01
Background & Aims β-catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of β-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is one of the leading causes of cancer death. While activating mutations within β-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of β-catenin signaling in pancreas tumorigenesis. Methods Using Cre/lox technology, we conditionally activated β-catenin in a subset of murine pancreatic cells, in vivo. Results Activation of β-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based upon morphological and immunohistochemical comparisons. Interestingly, stabilization of β-catenin blocks the formation of pancreatic intraepithlelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to pancreatic ductal adenocarcinoma (PDA). Instead, mice in which β-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. Conclusions These results demonstrate that activation of β-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor. PMID:18725219
Kim, Sungjin; Yang, Xiangkun; Li, Qianjin; Wu, Meng; Costyn, Leah; Beharry, Zanna; Bartlett, Michael G; Cai, Houjian
2017-11-10
Exogenous fatty acids provide substrates for energy production and biogenesis of the cytoplasmic membrane, but they also enhance cellular signaling during cancer cell proliferation. However, it remains controversial whether dietary fatty acids are correlated with tumor progression. In this study, we demonstrate that increased Src kinase activity is associated with high-fat diet-accelerated progression of prostate tumors and that Src kinases mediate this pathological process. Moreover, in the in vivo prostate regeneration assay, host SCID mice carrying Src(Y529F)-transduced regeneration tissues were fed a low-fat diet or a high-fat diet and treated with vehicle or dasatinib. The high-fat diet not only accelerated Src-induced prostate tumorigenesis in mice but also compromised the inhibitory effect of the anticancer drug dasatinib on Src kinase oncogenic potential in vivo We further show that myristoylation of Src kinase is essential to facilitate Src-induced and high-fat diet-accelerated tumor progression. Mechanistically, metabolism of exogenous myristic acid increased the biosynthesis of myristoyl CoA and myristoylated Src and promoted Src kinase-mediated oncogenic signaling in human cells. Of the fatty acids tested, only exogenous myristic acid contributed to increased intracellular myristoyl CoA levels. Our results suggest that targeting Src kinase myristoylation, which is required for Src kinase association at the cellular membrane, blocks dietary fat-accelerated tumorigenesis in vivo Our findings uncover the molecular basis of how the metabolism of myristic acid stimulates high-fat diet-mediated prostate tumor progression. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate.
Arwert, Esther N; Lal, Rohit; Quist, Sven; Rosewell, Ian; van Rooijen, Nico; Watt, Fiona M
2010-11-16
In mammalian epidermis, integrin expression is normally confined to the basal proliferative layer that contains stem cells. However, in epidermal hyperproliferative disorders and tumors, integrins are also expressed by suprabasal cells, with concomitant up-regulation of Erk mitogen-activated protein kinase (MAPK) signaling. In transgenic mice, expression of activated MAPK kinase 1 (MEK1) in the suprabasal, nondividing, differentiated cell layers (InvEE transgenics) results in epidermal hyperproliferation and skin inflammation. We now demonstrate that wounding induces benign tumors (papillomas and keratoacanthomas) in InvEE mice. By generating chimeras between InvEE mice and mice that lack the MEK1 transgene, we demonstrate that differentiating, nondividing cells that express MEK1 stimulate adjacent transgene-negative cells to divide and become incorporated into the tumor mass. Dexamethasone treatment inhibits tumor formation, suggesting that inflammation is involved. InvEE skin and tumors express high levels of IL1α; treatment with an IL1 receptor antagonist delays tumor onset and reduces incidence. Depletion of γδ T cells and macrophages also reduces tumor incidence. Because a hallmark of cancer is uncontrolled proliferation, it is widely assumed that tumors arise only from dividing cells. In contrast, our studies show that differentiated epidermal cells can initiate tumor formation without reacquiring the ability to divide and that they do so by triggering an inflammatory infiltrate.
Solid-particle jet formation under shock-wave acceleration.
Rodriguez, V; Saurel, R; Jourdan, G; Houas, L
2013-12-01
When solid particles are impulsively dispersed by a shock wave, they develop a spatial distribution which takes the form of particle jets whose selection mechanism is still unidentified. The aim of the present experimental work is to study particle dispersal with fingering effects in an original quasi-two-dimensional experiment facility in order to accurately extract information. Shock and blast waves are generated in the carrier gas at the center of a granular medium ring initially confined inside a Hele-Shaw cell and impulsively accelerated. With the present experimental setup, the particle jet formation is clearly observed. From fast flow visualizations, we notice, in all instances, that the jets are initially generated inside the particle ring and thereafter expelled outward. This point has not been observed in three-dimensional experiments. We highlight that the number of jets is unsteady and decreases with time. For a fixed configuration, considering the very early times following the initial acceleration, the jet size selection is independent of the particle diameter. Moreover, the influence of the initial overpressure and the material density on the particle jet formation have been studied. It is shown that the wave number of particle jets increases with the overpressure and with the decrease of the material density. The normalized number of jets as a function of the initial ring acceleration shows a power law valid for all studied configurations involving various initial pressure ratios, particle sizes, and particle materials.
The accelerating pace of star formation
NASA Astrophysics Data System (ADS)
Caldwell, Spencer; Chang, Philip
2018-03-01
We study the temporal and spatial distribution of star formation rates in four well-studied star-forming regions in local molecular clouds (MCs): Taurus, Perseus, ρ Ophiuchi, and Orion A. Using published mass and age estimates for young stellar objects in each system, we show that the rate of star formation over the last 10 Myr has been accelerating and is (roughly) consistent with a t2 power law. This is in line with previous studies of the star formation history of MCs and with recent theoretical studies. We further study the clustering of star formation in the Orion nebula cluster. We examine the distribution of young stellar objects as a function of their age by computing an effective half-light radius for these young stars subdivided into age bins. We show that the distribution of young stellar objects is broadly consistent with the star formation being entirely localized within the central region. We also find a slow radial expansion of the newly formed stars at a velocity of v = 0.17 km s-1, which is roughly the sound speed of the cold molecular gas. This strongly suggests the dense structures that form stars persist much longer than the local dynamical time. We argue that this structure is quasi-static in nature and is likely the result of the density profile approaching an attractor solution as suggested by recent analytic and numerical analysis.
Hypercholesterolemia induces angiogenesis and accelerates growth of breast tumors in vivo.
Pelton, Kristine; Coticchia, Christine M; Curatolo, Adam S; Schaffner, Carl P; Zurakowski, David; Solomon, Keith R; Moses, Marsha A
2014-07-01
Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Powan, Phattrakorn; Luanpitpong, Sudjit; He, Xiaoqing; Rojanasakul, Yon; Chanvorachote, Pithi
2017-11-01
The epithelial-to-mesenchymal transition is proposed to be a key mechanism responsible for metastasis-related deaths. Similarly, cancer stem cells (CSCs) have been proposed to be a key driver of tumor metastasis. However, the link between the two events and their control mechanisms is unclear. We used a three-dimensional (3D) tumor spheroid assay and other CSC-indicating assays to investigate the role of E-cadherin in CSC regulation and its association to epithelial-to-mesenchymal transition in lung cancer cells. Ectopic overexpression and knockdown of E-cadherin were found to promote and retard, respectively, the formation of tumor spheroids in vitro but had opposite effects on tumor formation and metastasis in vivo in a xenograft mouse model. We explored the discrepancy between the in vitro and in vivo results and demonstrated, for the first time, that E-cadherin is required as a component of a major survival pathway under detachment conditions. Downregulation of E-cadherin increased the stemness of lung cancer cells but had an adverse effect on their survival, particularly on non-CSCs. Such downregulation also promoted anoikis resistance and invasiveness of lung cancer cells. These results suggest that anoikis assay could be used as an alternative method for in vitro assessment of CSCs that involves dysregulated adhesion proteins. Our data also suggest that agents that restore E-cadherin expression may be used as therapeutic agents for metastatic cancers. Copyright © 2017 the American Physiological Society.
Yu, Linfen; Chen, Michael C W; Cheung, Karen C
2010-09-21
Creating multicellular tumor spheroids is critical for characterizing anticancer treatments since it may provide a better model than monolayer culture of tumor cells. Moreover, continuous dynamic perfusion allows the establishment of long term cell culture and subsequent multicellular spheroid formation. A droplet-based microfluidic system was used to form alginate beads with entrapped breast tumor cells. After gelation, the alginate beads were trapped in microsieve structures for cell culture in a continuous perfusion system. The alginate environment permitted cell proliferation and the formation of multicellular spheroids was observed. The dose-dependent response of the tumor spheroids to doxorubicin, and anticancer drug, showed multicellular resistance compared to conventional monolayer culture. The microsieve structures maintain constant location of each bead in the same position throughout the device seeding process, cell proliferation and spheroid formation, treatment with drug, and imaging, permitting temporal and spatial tracking.
Tetramer formation of tumor suppressor protein p53: Structure, function, and applications.
Kamada, Rui; Toguchi, Yu; Nomura, Takao; Imagawa, Toshiaki; Sakaguchi, Kazuyasu
2016-11-04
Tetramer formation of p53 is essential for its tumor suppressor function. p53 not only acts as a tumor suppressor protein by inducing cell cycle arrest and apoptosis in response to genotoxic stress, but it also regulates other cellular processes, including autophagy, stem cell self-renewal, and reprogramming of differentiated cells into stem cells, immune system, and metastasis. More than 50% of human tumors have TP53 gene mutations, and most of them are missense mutations that presumably reduce tumor suppressor activity of p53. This review focuses on the role of the tetramerization (oligomerization), which is modulated by the protein concentration of p53, posttranslational modifications, and/or interactions with its binding proteins, in regulating the tumor suppressor function of p53. Functional control of p53 by stabilizing or inhibiting oligomer formation and its bio-applications are also discussed. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 598-612, 2016. © 2015 Wiley Periodicals, Inc.
Yin, Mingzhu; Li, Xia; Tan, Shu; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge
2016-01-01
Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers. PMID:27721235
Hypercholesterolemia Induces Angiogenesis and Accelerates Growth of Breast Tumors in Vivo
Pelton, Kristine; Coticchia, Christine M.; Curatolo, Adam S.; Schaffner, Carl P.; Zurakowski, David; Solomon, Keith R.; Moses, Marsha A.
2015-01-01
Obesity and metabolic syndrome are linked to an increased prevalence of breast cancer among postmenopausal women. A common feature of obesity, metabolic syndrome, and a Western diet rich in saturated fat is a high level of circulating cholesterol. Epidemiological reports investigating the relationship between high circulating cholesterol levels, cholesterol-lowering drugs, and breast cancer are conflicting. Here, we modeled this complex condition in a well-controlled, preclinical animal model using innovative isocaloric diets. Female severe combined immunodeficient mice were fed a low-fat/no-cholesterol diet and then randomized to four isocaloric diet groups: low-fat/no-cholesterol diet, with or without ezetimibe (cholesterol-lowering drug), and high-fat/high-cholesterol diet, with or without ezetimibe. Mice were implanted orthotopically with MDA-MB-231 cells. Breast tumors from animals fed the high-fat/high-cholesterol diet exhibited the fastest progression. Significant differences in serum cholesterol level between groups were achieved and maintained throughout the study; however, no differences were observed in intratumoral cholesterol levels. To determine the mechanism of cholesterol-induced tumor progression, we analyzed tumor proliferation, apoptosis, and angiogenesis and found a significantly greater percentage of proliferating cells from mice fed the high-fat/high-cholesterol diet. Tumors from hypercholesterolemic animals displayed significantly less apoptosis compared with the other groups. Tumors from high-fat/high-cholesterol mice had significantly higher microvessel density compared with tumors from the other groups. These results demonstrate that hypercholesterolemia induces angiogenesis and accelerates breast tumor growth in vivo. PMID:24952430
Yu, Qingxiong; Sheng, Lingling; Yang, Mei; Zhu, Ming; Huang, Xiaolu; Li, Qingfeng
2014-01-01
The tissue expansion technique has been applied to obtain new skin tissue to repair large defects in clinical practice. The implantation of tissue expander could initiate a host response to foreign body (FBR), which leads to fibrotic encapsulation around the expander and prolongs the period of tissue expansion. Tanshinon IIA (Tan IIA) has been shown to have anti-inflammation and immunoregulation effect. The rat tissue expansion model was used in this study to observe whether Tan IIA injection systematically could inhibit the FBR to reduce fibrous capsule formation and accelerate the process of tissue expansion. Forty-eight rats were randomly divided into the Tan IIA group and control group with 24 rats in each group. The expansion was conducted twice a week to maintain a capsule pressure of 60 mmHg. The expansion volume and expanded area were measured. The expanded tissue in the two groups was harvested, and histological staining was performed; proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) and transforming growth factor-β (TGF-β) were examined. The expansion volume and the expanded area in the Tan IIA group were greater than that of the control group. The thickness of the fibrous capsule in the Tan IIA group was reduced with no influence on the normal skin regeneration. Decreased infiltration of macrophages, lower level of TNF-α, IL-6, IL-1β and TGF-β, less proliferating myofibroblasts and enhanced neovascularization were observed in the Tan IIA group. Our findings indicated that the Tan IIA injection reduced the formation of the fibrous capsule and accelerated the process of tissue expansion by inhibiting the FBR.
Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model.
Urrutia-Ortega, Ismael M; Garduño-Balderas, Luis G; Delgado-Buenrostro, Norma L; Freyre-Fonseca, Verónica; Flores-Flores, José O; González-Robles, Arturo; Pedraza-Chaverri, José; Hernández-Pando, Rogelio; Rodríguez-Sosa, Miriam; León-Cabrera, Sonia; Terrazas, Luis I; van Loveren, Henk; Chirino, Yolanda I
2016-07-01
Colorectal cancer is the fourth worldwide cause of death and even if some dietary habits are consider risk factors, the contribution of food additives including foodgrade titanium dioxide (TiO2), designated as E171, has been poorly investigated. We hypothesized that oral E171 intake could have impact on the enhancement of colorectal tumor formation and we aimed to investigate if E171 administration could enhance tumor formation in a colitis associated cancer (CAC) model. BALB/c male mice were grouped as follows: a) control, b) E171, c) CAC and d) CAC + E171 group (n = 6). E171 used in this study formed agglomerates of 300 nm in water. E171 intragastric administration (5 mg/kg body weight/5 days/10 weeks) was unable to induce tumor formation but dysplastic alterations were observed in the distal colon but enhanced the tumor formation in distal colon (CAC + E171 group) measured by tumor progression markers. Some E171 particles were internalized in colonic cells of the E171 and CAC + E171 groups and both groups showed a decrease in goblet cells in the distal colon. However the CAC + E171 group showed a higher decrease of these cells that act as protection barrier in colon. These results suggest that E171 could worsen pre-existent intestinal diseases. Copyright © 2016 Elsevier Ltd. All rights reserved.
Accelerator-based epithermal neutron sources for boron neutron capture therapy of brain tumors.
Blue, Thomas E; Yanch, Jacquelyn C
2003-01-01
This paper reviews the development of low-energy light ion accelerator-based neutron sources (ABNSs) for the treatment of brain tumors through an intact scalp and skull using boron neutron capture therapy (BNCT). A major advantage of an ABNS for BNCT over reactor-based neutron sources is the potential for siting within a hospital. Consequently, light-ion accelerators that are injectors to larger machines in high-energy physics facilities are not considered. An ABNS for BNCT is composed of: (1) the accelerator hardware for producing a high current charged particle beam, (2) an appropriate neutron-producing target and target heat removal system (HRS), and (3) a moderator/reflector assembly to render the flux energy spectrum of neutrons produced in the target suitable for patient irradiation. As a consequence of the efforts of researchers throughout the world, progress has been made on the design, manufacture, and testing of these three major components. Although an ABNS facility has not yet been built that has optimally assembled these three components, the feasibility of clinically useful ABNSs has been clearly established. Both electrostatic and radio frequency linear accelerators of reasonable cost (approximately 1.5 M dollars) appear to be capable of producing charged particle beams, with combinations of accelerated particle energy (a few MeV) and beam currents (approximately 10 mA) that are suitable for a hospital-based ABNS for BNCT. The specific accelerator performance requirements depend upon the charged particle reaction by which neutrons are produced in the target and the clinical requirements for neutron field quality and intensity. The accelerator performance requirements are more demanding for beryllium than for lithium as a target. However, beryllium targets are more easily cooled. The accelerator performance requirements are also more demanding for greater neutron field quality and intensity. Target HRSs that are based on submerged-jet impingement and
Han, Kai; Zhang, Jin; Zhang, Weiyun; Wang, Shibo; Xu, Luming; Zhang, Chi; Zhang, Xianzheng; Han, Heyou
2017-03-28
Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this article, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy, and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.
Vortex Formation and Acceleration of a Fish-Inspired Robot Performing Starts from Rest
NASA Astrophysics Data System (ADS)
Devoria, Adam; Bapst, Jonathan; Ringuette, Matthew
2009-11-01
We investigate the unsteady flow of a fish-inspired robot executing starts from rest, with the objective of understanding the connection among the kinematics, vortex formation, and acceleration performance. Several fish perform ``fast starts,'' where the body bends into a ``C'' or ``S'' shape while turning (phase I), followed by a straightening of the body and caudal fin and a linear acceleration (phase II). The resulting highly 3-D, unsteady vortex formation and its relationship to the acceleration are not well understood. The self-propelled robotic model contains motor-driven joints with programmable motion to emulate phase II of a simplified C-start. The experiments are conducted in a water tank, and the model is constrained to 1 direction along rails. The velocity is measured using digital particle image velocimetry (DPIV) in multiple planes. Vortex boundaries are identified using the finite-time Lyapunov exponent, then the unsteady vortex circulation is computed. The thrust is estimated from the identified vortices, and correlated with the circulation and model acceleration for different kinematics.
Collisionless shock formation and the prompt acceleration of solar flare ions
NASA Technical Reports Server (NTRS)
Cargill, P. J.; Goodrich, C. C.; Vlahos, L.
1988-01-01
The formation mechanisms of collisionless shocks in solar flare plasmas are investigated. The priamry flare energy release is assumed to arise in the coronal portion of a flare loop as many small regions or 'hot spots' where the plasma beta locally exceeds unity. One dimensional hybrid numerical simulations show that the expansion of these 'hot spots' in a direction either perpendicular or oblique to the ambient magnetic field gives rise to collisionless shocks in a few Omega(i), where Omega(i) is the local ion cyclotron frequency. For solar parameters, this is less than 1 second. The local shocks are then subsequently able to accelerate particles to 10 MeV in less than 1 second by a combined drift-diffusive process. The formation mechanism may also give rise to energetic ions of 100 keV in the shock vicinity. The presence of these energetic ions is due either to ion heating or ion beam instabilities and they may act as a seed population for further acceleration. The prompt acceleration of ions inferred from the Gamma Ray Spectrometer on the Solar Maximum Mission can thus be explained by this mechanism.
Accelerated formation of cubic phases in phosphatidylethanolamine dispersions.
Tenchov, B; Koynova, R; Rapp, G
1998-01-01
By means of x-ray diffraction we show that several sodium salts and the disaccharides sucrose and trehalose strongly accelerate the formation of cubic phases in phosphatidylethanolamine (PE) dispersions upon temperature cycling through the lamellar liquid crystalline-inverted hexagonal (Lalpha-HII) phase transition. Ethylene glycol does not have such an effect. The degree of acceleration increases with the solute concentration. Such an acceleration has been observed for dielaidoyl PE (DEPE), dihexadecyl PE, and dipalmitoyl PE. It was investigated in detail for DEPE dispersions. For DEPE (10 wt% of lipid) aqueous dispersions at 1 M solute concentration, 10-50 temperature cycles typically result in complete conversion of the Lalpha phase into cubic phase. Most efficient is temperature cycling executed by laser flash T-jumps. In that case the conversion completes within 10-15 cycles. However, the cubic phases produced by laser T-jumps are less ordered in comparison to the rather regular cubic structures produced by linear, uniform temperature cycling at 10 degrees C/min. Temperature cycles at scan rates of 1-3 degrees C/min also induce the rapid formation of cubic phases. All solutes used induce the formation of Im3m (Q229) cubic phase in 10 wt% DEPE dispersions. The initial Im3m phases appearing during the first temperature cycles have larger lattice parameters that relax to smaller values with continuation of the cycling after the disappearance of the Lalpha phase. A cooperative Im3m --> Pn3m transition takes place at approximately 85 degrees C and transforms the Im3m phase into a mixture of coexisting Pn3m (Q224) and Im3m phases. The Im3m/Pn3m lattice parameter ratio is 1. 28, as could be expected from a representation of the Im3m and Pn3m phases with the primitive and diamond infinite periodic minimal surfaces, respectively. At higher DEPE contents ( approximately 30 wt%), cubic phase formation is hindered after 20-30 temperature cycles. The conversion does not go
Disruption of the RP-MDM2-p53 pathway accelerates APC loss-induced colorectal tumorigenesis.
Liu, S; Tackmann, N R; Yang, J; Zhang, Y
2017-03-01
Inactivation of the adenomatous polyposis coli (APC) tumor suppressor is frequently found in colorectal cancer. Loss of APC function results in deregulation of the Wnt/β-catenin signaling pathway causing overexpression of the c-MYC oncogene. In lymphoma, both p19ARF and ribosomal proteins RPL11 and RPL5 respond to c-MYC activation to induce p53. Their role in c-MYC-driven colorectal carcinogenesis is unclear, as p19ARF deletion does not accelerate APC loss-triggered intestinal tumorigenesis. To determine the contribution of the ribosomal protein (RP)-murine double minute 2 (MDM2)-p53 pathway to APC loss-induced tumorigenesis, we crossed mice bearing MDM2 C305F mutation, which disrupts RPL11- and RPL5-MDM2 binding, with Apc min/+ mice, which are prone to intestinal tumor formation. Interestingly, loss of RP-MDM2 binding significantly accelerated colorectal tumor formation while having no discernable effect on small intestinal tumor formation. Mechanistically, APC loss leads to overexpression of c-MYC, RPL11 and RPL5 in mouse colonic tumor cells irrespective of MDM2 C305F mutation. However, notable p53 stabilization and activation were observed only in Apc min/+ ;Mdm2 +/+ but not Apc min/+ ;Mdm2 C305F/C305F colon tumors. These data establish that the RP-MDM2-p53 pathway, in contrast to the p19ARF-MDM2-p53 pathway, is a critical mediator of colorectal tumorigenesis following APC loss.
3D Resistive MHD Simulations of Formation, Compression, and Acceleration of Compact Tori
NASA Astrophysics Data System (ADS)
Woodruff, Simon; Meyer, Thomas; Stuber, James; Romero-Talamas, Carlos; Brown, Michael; Kaur, Manjit; Schaffner, David
2017-10-01
We present results from extended resistive 3D MHD simulations (NIMROD) pertaining to a new formation method for toroidal plasmas using a reconnection region that forms in a radial implosion, and results from the acceleration of CTs along a drift tube that are accelerated by a coil and are allowed to go tilt unstable and form a helical minimum energy state. The new formation method results from a reconnection region that is generated between two magnetic compression coils that are ramped to 320kV in 2 μs. When the compressing field is aligned anti-parallel to a pre-existing CT, a current sheet and reconnection region forms that accelerates plasma radially inwards up to 500km/s which stagnates and directed energy converts to thermal, raising temperatures to 500eV. When field is aligned parallel to the pre-existing CT, the configuration can be accelerated along a drift tube. For certain ratios of magnetic field to density, the CT goes tilt-unstable forming a twisted flux rope, which can also be accelerated and stagnated on an end wall, where temperature and field increases as the plasma compresses. We compare simulation results with adiabatic scaling relations. Work supported by ARPA-E ALPHA program and DARPA.
Tokuda, Junichi; Plishker, William; Torabi, Meysam; Olubiyi, Olutayo I; Zaki, George; Tatli, Servet; Silverman, Stuart G; Shekher, Raj; Hata, Nobuhiko
2015-06-01
Accuracy and speed are essential for the intraprocedural nonrigid magnetic resonance (MR) to computed tomography (CT) image registration in the assessment of tumor margins during CT-guided liver tumor ablations. Although both accuracy and speed can be improved by limiting the registration to a region of interest (ROI), manual contouring of the ROI prolongs the registration process substantially. To achieve accurate and fast registration without the use of an ROI, we combined a nonrigid registration technique on the basis of volume subdivision with hardware acceleration using a graphics processing unit (GPU). We compared the registration accuracy and processing time of GPU-accelerated volume subdivision-based nonrigid registration technique to the conventional nonrigid B-spline registration technique. Fourteen image data sets of preprocedural MR and intraprocedural CT images for percutaneous CT-guided liver tumor ablations were obtained. Each set of images was registered using the GPU-accelerated volume subdivision technique and the B-spline technique. Manual contouring of ROI was used only for the B-spline technique. Registration accuracies (Dice similarity coefficient [DSC] and 95% Hausdorff distance [HD]) and total processing time including contouring of ROIs and computation were compared using a paired Student t test. Accuracies of the GPU-accelerated registrations and B-spline registrations, respectively, were 88.3 ± 3.7% versus 89.3 ± 4.9% (P = .41) for DSC and 13.1 ± 5.2 versus 11.4 ± 6.3 mm (P = .15) for HD. Total processing time of the GPU-accelerated registration and B-spline registration techniques was 88 ± 14 versus 557 ± 116 seconds (P < .000000002), respectively; there was no significant difference in computation time despite the difference in the complexity of the algorithms (P = .71). The GPU-accelerated volume subdivision technique was as accurate as the B-spline technique and required significantly less processing time. The GPU-accelerated
CCL11-induced eosinophils inhibit the formation of blood vessels and cause tumor necrosis.
Xing, Yanjiang; Tian, Yijun; Kurosawa, Takamasa; Matsui, Sayaka; Touma, Maki; Yanai, Takanori; Wu, Qiong; Sugimoto, Kenkichi
2016-06-01
We previously demonstrated that IL-18 and CCL11 were highly expressed in an NFSA tumor cell line that showed limited angiogenesis and severe necrosis. However, IL-18 was not responsible for the immune cell accumulation and necrosis. Here, we attempted to clarify the relevance of CCL11 in angiogenesis and tumor formation. We established CCL11-overexpressing MS-K cell clones (MS-K-CCL11) to assess the role of CCL11 in immune cell accumulation and angiogenesis. The MS-K-CCL11 cells did not form tumors in mice. MS-K-CCL11-conditioned medium (CM) and recombinant CCL11 induced macrophage and eosinophil differentiation from bone marrow cells. The MS-K-CCL11-CM effectively recruited the differentiated eosinophils. Furthermore, the eosinophils damaged the MS-K, NFSA and endothelial cells in a dose-dependent manner. Administration of an antagonist of CCR3, a CCL11 receptor, to NFSA tumor-bearing mice restored the blood vessel formation and blocked the eosinophil infiltration into the NFSA tumors. Furthermore, other CCL11-overexpressing LM8 clones were established, and their tumor formation ability was reduced compared to the parental LM8 cells, accompanied by increased eosinophil infiltration, blockade of angiogenesis and necrosis. These results indicate that CCL11 was responsible for the limited angiogenesis and necrosis by inducing and attracting eosinophils in the tumors. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.
In Vitro, Matrix-Free Formation Of Solid Tumor Spheroids
NASA Technical Reports Server (NTRS)
Gonda, Steve R.; Marley, Garry M.
1993-01-01
Cinostatic bioreactor promotes formation of relatively large solid tumor spheroids exhibiting diameters from 750 to 2,100 micrometers. Process useful in studying efficacy of chemotherapeutic agents and of interactions between cells not constrained by solid matrices. Two versions have been demonstrated; one for anchorage-independent cells and one for anchorage-dependent cells.
Incio, Joao; Tam, Josh; Rahbari, Nuh N; Suboj, Priya; McManus, Dan T; Chin, Shan M; Vardam, Trupti D; Batista, Ana; Babykutty, Suboj; Jung, Keehoon; Khachatryan, Anna; Hato, Tai; Ligibel, Jennifer A; Krop, Ian E; Puchner, Stefan B; Schlett, Christopher L; Hoffmman, Udo; Ancukiewicz, Marek; Shibuya, Masabumi; Carmeliet, Peter; Soares, Raquel; Duda, Dan G; Jain, Rakesh K; Fukumura, Dai
2016-06-15
Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993-3004. ©2016 AACR. ©2016 American Association for Cancer Research.
Loeffler, J S; Rossitch, E; Siddon, R; Moore, M R; Rockoff, M A; Alexander, E
1990-05-01
Between 1986 and 1988, 16 children were treated for 10 arteriovenous malformations and 6 recurrent intracranial tumors with stereotactic radiation therapy using a modified Clinac 6/100 linear accelerator. The median age of our patients was 10.5 years. For the group with arteriovenous malformation, follow-up ranged from 6 months to 37 months (median was 20 months). No patient bled during the follow-up period. Five of eight patients with follow-up longer than 12 months have achieved complete obliteration of their arteriovenous malformation by angiogram. The four remaining patients who have not achieved a complete obliteration are awaiting their 2-year posttreatment angiogram. The other patient has been treated within the year and have not yet been studied. Five of the six recurrent tumor patients are alive with a median follow-up of 8 months. The remaining patient was controlled locally, but he died of recurrent disease outside the area treated with radiosurgery. The radiographic responses of these patients have included three complete responses, two substantial reductions in tumor volume (greater than 50%) and one stabilization. Despite previous radiotherapy, there have been no significant complications in these patients. We conclude that stereotactic radiation therapy using a standard linear accelerator is an effective and safe technique in the treatment of selected intracranial arteriovenous malformations and tumors in children. In addition, stereotactic radiosurgery may have unique applications in the treatment of localized primary and recurrent pediatric brain tumors.
FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.
Noreen, Razia; Chien, Chia-Chi; Chen, Hsiang-Hsin; Bobroff, Vladimir; Moenner, Michel; Javerzat, Sophie; Hwu, Yeukuang; Petibois, Cyril
2013-11-01
Evidence has recently emerged that solid and diffuse tumors produce a specific extracellular matrix (ECM) for division and diffusion, also developing a specific interface with microvasculature. This ECM is mainly composed of collagens and their scaffolding appears to drive tumor growth. Although collagens are not easily analyzable by UV-fluorescence means, FTIR imaging has appeared as a valuable tool to characterize collagen contents in tissues, specially the brain, where ECM is normally devoid of collagen proteins. Here, we used FTIR imaging to characterize collagen content changes in growing glioma tumors. We could determine that C6-derived solid tumors presented high content of triple helix after 8-11 days of growth (typical of collagen fibrils formation; 8/8 tumor samples; 91 % of total variance), and further turned to larger α-helix (days 12-15; 9/10 of tumors; 94 % of variance) and β-turns (day 18-21; 7/8 tumors; 97 % of variance) contents, which suggest the incorporation of non-fibrillar collagen types in ECM, a sign of more and more organized collagen scaffold along tumor progression. The growth of tumors was also associated to the level of collagen produced (P < 0.05). This study thus confirms that collagen scaffolding is a major event accompanying the angiogenic shift and faster tumor growth in solid glioma phenotypes.
Scribner, J D; Mottet, N K
1981-01-01
2-Acetamidophenanthrene (AAP) yields adducts to rat liver DNA and RNA in amounts comparable to those found for the potent hepatocarcinogen 2-acetamidofluorene, but is not hepatocarcinogenic. This suggested that AAP might initiate liver tumors, but was incapable of causing their progression to a detectable state. To test this hypothesis, the protocol devised by Peraino was used, in which 21-day-old male Sprague-Dawley rats were fed 0.02% AAP in a grain diet for three weeks. this was followed by long-term feeding of 0.05% 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT). The mean latent period of all tumors (primarily mammary tumors) was reduced about six months by the DDT feeding. No tumors were found in rats treated with DDT only. Livers in all animals appeared normal at autopsy or on laparotomy, and showed barely detectable signs of toxicity upon histological examination. Thus, we have found that a once wide-spread environmental chemical acts as a tumor accelerator on a major target for human tumors. Because this finding is in the male rat, the significance of this result for breast cancer in women is uncertain.
Dust formation and wind acceleration around the aluminum oxide-rich AGB star W Hydrae
NASA Astrophysics Data System (ADS)
Takigawa, Aki; Kamizuka, Takafumi; Tachibana, Shogo; Yamamura, Issei
2017-11-01
Dust grains, formed around asymptotic giant branch (AGB) stars, are accelerated by stellar radiation to drive stellar winds, which supply freshly synthesized nuclides to the Galaxy. Silicate is the dominant dust species in space, but 40% of oxygen-rich AGB stars are thought to have comparable amounts of aluminum oxide dust. Dust formation and the wind-driving mechanism around these oxygen-rich stars, however, are poorly understood. We report on the spatial distributions of AlO and 29SiO molecules around an aluminum oxide-rich M-type AGB star, W Hydrae, based on observations obtained with the Atacama Large Millimeter/submillimeter Array. AlO molecules were only observed within three stellar radii (Rstar), whereas 29SiO was distributed in the accelerated wind beyond 5 Rstar without significant depletion. This strongly suggests that condensed aluminum oxide dust plays a key role in accelerating the stellar wind and in preventing the efficient formation of silicate dust around W Hydrae.
Dust formation and wind acceleration around the aluminum oxide–rich AGB star W Hydrae
Takigawa, Aki; Kamizuka, Takafumi; Tachibana, Shogo; Yamamura, Issei
2017-01-01
Dust grains, formed around asymptotic giant branch (AGB) stars, are accelerated by stellar radiation to drive stellar winds, which supply freshly synthesized nuclides to the Galaxy. Silicate is the dominant dust species in space, but ~40% of oxygen-rich AGB stars are thought to have comparable amounts of aluminum oxide dust. Dust formation and the wind-driving mechanism around these oxygen-rich stars, however, are poorly understood. We report on the spatial distributions of AlO and 29SiO molecules around an aluminum oxide–rich M-type AGB star, W Hydrae, based on observations obtained with the Atacama Large Millimeter/submillimeter Array. AlO molecules were only observed within three stellar radii (Rstar), whereas 29SiO was distributed in the accelerated wind beyond 5 Rstar without significant depletion. This strongly suggests that condensed aluminum oxide dust plays a key role in accelerating the stellar wind and in preventing the efficient formation of silicate dust around W Hydrae. PMID:29109978
Wu, Jinghai; Dauchy, Robert T; Tirrell, Paul C; Wu, Steven S; Lynch, Darin T; Jitawatanarat, Potjana; Burrington, Christine M; Dauchy, Erin M; Blask, David E; Greene, Michael W
2011-04-01
Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling.
Quantitative phase imaging characterization of tumor-associated blood vessel formation on a chip
NASA Astrophysics Data System (ADS)
Guo, Peng; Huang, Jing; Moses, Marsha A.
2018-02-01
Angiogenesis, the formation of new blood vessels from existing ones, is a biological process that has an essential role in solid tumor growth, development, and progression. Recent advances in Lab-on-a-Chip technology has created an opportunity for scientists to observe endothelial cell (EC) behaviors during the dynamic process of angiogenesis using a simple and economical in vitro platform that recapitulates in vivo blood vessel formation. Here, we use quantitative phase imaging (QPI) microscopy to continuously and non-invasively characterize the dynamic process of tumor cell-induced angiogenic sprout formation on a microfluidic chip. The live tumor cell-induced angiogenic sprouts are generated by multicellular endothelial sprouting into 3 dimensional (3D) Matrigel using human umbilical vein endothelial cells (HUVECs). By using QPI, we quantitatively measure a panel of cellular morphological and behavioral parameters of each individual EC participating in this sprouting. In this proof-of-principle study, we demonstrate that QPI is a powerful tool that can provide real-time quantitative analysis of biological processes in in vitro 3D biomimetic devices, which, in turn, can improve our understanding of the biology underlying functional tissue engineering.
Hans, M A; Müller, M; Meyer-Ficca, M; Bürkle, A; Küpper, J H
1999-11-25
Poly(ADP-ribose) polymerase (PARP4) catalyzes the formation of ADP-ribose polymers covalently attached to proteins by using NAD+ as substrate. PARP is strongly activated by DNA single- or double-strand breaks and is thought to be involved in cellular responses to DNA damage. We characterized a dominant negative PARP mutant, i.e. the DNA-binding domain of this enzyme, whose overexpression in cells leads to increased genetic instability following DNA damage. In order to study whether PARP activity is also implicated in the process of tumorigenesis, we generated stably transfected HeLa cell clones with constitutive overexpression of dominant negative PARP and investigated tumor formation of these clones in nude mice. We found that inhibition of PARP activity dramatically reduces tumor forming ability of HeLa cells. Moreover, we provide strong evidence that the observed reduction in tumor forming ability is due to increased tumor cell apoptosis in vivo. Viewed together, our data and those from other groups show that inhibition of PARP enzyme activity interferes with DNA base excision repair and leads to increased genetic instability and recombination but, on the other hand, can sensitize cells to apoptotic stimuli and by this mechanism may prevent tumor formation.
An HTS-compatible 3D colony formation assay to identify tumor-specific chemotherapeutics.
Horman, Shane R; To, Jeremy; Orth, Anthony P
2013-12-01
There has been increasing interest in the development of cellular behavior models that take advantage of three-dimensional (3D) cell culture. To enable assessment of differential perturbagen impacts on cell growth in 2D and 3D, we have miniaturized and adapted for high-throughput screening (HTS) the soft agar colony formation assay, employing a laser-scanning cytometer to image and quantify multiple cell types simultaneously. The assay is HTS compatible, providing high-quality, image-based, replicable data for multiple, co-cultured cell types. As proof of concept, we subjected colorectal carcinoma colonies in 3D soft agar to a mini screen of 1528 natural product compounds. Hit compounds from the primary screen were rescreened in an HTS 3D co-culture matrix containing colon stromal cells and cancer cells. By combining tumor cells and normal, nontransformed colon epithelial cells in one primary screening assay, we were able to obtain differential IC50 data, thereby distinguishing tumor-specific compounds from general cytotoxic compounds. Moreover, we were able to identify compounds that antagonized tumor colony formation in 3D only, highlighting the importance of this assay in identifying agents that interfere with 3D tumor structural growth. This screening platform provides a fast, simple, and robust method for identification of tumor-specific agents in a biologically relevant microenvironment.
Chen, Chun-Nan; Chen, You-Tzung; Yang, Tsung-Lin
2017-12-01
Tumor satellite formation is an indicator of cancer invasiveness and correlates with recurrence, metastasis, and poorer prognosis. By analyzing pathological specimens, tumor satellites formed at the tumor-host interface reflect the phenomena of epithelial-mesenchymal transition. It is impossible to reveal the dynamic processes and the decisive factors of tumor satellite formation using clinicopathological approaches alone. Therefore, establishment of an in vitro system to monitor the phenomena is important to explicitly elucidate underlying mechanisms. In this study, we explored the feasibility of creating an in vitro three-dimensional collagen culture system to recapitulate the process of tumor satellite formation. This data presented here are referred to the research article (Chen et al., 2017) [1]. Using this model, the dynamic process of tumor satellite formation could be recapitulated in different types of human cancer cells. Induced by calcium deprivation, the treated cells increased the incidence and migratory distance of tumor satellites. E-cadherin internalization and invadopodia formation were enhanced by calcium deprivation and were associated with cellular dynamic change during tumor satellite formation. The data confirmed the utility of this culture system to recapitulate dynamic cellular alteration and to explore the potential mechanisms of tumor satellite formation.
Adhikary, Gautam; Grun, Dan; Kerr, Candace; Balasubramanian, Sivaprakasam; Rorke, Ellen A.; Vemuri, Mohan; Boucher, Shayne; Bickenbach, Jackie R.; Hornyak, Thomas; Xu, Wen; Fisher, Matthew L.; Eckert, Richard L.
2013-01-01
Epidermal squamous cell carcinoma is among the most common cancers in humans. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. We show that spheroid-selected cells form faster growing and larger tumors in immune-compromised mice as compared to non-selected cells. Moreover, spheroid-selected cells gave rise to tumors following injection of as few as one hundred cells, suggesting these cells have enhanced tumor-forming potential. Cells isolated from spheroid-selected tumors retain an enhanced ability to grow as spheroids when grown in non-attached culture conditions. Thus, these tumor-forming cells retain their phenotype following in vivo passage as tumors. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including aldehyde dehydrogenase 1, keratin 15, CD200, keratin 19, Oct4, Bmi-1, Ezh2 and trimethylated histone H3. These studies indicate that a subpopulation of cells that possess stem cell-like properties and express stem cell markers can be derived from human epidermal cancer cells and that these cells display enhanced ability to drive tumor formation. PMID:24376802
Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo
1994-01-01
Members of the TGF-beta superfamily appear to modulate mesenchymal differentiation, including the processes of cartilage and bone formation. Nothing is yet known about the function of the TGF-beta- related factor vgr-1, also called bone morphogenetic protein-6 (BMP-6), and only limited studies have been conducted on the most closely related factors BMP-5, osteogenic protein-1 (OP-1) or BMP-7, and OP-2. Because vgr-1 mRNA has been localized in hypertrophic cartilage, this factor may play a vital role in endochondral bone formation. We developed antibodies to vgr-1, and documented that vgr-1 protein was expressed in hypertrophic cartilage of mice. To further characterize the role of this protein in bone differentiation, we generated CHO cells that overexpressed recombinant murine vgr-1 protein. Western blot analysis documented that recombinant vgr-1 protein was secreted into the media and was proteolytically processed to yield the mature vgr-1 molecule. To assess the biological activity of recombinant vgr-1 in vivo, we introduced the vgr-1-expressing CHO cells directly into the subcutaneous tissue of athymic nude mice. CHO-vgr-1 cells produced localized tumors, and the continuous secretion of vgr-1 resulted in tumors with a strikingly different gross and histological appearance as compared to the parental CHO cells. The tumors of control CHO cells were hemorrhagic, necrotic, and friable, whereas the CHO-vgr-1 tumors were dense, firm, and fibrotic. In contrast with control CHO tumors, the nests of CHO-vgr-1 tumor cells were surrounded by extensive connective tissue, which contained large regions of cartilage and bone. Further analysis indicated that secretion of vgr-1 from the transfected CHO tumor cells induced the surrounding host mesenchymal cells to develop along the endochondral bone pathway. These findings suggest that endochondral bone formation. PMID:8089189
Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.
Amirkhosravi, M; Francis, J L
1995-01-01
Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)
Nyman, Patricia J; Wamer, Wayne G; Begley, Timothy H; Diachenko, Gregory W; Perfetti, Gracia A
2010-04-01
Under certain conditions, benzene can form in beverages containing benzoic and ascorbic acids. The American Beverage Assn. (ABA) has published guidelines to help manufacturers mitigate benzene formation in beverages. These guidelines recommend accelerated testing conditions to test product formulations, because exposure to ultraviolet (UV) light and elevated temperature over the shelf life of the beverage may result in benzene formation in products containing benzoic and ascorbic acids. In this study, the effects of UVA exposure on benzene formation were determined. Benzene formation was examined for samples contained in UV stabilized and non-UV stabilized packaging. Additionally, the usefulness of accelerated thermal testing to simulate end of shelf-life benzene formation was evaluated for samples containing either benzoic or ascorbic acid, or both. The 24 h studies showed that under intense UVA light benzene levels increased by as much as 53% in model solutions stored in non-UV stabilized bottles, whereas the use of UV stabilized polyethylene terephthalate bottles reduced benzene formation by about 13% relative to the non-UV stabilized bottles. Similar trends were observed for the 7 d study. Retail beverages and positive and negative controls were used to study the accelerated thermal testing conditions. The amount of benzene found in the positive controls and cranberry juice suggests that testing at 40 degrees C for 14 d may more reliably simulate end of shelf-life benzene formation in beverages. Except for cranberry juice, retail beverages were not found to contain detectable amounts of benzene (<0.05 ng/g) at the end of their shelf lives.
Formation of Ultrarelativistic Electron Rings from a Laser-Wakefield Accelerator.
Pollock, B B; Tsung, F S; Albert, F; Shaw, J L; Clayton, C E; Davidson, A; Lemos, N; Marsh, K A; Pak, A; Ralph, J E; Mori, W B; Joshi, C
2015-07-31
Ultrarelativistic-energy electron ring structures have been observed from laser-wakefield acceleration experiments in the blowout regime. These electron rings had 170-280 MeV energies with 5%-25% energy spread and ∼10 pC of charge and were observed over a range of plasma densities and compositions. Three-dimensional particle-in-cell simulations show that laser intensity enhancement in the wake leads to sheath splitting and the formation of a hollow toroidal pocket in the electron density around the wake behind the first wake period. If the laser propagates over a distance greater than the ideal dephasing length, some of the dephasing electrons in the second period can become trapped within the pocket and form an ultrarelativistic electron ring that propagates in free space over a meter-scale distance upon exiting the plasma. Such a structure acts as a relativistic potential well, which has applications for accelerating positively charged particles such as positrons.
Kerr, Candace; Adhikary, Gautam; Grun, Daniel; George, Nicholas; Eckert, Richard L
2018-01-01
Epidermal squamous cell carcinoma is an extremely common type of cancer. Early tumors can be successfully treated by surgery, but recurrent disease is aggressive and resistant to therapy. Cisplatin is often used as a treatment, but the outcome is rarely satisfactory. For this reason new strategies are required. Sulforaphane is a diet-derived cancer prevention agent that is effective in suppressing tumor growth in animal models of skin cancer. We monitored the efficacy of sulforaphane and cisplatin as a combined therapy for squamous cell carcinoma. Both agents suppress cell proliferation, growth of cancer stem cell spheroids, matrigel invasion and migration of SCC-13 and HaCaT cells, and combination treatment is more efficient. In addition, SCC-13 cell derived cancer stem cells are more responsive to these agents than non-stem cancer cells. Both agents suppress tumor formation, but enhanced suppression is observed with combined treatment. Moreover, both agents reduce the number of tumor-resident cancer stem cells. SFN treatment of cultured cells or tumors increases apoptosis and p21 Cip1 level, and both agents increase tumor apoptosis. We suggest that combined therapy with sulforaphane and cisplatin is efficient in suppressing tumor formation and may be a treatment option for advanced epidermal squamous cell carcinoma. © 2017 Wiley Periodicals, Inc.
Mally, Angela
2012-06-01
The mycotoxin and food contaminant ochratoxin A (OTA) is a potent renal carcinogen in rodents, but its mode of action (MoA) is still poorly defined. In 2006, the European Food Safety Authority concluded that there is a "lack of evidence for the existence of OTA-DNA adducts" and thus insufficient evidence to establish DNA reactivity as a MoA for tumor formation by OTA. In reviewing the available database on OTA toxicity, a MoA for renal carcinogenicity of OTA is developed that involves a combination of genetic instability and increased proliferative drive as consequences of OTA-mediated disruption of mitosis, whereby the organ- and site-specificity of tumor formation by OTA is determined by selective renal uptake of OTA into the proximal tubule epithelium. The proposed MoA is critically assessed with respect to concordance of dose-response of the suggested key events and tumor formation, their temporal association, consistency, and biological plausibility. Uncertainties, data gaps and needs for further research are highlighted.
Brinster, Lauren R; Omeir, Romelda L; Foseh, Gideon S; Macauley, Juliete N; Snoy, Philip J; Beren, Joel J; Teferedegne, Belete; Peden, Keith; Lewis, Andrew M
2013-01-01
Tumors that formed in newborn nude mice that were inoculated with 107 Madin–Darby canine kidney (MDCK) cells were associated with a failure-to-thrive (FTT) syndrome consisting of growth retardation, lethargy, weakness, and dehydration. Scoliosis developed in 41% of affected pups. Pups were symptomatic by week 2; severely affected pups became moribund and required euthanasia within 3 to 4 wk. Mice with FTT were classified into categories of mild, moderate, and severe disease by comparing their weight with that of age-matched normal nude mice. The MDCK-induced tumors were adenocarcinomas that invaded adjacent muscle, connective tissue, and bone; 6 of the 26 pups examined had lung metastases. The induction of FTT did not correlate with cell-line aggressiveness as estimated by histopathology or the efficiency of tumor formation (tumor-forming dose 50% endpoint range = 102.8 to 107.5); however, tumor invasion of the paravertebral muscles likely contributed to the scoliosis noted. In contrast to the effect of MDCK cells, tumor formation observed in newborn mice inoculated with highly tumorigenic, human-tumor–derived cell lines was not associated with FTT development. We suggest that tumor formation and FTT are characteristics of these MDCK cell inocula and that FTT represents a new syndrome that may be similar to the cachexia that develops in humans with cancer or other diseases. PMID:24209967
NASA Technical Reports Server (NTRS)
Polzin, Kurt A.; Hallock, Ashley K.; Choueiri, Edgar Y.
2008-01-01
Data from an inductive conical theta pinch accelerator are presented to gain insight into the process of inductive current sheet formation in the presence of a preionized background gas produced by a steady-state RF-discharge. The presence of a preionized plasma has been previously shown to allow for current sheet formation at lower discharge voltages and energies than those found in other pulsed inductive accelerator concepts, leading to greater accelerator efficiencies at lower power levels. Time-resolved magnetic probe measurements are obtained for different background pressures and pulse energies to characterize the effects of these parameters on current sheet formation. Indices are defined that describe time-resolved current sheet characteristics, such as the total current owing in the current sheet, the time-integrated total current ('strength'), and current sheet velocity. It is found that for a given electric field strength, maximums in total current, strength, and velocity occur for one particular background pressure. At other pressures, these current sheet indices are considerably smaller. The trends observed in these indices are explained in terms of the principles behind Townsend breakdown that lead to a dependence on the ratio of the electric field to the background pressure. Time-integrated photographic data are also obtained at the same experimental conditions, and qualitatively they compare quite favorably with the time-resolved magnetic field data.
Bruemmer, Dennis; Collins, Alan R.; Noh, Grace; Wang, Wei; Territo, Mary; Arias-Magallona, Sarah; Fishbein, Michael C.; Blaschke, Florian; Kintscher, Ulrich; Graf, Kristof; Law, Ronald E.; Hsueh, Willa A.
2003-01-01
Osteopontin (OPN) is expressed in atherosclerotic lesions, particularly in diabetic patients. To determine the role of OPN in atherogenesis, ApoE–/–OPN+/+, ApoE–/–OPN+/–, and ApoE–/–OPN–/– mice were infused with Ang II, inducing vascular OPN expression and accelerating atherosclerosis. Compared with ApoE–/–OPN+/+ mice, ApoE–/–OPN+/– and ApoE–/–OPN–/– mice developed less Ang II–accelerated atherosclerosis. ApoE–/– mice transplanted with bone marrow derived from ApoE–/–OPN–/– mice had less Ang II–induced atherosclerosis compared with animals receiving ApoE–/–OPN+/+ cells. Aortae from Ang II–infused ApoE–/–OPN–/– mice expressed less CD68, C-C-chemokine receptor 2, and VCAM-1. In response to intraperitoneal thioglycollate, recruitment of leukocytes in OPN–/– mice was impaired, and OPN–/– leukocytes exhibited decreased basal and MCP-1–directed migration. Furthermore, macrophage viability in atherosclerotic lesions from Ang II–infused ApoE–/–OPN–/– mice was decreased. Finally, Ang II–induced abdominal aortic aneurysm formation in ApoE–/–OPN–/– mice was reduced and associated with decreased MMP-2 and MMP-9 activity. These data suggest an important role for leukocyte-derived OPN in mediating Ang II–accelerated atherosclerosis and aneurysm formation. PMID:14597759
Nonlinear ghost waves accelerate the progression of high-grade brain tumors
NASA Astrophysics Data System (ADS)
Pardo, Rosa; Martínez-González, Alicia; Pérez-García, Víctor M.
2016-10-01
We study a reduced continuous model describing the evolution of high grade gliomas in response to hypoxic events through the interplay of different cellular phenotypes. We show that hypoxic events, even when sporadic and/or limited in space, may have a crucial role on the acceleration of high grade gliomas growth. Our modeling approach is based on two cellular phenotypes. One of them is more migratory and a second one is more proliferative. Transitions between both phenotypes are driven by the local oxygen values, assumed in this simple model to be uniform. Surprisingly, even very localized in time hypoxia events leading to transient migratory populations have the potential to accelerate the tumor's invasion speed up to speeds close to those of the migratory phenotype. The high invasion speed persists for times much longer than the lifetime of the hypoxic event. Moreover, the phenomenon is observed both when the migratory cells form a persistent wave of cells located on the invasion front and when they form a evanescent "ghost" wave disappearing after a short time by decay to the more proliferative phenotype. Our findings are obtained through numerical simulations of the model equations both in 1D and higher dimensional scenarios. We also provide a deeper mathematical analysis of some aspects of the problem such as the conditions for the existence of persistent waves of cells with a more migratory phenotype.
Characterising the acceleration phase of blast wave formation
DOE Office of Scientific and Technical Information (OSTI.GOV)
Fox, T. E., E-mail: tef503@york.ac.uk; Pasley, J.; Central Laser Facility, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot OX11 0QX
2014-10-15
Intensely heated, localised regions in uniform fluids will rapidly expand and generate an outwardly propagating blast wave. The Sedov-Taylor self-similar solution for such blast waves has long been studied and applied to a variety of scenarios. A characteristic time for their formation has also long been identified using dimensional analysis, which by its very nature, can offer several interpretations. We propose that, rather than simply being a characteristic time, it may be interpreted as the definitive time taken for a blast wave resulting from an intense explosion in a uniform media to contain its maximum kinetic energy. A scaling relationmore » for this measure of the acceleration phase, preceding the establishment of the blast wave, is presented and confirmed using a 1D planar hydrodynamic model.« less
Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica.
Levy, Joseph S; Fountain, Andrew G; Dickson, James L; Head, James W; Okal, Marianne; Marchant, David R; Watters, Jaclyn
2013-01-01
Thermokarst is a land surface lowered and disrupted by melting ground ice. Thermokarst is a major driver of landscape change in the Arctic, but has been considered to be a minor process in Antarctica. Here, we use ground-based and airborne LiDAR coupled with timelapse imaging and meteorological data to show that 1) thermokarst formation has accelerated in Garwood Valley, Antarctica; 2) the rate of thermokarst erosion is presently ~ 10 times the average Holocene rate; and 3) the increased rate of thermokarst formation is driven most strongly by increasing insolation and sediment/albedo feedbacks. This suggests that sediment enhancement of insolation-driven melting may act similarly to expected increases in Antarctic air temperature (presently occurring along the Antarctic Peninsula), and may serve as a leading indicator of imminent landscape change in Antarctica that will generate thermokarst landforms similar to those in Arctic periglacial terrains.
Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica
Levy, Joseph S.; Fountain, Andrew G.; Dickson, James L.; Head, James W.; Okal, Marianne; Marchant, David R.; Watters, Jaclyn
2013-01-01
Thermokarst is a land surface lowered and disrupted by melting ground ice. Thermokarst is a major driver of landscape change in the Arctic, but has been considered to be a minor process in Antarctica. Here, we use ground-based and airborne LiDAR coupled with timelapse imaging and meteorological data to show that 1) thermokarst formation has accelerated in Garwood Valley, Antarctica; 2) the rate of thermokarst erosion is presently ~ 10 times the average Holocene rate; and 3) the increased rate of thermokarst formation is driven most strongly by increasing insolation and sediment/albedo feedbacks. This suggests that sediment enhancement of insolation-driven melting may act similarly to expected increases in Antarctic air temperature (presently occurring along the Antarctic Peninsula), and may serve as a leading indicator of imminent landscape change in Antarctica that will generate thermokarst landforms similar to those in Arctic periglacial terrains. PMID:23881292
ERIC Educational Resources Information Center
Gupta, Kalpana
2012-01-01
This study was focused on investigating inclusive learning environments in accelerated classroom formats. Three 8-week sections of an undergraduate course at Regis University were examined. Results from observations and surveys were analyzed to determine the effectiveness and consistency of 13 inclusive strategies derived from Wlodkowski and…
Core-shell hydrogel beads with extracellular matrix for tumor spheroid formation.
Yu, L; Grist, S M; Nasseri, S S; Cheng, E; Hwang, Y-C E; Ni, C; Cheung, K C
2015-03-01
Creating multicellular tumor spheroids is critical for characterizing anticancer treatments since they may provide a better model of the tumor than conventional monolayer culture. Moreover, tumor cell interaction with the extracellular matrix can determine cell organization and behavior. In this work, a microfluidic system was used to form cell-laden core-shell beads which incorporate elements of the extracellular matrix and support the formation of multicellular spheroids. The bead core (comprising a mixture of alginate, collagen, and reconstituted basement membrane, with gelation by temperature control) and shell (comprising alginate hydrogel, with gelation by ionic crosslinking) were simultaneously formed through flow focusing using a cooled flow path into the microfluidic chip. During droplet gelation, the alginate acts as a fast-gelling shell which aids in preventing droplet coalescence and in maintaining spherical droplet geometry during the slower gelation of the collagen and reconstituted basement membrane components as the beads warm up. After droplet gelation, the encapsulated MCF-7 cells proliferated to form uniform spheroids when the beads contained all three components: alginate, collagen, and reconstituted basement membrane. The dose-dependent response of the MCF-7 cell tumor spheroids to two anticancer drugs, docetaxel and tamoxifen, was compared to conventional monolayer culture.
Książkiewicz, Magdalena; Markiewicz, Aleksandra; Zaczek, Anna J
2012-01-01
The occurrence of either regional or distant metastases is an indicator of poor prognosis for cancer patients. The mechanism of their formation has not yet been fully uncovered, which limits the possibility of developing new therapeutic strategies. Nevertheless, the discovery of circulating tumor cells (CTCs), which are responsible for tumor dissemination, and cancer stem cells (CSCs), required for tumor growth maintenance, shed light on the metastatic cascade. It seems that CTCs and CSCs are not necessarily separate populations of cancer cells, as CTCs generated in the process of epithelial-mesenchymal transition (EMT) can bear features characteristic of CSCs. This article describes the mechanisms of CTC and CSC formation and characterizes their molecular hallmarks. Moreover, we present different types of EMT occurring in physiological and pathological conditions, and we demonstrate its crucial role in providing CTCs with a CSC phenotype. The article delineates molecular changes acquired by cancer cells undergoing EMT that facilitate metastasis formation. Deeper understanding of those processes is of fundamental importance for the development of new strategies of early cancer detection and effective cancer treatment approaches that will be translated into clinical practice. Copyright © 2012 S. Karger AG, Basel.
Preventive effect of chemical peeling on ultraviolet induced skin tumor formation.
Abdel-Daim, Mohamed; Funasaka, Yoko; Kamo, Tsuneyoshi; Ooe, Masahiko; Matsunaka, Hiroshi; Yanagita, Emmy; Itoh, Tomoo; Nishigori, Chikako
2010-10-01
Chemical peeling is one of the dermatological treatments available for certain cutaneous diseases and conditions or improvement of cosmetic appearance of photoaged skin. We assessed the photochemopreventive effect of several clinically used chemical peeling agents on the ultraviolet (UV)-irradiated skin of hairless mice. Chemical peeling was done using 35% glycolic acid dissolved in distilled water, 30% salicylic acid in ethanol, 10% or 35% trichloroacetic acid (TCA) in distilled water at the right back of UV-irradiated hairless mice every 2 weeks in case of glycolic acid, salicylic acid, and 10% TCA and every 4 weeks in case of 35% TCA for totally 18 weeks after the establishment of photoaged mice by irradiation with UVA+B range light three times a week for 10 weeks at a total dose of 420 J/cm(2) at UVA and 9.6 J/cm(2) at UVB. Tumor formation was assessed every week. Skin specimens were taken from treated and non-treated area for evaluation under microscopy, evaluation of P53 expression, and mRNA expression of cyclooxygenase (COX)-2. Serum level of prostaglandin E(2) was also evaluated. All types of chemical peeling reduced tumor formation in treated mice, mostly in the treated area but also non-treated area. Peeling suppressed clonal retention of p53 positive abnormal cells and reduced mRNA expression of COX-2 in treated skin. Further, serum prostaglandin E(2) level was decreased in chemical peeling treated mice. These results indicate that chemical peeling with glycolic acid, salicylic acid, and TCA could serve tumor prevention by removing photodamaged cells. Copyright © 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Zhang, Yan; Daquinag, Alexes; Traktuev, Dmitry O.; Amaya-Manzanares, Felipe; Simmons, Paul J.; March, Keith L.; Pasqualini, Renata; Arap, Wadih; Kolonin, Mikhail G.
2010-01-01
The connection between obesity and accelerated cancer progression has been established, but the mediating mechanisms are not well understood. We have shown that stromal cells from white adipose tissue (WAT) cooperate with the endothelium to promote blood vessel formation through the secretion of soluble trophic factors. Here, we hypothesize that WAT directly mediates cancer progression by serving as a source of cells that migrate to tumors and promote neovascularization. To test this hypothesis, we have evaluated the recruitment of WAT-derived cells by tumors and the effect of their engraftment on tumor growth by integrating a transgenic mouse strain engineered for expansion of traceable cells with established allograft and xenograft cancer models. Our studies show that entry of adipose stromal and endothelial cells into systemic circulation leads to their homing to and engraftment into tumor stroma and vasculature, respectively. We show that recruitment of adipose stromal cells by tumors is sufficient to promote tumor growth. Finally, we show that migration of stromal and vascular progenitor cells from WAT grafts to tumors is also associated with acceleration of cancer progression. These results provide a biological insight for the clinical association between obesity and cancer, thus outlining potential avenues for preventive and therapeutic strategies. PMID:19491274
NASA Astrophysics Data System (ADS)
Timms, W. A.; Crane, R.; Anderson, D. J.; Bouzalakos, S.; Whelan, M.; McGeeney, D.; Rahman, P. F.; Guinea, A.; Acworth, R. I.
2015-03-01
Evaluating the possibility of leakage through low permeability geological strata is critically important for sustainable water supplies, the extraction of fuels from strata such as coal beds, and the confinement of waste within the earth. The current work demonstrates that relatively rapid and reliable hydraulic conductivity (K) measurement of aquitard cores using accelerated gravity can inform and constrain larger scale assessments of hydraulic connectivity. Steady state fluid velocity through a low K porous sample is linearly related to accelerated gravity (g-level) in a centrifuge permeameter (CP) unless consolidation or geochemical reactions occur. The CP module was custom designed to fit a standard 2 m diameter geotechnical centrifuge (550 g maximum) with a capacity for sample dimensions of 30 to 100 mm diameter and 30 to 200 mm in length, and a maximum total stress of ~2 MPa at the base of the core. Formation fluids were used as influent to limit any shrink-swell phenomena which may alter the permeability. Vertical hydraulic conductivity (Kv) results from CP testing of cores from three sites within the same regional clayey silt formation varied (10-7 to 10-9 m s-1, n = 14). Results at one of these sites (1.1 × 10-10 to 3.5 × 10-9 m s-1, n = 5) that were obtained in < 24 h were similar to in situ Kv values (3 × 10-9 m s-1) from pore pressure responses over several weeks within a 30 m clayey sequence. Core scale and in situ Kv results were compared with vertical connectivity within a regional flow model, and considered in the context of heterogeneity and preferential flow paths at site and formation scale. More reliable assessments of leakage and solute transport though aquitards over multi-decadal timescales can be achieved by accelerated core testing together with advanced geostatistical and numerical methods.
Lotti, Roberta; Palazzo, Elisabetta; Petrachi, Tiziana; Dallaglio, Katiuscia; Saltari, Annalisa; Truzzi, Francesca; Quadri, Marika; Puviani, Mario; Maiorana, Antonino; Marconi, Alessandra; Pincelli, Carlo
2016-01-01
Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, β1-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in RasG12V-IκBα-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1α, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development. PMID:26771605
Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.
Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus
2016-12-15
Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.
Time-dependent Electron Acceleration in Blazar Transients: X-Ray Time Lags and Spectral Formation
NASA Astrophysics Data System (ADS)
Lewis, Tiffany R.; Becker, Peter A.; Finke, Justin D.
2016-06-01
Electromagnetic radiation from blazar jets often displays strong variability, extending from radio to γ-ray frequencies. In a few cases, this variability has been characterized using Fourier time lags, such as those detected in the X-rays from Mrk 421 using BeppoSAX. The lack of a theoretical framework to interpret the data has motivated us to develop a new model for the formation of the X-ray spectrum and the time lags in blazar jets based on a transport equation including terms describing stochastic Fermi acceleration, synchrotron losses, shock acceleration, adiabatic expansion, and spatial diffusion. We derive the exact solution for the Fourier transform of the electron distribution and use it to compute the Fourier transform of the synchrotron radiation spectrum and the associated X-ray time lags. The same theoretical framework is also used to compute the peak flare X-ray spectrum, assuming that a steady-state electron distribution is achieved during the peak of the flare. The model parameters are constrained by comparing the theoretical predictions with the observational data for Mrk 421. The resulting integrated model yields, for the first time, a complete first-principles physical explanation for both the formation of the observed time lags and the shape of the peak flare X-ray spectrum. It also yields direct estimates of the strength of the shock and the stochastic magnetohydrodynamical wave acceleration components in the Mrk 421 jet.
Kato, Yusuke; Yagi, Hisashi; Kaji, Yuichi; Oshika, Tetsuro; Goto, Yuji
2013-08-30
Corneal dystrophies are genetic disorders resulting in progressive corneal clouding due to the deposition of amyloid fibrils derived from keratoepithelin, also called transforming growth factor β-induced protein (TGFBI). The formation of amyloid fibrils is often accelerated by surfactants such as sodium dodecyl sulfate (SDS). Most eye drops contain benzalkonium chloride (BAC), a cationic surfactant, as a preservative substance. In the present study, we aimed to reveal the role of BAC in the amyloid fibrillation of keratoepithelin-derived peptides in vitro. We used three types of 22-residue synthetic peptides covering Leu110-Glu131 of the keratoepithelin sequence: an R-type peptide with wild-type R124, a C-type peptide with C124 associated with lattice corneal dystrophy type I, and a H-type peptide with H124 associated with granular corneal dystrophy type II. The time courses of spontaneous amyloid fibrillation and seed-dependent fibril elongation were monitored in the presence of various concentrations of BAC or SDS using thioflavin T fluorescence. BAC and SDS accelerated the fibrillation of all synthetic peptides in the absence and presence of seeds. Optimal acceleration occurred near the CMC, which suggests that the unstable and dynamic interactions of keratoepithelin peptides with amphipathic surfactants led to the formation of fibrils. These results suggest that eye drops containing BAC may deteriorate corneal dystrophies and that those without BAC are preferred especially for patients with corneal dystrophies.
Kato, Yusuke; Yagi, Hisashi; Kaji, Yuichi; Oshika, Tetsuro; Goto, Yuji
2013-01-01
Corneal dystrophies are genetic disorders resulting in progressive corneal clouding due to the deposition of amyloid fibrils derived from keratoepithelin, also called transforming growth factor β-induced protein (TGFBI). The formation of amyloid fibrils is often accelerated by surfactants such as sodium dodecyl sulfate (SDS). Most eye drops contain benzalkonium chloride (BAC), a cationic surfactant, as a preservative substance. In the present study, we aimed to reveal the role of BAC in the amyloid fibrillation of keratoepithelin-derived peptides in vitro. We used three types of 22-residue synthetic peptides covering Leu110-Glu131 of the keratoepithelin sequence: an R-type peptide with wild-type R124, a C-type peptide with C124 associated with lattice corneal dystrophy type I, and a H-type peptide with H124 associated with granular corneal dystrophy type II. The time courses of spontaneous amyloid fibrillation and seed-dependent fibril elongation were monitored in the presence of various concentrations of BAC or SDS using thioflavin T fluorescence. BAC and SDS accelerated the fibrillation of all synthetic peptides in the absence and presence of seeds. Optimal acceleration occurred near the CMC, which suggests that the unstable and dynamic interactions of keratoepithelin peptides with amphipathic surfactants led to the formation of fibrils. These results suggest that eye drops containing BAC may deteriorate corneal dystrophies and that those without BAC are preferred especially for patients with corneal dystrophies. PMID:23861389
TIME-DEPENDENT ELECTRON ACCELERATION IN BLAZAR TRANSIENTS: X-RAY TIME LAGS AND SPECTRAL FORMATION
DOE Office of Scientific and Technical Information (OSTI.GOV)
Lewis, Tiffany R.; Becker, Peter A.; Finke, Justin D., E-mail: pbecker@gmu.edu, E-mail: tlewis13@gmu.edu, E-mail: justin.finke@nrl.navy.mil
2016-06-20
Electromagnetic radiation from blazar jets often displays strong variability, extending from radio to γ -ray frequencies. In a few cases, this variability has been characterized using Fourier time lags, such as those detected in the X-rays from Mrk 421 using Beppo SAX. The lack of a theoretical framework to interpret the data has motivated us to develop a new model for the formation of the X-ray spectrum and the time lags in blazar jets based on a transport equation including terms describing stochastic Fermi acceleration, synchrotron losses, shock acceleration, adiabatic expansion, and spatial diffusion. We derive the exact solution formore » the Fourier transform of the electron distribution and use it to compute the Fourier transform of the synchrotron radiation spectrum and the associated X-ray time lags. The same theoretical framework is also used to compute the peak flare X-ray spectrum, assuming that a steady-state electron distribution is achieved during the peak of the flare. The model parameters are constrained by comparing the theoretical predictions with the observational data for Mrk 421. The resulting integrated model yields, for the first time, a complete first-principles physical explanation for both the formation of the observed time lags and the shape of the peak flare X-ray spectrum. It also yields direct estimates of the strength of the shock and the stochastic magnetohydrodynamical wave acceleration components in the Mrk 421 jet.« less
Aghdassi, Ali; Christoph, Agnes; Dombrowski, Frank; Döring, Paula; Barth, Christoph; Christoph, Jan; Lerch, Markus M; Simon, Peter
2018-06-05
Gastrointestinal stromal tumors (GISTs) are rare malignancies but the most common mesenchymal tumors of the digestive tract. Recent advances in diagnostic imaging and an increasing incidence will confront us more frequently with stromal tumors. This single center study aimed to characterize GIST patients in terms of tumor location, clinical presentation, metastasis formation, as well as associated secondary malignancies. In a retrospective study, 104 patients with a histologically confirmed diagnosis of GIST, collected between 1993 and 2011, were characterized for several clinical features. The most common GIST location was the stomach (67.6%) followed by the small intestine (16.2%). Gastrointestinal bleeding (55.8%) and abdominal pain (38.5%) were the most frequently reported symptoms whereas about one-third of patients remained clinically asymptomatic (31.6%); 14.4% of patients had either synchronous or metachronous metastases and there was a significant prevalence also in the low risk group. The proportion of secondary malignant associated neoplasms was 31% in our GIST cohort, among which gastrointestinal, genitourinary tumors, and breast cancer were the most prevalent. There was a considerable risk for metastasis formation and the development of secondary neoplasias that should encourage discussion about the appropriate surveillance strategy after surgery for GIST. © 2018 S. Karger AG, Basel.
Park, William Keun Chan; Maxwell, Aaron Wilhelm Palmer; Frank, Victoria Elizabeth; Primmer, Michael Patrick; Collins, Scott Andrew; Baird, Grayson Luderman; Dupuy, Damian Edward
2017-01-01
The primary challenge in thermal ablation of liver tumors (e.g. hepatocellular carcinoma and hepatic colorectal cancer) is the relatively high recurrence rate (~30%) for which incomplete ablation at the periphery of the tumor is the most common reason. In an attempt to overcome this, we have developed a novel thermal accelerant (TA) agent capable of augmenting microwave energy from a distance normally unattainable by a single microwave ablation antenna. This cesium-based block co-polymer compound transforms from a liquid to a gel at body temperature and is intrinsically visible by computed tomography. Using an agarose phantom model, herein we demonstrate that both the rate and magnitude of temperature increase during microwave ablation were significantly greater in the presence of TA when compared with controls. These results suggest robust augmentation of microwave energy, and may translate into larger ablation zone volumes within biologic tissues. Further work using in vivo techniques is necessary to confirm these findings.
alpha-Lactalbumin species variation, HAMLET formation, and tumor cell death.
Pettersson, Jenny; Mossberg, Ann-Kristin; Svanborg, Catharina
2006-06-23
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a tumoricidal complex of apo alpha-lactalbumin and oleic acid, formed in casein after low pH treatment of human milk. This study examined if HAMLET-like complexes are present in casein from different species and if isolated alpha-lactalbumin from those species can form such complexes with oleic acid. Casein from human, bovine, equine, and porcine milk was separated by ion exchange chromatography and active complexes were only found in human casein. This was not explained by alpha-lactalbumin sequence variation, as purified bovine, equine, porcine, and caprine alpha-lactalbumins formed complexes with oleic acid with biological activity similar to HAMLET. We conclude that structural variation of alpha-lactalbumins does not preclude the formation of HAMLET-like complexes and that natural HAMLET formation in casein was unique to human milk, which also showed the highest oleic acid content.
Sun, Baocun; Zhang, Danfang; Zhao, Nan; Zhao, Xiulan
2017-05-02
Vasculogenic mimicry (VM) is a functional microcirculation pattern in malignant tumors accompanied by endothelium-dependent vessels and mosaic vessels. VM has been identified in more than 15 solid tumor types and is associated with poor differentiation, late clinical stage and poor prognosis. Classic anti-angiogenic agents do not target endothelium-dependent vessels and are not efficacious against tumors exhibiting VM. Further insight into the molecular signaling that triggers and promotes VM formation could improve anti-angiogenic therapeutics. Recent studies have shown that cancer stem cells (CSCs) and epithelium-to-endothelium transition (EET), a subtype of epithelial-to-mesenchymal transition (EMT), accelerate VM formation by stimulating tumor cell plasticity, remodeling the extracellular matrix (ECM) and connecting VM channels with host blood vessels. VM channel-lining cells originate from CSCs due to expression of EMT inducers such as Twist1, which promote EET and ECM remodeling. Hypoxia and high interstitial fluid pressure in the tumor microenvironment induce a specific type of cell death, linearly patterned programmed cell necrosis (LPPCN), which spatially guides VM and endothelium-dependent vessel networks. This review focuses on the roles of CSCs and EET in VM, and on possible novel anti-angiogenic strategies against alternative tumor vascularization.
LANDSAT-D accelerated payload correction subsystem output computer compatible tape format
NASA Technical Reports Server (NTRS)
1982-01-01
The NASA GSFC LANDSAT-D Ground Segment (GS) is developing an Accelerated Payload Correction Subsystem (APCS) to provide Thematic Mapper (TM) image correction data to be used outside the GS. This correction data is computed from a subset of the TM Payload Correction Data (PCD), which is downlinked from the spacecraft in a 32 Kbps data stream, and mirror scan correction data (MSCD), which is extracted from the wideband video data. This correction data is generated in the GS Thematic Mapper Mission Management Facility (MMF-T), and is recorded on a 9-track 1600 bit per inch computer compatible tape (CCT). This CCT is known as a APCS Output CCT (AOT). The AOT follows standardized corrections with respect to data formats, record construction and record identification. Applicable documents are delineated; common conventions which are used in further defining the structure, format and content of the AOT are defined; and the structure and content of the AOT are described.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hong, Linda X.; Garg, Madhur; Lasala, Patrick
2011-03-15
Purpose: Sharp dose fall off outside a tumor is essential for high dose single fraction stereotactic radiosurgery (SRS) plans. This study explores the relationship among tumor dose inhomogeneity, conformity, and dose fall off in normal tissues for micromultileaf collimator (mMLC) linear accelerator (LINAC) based cranial SRS plans. Methods: Between January 2007 and July 2009, 65 patients with single cranial lesions were treated with LINAC-based SRS. Among them, tumors had maximum diameters {<=}20 mm: 31; between 20 and 30 mm: 21; and >30 mm: 13. All patients were treated with 6 MV photons on a Trilogy linear accelerator (Varian Medical Systems,more » Palo Alto, CA) with a tertiary m3 high-resolution mMLC (Brainlab, Feldkirchen, Germany), using either noncoplanar conformal fixed fields or dynamic conformal arcs. The authors also created retrospective study plans with identical beam arrangement as the treated plan but with different tumor dose inhomogeneity by varying the beam margins around the planning target volume (PTV). All retrospective study plans were normalized so that the minimum PTV dose was the prescription dose (PD). Isocenter dose, mean PTV dose, RTOG conformity index (CI), RTOG homogeneity index (HI), dose gradient index R{sub 50}-R{sub 100} (defined as the difference between equivalent sphere radius of 50% isodose volume and prescription isodose volume), and normal tissue volume (as a ratio to PTV volume) receiving 50% prescription dose (NTV{sub 50}) were calculated. Results: HI was inversely related to the beam margins around the PTV. CI had a ''V'' shaped relationship with HI, reaching a minimum when HI was approximately 1.3. Isocenter dose and mean PTV dose (as percentage of PD) increased linearly with HI. R{sub 50}-R{sub 100} and NTV{sub 50} initially declined with HI and then reached a plateau when HI was approximately 1.3. These trends also held when tumors were grouped according to their maximum diameters. The smallest tumor group (maximum
CHL1 gene acts as a tumor suppressor in human neuroblastoma.
Ognibene, Marzia; Pagnan, Gabriella; Marimpietri, Danilo; Cangelosi, Davide; Cilli, Michele; Benedetti, Maria Chiara; Boldrini, Renata; Garaventa, Alberto; Frassoni, Francesco; Eva, Alessandra; Varesio, Luigi; Pistoia, Vito; Pezzolo, Annalisa
2018-05-25
Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system that accounts for 15% of pediatric cancer deaths. A distal portion of human chromosome 3p is often deleted in neuroblastoma, this region may contain one or more putative tumor suppressor genes. A 2.54 Mb region at 3p26.3 encompassing the smallest region of deletion pinpointed CHL1 gene, the locus for neuronal cell adhesion molecule close homolog of L1. We found that low CHL1 expression predicted poor outcome in neuroblastoma patients. Here we have used two inducible cell models to analyze the impact of CHL1 on neuroblastoma biology. Over-expression of CHL1 induced neurite-like outgrowth and markers of neuronal differentiation in neuroblastoma cells, halted tumor progression, inhibited anchorage-independent colony formation, and suppressed the growth of human tumor xenografts. Conversely, knock-down of CHL1 induced neurite retraction and activation of Rho GTPases, enhanced cell proliferation and migration, triggered colony formation and anchorage-independent growth, accelerated growth in orthotopic xenografts mouse model. Our findings demonstrate unambiguously that CHL1 acts as a regulator of proliferation and differentiation of neuroblastoma cells through inhibition of the MAPKs and Akt pathways. CHL1 is a novel candidate tumor suppressor in neuroblastoma, and its associated pathways may represent a promising target for future therapeutic interventions.
Thomas, Grace M.; Panicot-Dubois, Laurence; Lacroix, Romaric; Dignat-George, Françoise; Lombardo, Dominique
2009-01-01
Recent publications have demonstrated the presence of tissue factor (TF)–bearing microparticles (MPs) in the blood of patients suffering from cancer. However, whether these MPs are involved in thrombosis remains unknown. We show that pancreatic and lung cancer cells produce MPs that express active TF and P-selectin glycoprotein ligand 1 (PSGL-1). Cancer cell–derived MPs aggregate platelets via a TF-dependent pathway. In vivo, cancer cell–derived MPs, but not their parent cells, infused into a living mouse accumulate at the site of injury and reduce tail bleeding time and the time to occlusion of venules and arterioles. This thrombotic state is also observed in mice developing tumors. In such mice, the amount of circulating platelet-, endothelial cell–, and cancer cell–derived MPs is increased. Endogenous cancer cell–derived MPs shed from the growing tumor are able to accumulate at the site of injury. Infusion of a blocking P-selectin antibody abolishes the thrombotic state observed after injection of MPs or in mice developing a tumor. Collectively, our results indicate that cancer cell–derived MPs bearing PSGL-1 and TF play a key role in thrombus formation in vivo. Targeting these MPs could be of clinical interest in the prevention of thrombosis and to limit formation of metastasis in cancer patients. PMID:19667060
Wang, Yi-Zarn; King, Heather; Diebold, Anne
2013-08-01
Neuroendocrine tumors (NETs) are relatively rare with an indolent nature. As a result, treatment is often delayed and passive. The most commonly recognized disease progression leading to death is from the sequelae of bowel obstruction, ischemia, or liver failure secondary to liver metastasis. We recently recognized a rare cocoon-like formation in patients with metastatic gastroenteropancreatic NETs and hypothesize that this may be a distinct, final pathway for these patients. Ten patients with stage IV gastroenteropancreatic NETs, seen at our center between October 2008 and November 2011, who developed a cocoon were identified. Patient's charts, operative reports, pathology, and tumor markers were reviewed. No discernable predictors were identified as precursors to this condition. One patient survived 13 months after cocoon diagnosis, and the remaining 9 patients were all deceased within 5 months. Surgical treatment was attempted in 6 patients and was only partially successful in 1 patient who had the earliest stage of cocoon formation (type 1). Cocoon-like formations in patients with stage IV gastroenteropancreatic NETs is rare and may be a terminal disease progression that has not been previously recognized. The best treatment option remains unknown. Surgical treatment is not advisable, with the exception of type 1 abdominal cocoons.
Accelerator based epithermal neutron source
NASA Astrophysics Data System (ADS)
Taskaev, S. Yu.
2015-11-01
We review the current status of the development of accelerator sources of epithermal neutrons for boron neutron capture therapy (BNCT), a promising method of malignant tumor treatment. Particular attention is given to the source of epithermal neutrons on the basis of a new type of charged particle accelerator: tandem accelerator with vacuum insulation and lithium neutron-producing target. It is also shown that the accelerator with specialized targets makes it possible to generate fast and monoenergetic neutrons, resonance and monoenergetic gamma-rays, alpha-particles, and positrons.
NASA Astrophysics Data System (ADS)
Pakdaman, S. A.; Garcia, M.; Teh, E.; Lincoln, D.; Trivedi, M.; Alves, M.; Johansen, C.
2016-11-01
Shock wave formation and acceleration in a high-aspect ratio cross section shock tube were studied experimentally and numerically. The relative importance of geometric effects and diaphragm opening time on shock formation are assessed. The diaphragm opening time was controlled through the use of slit-type (fast opening time) and petal-type (slow opening time) diaphragms. A novel method of fabricating the petal-type diaphragms, which results in a consistent burst pressure and symmetric opening without fragmentation, is presented. High-speed schlieren photography was used to visualize the unsteady propagation of the lead shock wave and trailing gas dynamic structures. Surface-mounted pressure sensors were used to capture the spatial and temporal development of the pressure field. Unsteady Reynolds-Averaged Navier-Stokes simulation predictions using the shear-stress-transport turbulence model are compared to the experimental data. Simulation results are used to explain the presence of high-frequency pressure oscillations observed experimentally in the driver section as well as the cause of the initial acceleration and subsequent rapid decay of shock velocity measured along the top and bottom channel surfaces. A one-dimensional theoretical model predicting the effect of the finite opening time of the diaphragm on the rate of driver depressurization and shock acceleration is proposed. The model removes the large amount of empiricism that accompanies existing models published in the literature. Model accuracy is assessed through comparisons with experiments and simulations. Limitations of and potential improvements in the model are discussed.
Abrupt plate acceleration during rifted margin formation: Cause and effect
NASA Astrophysics Data System (ADS)
Brune, Sascha; Williams, Simon; Butterworth, Nathaniel; Müller, Dietmar
2017-04-01
Extension rate is known to control key processes during rifted margin formation such as crust-mantle coupling, decompression melting, magmatism, and serpentinisation. Here we build on recent advances in plate tectonic reconstructions by quantifying the extension velocity history of Earth's major rifted margins during the last 240 million years. We find that many successful rifts start with a slow phase of extension followed by rapid acceleration that introduces a fast phase. The transition from slow to fast rifting takes place long before crustal break-up: approximately half of the present day rifted margin area was created during the slow, and the other half during the fast rift phase. We reproduce the rapid transition from slow to fast extension using analytical and numerical modelling with constant force boundary conditions. In these models, rift velocities are not imposed but instead evolve naturally in response to the changing strength of the rift. Our results demonstrate that abrupt plate acceleration during continental rifting is controlled by a rift-intrinsic strength-velocity feedback. The abruptness of rift acceleration is thereby governed by the nonlinearity of lithospheric localization. Realistic brittle and power-law rheologies lead to a speed-up duration between two and ten million years. For successful rifts that generate a new ocean basin, the duration of rift speed-up is notably almost independent of the applied extensional force. Instead, the force controls the duration of the slow phase: higher forces shorten the slow phase while lower forces prolong it. If the force is too low, however, delocalisation processes prevent the rift from reaching the point of speed-up and produce a failed rift, even if the extensional system was active for many million years.
Martínez-Cruz, Ana Belén; Santos, Mirentxu; Lara, M Fernanda; Segrelles, Carmen; Ruiz, Sergio; Moral, Marta; Lorz, Corina; García-Escudero, Ramón; Paramio, Jesús M
2008-02-01
Squamous cell carcinomas (SCC) represent the most aggressive type of nonmelanoma skin cancer. Although little is known about the causal alterations of SCCs, in organ-transplanted patients the E7 and E6 oncogenes of human papillomavirus, targeting the p53- and pRb-dependent pathways, have been widely involved. Here, we report the functional consequences of the simultaneous elimination of Trp53 and retinoblastoma (Rb) genes in epidermis using Cre-loxP system. Loss of p53, but not pRb, produces spontaneous tumor development, indicating that p53 is the predominant tumor suppressor acting in mouse epidermis. Although the simultaneous inactivation of pRb and p53 does not aggravate the phenotype observed in Rb-deficient epidermis in terms of proliferation and/or differentiation, spontaneous SCC development is severely accelerated in doubly deficient mice. The tumors are aggressive and undifferentiated and display a hair follicle origin. Detailed analysis indicates that the acceleration is mediated by premature activation of the epidermal growth factor receptor/Akt pathway, resulting in increased proliferation in normal and dysplastic hair follicles and augmented tumor angiogenesis. The molecular characteristics of this model provide valuable tools to understand epidermal tumor formation and may ultimately contribute to the development of therapies for the treatment of aggressive squamous cancer.
Brasher, Megan I; Martynowicz, David M; Grafinger, Olivia R; Hucik, Andrea; Shanks-Skinner, Emma; Uniacke, James; Coppolino, Marc G
2017-09-29
Tumor cell invasion involves targeted localization of proteins required for interactions with the extracellular matrix and for proteolysis. The localization of many proteins during these cell-extracellular matrix interactions relies on membrane trafficking mediated in part by SNAREs. The SNARE protein syntaxin4 (Stx4) is involved in the formation of invasive structures called invadopodia; however, it is unclear how Stx4 function is regulated during tumor cell invasion. Munc18c is known to regulate Stx4 activity, and here we show that Munc18c is required for Stx4-mediated invadopodium formation and cell invasion. Biochemical and microscopic analyses revealed a physical association between Munc18c and Stx4, which was enhanced during invadopodium formation, and that a reduction in Munc18c expression decreases invadopodium formation. We also found that an N-terminal Stx4-derived peptide associates with Munc18c and inhibits endogenous interactions of Stx4 with synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2). Furthermore, expression of the Stx4 N-terminal peptide decreased invadopodium formation and cell invasion in vitro Of note, cells expressing the Stx4 N-terminal peptide exhibited impaired trafficking of membrane type 1 matrix metalloproteinase (MT1-MMP) and EGF receptor (EGFR) to the cell surface during invadopodium formation. Our findings implicate Munc18c as a regulator of Stx4-mediated trafficking of MT1-MMP and EGFR, advancing our understanding of the role of SNARE function in the localization of proteins that drive tumor cell invasion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy
Aqbi, Hussein F.; Tyutyunyk-Massey, Liliya; Keim, Rebecca C.; Butler, Savannah E.; Thekkudan, Theresa; Joshi, Supriya; Smith, Timothy M.; Bandyopadhyay, Dipankar; Idowu, Michael O.; Bear, Harry D.; Payne, Kyle K.; Gewirtz, David A.; Manjili, Masoud H.
2018-01-01
Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy. PMID:29774126
Yang, Jing; Wang, Rong; Li, Hongjiang; Lv, Qing; Meng, Wentong; Yang, Xiaoqin
2016-07-08
Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN) or cluster of differentiation 147 (CD147), a glycoprotein enriched on the plasma membrane of tumor cells, promotes proliferation, invasion, metastasis, and survival of malignant tumor cells. In this study, we sought to examine the expression of EMMPRIN in breast tumors, and to identify the potential roles of EMMPRIN on breast cancer cells. EMMPRIN expression in breast cancer tissues was assessed by immunohistochemistry. We used a lentivirus vector-based RNA interference (RNAi) approach expressing short hairpin RNA (shRNA) to knockdown EMMPRIN gene in breast cancer cell lines MDA-MB-231 and MCF-7. In vitro, Cell proliferative, invasive potential were determined by Cell Counting Kit (CCK-8), cell cycle analysis and matrigel invasion assay, respectively. In vivo, tumorigenicity was monitored by inoculating tumor cells into breast fat pad of female nude mice. EMMPRIN was over-expressed in breast tumors and breast cancer cell lines. Down-regulation of EMMPRIN by lentivirus vector-based RNAi led to decreased cell proliferative, decreased matrigel invasion in vitro, and attenuated tumor formation in vivo. High expression of EMMPRIN plays a crucial role in breast cancer cell proliferation, matrigel invasion and tumor formation.
NASA Astrophysics Data System (ADS)
Osnes, A. N.; Vartdal, M.; Pettersson Reif, B. A.
2018-05-01
The formation of jets from a shock-accelerated cylindrical shell of particles, confined in a Hele-Shaw cell, is studied by means of numerical simulation. A number of simulations have been performed, systematically varying the coupling between the gas and solid phases in an effort to identify the primary mechanism(s) responsible for jet formation. We find that coupling through drag is sufficient for the formation of jets. Including the effect of particle volume fraction and particle collisions did not alter the general behaviour, but had some influence on the length, spacing and number of jets. Furthermore, we find that the jet selection process starts early in the dispersal process, during the initial expansion of the particle layer.
Carbon nanotubes with high bone-tissue compatibility and bone-formation acceleration effects.
Usui, Yuki; Aoki, Kaoru; Narita, Nobuyo; Murakami, Narumichi; Nakamura, Isao; Nakamura, Koichi; Ishigaki, Norio; Yamazaki, Hiroshi; Horiuchi, Hiroshi; Kato, Hiroyuki; Taruta, Seiichi; Kim, Yoong Ahm; Endo, Morinobu; Saito, Naoto
2008-02-01
Carbon nanotubes (CNTs) have been used in various fields as composites with other substances or alone to develop highly functional materials. CNTs hold great interest with respect to biomaterials, particularly those to be positioned in contact with bone such as prostheses for arthroplasty, plates or screws for fracture fixation, drug delivery systems, and scaffolding for bone regeneration. Accordingly, bone-tissue compatibility of CNTs and CNT influence on bone formation are important issues, but the effects of CNTs on bone have not been delineated. Here, it is found that multi-walled CNTs adjoining bone induce little local inflammatory reaction, show high bone-tissue compatibility, permit bone repair, become integrated into new bone, and accelerate bone formation stimulated by recombinant human bone morphogenetic protein-2 (rhBMP-2). This study provides an initial investigational basis for CNTs in biomaterials that are used adjacent to bone, including uses to promote bone regeneration. These findings should encourage development of clinical treatment modalities involving CNTs.
Interplay between TGF-β signaling and receptor tyrosine kinases in tumor development.
Shi, Qiaoni; Chen, Ye-Guang
2017-10-01
Transforming growth factor-β (TGF-β) signaling regulates cell proliferation, differentiation, migration and death, and plays a critical role in embryogenesis and tissue homeostasis. Its deregulation results in various diseases including tumor formation. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), also play key roles in the development and progression of many types of tumors. It has been realized that TGF-β signaling and RTK pathways interact with each other and their interplay is important for cancer development. They are mutually regulated and cooperatively modulate cell survival and migration, epithelial-mesenchymal transition, and tumor microenvironment to accelerate tumorigenesis and tumor metastasis. RTKs can modulate Smad-dependent transcription or cooperate with TGF-β to potentiate its oncogenic activity, while TGF-β signaling can in turn control RTK signaling by regulating their activities or expression. This review summarizes current understandings of the interplay between TGF-β signaling and RTKs and its influence on tumor development.
NASA Astrophysics Data System (ADS)
Timms, W. A.; Crane, R.; Anderson, D. J.; Bouzalakos, S.; Whelan, M.; McGeeney, D.; Rahman, P. F.; Acworth, R. I.
2016-01-01
Evaluating the possibility of leakage through low-permeability geological strata is critically important for sustainable water supplies, the extraction of fuels from coal and other strata, and the confinement of waste within the earth. The current work demonstrates that relatively rapid and realistic vertical hydraulic conductivity (Kv) measurements of aquitard cores using accelerated gravity can constrain and compliment larger-scale assessments of hydraulic connectivity. Steady-state fluid velocity through a low-K porous sample is linearly related to accelerated gravity (g level) in a centrifuge permeameter (CP) unless consolidation or geochemical reactions occur. A CP module was custom designed to fit a standard 2 m diameter geotechnical centrifuge (550 g maximum) with a capacity for sample dimensions up to 100 mm diameter and 200 mm length, and a total stress of ˜ 2 MPa at the base of the core. Formation fluids were used as influent to limit any shrink-swell phenomena, which may alter the permeability. Kv results from CP testing of minimally disturbed cores from three sites within a clayey-silt formation varied from 10-10 to 10-7 m s-1 (number of samples, n = 18). Additional tests were focussed on the Cattle Lane (CL) site, where Kv within the 99 % confidence interval (n = 9) was 1.1 × 10
AIP1 expression in tumor niche suppresses tumor progression and metastasis
Ji, Weidong; Li, Yonghao; He, Yun; Yin, Mingzhu; Zhou, Huanjiao Jenny; Boggon, Titus J.; Zhang, Haifeng; Min, Wang
2015-01-01
Studies from tumor cells suggest that tumor suppressor AIP1 inhibits epithelial-mesenchymal transition (EMT). However, the role of AIP1 in the tumor microenvironment has not been examined. We show that a global or vascular endothelial cell (EC)-specific deletion of the AIP1 gene in mice augments tumor growth and metastasis in melanoma and breast cancer models. AIP1-deficient vascular environment not only enhances tumor neovascularization and increases pre-metastatic niche formation, but also secrets tumor EMT-promoting factors. These effects from AIP1 loss are associated with increased VEGFR2 signaling in the vascular EC and could be abrogated by systemic administration of VEGFR2 kinase inhibitors. Mechanistically, AIP1 blocks VEGFR2-dependent signaling by directly binding to the phosphotyrosine residues within the activation loop of VEGFR2. Our data reveal that AIP1, by inhibiting VEGFR2-dependent signaling in tumor niche, suppresses tumor EMT switch, tumor angiogenesis and tumor pre-metastatic niche formation to limit tumor growth and metastasis. PMID:26139244
Praticò, D; Tillmann, C; Zhang, Z B; Li, H; FitzGerald, G A
2001-03-13
The cyclooxygenase (COX) product, prostacyclin (PGI(2)), inhibits platelet activation and vascular smooth-muscle cell migration and proliferation. Biochemically selective inhibition of COX-2 reduces PGI(2) biosynthesis substantially in humans. Because deletion of the PGI(2) receptor accelerates atherogenesis in the fat-fed low density lipoprotein receptor knockout mouse, we wished to determine whether selective inhibition of COX-2 would accelerate atherogenesis in this model. To address this hypothesis, we used dosing with nimesulide, which inhibited COX-2 ex vivo, depressed urinary 2,3 dinor 6-keto PGF(1alpha) by approximately 60% but had no effect on thromboxane formation by platelets, which only express COX-1. By contrast, the isoform nonspecific inhibitor, indomethacin, suppressed platelet function and thromboxane formation ex vivo and in vivo, coincident with effects on PGI(2) biosynthesis indistinguishable from nimesulide. Indomethacin reduced the extent of atherosclerosis by 55 +/- 4%, whereas nimesulide failed to increase the rate of atherogenesis. Despite their divergent effects on atherogenesis, both drugs depressed two indices of systemic inflammation, soluble intracellular adhesion molecule-1, and monocyte chemoattractant protein-1 to a similar but incomplete degree. Neither drug altered serum lipids and the marked increase in vascular expression of COX-2 during atherogenesis. Accelerated progression of atherosclerosis is unlikely during chronic intake of specific COX-2 inhibitors. Furthermore, evidence that COX-1-derived prostanoids contribute to atherogenesis suggests that controlled evaluation of the effects of nonsteroidal anti-inflammatory drugs and/or aspirin on plaque progression in humans is timely.
Ibrahim, Nafisa B; Anandan, Srividya; Hartman, Audrey L; McSweeney, Michelle; Chun, Jeanette; McKee, Andrea; Yang, Rebecca; Kim, Cathleen
2015-01-01
The use of accelerated partial breast irradiation (APBI) following breast-conserving surgery is rapidly gaining popularity as an alternative to whole-breast irradiation (WBI) in selected patients with early-stage breast cancer. Although data on the long-term effectiveness and safety of APBI accelerated partial breast irradiation are still being gathered, the shorter treatment course and narrowed radiation target of APBI accelerated partial breast irradiation provide an attractive alternative for carefully selected patients. These patients include those with relatively small tumors (≤3 cm), negative or close margins, and negative sentinel lymph nodes. Possible long-term complications include telangiectasia and the development of a palpable mass at the lumpectomy site. Mammographic findings in patients who have undergone APBI accelerated partial breast irradiation are distinct from those in patients who have undergone conventional WBI whole-breast irradiation . The most common post-APBI accelerated partial breast irradiation radiographic findings include formation of seromas at the lumpectomy site, focal parenchymal changes such as increased trabeculation and parenchymal distortion, fat necrosis, and skin changes such as thickening or retraction. Given the continued evolution of breast cancer treatment, it is important that radiologists have a comprehensive understanding of APBI accelerated partial breast irradiation in terms of rationale, patient selection criteria, common postprocedural radiographic findings (and how they differ from post-WBI whole-breast irradiation findings), and advantages and potential complications. RSNA, 2015
One-Dimensional Shock Wave Formation by an Accelerating Piston. Ph.D. Thesis - Ohio State Univ.
NASA Technical Reports Server (NTRS)
Mann, M. J.
1970-01-01
The formation of a shock wave by a solid accelerating piston was studied. A theoretical solution using the method of characteristics for a perfect gas showed that a complex wave system exists, and that the compressed gas can have large gradients in temperature, density and entropy. Experiments were performed with a piston tube where piston speed, shock speed and pressure were measured. The comparison of theory and experiment was good.
Hufbauer, Martin; Lazić, Daliborka; Reinartz, Markus; Akgül, Baki; Pfister, Herbert; Weissenborn, Sönke Jan
2011-10-01
Dysregulation of microRNA (miRNA) expression is regularly found in various types of cancer and contributes to tumorigenic processes. However, little is known about miRNA expression in non-melanoma skin cancer in which a pathogenic role of beta human papillomaviruses (HPV) is discussed. A carcinogenic potential of beta HPV8 could be demonstrated in a transgenic mouse model, expressing all early genes of HPV8 (HPV8-CER). A single UVA/B-dose induced oncogene expression and led to papilloma growth within three weeks. Expression of miRNAs and their targets during HPV8-mediated tumor formation in mice. Skin of untreated or UV-irradiated wild-type and HPV8-CER mice was analyzed for miRNA expression and localization by qPCR and in situ hybridization. MiRNA target protein expression was analyzed by immunohistochemical staining. Early steps in skin tumor formation in HPV8-CER mice were associated with an upregulation of the oncogenic miRNA-17-5p, -21 and -106a and a downregulation of the tumor-suppressive miRNA-155 and -206, which could be demonstrated by qPCR and in situ hybridization. The respective targets of miRNA-21 and -106a, the tumor suppressors PTEN, PDCD4 and Rb with their pivotal role in cell cycle regulation, apoptosis and proliferation were found to be downregulated. This is the first report demonstrating that a cutaneous HPV type deregulates the expression of miRNAs. These deregulations are closely related to the UV-induced upregulation of HPV8 oncogene levels, which suggest a direct or indirect HPV8-specific effect on miRNA expression. These data presume that HPV8 interferes with the miRNA mediated gene regulation to induce tumorigenesis. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Katsukawa, Mitsuko; Nakajima, Yusuke; Fukumoto, Akiko; Doi, Daisuke; Takahashi, Jun
2016-06-01
Cell replacement therapy holds great promise for Parkinson's disease (PD), but residual undifferentiated cells and immature neural progenitors in the therapy may cause tumor formation. Although cell sorting could effectively exclude these proliferative cells, from the viewpoint of clinical application, there exists no adequate coping strategy in the case of their contamination. In this study, we analyzed a component of proliferative cells in the grafts of human-induced pluripotent stem cell-derived neural progenitors and investigated the effect of radiation therapy on tumor formation. In our differentiating protocol, analyses of neural progenitors (day 19) revealed that the proliferating cells expressed early neural markers (SOX1, PAX6) or a dopaminergic neuron progenitor marker (FOXA2). When grafted into the rat striatum, these immature neurons gradually became postmitotic in the brain, and the rosette structures disappeared at 14 weeks. However, at 4-8 weeks, the SOX1(+)PAX6(+) cells formed rosette structures in the grafts, suggesting their tumorigenic potential. Therefore, to develop a fail-safe therapy against tumor formation, we investigated the effect of radiation therapy. At 4 weeks posttransplantation, when KI67(+) cells comprised the highest ratio, radiation therapy with (137)Cs Gammacell Exactor for tumor-bearing immunodeficient rats showed a significant decrease in graft volume and percentage of SOX1(+)KI67(+) cells in the graft, thus demonstrating the preventive effect of gamma-ray irradiation against tumorigenicity. These results give us critical criteria for the safety of future cell replacement therapy for PD.
Load-sharing through elastic micro-motion accelerates bone formation and interbody fusion.
Ledet, Eric H; Sanders, Glenn P; DiRisio, Darryl J; Glennon, Joseph C
2018-02-13
Achieving a successful spinal fusion requires the proper biological and biomechanical environment. Optimizing load-sharing in the interbody space can enhance bone formation. For anterior cervical discectomy and fusion (ACDF), loading and motion are largely dictated by the stiffness of the plate, which can facilitate a balance between stability and load-sharing. The advantages of load-sharing may be substantial for patients with comorbidities and in multilevel procedures where pseudarthrosis rates are significant. We aimed to evaluate the efficacy of a novel elastically deformable, continuously load-sharing anterior cervical spinal plate for promotion of bone formation and interbody fusion relative to a translationally dynamic plate. An in vivo animal model was used to evaluate the effects of an elastically deformable spinal plate on bone formation and spine fusion. Fourteen goats underwent an ACDF and received either a translationally dynamic or elastically deformable plate. Animals were followed up until 18 weeks and were evaluated by plain x-ray, computed tomography scan, and undecalcified histology to evaluate the rate and quality of bone formation and interbody fusion. Animals treated with the elastically deformable plate demonstrated statistically significantly superior early bone formation relative to the translationally dynamic plate. Trends in the data from 8 to 18 weeks postoperatively suggest that the elastically deformable implant enhanced bony bridging and fusion, but these enhancements were not statistically significant. Load-sharing through elastic micro-motion accelerates bone formation in the challenging goat ACDF model. The elastically deformable implant used in this study may promote early bony bridging and increased rates of fusion, but future studies will be necessary to comprehensively characterize the advantages of load-sharing through micro-motion. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
NASA Astrophysics Data System (ADS)
Chernousov, Yu. D.; Shebolaev, I. V.; Ikryanov, I. M.
2018-01-01
An electron beam with a high (close to 100%) coefficient of electron capture into the regime of acceleration has been obtained in a linear electron accelerator based on a parallel coupled slow-wave structure, electron gun with microwave-controlled injection current, and permanent-magnet beam-focusing system. The high capture coefficient was due to the properties of the accelerating structure, beam-focusing system, and electron-injection system. Main characteristics of the proposed systems are presented.
Cui, Xiaochun; Huo, Mingxin; Chen, Congli; Yu, Zhisen; Zhou, Chen; Li, Anran; Qiao, Bingqian; Zhou, Dandan; Crittenden, John C
2018-09-01
Residual Al(III) (at low concentration) is common in water treatment plants (WTPs) and is associated with bacteria. We hypothesize that Al(III) accelerate biofouling due to its hydrolysis and hormesis characteristics, as compared with other cations. To verify this, we elaborated the roles of Al(III) at low concentrations on the biofilm formation. Al(III) hormesis (<2.0mg/L) stimulated bacteria growth increased by ~3.7 times, and extracellular polymeric substances production also enhanced. Al(III) flocculation resulted in the suspended cells precipitation instantly, for Al(III) dosages of 0.6 and 2.0mg/L and the concentration of Al(III) decreased by 0.07 and 0.14mg/L, respectively. Al(III) poisoned the bridged bacterial cells and decreased their ATP by 22.36% and 55.91%, respectively. Al(III) formed polymer presented strong affinity with bacterial outer membrane, and this damaged the bacterial outer membrane. This caused proteins to leak at the combined point. Al-polymer bound to NH 2 and/or NH on the leaked protein, contributed to biofilm formation. Biofilm maturity was aided by polysaccharides, which shielded Al(III) toxicity for the formed biofilm. Thus, the biofilm exhibited a distinguished double-layer microstructure, principally with proteins and inactivated cells at the bottom, polysaccharides and activated cells at the top. Thus, hormesis and flocculation caused by low concentration Al(III) mutually promoted each other, and together accelerated biofilm formation. Copyright © 2018 Elsevier B.V. All rights reserved.
NASA Technical Reports Server (NTRS)
Hallock, Ashley K.; Choueiri, Edgar Y.; Polzin, Kurt A.
2007-01-01
The inductive formation of current sheets in a conical theta pinch FARAD (Faraday Accelerator with Radio-frequency Assisted Discharge) thruster is investigated experimentally with time-integrated photography. The goal is to help in understanding the mechanisms and conditions controlling the strength and extent of the current sheet, which are two indices important for FARAD as a propulsion concept. The profiles of these two indices along the inside walls of the conical acceleration coil are assumed to be related to the profiles of the strength and extent of the luminosity pattern derived from photographs of the discharge. The variations of these profiles as a function of uniform back-fill neutral pressure (with no background magnetic field and all parameters held constant) provided the first clues on the nature and qualitative dependencies of current sheet formation. It was found that there is an optimal pressure for which both indices reach a maximum and that the rate of change in these indices with pressure differs on either side of this optimal pressure. This allowed the inference that current sheet formation follows a Townsend-like breakdown mechanism modified by the existence of a finite pressure-dependent radio-frequency-generated electron density background. The observation that the effective location of the luminosity pattern favors the exit-half of the conical coil is explained as the result of the tendency of the inductive discharge circuit to operate near its minimal self-inductance. Movement of the peak in the luminosity pattern towards the upstream side of the cone with increasing pressure is believed to result from the need of the circuit to compensate for the increase in background plasma resistivity due to increasing pressure.
Mafuvadze, Benford; Benakanakere, Indira; Lopez, Franklin; Besch-Williford, Cynthia; Ellersieck, Mark R.; Hyder, Salman M.
2011-01-01
The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins. PMID:21505181
Treatment Planning for Accelerator-Based Boron Neutron Capture Therapy
NASA Astrophysics Data System (ADS)
Herrera, María S.; González, Sara J.; Minsky, Daniel M.; Kreiner, Andrés J.
2010-08-01
Glioblastoma multiforme and metastatic melanoma are frequent brain tumors in adults and presently still incurable diseases. Boron Neutron Capture Therapy (BNCT) is a promising alternative for this kind of pathologies. Accelerators have been proposed for BNCT as a way to circumvent the problem of siting reactors in hospitals and for their relative simplicity and lower cost among other advantages. Considerable effort is going into the development of accelerator-based BNCT neutron sources in Argentina. Epithermal neutron beams will be produced through appropriate proton-induced nuclear reactions and optimized beam shaping assemblies. Using these sources, computational dose distributions were evaluated in a real patient with diagnosed glioblastoma treated with BNCT. The simulated irradiation was delivered in order to optimize dose to the tumors within the normal tissue constraints. Using Monte Carlo radiation transport calculations, dose distributions were generated for brain, skin and tumor. Also, the dosimetry was studied by computing cumulative dose-volume histograms for volumes of interest. The results suggest acceptable skin average dose and a significant dose delivered to tumor with low average whole brain dose for irradiation times less than 60 minutes, indicating a good performance of an accelerator-based BNCT treatment.
Treatment Planning for Accelerator-Based Boron Neutron Capture Therapy
DOE Office of Scientific and Technical Information (OSTI.GOV)
Herrera, Maria S.; Gonzalez, Sara J.; Minsky, Daniel M.
2010-08-04
Glioblastoma multiforme and metastatic melanoma are frequent brain tumors in adults and presently still incurable diseases. Boron Neutron Capture Therapy (BNCT) is a promising alternative for this kind of pathologies. Accelerators have been proposed for BNCT as a way to circumvent the problem of siting reactors in hospitals and for their relative simplicity and lower cost among other advantages. Considerable effort is going into the development of accelerator-based BNCT neutron sources in Argentina. Epithermal neutron beams will be produced through appropriate proton-induced nuclear reactions and optimized beam shaping assemblies. Using these sources, computational dose distributions were evaluated in a realmore » patient with diagnosed glioblastoma treated with BNCT. The simulated irradiation was delivered in order to optimize dose to the tumors within the normal tissue constraints. Using Monte Carlo radiation transport calculations, dose distributions were generated for brain, skin and tumor. Also, the dosimetry was studied by computing cumulative dose-volume histograms for volumes of interest. The results suggest acceptable skin average dose and a significant dose delivered to tumor with low average whole brain dose for irradiation times less than 60 minutes, indicating a good performance of an accelerator-based BNCT treatment.« less
Li, Hui; Xu, Fangying; Li, Si; Zhong, Anjing; Meng, Xianwen; Lai, Maode
2016-01-01
ABSTRACT Tumor budding occurs at the invasive front of cancer; the tumor cells involved have metastatic and stemness features, indicating a poor prognosis. Tumor budding is partly responsible for cancer metastasis, and its initiation is based on the epithelial-mesenchymal transition (EMT) process. The EMT process involves the conversion of epithelial cells into migratory and invasive cells, and is a profound event in tumorigenesis. The EMT, associated with the formation of cancer stem cells (CSCs) and resistance to therapy, results from a combination of gene mutation, epigenetic regulation, and microenvironmental control. Tumor budding can be taken to represent the EMT in vivo. The EMT process is under the influence of the tumor microenvironment as well as tumor cells themselves. Here, we demonstrate that the tumor microenvironment dominates EMT development and impacts cancer metastasis, as well as promotes CSC formation and mediates drug resistance. In this review, we mainly discuss components of the microenvironment, such as the extracellular matrix (ECM), inflammatory cytokines, metabolic products, and hypoxia, that are involved in and impact on the acquisition of tumor-cell motility and dissemination, the EMT, metastatic tumor-cell formation, tumor budding and CSCs, and cancer metastasis, including subsequent chemo-resistance. From our point of view, the tumor microenvironment now constitutes a promising target for cancer therapy. PMID:26743180
2014-09-01
hollow metal sphere. Voltages of over 10 MV can be reached if used with an insulating gas. Corona discharge limits all electrostatic accelerators to...laser field. Lasers can have strong electric fields with frequencies high enough to avoid corona formation and break- down. The key is to couple the...leading to a spark discharge in the accelerator and thus a breakdown of the electrostatic field [6], [7]. Figure 1.1: Cockroft-Walton cascade generator
Tulpule, Ketki; Dringen, Ralf
2012-04-01
Formaldehyde is a neurotoxic compound that can be endogenously generated in the brain. Because astrocytes play a key role in metabolism and detoxification processes in brain, we have investigated the capacity of these cells to metabolize formaldehyde using primary astrocyte-rich cultures as a model system. Application of formaldehyde to these cultures resulted in the appearance of formate in cells and in a time-, concentration- and temperature-dependent disappearance of formaldehyde from the medium that was accompanied by a matching extracellular accumulation of formate. This formaldehyde-oxidizing capacity of astrocyte cultures is likely to be catalyzed by alcohol dehydrogenase 3 and aldehyde dehydrogenase 2, because the cells of the cultures contain the mRNAs of these formaldehyde-oxidizing enzymes. In addition, exposure to formaldehyde increased both glucose consumption and lactate production by the cells. Both the strong increase in the cellular formate content and the increase in glycolytic flux were only observed after application of formaldehyde to the cells, but not after treatment with exogenous methanol or formate. The accelerated lactate production was not additive to that obtained for azide, a known inhibitor of complex IV of the respiratory chain, and persisted after removal of formaldehyde after a formaldehyde exposure for 1.5 h. These data demonstrate that cultured astrocytes efficiently oxidize formaldehyde to formate, which subsequently enhances glycolytic flux, most likely by inhibition of mitochondrial respiration. Copyright © 2012 Wiley Periodicals, Inc.
NASA Astrophysics Data System (ADS)
Westphal, A. J.; Bradley, J. P.
2004-12-01
Interplanetary dust particles (IDPs) contain enigmatic submicron components called GEMS (glass with embedded metal and sulfides). The compositions and structures of GEMS indicate that they have been processed by exposure to ionizing radiation, but details of the actual irradiation environment(s) have remained elusive. Here we propose a mechanism and astrophysical site for GEMS formation that explains for the first time the following key properties of GEMS: they are stoichiometrically enriched in oxygen and systematically depleted in S, Mg, Ca, and Fe (relative to solar abundances); most have normal (solar) oxygen isotopic compositions; they exhibit a strikingly narrow size distribution (0.1-0.5 μm diameter); and some of them contain ``relict'' crystals within their silicate glass matrices. We show that the compositions, size distribution, and survival of relict crystals are inconsistent with amorphization by particles accelerated by diffusive shock acceleration. Instead, we propose that GEMS are formed from crystalline grains that condense in stellar outflows from massive stars in OB associations, are accelerated in encounters with frequent supernova shocks inside the associated superbubble (SB), and are implanted with atoms from the hot gas in the SB interior. We thus reverse the usual roles of target and projectile. Rather than being bombarded at rest by energetic ions, grains are accelerated and bombarded by a nearly monovelocity beam of atoms as viewed in their rest frame. Meyer, Drury, and Ellison have proposed that Galactic cosmic rays (GCRs) originate from ions sputtered from such accelerated dust grains. We suggest that GEMS are surviving members of a population of fast grains that constitute the long-sought source material for GCRs. Thus, representatives of the GCR source material may have been awaiting discovery in cosmic dust labs for the last 30 yr.
Is IGSF1 involved in human pituitary tumor formation?
Faucz, Fabio R.; Horvath, Anelia D.; Azevedo, Monalisa F.; Levy, Isaac; Bak, Beata; Wang, Ying; Xekouki, Paraskevi; Szarek, Eva; Gourgari, Evgenia; Manning, Allison D.; de Alexandre, Rodrigo Bertollo; Saloustros, Emmanouil; Trivellin, Giampaolo; Lodish, Maya; Hofman, Paul; Anderson, Yvonne C; Holdaway, Ian; Oldfield, Edward; Chittiboina, Prashant; Nesterova, Maria; Biermasz, Nienke R.; Wit, Jan M.; Bernard, Daniel J.; Stratakis, Constantine A.
2014-01-01
IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in sections from GH-producing adenomas, familial somatomammotroph hyperplasia and in normal pituitary. In two male patients, and in one female, with somatomammotroph hyperplasia from the same family, we identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function. Of 60 female controls, two carried the same variant, and seven were heterozygous for other variants. Immunohistochemistry showed increase IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared to a GH-producing adenoma from a patient negative for any IGSF1 variants and to normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation. PMID:25527509
Kulla, Hannes; Greiser, Sebastian; Benemann, Sigrid; Rademann, Klaus; Emmerling, Franziska
2016-07-14
A new cocrystal of pyrazinamide with oxalic acid was prepared mechanochemically and characterized by PXRD, Raman spectroscopy, solid-state NMR spectroscopy, DTA-TG, and SEM. Based on powder X-ray diffraction data the structure was solved. The formation pathway of the reaction was studied in situ using combined synchrotron PXRD and Raman spectroscopy. Using oxalic acid dihydrate the initially neat grinding turned into a rapid self-accelerated liquid-assisted grinding process by the release of crystallization water. Under these conditions, the cocrystal was formed directly within two minutes.
Li, Yafan; Wheeler, Deric L; Ananthaswamy, Honnavara N; Verma, Ajit K; Oberley, Terry D
2007-12-01
Our previous studies showed that protein kinase Cepsilon (PKCepsilon) verexpression in mouse skin resulted in metastatic squamous cell carcinoma (SCC) elicited by single 7,12-dimethylbenz(a)anthracene (DMBA)-initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promotion in the absence of preceding papilloma formation as is typically observed in wild type mice. The present study demonstrates that double-DMBA initiation modulates tumor incidence, multiplicity, and latency period in both wild type and PKCepsilon overexpression transgenic (PKCepsilon-Tg) mice. After 17 weeks (wks) of tumor promotion, a reduction in papilloma multiplicity was observed in double- versus single-DMBA initiated wild type mice. Papilloma multiplicity was inversely correlated with cell death indices of interfollicular keratinocytes, indicating decreased papilloma formation was caused by increased cell death and suggesting the origin of papillomas is in interfollicular epidermis. Double-initiated PKCepsilon-Tg mice had accelerated carcinoma formation and cancer incidence in comparison to single-initiated PKCepsilon-Tg mice. Morphologic analysis of mouse skin following double initiation and tumor promotion showed a similar if not identical series of events to those previously observed following single initiation and tumor promotion: putative preneoplastic cells were observed arising from hyperplastic hair follicles (HFs) with subsequent cancer cell infiltration into the dermis. Single-initiated PKCepsilon-Tg mice exhibited increased mitosis in epidermal cells of HFs during tumor promotion.
Boolbol, S K; Dannenberg, A J; Chadburn, A; Martucci, C; Guo, X J; Ramonetti, J T; Abreu-Goris, M; Newmark, H L; Lipkin, M L; DeCosse, J J; Bertagnolli, M M
1996-06-01
Inducible cyclooxygenase (Cox-2), also known as prostaglandin H synthase 2 (PGH-2) is a key enzyme in the formation of prostaglandins and thromboxanes. Cox-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers and suppression of apoptosis in cultured epithelia] cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide. To address the relationship between Cox-2, apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the Apc gene, leading to the development of gastrointestinal adenomas by 110 days of age. Min mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/day) in drinking water. Control Min mice and homozygous C57BL/6J-+/+ normal littermates lacking the Apc mutation (+/+) were fed AIN-76A diet and given tap water to drink. At 110 days of age, all mice were sacrificed, and their intestinal tracts were examined. Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for sulindac-treated Min mice. As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from Min animals revealed increased amounts of Cox-2 and prostaglandin E(2) compared to +/+ littermates. Using two different in situ techniques, terminal transferase-mediated dUTP nick end labeling and a direct immunoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals. Treatment with sulindac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E(2) to baseline and restored normal levels of apoptosis. These data suggest that overexpression of Cox-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.
Durso, Danielle Fernandes; Bacalini, Maria Giulia; Sala, Claudia; Pirazzini, Chiara; Marasco, Elena; Bonafé, Massimiliano; do Valle, Ítalo Faria; Gentilini, Davide; Castellani, Gastone; Faria, Ana Maria Caetano; Franceschi, Claudio; Garagnani, Paolo; Nardini, Christine
2017-04-04
Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat
2012-01-06
Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, wemore » generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.« less
Accelerated Tumor Cell Death by Angiogenic Modifiers
2004-08-01
factors; extracellular matrix; 3-D cell culture; cancer metastasis Running title: Tumor-Stroma Interaction Abbreviations: BSP, bone sialoprotein ; ECM...such as osteocalcin (OC), bone sialoprotein (BSP), osteopontin (OPN), osteonectin (ON or SPARC), 18 osteoprotegerin (OPG), PTHrP, M-CSF, RANK and...Waltregny, D., Bellahcene, A., Van Riet, I., Fisher, L. W., Young, M., Fernandez, P. and et al. Prognostic value of bone sialoprotein expression in
Influence of solidification accelerators on structure formation of anhydrite-containing binders
NASA Astrophysics Data System (ADS)
Anikanova, L.; Volkova, O.; Kudyakov, A.; Sarkisov, Y.; Tolstov, D.
2016-01-01
The article presents results of scientific analysis of chemical additives influence on acid fluoride binder. It was found that the influence of sulfate nature additives on the process of hydration and solidification of the binder is similar to influence of additives on indissoluble anhydrite. Additives with SO42- anion NO- are more efficient. The mentioned additives according to accelerating effect belong to the following succession: K2SO4 > Na2SO4 > FeSO4 > MgSO4. Facilitation of the process of hydration and solidification of the binder, increase in density and durability of the binder (32 MPa) is to the greatest extent achieved with the introduction of 2% sodium sulfate additive of the binder's mass into the composition of the binder along with the ultrasonic treatment of water solution. Directed crystal formation process with healing of porous structure by new growths presented as calcium sulfate dehydrate and hydroglauberite provides positive effect.
Cander, Soner; Ertürk, Erdinç; Karkucak, Mutlu; Oz Gül, Ozen; Görükmez, Orhan; Yakut, Tahsin; Unal, Oğuz Kaan; Ersoy, Canan; Tuncel, Ercan; Imamoğlu, Sazi
2012-11-01
The objective of this study was to investigate the effect of G870A gene polymorphism of CCND1 on the formation and behavioral features of prolactinomas. One hundred and thirteen patients with prolactinoma and 108 age and gender matched control were included in the study. The patients were divided into two groups as noninvasive and invasive tumors. CCND1 G870A gene polymorphism was compared in patients/control and invasive/noninvasive groups. A and G allele frequencies were found as 41.7% and 58.3% in the controls, and 61.1% and 38.9% in the patients (p<0.01). Rates of G/G, G/A and A/A genotypes were found as 11.8%, 55.9% and 32.4% in the noninvasive group, and 15.6%, 44.4% and 40.0% in the invasive group, respectively. Differences between patient and control groups were significant but were not between invasive and noninvasive groups in terms of the allele frequencies and genotype distribution. Mean tumor size and serum levels of prolactin at the time of diagnosis and change in these values after the treatment were not found statistically significant in genotype subgroups. CCND1 G870A gene polymorphism may be an important factor in the early stages of the tumor formation. However, it did not affect the features of the tumor. Copyright © 2012 Elsevier B.V. All rights reserved.
Is IGSF1 involved in human pituitary tumor formation?
Faucz, Fabio R; Horvath, Anelia D; Azevedo, Monalisa F; Levy, Isaac; Bak, Beata; Wang, Ying; Xekouki, Paraskevi; Szarek, Eva; Gourgari, Evgenia; Manning, Allison D; de Alexandre, Rodrigo Bertollo; Saloustros, Emmanouil; Trivellin, Giampaolo; Lodish, Maya; Hofman, Paul; Anderson, Yvonne C; Holdaway, Ian; Oldfield, Edward; Chittiboina, Prashant; Nesterova, Maria; Biermasz, Nienke R; Wit, Jan M; Bernard, Daniel J; Stratakis, Constantine A
2015-02-01
IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH-producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation. © 2015 Society for Endocrinology.
JP-8 jet fuel exposure potentiates tumor development in two experimental model systems.
Harris, D T; Sakiestewa, D; Titone, D; He, X; Hyde, J; Witten, M
2007-11-01
The US Air Force has implemented the widespread use of JP-8 jet fuel in its operations, although a thorough understanding of its potential effects upon exposed personnel is unclear. Previous work has reported that JP-8 exposure is immunosuppressive. Exposure of mice to JP-8 for 1 h/day resulted in immediate secretion of two immunosuppressive agents; namely, interleukin-10 (IL-10) and prostaglandin E2 (PGE2). Thus, it was of interest to determine if jet fuel exposure might promote tumor growth and metastasis. The syngeneic B16 tumor model was used for these studies. Animals were injected intravenously with tumor cells, and lung colonies were enumerated. Animals were also examined for metastatic spread of the tumor. Mice were either exposed to 1000 mg/m3 JP-8 (1 h/ day) for 7 days before tumor injection or were exposed to JP-8 at the time of tumor injection. All animals were killed 17 days after tumor injection. In the present study, JP8 exposure potentiated the growth and metastases of B16 tumors in an animal model. Exposure of mice to JP-8 for 1 h/day before tumor induction resulted in an approximately 8.7-fold increase in tumors, whereas those mice exposed to JP8 at the time of tumor induction had a 5.6-fold increase in tumor numbers. Thus, low concentration JP-8 jet fuel exposures have significant immune suppressive effects on the immune system that can result in increased tumor formation and metastases. We have now extended the observations to an experimental subcutaneous tumor model. JP8 exposure at the time of tumor induction in this model did not affect the growth of the tumor. However, JP8-exposed, tumor-bearing animals died at an accelerated rate as compared with air-exposed, tumor-bearing mice.
Accelerated tumor invasion under non-isotropic cell dispersal in glioblastomas
NASA Astrophysics Data System (ADS)
Fort, Joaquim; Solé, Ricard V.
2013-05-01
Glioblastomas are highly diffuse, malignant tumors that have so far evaded clinical treatment. The strongly invasive behavior of cells in these tumors makes them very resistant to treatment, and for this reason both experimental and theoretical efforts have been directed toward understanding the spatiotemporal pattern of tumor spreading. Although usual models assume a standard diffusion behavior, recent experiments with cell cultures indicate that cells tend to move in directions close to that of glioblastoma invasion, thus indicating that a biased random walk model may be much more appropriate. Here we show analytically that, for realistic parameter values, the speeds predicted by biased dispersal are consistent with experimentally measured data. We also find that models beyond reaction-diffusion-advection equations are necessary to capture this substantial effect of biased dispersal on glioblastoma spread.
Energy Metabolism Rewiring Precedes UVB-Induced Primary Skin Tumor Formation.
Hosseini, Mohsen; Dousset, Léa; Mahfouf, Walid; Serrano-Sanchez, Martin; Redonnet-Vernhet, Isabelle; Mesli, Samir; Kasraian, Zeinab; Obre, Emilie; Bonneu, Marc; Claverol, Stephane; Vlaski, Marija; Ivanovic, Zoran; Rachidi, Walid; Douki, Thierry; Taieb, Alain; Bouzier-Sore, Anne-Karine; Rossignol, Rodrigue; Rezvani, Hamid Reza
2018-06-19
Although growing evidence indicates that bioenergetic metabolism plays an important role in the progression of tumorigenesis, little information is available on the contribution of reprogramming of energy metabolism in cancer initiation. By applying a quantitative proteomic approach and targeted metabolomics, we find that specific metabolic modifications precede primary skin tumor formation. Using a multistage model of ultraviolet B (UVB) radiation-induced skin cancer, we show that glycolysis, tricarboxylic acid (TCA) cycle, and fatty acid β-oxidation are decreased at a very early stage of photocarcinogenesis, while the distal part of the electron transport chain (ETC) is upregulated. Reductive glutamine metabolism and the activity of dihydroorotate dehydrogenase (DHODH) are both necessary for maintaining high ETC. Mice with decreased DHODH activity or impaired ETC failed to develop pre-malignant and malignant lesions. DHODH activity represents a major link between DNA repair efficiency and bioenergetic patterning during skin carcinogenesis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
Wang, Li; Hoogcarspel, Stan Jelle; Wen, Zhifei; van Vulpen, Marco; Molkentine, David P; Kok, Jan; Lin, Steven H; Broekhuizen, Roel; Ang, Kie-Kian; Bovenschen, Niels; Raaymakers, Bas W; Frank, Steven J
2016-10-01
Devices that combine magnetic resonance imaging with linear accelerators (MRL) represent a novel tool for MR-guided radiotherapy. However, whether magnetic fields (MFs) generated by these devices affect the radiosensitivity of tumors is unknown. We investigated the influence of a 1.5-T MF on cell viability and radioresponse of human solid tumors. Human head/neck cancer and lung cancer cells were exposed to single or fractionated 6-MV X-ray radiation; effects of the MF on cell viability were determined by cell plating efficiency and on radioresponsiveness by clonogenic cell survival. Doses needed to reduce the fraction of surviving cells to 37% of the initial value (D0s) were calculated for multiple exposures to MF and radiation. Results were analyzed using Student's t-tests. Cell viability was no different after single or multiple exposures to MRL than after exposure to a conventional linear accelerator (Linac, without MR-generated MF) in 12 of 15 experiments (all P > 0.05). Single or multiple exposures to MF had no influence on cell radioresponse (all P > 0.05). Cells treated up to four times with an MRL or a Linac further showed no changes in D0s with MF versus without MF (all P > 0.05). In conclusion, MF within the MRL does not seem to affect in vitro tumor radioresponsiveness as compared with a conventional Linac. Bioelectromagnetics. 37:471-480, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.
Polo-like kinase 1 is essential for early embryonic development and tumor suppression.
Lu, Lin-Yu; Wood, Jamie L; Minter-Dykhouse, Katherine; Ye, Lin; Saunders, Thomas L; Yu, Xiaochun; Chen, Junjie
2008-11-01
Polo-like kinases (Plks) are serine/threonine kinases that are highly conserved in organisms from yeasts to humans. Previous reports have shown that Plk1 is critical for all stages of mitosis and may play a role in DNA replication during S phase. While much work has focused on Plk1, little is known about the physiological function of Plk1 in vivo. To address this question, we generated Plk1 knockout mice. Plk1 homozygous null mice were embryonic lethal, and early Plk1(-/-) embryos failed to survive after the eight-cell stage. Immunocytochemistry studies revealed that Plk1-null embryos were arrested outside the mitotic phase, suggesting that Plk1 is important for proper cell cycle progression. It has been postulated that Plk1 is a potential oncogene, due to its overexpression in a variety of tumors and tumor cell lines. While the Plk1 heterozygotes were healthy at birth, the incidence of tumors in these animals was threefold greater than that in their wild-type counterparts, demonstrating that the loss of one Plk1 allele accelerates tumor formation. Collectively, our data support that Plk1 is important for early embryonic development and may function as a haploinsufficient tumor suppressor.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Massimino, Maura; Gandola, Lorenza; Spreafico, Filippo
Purpose: Supratentorial primitive neuroectodermal tumors (S-PNET) are rare and have a grim prognosis, frequently taking an aggressive course with local relapse and metastatic spread. We report the results of a mono-institutional therapeutic trial. Methods and Materials: We enrolled 15 consecutive patients to preradiation chemotherapy (CT) consisting of high-dose methotrexate, high-dose etoposide, high-dose cyclophosphamide, and high-dose carboplatin, craniospinal irradiation (CSI) with hyperfractionated accelerated radiotherapy (HART) plus focal boost, maintenance with vincristine/lomustine or consolidation with high-dose thiotepa followed by autologous stem-cell rescue. Results: Median age was 9 years; 7 were male, 8 female. Site of disease was pineal in 3, elsewhere inmore » 12. Six patients were had no evidence of disease after surgery (NED). Of those with evidence of disease after surgery (ED), 2 had central nervous system spread. Of the 9 ED patients, 2 had complete response (CR) and 2 partial response (PR) after CT, 4 stable disease, and 1 progressive disease. Of the 7 ED patients before radiotherapy, 1 had CR, 4 PR, and 2 minor response, thus obtaining a 44% CR + PR after CT and 71% after HART. Because of rapid progression in 2 of the first 5 patients, high-dose thiotepa was systematically adopted after HART in the subsequent 10 patients. Six of 15 patients relapsed (4 locally, 1 locally with dissemination, 1 with dissemination) a mean of 6 months after starting CT, 2 developed second tumors; 5 of 6 relapsers died at a median of 13 months. Three-year progression-free survival, event-free survival, and overall survival were 54%, 34%, and 61%, respectively. Conclusion: Hyperfractionated accelerated RT was the main tool in obtaining responses in S-PNET; introducing the myeloablative phase improved the prognosis (3/10 vs. 3/5 relapses), though the outcome remained unsatisfactory despite the adoption of this intensive treatment.« less
Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome
Menendez, Javier A.; Folguera-Blasco, Núria; Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Joven, Jorge; Alarcón, Tomás
2016-01-01
The geroncogenesis hypothesis postulates that the decline in metabolic cellular health that occurs naturally with aging drives a “field effect” predisposing normal tissues for cancer development. We propose that mutations in the cancer susceptibility genes BRCA1/2 might trigger “accelerated geroncogenesis” in breast and ovarian epithelia. By speeding up the rate at which the metabolic threshold becomes “permissive” with survival and expansion of genomically unstable pre-tumoral epithelial cells, BRCA haploinsufficiency-driven metabolic reprogramming would operate as a bona fide oncogenic event enabling malignant transformation and tumor formation in BRCA carriers. The metabolic facet of BRCA1 one-hit might involve tissue-specific alterations in acetyl-CoA, α-ketoglutarate, NAD+, FAD, or S-adenosylmethionine, critical factors for de/methylation or de/acetylation dynamics in the nuclear epigenome. This in turn might induce faulty epigenetic reprogramming at the “install phase” that directs cell-specific differentiation of breast/ovarian epithelial cells, which can ultimately determine the penetrance of BRCA defects during developmental windows of susceptibility. This model offers a framework to study whether metabolic drugs that prevent or revert metabolic reprogramming induced by BRCA haploinsufficiency might displace the “geroncogenic risk” of BRCA carriers to the age typical for those without the mutation. The identification of the key nodes that directly communicate changes in cellular metabolism to the chromatin in BRCA haploinsufficient cells may allow the epigenetic targeting of genomic instability using exclusively metabolic means. The validation of accelerated geroncogenesis as an inherited “one-hit” metabolic “field effect” might offer new strategies to therapeutically revisit the apparently irreversible genetic-hereditary fate of women with hereditary breast-ovarian cancer syndrome. PMID:26943589
Jiang, Yan J; Teichert, Arnaud E; Fong, Frankie; Oda, Yuko; Bikle, Daniel D
2013-07-01
Ultra violet (UV) irradiation, in particular UVB, is the single most important carcinogen for skin tumor formation. UVB induces genetic mutations and immune suppression, which lead to abnormal cell proliferation and eventually tumor formation. Previously studies from our group and others demonstrated that both global and epidermal specific VDR knock out mice are predisposed to either chemical (DMBA)- or long-term UVB-induced skin tumor formation, paralleled by an increase in β-catenin signaling. Using primary cultured human keratinocytes, we further demonstrated that 1,25(OH)2-dihydroxyvitamin D3 (1,25(OH)2D3) suppresses cyclin D1 and Gli1 which are regulated by β-catenin/TCF signaling and have a critical role in epidermal carcinogenesis. Blockage of VDR by siRNA resulted in hyperproliferation of keratinocytes, and increased expression of cyclin D1 and Gli1. In addition, we also showed that 1,25(OH)2D3/VDR directly regulates transcriptional activity of β-catenin/TCF signaling using the -catenin reporter TopGlow. Using K14 driven tamoxifen-induced cre recombinase to delete both VDR and β-catenin in keratinocytes of mice following the first hair follicle cycle, we found that ablation of epidermal specific β-catenin cannot rescue VDR null mice from UVB-induced skin tumor formation. Further study using VDR or β-catenin single null mice is necessary to compare with the data from double null mice. This article is part of a Special Issue entitled 'Vitamin D Workshop'. Copyright © 2012 Elsevier Ltd. All rights reserved.
Fujimori, Kiyoshi; Lee, Hans; Sloey, Christopher; Ricci, Margaret S; Wen, Zai-Qing; Phillips, Joseph; Nashed-Samuel, Yasser
2016-01-01
Certain types of glass vials used as primary containers for liquid formulations of biopharmaceutical drug products have been observed with delamination that produced small glass like flakes termed lamellae under certain conditions during storage. The cause of this delamination is in part related to the glass surface defects, which renders the vials susceptible to flaking, and lamellae are formed during the high-temperature melting and annealing used for vial fabrication and shaping. The current European Pharmacopoeia method to assess glass vial quality utilizes acid titration of vial extract pools to determine hydrolytic resistance or alkalinity. Four alternative techniques with improved throughput, convenience, and/or comprehension were examined by subjecting seven lots of vials to analysis by all techniques. The first three new techniques of conductivity, flame photometry, and inductively coupled plasma mass spectrometry measured the same sample pools as acid titration. All three showed good correlation with alkalinity: conductivity (R(2) = 0.9951), flame photometry sodium (R(2) = 0.9895), and several elements by inductively coupled plasma mass spectrometry [(sodium (R(2) = 0.9869), boron (R(2) = 0.9796), silicon (R(2) = 0.9426), total (R(2) = 0.9639)]. The fourth technique processed the vials under conditions that promote delamination, termed accelerated lamellae formation, and then inspected those vials visually for lamellae. The visual inspection results without the lot with different processing condition correlated well with alkalinity (R(2) = 0.9474). Due to vial processing differences affecting alkalinity measurements and delamination propensity differently, the ratio of silicon and sodium measurements from inductively coupled plasma mass spectrometry was the most informative technique to assess overall vial quality and vial propensity for lamellae formation. The other techniques of conductivity, flame photometry, and accelerated lamellae formation
The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.
Liu, Rui; Zhang, Haiyang; Wang, Xia; Zhou, Likun; Li, Hongli; Deng, Ting; Qu, Yanjun; Duan, Jingjing; Bai, Ming; Ge, Shaohua; Ning, Tao; Zhang, Le; Huang, Dingzhi; Ba, Yi
2015-12-22
miRNAs are a group of small RNAs that have been reported to play a key role at each stage of tumorigenesis and are believed to have future practical value. We now demonstrate that Bim, which stimulates cell apoptosis, is obviously down-regulated in pancreatic cancer (PaC) tissues and cell lines. And Bim-related miR-24 is significantly up-regulated in PaC. The repressed expression of Bim is proved to be a result of miR-24, thus promoting cell growth of both cancer and vascular cells, and accelerating vascular ring formation. By using mouse tumor model, we clearly showed that miR-24 promotes tumor growth and angiogenesis by suppressing Bim expression in vivo. Therefore, a new pathway comprising miR-24 and Bim can be used in the exploration of drug-target therapy of PaC.
Orlando, Paul A.; Gatenby, Robert A.; Brown, Joel S.
2013-01-01
We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations. PMID:23508890
Orlando, Paul A; Gatenby, Robert A; Brown, Joel S
2013-01-01
We apply competition colonization tradeoff models to tumor growth and invasion dynamics to explore the hypothesis that varying selection forces will result in predictable phenotypic differences in cells at the tumor invasive front compared to those in the core. Spatially, ecologically, and evolutionarily explicit partial differential equation models of tumor growth confirm that spatial invasion produces selection pressure for motile phenotypes. The effects of the invasive phenotype on normal adjacent tissue determine the patterns of growth and phenotype distribution. If tumor cells do not destroy their environment, colonizer and competitive phenotypes coexist with the former localized at the invasion front and the latter, to the tumor interior. If tumors cells do destroy their environment, then cell motility is strongly selected resulting in accelerated invasion speed with time. Our results suggest that the widely observed genetic heterogeneity within cancers may not be the stochastic effect of random mutations. Rather, it may be the consequence of predictable variations in environmental selection forces and corresponding phenotypic adaptations.
Choudhry, H; Albukhari, A; Morotti, M; Haider, S; Moralli, D; Smythies, J; Schödel, J; Green, C M; Camps, C; Buffa, F; Ratcliffe, P; Ragoussis, J; Harris, A L; Mole, D R
2015-01-01
Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer. PMID:25417700
Influence of solidification accelerators on structure formation of anhydrite-containing binders
DOE Office of Scientific and Technical Information (OSTI.GOV)
Anikanova, L., E-mail: alasmit@mail.ru; Volkova, O., E-mail: v.olga.nikitina@gmail.com; Kudyakov, A.
2016-01-15
The article presents results of scientific analysis of chemical additives influence on acid fluoride binder. It was found that the influence of sulfate nature additives on the process of hydration and solidification of the binder is similar to influence of additives on indissoluble anhydrite. Additives with SO{sub 4}{sup 2−} anion NO{sup −} are more efficient. The mentioned additives according to accelerating effect belong to the following succession: K{sub 2}SO{sub 4} > Na{sub 2}SO{sub 4} > FeSO{sub 4} > MgSO{sub 4}. Facilitation of the process of hydration and solidification of the binder, increase in density and durability of the binder (32 MPa)more » is to the greatest extent achieved with the introduction of 2% sodium sulfate additive of the binder’s mass into the composition of the binder along with the ultrasonic treatment of water solution. Directed crystal formation process with healing of porous structure by new growths presented as calcium sulfate dehydrate and hydroglauberite provides positive effect.« less
Withaferin A inhibits in vivo growth of breast cancer cells accelerated by Notch2 knockdown.
Kim, Su-Hyeong; Hahm, Eun-Ryeong; Arlotti, Julie A; Samanta, Suman K; Moura, Michelle B; Thorne, Stephen H; Shuai, Yongli; Anderson, Carolyn J; White, Alexander G; Lokshin, Anna; Lee, Joomin; Singh, Shivendra V
2016-05-01
The present study offers novel insights into the molecular circuitry of accelerated in vivo tumor growth by Notch2 knockdown in triple-negative breast cancer (TNBC) cells. Therapeutic vulnerability of Notch2-altered growth to a small molecule (withaferin A, WA) is also demonstrated. MDA-MB-231 and SUM159 cells were used for the xenograft studies. A variety of technologies were deployed to elucidate the mechanisms underlying tumor growth augmentation by Notch2 knockdown and its reversal by WA, including Fluorescence Molecular Tomography for measurement of tumor angiogenesis in live mice, Seahorse Flux analyzer for ex vivo measurement of tumor metabolism, proteomics, and Luminex-based cytokine profiling. Stable knockdown of Notch2 resulted in accelerated in vivo tumor growth in both cells reflected by tumor volume and/or latency. For example, the wet tumor weight from mice bearing Notch2 knockdown MDA-MB-231 cells was about 7.1-fold higher compared with control (P < 0.0001). Accelerated tumor growth by Notch2 knockdown was highly sensitive to inhibition by a promising steroidal lactone (WA) derived from a medicinal plant. Molecular underpinnings for tumor growth intensification by Notch2 knockdown included compensatory increase in Notch1 activation, increased cellular proliferation and/or angiogenesis, and increased plasma or tumor levels of growth stimulatory cytokines. WA administration reversed many of these effects providing explanation for its remarkable anti-cancer efficacy. Notch2 functions as a tumor growth suppressor in TNBC and WA offers a novel therapeutic strategy for restoring this function.
Laser-driven proton and deuteron acceleration from a pure solid-density H2/D2 cryogenic jet
NASA Astrophysics Data System (ADS)
Kim, Jongjin; Gauthier, Maxence; Aurand, Bastian; Curry, Chandra; Goede, Sebastian; Goyon, Clement; Williams, Jackson; Kerr, Shaun; Ruby, John; Propp, Adrienne; Ramakrishna, Bhuvanesh; Pak, Art; Hazi, Andy; Glenzer, Siegfried; Roedel, Christian
2015-11-01
Laser-driven proton acceleration has become of tremendous interest for the fundamental science and the potential applications in tumor therapy and proton radiography. We have developed a cryogenic liquid hydrogen jet, which can deliver a self-replenishing target of pure solid-density hydrogen or deuterium. This allows for a target compatible with high-repetition-rate experiments and results in a pure hydrogen plasma, facilitating comparison with simulations. A new modification has allowed for the formation of jets with rectangular profiles, facilitating comparison with foil targets. This jet was installed at the Titan laser and driven by laser pulses of 40-60 J of 527 nm laser light in 1 ps. The resulting proton and deuteron spectra were measured in multiple directions with Thomson parabola spectrometers and RCF stacks. The spectral and angular information suggest contribution from both the TNSA and RPA acceleration mechanisms.
Tumoral and Choroidal Vascularization
Jost, Maud; Maillard, Catherine; Lecomte, Julie; Lambert, Vincent; Tjwa, Marc; Blaise, Pierre; Alvarez Gonzalez, Maria-Luz; Bajou, Khalid; Blacher, Silvia; Motte, Patrick; Humblet, Chantal; Defresne, Marie Paule; Thiry, Marc; Frankenne, Francis; Gothot, André; Carmeliet, Peter; Rakic, Jean-Marie; Foidart, Jean-Michel; Noël, Agnès
2007-01-01
An adequate balance between serine proteases and their plasminogen activator inhibitor-1 (PAI-1) is critical for pathological angiogenesis. PAI-1 deficiency in mice is associated with impaired choroidal neovascularization (CNV) and tumoral angiogenesis. In the present work, we demonstrate unexpected differences in the contribution of bone marrow (BM)-derived cells in these two processes regulated by PAI-1. PAI-1−/− mice grafted with BM-derived from wild-type mice were able to support laser-induced CNV formation but not skin carcinoma vascularization. Engraftment of irradiated wild-type mice with PAI-1−/− BM prevented CNV formation, demonstrating the crucial role of PAI-1 delivered by BM-derived cells. In contrast, the transient infiltration of tumor transplants by local PAI-1-producing host cells rather than by BM cells was sufficient to rescue tumor growth and angiogenesis in PAI-1-deficient mice. These data identify PAI-1 as a molecular determinant of a local permissive soil for tumor angiogenesis. Altogether, the present study demonstrates that different cellular mechanisms contribute to PAI-1-regulated tumoral and CNV. PAI-1 contributes to BM-dependent choroidal vascularization and to BM-independent tumor growth and angiogenesis. PMID:17717143
Majumder, Syamantak; Sowden, Mark P; Gerber, Scott A; Thomas, Tamlyn; Christie, Christine K; Mohan, Amy; Yin, Guoyong; Lord, Edith M; Berk, Bradford C; Pang, Jinjiang
2014-02-01
Recent evidence suggests G-protein-coupled receptor-2-interacting protein-1 (GIT1) overexpression in several human metastatic tumors, including breast, lung, and prostate. Tumor metastasis is associated with an increase in angiogenesis. We have showed previously that GIT1 is required for postnatal angiogenesis during lung development. However, the functional role of GIT1 in pathological angiogenesis during tumor growth is unknown. In the present study, we show inhibition of angiogenesis in matrigel implants as well as reduced tumor angiogenesis and melanoma tumor growth in GIT1-knockout mice. We demonstrate that this is a result of impaired directional migration of GIT1-depleted endothelial cells toward a vascular endothelial growth factor gradient. Cortactin-mediated lamellipodia formation in the leading edge is critical for directional migration. We observed a significant reduction in cortactin localization and lamellipodia formation in the leading edge of GIT1-depleted endothelial cells. We specifically identified that the Spa homology domain (aa 250-420) of GIT1 is required for GIT1-cortactin complex localization to the leading edge. The mechanisms involved extracellular signal-regulated kinases 1 and 2-mediated Cortactin-S405 phosphorylation and activation of Rac1/Cdc42. Finally, using gain of function studies, we show that a constitutively active mutant of cortactin restored directional migration of GIT1-depleted cells. Our data demonstrated that a GIT1-cortactin association through GIT1-Spa homology domain is required for cortactin localization to the leading edge and is essential for endothelial cell directional migration and tumor angiogenesis.
Tao, Li; Zhu, Kun; Zhu, Jungao; Xu, Xiaohan; Lin, Chen; Ma, Wenjun; Lu, Haiyang; Zhao, Yanying; Lu, Yuanrong; Chen, Jia-Er; Yan, Xueqing
2017-07-07
With the development of laser technology, laser-driven proton acceleration provides a new method for proton tumor therapy. However, it has not been applied in practice because of the wide and decreasing energy spectrum of laser-accelerated proton beams. In this paper, we propose an analytical model to reconstruct the spread-out Bragg peak (SOBP) using laser-accelerated proton beams. Firstly, we present a modified weighting formula for protons of different energies. Secondly, a theoretical model for the reconstruction of SOBPs with laser-accelerated proton beams has been built. It can quickly calculate the number of laser shots needed for each energy interval of the laser-accelerated protons. Finally, we show the 2D reconstruction results of SOBPs for laser-accelerated proton beams and the ideal situation. The final results show that our analytical model can give an SOBP reconstruction scheme that can be used for actual tumor therapy.
Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth
2006-11-01
LN -Shh xenograft tumors is unabated after castration of the host mouse. However, castration of mice bearing LNCaP + Gli3-/- UGSM bi-clonal...canonical xenograft undergoes involution and growth arrest, growth of LN -Shh xenograft tumors is unabated after castration. As we have shown...signalingindependent of Shh ligand in tumor stroma accelerates tumor growth. We have identified potential stromal Shh target genes in xenograft tumors and have begun
Perspectives of boron-neutron capture therapy of malignant brain tumors
NASA Astrophysics Data System (ADS)
Kanygin, V. V.; Kichigin, A. I.; Krivoshapkin, A. L.; Taskaev, S. Yu.
2017-09-01
Boron neutron capture therapy (BNCT) is characterized by a selective effect directly on the cells of malignant tumors. The carried out research showed the perspective of the given kind of therapy concerning malignant tumors of the brain. However, the introduction of BNCT into clinical practice is hampered by the lack of a single protocol for the treatment of patients and the difficulty in using nuclear reactors to produce a neutron beam. This problem can be solved by using a compact accelerator as a source of neutrons, with the possibility of installation in a medical institution. Such a neutron accelerator for BNCT was developed at Budker Institute of Nuclear Physics, Novosibirsk. A neutron beam was obtained on this accelerator, which fully complies with the requirements of BNCT, as confirmed by studies on cell cultures and experiments with laboratory animals. The conducted experiments showed the relative safety of the method with the absence of negative effects on cell cultures and living organisms, and also confirmed the effectiveness of BNCT for malignant brain tumors.
Mocellin, Simone; Lise, Mario; Nitti, Donato
2007-01-01
Advances in tumor immunology are supporting the clinical implementation of several immunological approaches to cancer in the clinical setting. However, the alternate success of current immunotherapeutic regimens underscores the fact that the molecular mechanisms underlying immune-mediated tumor rejection are still poorly understood. Given the complexity of the immune system network and the multidimensionality of tumor/host interactions, the comprehension of tumor immunology might greatly benefit from high-throughput microarray analysis, which can portrait the molecular kinetics of immune response on a genome-wide scale, thus accelerating the discovery pace and ultimately catalyzing the development of new hypotheses in cell biology. Although in its infancy, the implementation of microarray technology in tumor immunology studies has already provided investigators with novel data and intriguing new hypotheses on the molecular cascade leading to an effective immune response against cancer. Although the general principles of microarray-based gene profiling have rapidly spread in the scientific community, the need for mastering this technique to produce meaningful data and correctly interpret the enormous output of information generated by this technology is critical and represents a tremendous challenge for investigators, as outlined in the first section of this book. In the present Chapter, we report on some of the most significant results obtained with the application of DNA microarray in this oncology field.
Accelerators for Cancer Therapy
DOE R&D Accomplishments Database
Lennox, Arlene J.
2000-05-30
The vast majority of radiation treatments for cancerous tumors are given using electron linacs that provide both electrons and photons at several energies. Design and construction of these linacs are based on mature technology that is rapidly becoming more and more standardized and sophisticated. The use of hadrons such as neutrons, protons, alphas, or carbon, oxygen and neon ions is relatively new. Accelerators for hadron therapy are far from standardized, but the use of hadron therapy as an alternative to conventional radiation has led to significant improvements and refinements in conventional treatment techniques. This paper presents the rationale for radiation therapy, describes the accelerators used in conventional and hadron therapy, and outlines the issues that must still be resolved in the emerging field of hadron therapy.
Compact Torus Acceleration and Injection Experiment
NASA Astrophysics Data System (ADS)
Fukumoto, Naoyuki; Fujiwara, Makoto; Nagata, Masayoshi; Uyama, Tadao; Oda, Yasushi; Azuma, Kingo
1996-11-01
The spheromak-type compact torus (CT) acceleration and injection experiment has been carried out using the Himeji Institute of Technology Compact Torus Injector (HIT-CTI). We explore the possibility of refueling, density control, current drive, and edge electric field control of tokamak plasma by means of CT injection. In last September the new HIT-CTI was built up to achieve higher speed (Vct>200 km/s) and higher density CT plasmoid by improving the capacitor bank system and eliminating the impurity and neutral particles. At initial formation discharge tests the gun for formation and compression successfully produced a CT plasmoid and injected it between electrodes for acceleration. (Initial velocity Vct.ini. 32 km/s, Bct 1 kG, Rct=5.5 cm). The formation capacitor bank will be upgraded to two 36 mF capacitors operating at 20 kV (14.4 kJ). The acceleration capacitor bank will be also upgraded to two 36 mF capacitors operating at 20 kV (14.4 kJ). The HIT-CTI will be optimized to obtain suitable CT parameters after acceleration (Bct>5 kG, Lct 20 cm, Vct>200 km/s). In the respect of CT parameter measurement magnetic probes and a He-Ne laser interferometer will be employed in order to measure the CT magnetic field, velocity, density, and length. CT acceleration experimental data on the HIT-CTI and the plan of CT injection experiment on the JFT-2M tokamak (JAERI) will be presented at the meeting.
Poznanovic, Sheri A; Cass, Stephen P; Kavanagh, Brian D
2006-03-01
Glomus jugulare tumors (GJT) have traditionally been treated by surgery or fractionated external beam radiation therapy (XRT). This study evaluates acute toxicity and short-term efficacy of single-fraction stereotactic radiosurgery (SRS) for the treatment of GJT. Eight patients (age range 28-74) with GJT underwent SRS (Brainlab linear accelerator) as primary treatment. A nominal dose of 15-16 Gy was prescribed. After undergoing SRS, 7 of 8 patients (87.5%) reported complete resolution of presenting symptoms. Follow-up MRIs showed tumor stabilization in 100% of patients. Transient vertigo occurred in one patient. One patient suffered acute GI upset and transient lower cranial neuropathy. Stereotactic radiosurgery is an effective alternative for patients with GJT in achieving tumor control and resolution of symptoms. C-4.
Melanotic neuroectodermal tumor of the neurocranium in infancy.
Walsh, J W; Strand, R D
1982-01-01
Melanotic neuroectodermal tumors of the neurocranium are a rare but life-threatening disorder of infancy. 11 previously reported cases are reviewed in terms of clinical presentation, radiological diagnosis, and management. A twelfth case, a 4-month-old infant who developed three discrete sites of tumor unilaterally in the neurocranium is presented. Several hypotheses for the mechanism of formation of these tumors are reviewed. The authors propose that the mechanism of formation involves a dysontogenesis of neural crest tissue and that these tumors form, at least in part, from fragments of melanin-containing arachnoid villi which are displaced during embryonic development.
NASA Astrophysics Data System (ADS)
Hirata, Eri; Ménard-Moyon, Cécilia; Venturelli, Enrica; Takita, Hiroko; Watari, Fumio; Bianco, Alberto; Yokoyama, Atsuro
2013-11-01
Multi-walled carbon nanotubes (MWCNTs) were functionalized with fibroblast growth factor (FGF) and the advantages of their use as scaffolds for bone augmentation were evaluated in vitro and in vivo. The activity of FGF was assessed by measuring the effect on the proliferation of rat bone marrow stromal cells (RBMSCs). The presence of FGF enhanced the proliferation of RBMSCs and the FGF covalently conjugated to the nanotubes (FGF-CNT) showed the same effect as FGF alone. In addition, FGF-CNT coated sponges were implanted between the parietal bone and the periosteum of rats and the formation of new bone was investigated. At day 14 after implantation, a larger amount of newly formed bone was clearly observed in most pores of FGF-CNT coated sponges. These findings indicated that MWCNTs accelerated new bone formation in response to FGF, as well as the integration of particles into new bone during its formation. Scaffolds coated with FGF-CNT could be considered as promising novel substituting materials for bone regeneration in future tissue engineering applications.
Yadav, Suresh Singh; Prasad, Chandra Bhushan; Prasad, Shyam Babu; Pandey, Lakshmi Kant; Singh, Sunita; Pradhan, Satyajit; Narayan, Gopeshwar
2015-07-15
The fundamental events for cancer progression and metastases include loss of cell adhesion, cell proliferation, anchorage-independent cell growth (evading anoikis), cell migration and cell invasion. All these events leading to cancer progression happen in a favorable nurturing tumor microenvironment. This study was designed to explore the anti-tumor activity of staurosporine (a nonspecific protein kinase inhibitor) in the tumor microenvironment of cervical cancer. The anti-tumor activity of staurosporine was investigated by cell adhesion assay, colony formation assay, apoptosis assay and quantitative real-time polymerase chain reaction (PCR) in cervical cancer cell lines. The cell adhesion assay showed that staurosporine induces adhesion of cervical cancer cells to the extracellular matrix (ECM) protein fibronectin. The soft agar colony formation assay showed that staurosporine inhibits both the number and size of colony formation in a dose dependent manner and also induces adherent tendency in the cancer cells. Staurosporine also induces prominent apoptosis in single cell suspensions compared to adherent cells. Stroma cell induced transcription of matrix metalloprotease 1 (MMP1) and matrix metalloprotease 2 (MMP2) in cervical cancer cells was inhibited by staurosporine. Our results indicate that staurosporine induces anti-tumor response in the cervical tumor microenvironment by inhibiting the fundamental events for cancer progression and metastases. The present study represents an attractive area for further research and opens up new avenues towards the understanding of cervical cancer therapeutics. Copyright © 2015 Elsevier Inc. All rights reserved.
The NUP98 Gene as a Potential Modifier of NF2 Associated Tumors
2017-06-01
limited to observation, surgical removal, and stereotactic radiation [ 1 ]. However, surgery may not be possible if the tumor is inaccessible or when...there are too many tumors. Radiation treatment may cause malignant transformation and/or growth acceleration of benign tumor cells. In addition...genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas
Han, Bumsoo; Qu, Chunjing; Park, Kinam; Konieczny, Stephen F.; Korc, Murray
2016-01-01
Targeted delivery aims to selectively distribute drugs to targeted tumor tissue but not to healthy tissue. This can address many of clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicines. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery was discussed, and the current status and challenges for developing in vitro transport model systems was reviewed. PMID:26688098
Ito, A; Kawakami, H; Ishikawa, N; Ito, M; Oikawa, T; Sato, A; Umita, T
2017-05-01
Accelerated release of potassium (K), magnesium (Mg) and phosphorus (P) from surplus activated sludge (SAS) was investigated to develop a new system for the recovery of the elements. Anaerobic cultivation of SAS during 24 h released 78% of K and about 50% of Mg and P from SAS more effectively compared to aerobic cultivation (K: 40%, Mg: 15%, P: 15%). Furthermore, the addition of sodium acetate as an organic carbon source remarkably accelerated the release of K, Mg and P from SAS under anaerobic condition. However, no increase in the maximum release efficiencies was observed. The elements released from SAS could be transferred to separate liquid with the existing mechanical thickener and be recovered as MgKPO 4 by some additional process. Furthermore, the removal of the elements from SAS would inhibit the formation of struvite causing the blockage of sludge transport pipe after anaerobic digestion process of thickened sludge.
Kwon, Yi-Hong; Jung, Seok-Yun; Kim, Jae-Won; Lee, Sang-Hun; Lee, Jun-Hee; Lee, Boo-Yong; Kwon, Sang-Mo
2012-01-01
Background There is increasing evidence that phloroglucinol, a compound from Ecklonia cava, induces the apoptosis of cancer cells, eventually suppressing tumor angiogenesis. Methodology/Principal Findings This is the first report on phloroglucinol's ability to potentially inhibit the functional bioactivities of endothelial progenitor cells (EPCs) and thereby attenuate tumor growth and angiogenesis in the Lewis lung carcinoma (LLC)-tumor-bearing mouse model. Although Phloroglucinol did not affect their cell toxicity, it specifically inhibited vascular endothelial growth factor (VEGF) dependent migration and capillary-like tube formation of EPCs. Our matrigel plug assay clearly indicated that orally injected phloroglucinol effectively disrupts VEGF-induced neovessel formation. Moreover, we demonstrated that when phloroglucinol is orally administered, it significantly inhibits tumor growth and angiogenesis as well as CD45−/CD34+ progenitor mobilization into peripheral blood in vivo in the LLC-tumor-bearing mouse model. Conclusions/Significance These results suggest a novel role for phloroglucinol: Phloroglucinol might be a modulator of circulating EPC bioactivities, eventually suppressing tumorigenesis. Therefore, phloroglucinol might be a candidate compound for biosafe drugs that target tumor angiogenesis. PMID:22496756
CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.
Chen, X W; Yu, T J; Zhang, J; Li, Y; Chen, H L; Yang, G F; Yu, W; Liu, Y Z; Liu, X X; Duan, C F; Tang, H L; Qiu, M; Wang, C L; Zheng, H; Yue, J; Guo, A M; Yang, J
2017-08-31
Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A + TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1 + ) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10 high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10 high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1 + myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1 + myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1 + myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre
The secret origins and surprising fates of pancreas tumors
Bailey, Jennifer M.; DelGiorno, Kathleen E.; Crawford, Howard C.
2014-01-01
Pancreatic ductal adenocarcinoma (PDA) is especially deadly due to its recalcitrance to current therapies. One of the unique qualities of PDA that may contribute to this resistance is a striking plasticity of differentiation states starting at tumor formation and continuing throughout tumor progression, including metastasis. Here, we explore the earliest steps of tumor formation and neoplastic progression and how this results in a fascinating cellular heterogeneity that is probably critical for tumor survival and progression. We hypothesize that reinforcing differentiation pathways run awry or targeting morphologically and molecularly distinct tumor stem-like cells may hold promise for future treatments of this deadly disease. PMID:24583923
Accelerated and enhanced bone formation on novel simvastatin-loaded porous titanium oxide surfaces.
Nyan, Myat; Hao, Jia; Miyahara, Takayuki; Noritake, Kanako; Rodriguez, Reena; Kasugai, Shohei
2014-10-01
With increasing application of dental implants in poor-quality bones, the need for implant surfaces ensuring accelerated osseointegration and enhanced peri-implant bone regeneration is increased. A study was performed to evaluate the osseointegration and bone formation on novel simvastatin-loaded porous titanium oxide surface. Titanium screws were treated by micro-arc oxidation to form porous oxide surface and 25 or 50 μg of simvastatin was loaded. The nontreated control, micro-arc oxidized, and simvastatin-loaded titanium screws were surgically implanted into the proximal tibia of 16-week-old male Wistar rats (n = 36). Peri-implant bone volume, bone-implant contact, and mineral apposition rates were measured at 2 and 4 weeks. Data were analyzed by one-way analysis of variance followed by Tukey's post hoc test. New bone was formed directly on the implant surface in the bone marrow cavity in simvastatin-loaded groups since 2 weeks. Bone-implant contact values were significantly higher in simvastatin-loaded groups than control and micro-arc oxidized groups at both time points (p < .05). Peri-implant bone volume and mineral apposition rate of simvastatin-loaded groups were significantly higher than control and micro-arc oxidized groups at 2 weeks (p < .05). These data suggested that simvastatin-loaded porous titanium oxide surface provides faster osseointegration and peri-implant bone formation and it would be potentially applicable in poor-quality bones. © 2013 Wiley Periodicals, Inc.
Arabadzhieva, Elena; Yonkov, Atanas; Bonev, Sasho; Bulanov, Dimitar; Taneva, Ivanka; Vlahova, Alexandrina; Dikov, Tihomir; Dimitrova, Violeta
2016-11-15
Although gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, they comprise less than 1% of all gastrointestinal tumors. Neuroendocrine tumors (NET) of the gastro-enteropancreatic system are also rare, representing about 2% of all gastrointestinal neoplasms. Pancreatic localization of NET is extremely uncommon-these tumors are only 1-5% of all pancreatic cancers. We describe an unusual case with triple tumor localization-a gastric tumor, a formation in the pancreas, which involves the retroperitoneal space, and a uterine leiomyoma. The exact diagnosis was confirmed with immunohistochemical study after surgical treatment of the patient. Distal pancreatic resection, splenectomy, partial gastrectomy, omentectomy, and hysterectomy were performed. The histological examination proved an epithelioid type of gastric GIST. Immunostaining showed focal positive expression of c-kit and no mitotic figures per 50 HPF. Histology of the pancreatic and retroperitoneal formation proved a well-differentiated NET with origin from the islets of Langerhans. The immunohistochemical study demonstrated co-expression of chromogranin A and synaptophysin. This is the fourth case published so far of a patient with synchronous pancreatic NET and gastric GIST. The main objective of the study is to present a unique case because we have not found any reports for coexistence of the described three types of neoplasm, as in our patient, and we hope that it will be valuable in the future investigations about the genesis, diagnosis, and treatment of these types of tumors.
Lou, Yuanmei; McDonald, Paul C; Oloumi, Arusha; Chia, Stephen; Ostlund, Christina; Ahmadi, Ardalan; Kyle, Alastair; Auf dem Keller, Ulrich; Leung, Samuel; Huntsman, David; Clarke, Blaise; Sutherland, Brent W; Waterhouse, Dawn; Bally, Marcel; Roskelley, Calvin; Overall, Christopher M; Minchinton, Andrew; Pacchiano, Fabio; Carta, Fabrizio; Scozzafava, Andrea; Touisni, Nadia; Winum, Jean-Yves; Supuran, Claudiu T; Dedhar, Shoukat
2011-05-01
Carbonic anhydrase IX (CAIX) is a hypoxia and HIF-1-inducible protein that regulates intra- and extracellular pH under hypoxic conditions and promotes tumor cell survival and invasion in hypoxic microenvironments. Interrogation of 3,630 human breast cancers provided definitive evidence of CAIX as an independent poor prognostic biomarker for distant metastases and survival. shRNA-mediated depletion of CAIX expression in 4T1 mouse metastatic breast cancer cells capable of inducing CAIX in hypoxia resulted in regression of orthotopic mammary tumors and inhibition of spontaneous lung metastasis formation. Stable depletion of CAIX in MDA-MB-231 human breast cancer xenografts also resulted in attenuation of primary tumor growth. CAIX depletion in the 4T1 cells led to caspase-independent cell death and reversal of extracellular acidosis under hypoxic conditions in vitro. Treatment of mice harboring CAIX-positive 4T1 mammary tumors with novel CAIX-specific small molecule inhibitors that mimicked the effects of CAIX depletion in vitro resulted in significant inhibition of tumor growth and metastasis formation in both spontaneous and experimental models of metastasis, without inhibitory effects on CAIX-negative tumors. Similar inhibitory effects on primary tumor growth were observed in mice harboring orthotopic tumors comprised of lung metatstatic MDA-MB-231 LM2-4(Luc+) cells. Our findings show that CAIX is vital for growth and metastasis of hypoxic breast tumors and is a specific, targetable biomarker for breast cancer metastasis.
Li, Xiaofeng; Yu, Xiaozhou; Dai, Dong; Song, Xiuyu; Xu, Wengui
2016-01-01
Extracellular matrix metalloproteinase inducer, also knowns as cluster of differentiation 147 (CD147) or basigin, is a widely distributed cell surface glycoprotein that is involved in numerous physiological and pathological functions, especially in tumor invasion and metastasis. Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate across the plasma membrane to preserve the intracellular pH and maintain cell homeostasis. As a chaperone to some MCT isoforms, CD147 overexpression significantly contributes to the metabolic transformation of tumor. This overexpression is characterized by accelerated aerobic glycolysis and lactate efflux, and it eventually provides the tumor cells with a metabolic advantage and an invasive phenotype in the acidic tumor microenvironment. This review highlights the roles of CD147 and MCTs in tumor cell metabolism and the associated molecular mechanisms. The regulation of CD147 and MCTs may prove to be with a therapeutic potential for tumors through the metabolic modification of the tumor microenvironment. PMID:27009812
Moses, Katrin; Klein, Johanna C; Männ, Linda; Klingberg, Anika; Gunzer, Matthias; Brandau, Sven
2016-06-01
Expansion of Ly-6G(+) myeloid cells has been reported in most murine cancer models. However, divergent findings exist regarding the role and effect of these cells on host immunity and tumor progression. Antibody-mediated depletion of Ly-6G(+) cells is a common technique to assess the in vivo relevance of these cells. Interpretation of results crucially depends on the efficacy and course of depletion. We established murine head and neck cancer models and analyzed the efficacy of antibody-mediated depletion by flow cytometry, conventional histology, and intravital imaging with a novel Ly-6G-transgenic mouse model. The first phase of depletion was characterized by effective elimination of Ly-6G(+) cells from the peripheral blood. Nevertheless, viable, resistant cells were found to reside in the tumor tissue and spleen. This peripheral depletion phase was associated with high systemic levels of granulocyte colony-stimulating factor and KC and enhanced splenic production of Ly-6G(+) cells. Even under sustained treatment with either αGr-1 or αLy-6G antibodies, peripheral blood depletion ended after approximately 1 wk and was followed by reappearance of immature Ly-6G(+) cells with an immunoregulatory phenotype. Reappearance of these depletion-resistant immature cells was enhanced in tumor-bearing, compared with naïve, control mice. Collectively, our data suggest that depletion of Ly-6G(+) myeloid cells in tumor-bearing mice is counteracted by the persistence of intratumoral cells, enhanced extramedullary granulopoiesis, and accelerated reappearance of immature cells. Hence, extensive monitoring of in vivo kinetics and tissue distribution of Ly-6G(+) cells is required in depletion studies. © Society for Leukocyte Biology.
[Desmoid tumors in three patients].
Mohos, E; Kovács, T; Brittig, F; Nagy, A
2001-12-01
Desmoids are rare tumors of the connective tissue. It develops about 1:1000 times more in patients with familial adenomatous polyposis (FAP, Gardner syndrome) compared to normal population. It has been shown in molecular genetic examinations, that different mutations of the APC gene are responsible for desmoid tumors in FAP. It means, that this disease is one of the extraintestinal manifestations of Gardner syndrome. This tumor has high recurrence rate and is growing rapidly, and as a result it is the second most common cause of death in FAP patients. That is why genetic examination for FAP patients is advised to decide if the patient has higher risk for desmoid formation. If the result of the genetic test is positive, it is advisable to try to slow the progression of polyposis with medical treatment, and so to delay the date of the colectomy because the surgical intervention--and connective tissue damage--can induce desmoid formation in these patients. At the same time it is reasonable to examine and regularly control patients with sporadic desmoid tumors searching for other manifestations of Gardner syndrome (colon, stomach and duodenum polyposis, tumor of papilla Vateri, retinopathy, etc.). Palliative surgery is not indicated in patients with inoperable intraabdominal desmoid tumors, because partial resections (R1, R2, debulking) result in further tumor progression. In these patients medical treatment (sulindac, tamoxifen), chemotherapy (doxorubicin, dacarbazin) and radiotherapy or combination of them can result tumor remission. We describe our three patients (an abdominal wall desmoid four years following Cesarean section; a desmoid tumor in the retroperitoneum and in the pelvis diagnosed three years after total colectomy; and a retroperitoneal and abdominal wall desmoid one year after total colectomy) and etiology, diagnosis and therapy of desmoid tumors are discussed.
NASA Astrophysics Data System (ADS)
Salazar, F. J. T.; Masdemont, J. J.; Gómez, G.; Macau, E. E.; Winter, O. C.
2014-11-01
Assume a constellation of satellites is flying near a given nominal trajectory around L4 or L5 in the Earth-Moon system in such a way that there is some freedom in the selection of the geometry of the constellation. We are interested in avoiding large variations of the mutual distances between spacecraft. In this case, the existence of regions of zero and minimum relative radial acceleration with respect to the nominal trajectory will prevent from the expansion or contraction of the constellation. In the other case, the existence of regions of maximum relative radial acceleration with respect to the nominal trajectory will produce a larger expansion and contraction of the constellation. The goal of this paper is to study these regions in the scenario of the Circular Restricted Three Body Problem by means of a linearization of the equations of motion relative to the periodic orbits around L4 or L5. This study corresponds to a preliminar planar formation flight dynamics about triangular libration points in the Earth-Moon system. Additionally, the cost estimate to maintain the constellation in the regions of zero and minimum relative radial acceleration or keeping a rigid configuration is computed with the use of the residual acceleration concept. At the end, the results are compared with the dynamical behavior of the deviation of the constellation from a periodic orbit.
Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis.
Lee, Jaejoon; Luria, Ayala; Rhodes, Christopher; Raghu, Harini; Lingampalli, Nithya; Sharpe, Orr; Rada, Balazs; Sohn, Dong Hyun; Robinson, William H; Sokolove, Jeremy
2017-04-01
The aim was to investigate the effects of nicotine on neutrophil extracellular traps (NETs) formation in current and non-smokers and on a murine model of RA. We compared spontaneous and phorbol 12-myristate 13-acetate-induced NETosis between current and non-smokers by DNA release binding. Nicotine-induced NETosis from non-smokers was assessed by DNA release binding, NET-specific (myeloperoxidase (MPO)-DNA complex) ELISA and real-time fluorescence microscopy. We also used immunofluorescent staining to detect nicotinic acetylcholine receptors (nAChRs) on neutrophils and performed a functional analysis to assess the role of nAChRs in nicotine-induced NETosis. Finally, we investigated the effects of systemic nicotine exposure on arthritis severity and NETosis in the CIA mouse model. Neutrophils derived from current smokers displayed elevated levels of spontaneous and phorbol 12-myristate 13-acetate-induced NETosis. Nicotine induced dose-dependent NETosis in ex vivo neutrophils from healthy non-smokers, and co-incubation with ACPA-immune complexes or TNF-α facilitated a synergistic effect on NETosis. Real-time fluorescence microscopy revealed robust formation of NET-like structures in nicotine-exposed neutrophils. Immunofluorescent staining demonstrated the presence of the α7 subunit of the nAChR on neutrophils. Stimulation of neutrophils with an α7-specific nAChR agonist induced NETosis, whereas pretreatment with an nAChR antagonist attenuated nicotine-induced NETosis. Nicotine administration to mice with CIA exacerbated inflammatory arthritis, with higher plasma levels of NET-associated MPO-DNA complex. We demonstrate that nicotine is a potent inducer of NETosis, which may play an important role in accelerating arthritis in the CIA model. This study generates awareness of and the mechanisms by which nicotine-containing products, including e-cigarettes, may have deleterious effects on patients with RA. Published by Oxford University Press 2016. This work is written
De Vlieghere, Elly; Gremonprez, Félix; Verset, Laurine; Mariën, Lore; Jones, Christopher J; De Craene, Bram; Berx, Geert; Descamps, Benedicte; Vanhove, Christian; Remon, Jean-Paul; Ceelen, Wim; Demetter, Pieter; Bracke, Marc; De Geest, Bruno G; De Wever, Olivier
2015-06-01
Peritoneal metastasis is life threatening and is the result of an extensive communication between disseminated cancer cells, mesothelial cells and cancer-associated fibroblasts (CAF). CAFs secrete extracellular matrix (ECM) proteins creating a receptive environment for peritoneal implantation. Considering cancer as an ecosystem may provide opportunities to exploit CAFs to create biomimetic traps to deceive and redirect cancer cells. We have designed microparticles (MP) containing a CAF-derived ECM-surface that is intended to compete with natural niches. CAFs were encapsulated in alginate/gelatine beads (500-750 μm in diameter) functionalised with a polyelectrolyte coating (MP[CAF]). The encapsulated CAFs remain viable and metabolically active (≥35 days), when permanently encapsulated. CAF-derived ECM proteins are retained by the non-biodegradable coating. Adhesion experiments mimicking the environment of the peritoneal cavity show the selective capture of floating cancer cells from different tumor origins by MP[CAF] compared to control MP. MP[CAF] are distributed throughout the abdominal cavity without attachment to intestinal organs and without signs of inflammatory reaction. Intraperitoneal delivery of MP[CAF] and sequential removal redirects cancer cell adhesion from the surgical wound to the MP[CAF], delays peritoneal metastasis formation and prolongs animal survival. Our experiments suggest the use of a biomimetic trap based on tumor-environment interactions to delay peritoneal metastasis. Copyright © 2015 Elsevier Ltd. All rights reserved.
NASA Astrophysics Data System (ADS)
Joshi, C.
2012-12-01
The first Advanced Acceleration of Particles-AAC-Workshop (actually named Laser Acceleration of Particles Workshop) was held at Los Alamos in January 1982. The workshop lasted a week and divided all the acceleration techniques into four categories: near field, far field, media, and vacuum. Basic theorems of particle acceleration were postulated (later proven) and specific experiments based on the four categories were formulated. This landmark workshop led to the formation of the advanced accelerator R&D program in the HEP office of the DOE that supports advanced accelerator research to this day. Two major new user facilities at Argonne and Brookhaven and several more directed experimental efforts were built to explore the advanced particle acceleration schemes. It is not an exaggeration to say that the intellectual breadth and excitement provided by the many groups who entered this new field provided the needed vitality to then recently formed APS Division of Beams and the new online journal Physical Review Special Topics-Accelerators and Beams. On this 30th anniversary of the AAC Workshops, it is worthwhile to look back at the legacy of the first Workshop at Los Alamos and the fine groundwork it laid for the field of advanced accelerator concepts that continues to flourish to this day.
A novel thermal accelerant for augmentation of microwave energy during image-guided tumor ablation
NASA Astrophysics Data System (ADS)
Park, William K. C.; Maxwell, Aaron W. P.; Frank, Victoria E.; Primmer, Michael P.; Paul, Jarod B.; Susai, Cynthia; Collins, Scott A.; Borjeson, Tiffany M.; Baird, Greyson L.; Lombardo, Kara A.; Dupuy, Damian E.
2017-02-01
The greatest challenge in image-guided thermal ablation (IGTA) of liver tumors is a relatively high recurrence rate (ca. 30%) due to incomplete ablation. To meet this challenge, we have developed a novel Thermal Accelerator (TA) to demonstrate its capability to, 1) augment microwave (MW) energy from a distance unattainable by antenna alone; 2) turn into a gel at body temperature; 3) act as a CT or US contrast. We have examined the TA efficiency using in vitro and ex vivo models: microwave power, TA dose, frequencies and TA-to-tip distance were varied, and temperature readings compared with and without TA. Using the in vitro model, it was established that both the rate and magnitude of increase in ablation zone temperature were significantly greater with TA under all tested conditions (p<0.0001). On ultrasound imaging, the TA was echogenic as gel. On CT, TA density was proportional to dose, with average values ranging from 329 HU to 3071 HU at 10 mg/mL and 1,000mg/mL, respectively. TA can be accurately deposited to a target area using CT or US as image-guidance and augment MW energy effectively so that ablation time is significantly reduced, which will contribute to complete ablation. The preliminary results obtained from in vivo experiments using swine as an animal model are consistent with the observations made in in vitro and en vivo studies.
The Tumor Suppressor Actions of the Vitamin D Receptor in Skin
2014-10-01
induced tumor formation. In previous studies we determined that the hedgehog (HH) and wnt/β-catenin pathways were activated in the skin of VDR null...SUBJECT TERMS epidermal tumors, keratinocytes, vitamin D receptor, sonic hedgehog , β-catenin, UVB 16. SECURITY CLASSIFICATION OF: 17. LIMITATION...epidermal tumor formation by blocking the β-catenin and hedgehog pathways, key pathways in keratinocyte proliferation that if left unchecked lead to
Increase in the Acceleration Efficiency of Solids in a Hybrid Coaxial Magnetoplasma Accelerator
NASA Astrophysics Data System (ADS)
Gerasimov, D. Yu.; Sivkov, A. A.
2018-01-01
It is shown that in a hybrid coaxial magnetoplasma accelerator with a channel length of 350 mm and a diameter of 23 mm, the acceleration velocity and the energy conversion efficiency increase as the length of the plasma structure formation channel filled with a gas-generating material decreases from 17 to 9 mm. It is found that it is reasonable to use paraffin as the gas-generating material as it has a less significant deionizing effect on the high-current arc discharge and hence causes a less significant decrease in the discharge current intensity and an increase in conductive and inductive electrodynamic forces.
Heat-directed tumor cell fusion.
Brade, Anthony M; Szmitko, Paul; Ngo, Duc; Liu, Fei-Fei; Klamut, Henry J
2003-03-20
In previous studies we demonstrated that a modified human HSP70b promoter (HSE.70b) directs high levels of gene expression to tumor cells after mild hyperthermia treatment in the range of 41.5-44 degrees C. This transcriptional targeting system exhibits low basal activity at 37 degrees C, is highly induced (950-fold) after mild heat treatment (43 degrees C/30 min), and returns to basal activity levels within 12-24 hours of activation. Here we describe heat-directed targeting of an activated form of the Gibbon ape leukemia virus env protein (GALV FMG) to tumor cells. GALV FMG mediates cell-cell fusion, and when expressed in tumor cells can produce bystander effects of up to 1:200. Transient transfection of a HSE70b.GALV FMG minigene caused extensive syncytia formation in HeLa and HT-1080 cells following mild heat treatment (44 degrees C/30 min). Stable transfection into HT-1080 cells produced a cell line (HG5) that exhibits massive syncytia formation and a 60% reduction in viability relative to a vector-only control (CI1) following heat treatment in vitro. Mild hyperthermia also resulted in syncytia formation, necrosis, and complete macroscopic regression of HG5 xenograft tumors grown in the footpads of mice with severe combined immunodeficiency disorders (SCID). Median survival increased from 12.5 (in heated CI1 controls) to 52 days after a single heat treatment. Heat-directed tumor cell fusion may prove to be a highly beneficial adjunct to existing cancer treatment strategies that take advantage of the synergistic interaction between mild hyperthermia and radiation or chemotherapeutic drugs.
Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat; Sharkar, Mohammad Tofael Kabir; Noritake, Hidenao; Kimura, Wataru; Wu, Yi-Xin; Kobayashi, Yoshimasa; Uezato, Tadayoshi; Miura, Naoyuki
2012-01-06
The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with ∼50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age. Copyright © 2011 Elsevier Inc. All rights reserved.
Masunaga, Shin-Ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji
2015-08-01
The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon-ion beam irradiation. With RDRI
Masunaga, Shin-ichiro; Uzawa, Akiko; Hirayama, Ryoichi; Matsumoto, Yoshitaka; Sakurai, Yoshinori; Tanaka, Hiroki; Tano, Keizo; Sanada, Yu; Suzuki, Minoru; Maruhashi, Akira; Ono, Koji
2015-01-01
Background The aim of the study was to clarify the effect of p53 status of tumor cells on radiosensitivity of solid tumors following accelerated carbon-ion beam irradiation compared with γ-rays or reactor neutron beams, referring to the response of intratumor quiescent (Q) cells. Methods Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector (SAS/neo) were injected subcutaneously into hind legs of nude mice. Tumor-bearing mice received 5-bromo-2’-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received γ-rays or accelerated carbon-ion beams at a high or reduced dose-rate. Other tumor-bearing mice received reactor thermal or epithermal neutrons at a reduced dose-rate. Immediately or 9 hours after the high dose-rate irradiation (HDRI), or immediately after the reduced dose-rate irradiation (RDRI), the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (Q cells) was determined using immunofluorescence staining for BrdU. Results The difference in radiosensitivity between the total (P + Q) and Q cells after γ-ray irradiation was markedly reduced with reactor neutron beams or carbon-ion beams, especially with a higher linear energy transfer (LET) value. Following γ-ray irradiation, SAS/neo tumor cells, especially intratumor Q cells, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q cells within SAS/mp53 tumors that showed little repair capacity. In both total and Q cells within both SAS/neo and SAS/mp53 tumors, carbon-ion beam irradiation, especially with a higher LET, showed little recovery capacity through leaving an interval between HDRI and the assay or decreasing the dose-rate. The recovery from radiation-induced damage after γ-ray irradiation was a p53-dependent event, but little recovery was found after carbon
Modeling of thermalization phenomena in coaxial plasma accelerators
NASA Astrophysics Data System (ADS)
Subramaniam, Vivek; Panneerchelvam, Premkumar; Raja, Laxminarayan L.
2018-05-01
Coaxial plasma accelerators are electromagnetic acceleration devices that employ a self-induced Lorentz force to produce collimated plasma jets with velocities ~50 km s‑1. The accelerator operation is characterized by the formation of an ionization/thermalization zone near gas inlet of the device that continually processes the incoming neutral gas into a highly ionized thermal plasma. In this paper, we present a 1D non-equilibrium plasma model to resolve the plasma formation and the electron-heavy species thermalization phenomena that take place in the thermalization zone. The non-equilibrium model is based on a self-consistent multi-species continuum description of the plasma with finite-rate chemistry. The thermalization zone is modelled by tracking a 1D gas-bit as it convects down the device with an initial gas pressure of 1 atm. The thermalization process occurs in two stages. The first is a plasma production stage, associated with a rapid increase in the charged species number densities facilitated by cathode surface electron emission and volumetric production processes. The production stage results in the formation of a two-temperature plasma with electron energies of ~2.5 eV in a low temperature background gas of ~300 K. The second, a temperature equilibration stage, is characterized by the energy transfer between the electrons and heavy species. The characteristic length scale for thermalization is found to be comparable to axial length of the accelerator thus putting into question the equilibrium magnetohydrodynamics assumption used in modeling coaxial accelerators.
Genetically Engineered Mouse Models of Pituitary Tumors
Cano, David A.; Soto-Moreno, Alfonso; Leal-Cerro, Alfonso
2014-01-01
Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary-tumor formation remain poorly understood, particularly in sporadic adenomas, thus, making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, we review various GEMMs of pituitary tumors, highlighting their contributions and limitations, and discuss opportunities for research in the field. PMID:25136513
Anti-tumor effects of an engineered 'killer' transfer RNA
DOE Office of Scientific and Technical Information (OSTI.GOV)
Zhou, Dong-hui; Lee, Jiyoung; Frankenberger, Casey
2012-10-12
Highlights: Black-Right-Pointing-Pointer tRNA with anti-cancer effects. Black-Right-Pointing-Pointer tRNA induced protein misfolding. Black-Right-Pointing-Pointer tRNA as anti-tumor agent. -- Abstract: A hallmark of cancer cells is their ability to continuously divide; and rapid proliferation requires increased protein translation. Elevating levels of misfolded proteins can elicit growth arrest due to ER stress and decreased global translation. Failure to correct prolonged ER stress eventually results in cell death via apoptosis. tRNA{sup Ser}(AAU) is an engineered human tRNA{sup Ser} with an anticodon coding for isoleucine. Here we test the possibility that tRNA{sup Ser}(AAU) can be an effective killing agent of breast cancer cells and canmore » effectively inhibit tumor-formation in mice. We found that tRNA{sup Ser}(AAU) exert strong effects on breast cancer translation activity, cell viability, and tumor formation. Translation is strongly inhibited by tRNA{sup Ser}(AAU) in both tumorigenic and non-tumorigenic cells. tRNA{sup Ser}(AAU) significantly decreased the number of viable cells over time. A short time treatment with tRNA{sup Ser}(AAU) was sufficient to eliminate breast tumor formation in a xenograft mouse model. Our results indicate that tRNA{sup Ser}(AAU) can inhibit breast cancer metabolism, growth and tumor formation. This RNA has strong anti-cancer effects and presents an opportunity for its development into an anti-tumor agent. Because tRNA{sup Ser}(AAU) corrupts the protein synthesis mechanism that is an integral component of the cell, it would be extremely difficult for tumor cells to evolve and develop resistance against this anti-tumor agent.« less
High-fat Diet-induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling.
Hayashi, Takuji; Fujita, Kazutoshi; Nojima, Satoshi; Hayashi, Yujiro; Nakano, Kosuke; Ishizuya, Yu; Wang, Cong; Yamamoto, Yoshiyuki; Kinouchi, Toshiro; Matsuzaki, Kyosuke; Jingushi, Kentaro; Kato, Taigo; Kawashima, Atsunari; Nagahara, Akira; Ujike, Takeshi; Uemura, Motohide; Rodriguez Pena, Maria Del Carmen; Gordetsky, Jennifer B; Morii, Eiichi; Tsujikawa, Kazutake; Netto, George J; Nonomura, Norio
2018-05-18
High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre+; Pten(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. Immunohistochemical analyses using prostatectomy specimens of obese patients were performed. HFD accelerated tumor growth, and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated signal transducer and activator of transcription 3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of non-obese prostate cancer patients. HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese prostate cancer patients. IL6-mediated inflammation could be a therapeutic target for prostate cancer. Copyright ©2018, American Association for Cancer Research.
Xiao, Huaixian; Liu, Na; Tian, Ke; Liu, Shixiang; Ge, Fei
2018-09-01
Nanoparticles have been reported to induce toxicity to aquatic organisms, however, their potential impacts on phosphorus removal from wastewater by algae are unclear. In this study, the effects of nanoparticle ZnO (nano-ZnO) on phosphate (PO 4 3- ) removal by a green alga Chlorella vulgaris were investigated. We found that PO 4 3- removal efficiency was accelerated with high concentrations of nano-ZnO (0.04-0.15mM) but reduced with low concentrations of nano-ZnO (0.005-0.04mM) compared to the control (without nano-ZnO), suggesting that PO 4 3- removal efficiency by C. vulgaris was related to nano-ZnO concentrations. Moreover, we observed changes of nano-ZnO morphology and detected element P on the surface of nano-ZnO by using transmission electronic microscopy (TEM) combined with energy dispersive X-ray spectroscopy (EDX), indicating that PO 4 3- was interacted with nano-ZnO or the dissolved Zn 2+ from nano-ZnO. Furthermore, we confirmed this interaction induced the formation of Zn 3 (PO 4 ) 2 crystallites sedimentation by employing X-ray diffraction analysis (XRD) and X-ray photoelectron spectroscopy (XPS), which finally accelerates the removal of PO 4 3- . Copyright © 2018 Elsevier B.V. All rights reserved.
Nguyen, Duong H; Chen, Nanhai G; Zhang, Qian; Le, Ha T; Aguilar, Richard J; Yu, Yong A; Cappello, Joseph; Szalay, Aladar A
2013-01-01
Recombinant human erythropoietin (rhEPO), a glycoprotein hormone regulating red blood cell (RBC) formation, is used for the treatment of cancer-related anemia. The effect of rhEPO on tumor growth, however, remains controversial. Here, we report the construction and characterization of the recombinant vaccinia virus (VACV) GLV-1h210, expressing hEPO. GLV-1h210 was shown to replicate in and kill A549 lung cancer cells in culture efficiently. In mice bearing A549 lung cancer xenografts, treatment with a single intravenous dose of GLV-1h210 resulted in tumor-specific production and secretion of functional hEPO, which exerted an effect on RBC progenitors and precursors in the mouse bone marrow, leading to a significant increase in the number of RBCs and in the level of hemoglobin. Furthermore, virally expressed hEPO, but not exogenously added rhEPO, enhanced virus-mediated green fluorescent protein (GFP) expression in tumors and subsequently accelerated tumor regression when compared with the treatment with the parental virus GLV-1h68 or GLV-1h209 that expressed a nonfunctional hEPO protein. Moreover, intratumorally expressed hEPO caused enlarged tumoral microvessels, likely facilitating virus spreading. Taken together, VACV-mediated intratumorally expressed hEPO not only enhanced oncolytic virotherapy but also simultaneously alleviated cancer-related anemia. PMID:23765443
Design of a Microwave Assisted Discharge Inductive Plasma Accelerator
NASA Technical Reports Server (NTRS)
Hallock, Ashley K.; Polzin, Kurt A.
2010-01-01
A new plasma accelerator concept that employs electrodeless plasma preionization and pulsed inductive acceleration is presented. Preionization is achieved through an electron cyclotron resonance discharge that produces a weakly-ionized plasma at the face of a conical theta pinch-shaped inductive coil. The presence of the preionized plasma allows for current sheet formation at lower discharge voltages than those found in other pulsed inductive accelerators. The location of an electron cyclotron resonance discharge can be controlled through the design of the applied magnetic field in the thruster. A finite-element model of the magnetic field was used as a design tool, allowing for the implementation of an arrangement of permanent magnets that yields a small volume of preionized propellant at the coil face. This allows for current sheet formation at the face of the inductive coil, minimizing the initial inductance of the pulse circuit and maximizing the potential efficiency of the new accelerator.
Rosu-Myles, Michael; Taylor, Barbara J; Wolff, Linda
2007-03-01
The tumor suppressor p15Ink4b (Ink4b) is a cell-cycle inhibitor that is inactivated in a high percentage of acute myeloid leukemia and myeloid dysplasia syndrome cases. Despite this, the role of Ink4b in hematopoiesis remains unclear. Here we examined the role of Ink4b in blood cell formation using Ink4b-deficient (Ink4b(-/-)) mice. We compared the bone marrow (BM) of Ink4b(-/-) and wild-type mice using flow cytometric, colony-forming unit and competitive repopulating assays (CRA). The proliferation, differentiation, self-renewal, and apoptosis of progenitor cells were further compared by in vitro and in vivo methods. BM from Ink4b(-/-) mice contained increased numbers of granulocyte-monocyte progenitors and Gr-1(+) cells and showed a competitive advantage over wild-type cells in myeloid cell formation by CRA. Ink4b(-/-) progenitors did not demonstrate increased proliferation, self-renewing potential, or reduced apoptosis. Instead, Ink4b(-/-) common myeloid progenitors (CMPs) showed increased myeloid progenitor formation concomitant with reduced erythroid potential. This work establishes a role for Ink4b in regulating the differentiation of CMPs and indicates that loss of Ink4b enhances the formation of myeloid progenitors.
Gaul, Daniel S; Weber, Julien; van Tits, Lambertus J; Sluka, Susanna; Pasterk, Lisa; Reiner, Martin F; Calatayud, Natacha; Lohmann, Christine; Klingenberg, Roland; Pahla, Jürgen; Vdovenko, Daria; Tanner, Felix C; Camici, Giovanni G; Eriksson, Urs; Auwerx, Johan; Mach, François; Windecker, Stephan; Rodondi, Nicolas; Lüscher, Thomas F; Winnik, Stephan; Matter, Christian M
2018-01-01
Abstract Aims Sirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI). Methods and results Using a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3−/− mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P < 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3−/− compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3−/− mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3−/− bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3−/− mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3−/− neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P < 0.01). Conclusions Sirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore
Ponert, Jan Moritz; Schwarz, Svenja; Haschemi, Reza; Müller, Jens; Pötzsch, Bernd; Bendas, Gerd
2018-01-01
Metastasis is responsible for the majority of cancer associated fatalities. Tumor cells leaving the primary tumor and entering the blood flow immediately interact with platelets. Activated platelets contribute in different ways to cancer cell survival and proliferation, e.g. in formation of the early metastatic niche by release of different growth factors and chemokines. Here we show that a direct interaction between platelets and MV3 melanoma or MCF7 breast cancer cells induces platelet activation and a VEGF release in citrated plasma that cannot be further elevated by the coagulation cascade and generated thrombin. In contrast, the release of platelet-derived chemokines CXCL5 and CXCL7 depends on both, a thrombin-mediated platelet activation and a direct interaction between tumor cells and platelets. Preincubation of platelets with therapeutic concentrations of unfractionated heparin reduces the tumor cell initiated VEGF release from platelets. In contrast, tumor cell induced CXCL5 and CXCL7 release from platelets was not impacted by heparin pretreatment in citrated plasma. In defibrinated, recalcified plasma, on the contrary, heparin is able to reduce CXCL5 and CXCL7 release from platelets by thrombin inhibition. Our data indicate that different chemokines and growth factors in diverse platelet granules are released in tightly regulated processes by various trigger mechanisms. We show for the first time that heparin is able to reduce the mediator release induced by different tumor cells both in a contact and coagulation dependent manner. PMID:29346400
Yamashita, Fumiaki; Komoto, Ikumi; Oka, Hiroaki; Kuwata, Keizo; Takeuchi, Mayuko; Nakagawa, Fumio; Yoshisue, Kunihiro; Chiba, Masato
2015-08-01
Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.
Masunaga, Shin-Ichiro; Ando, Koichi; Uzawa, Akiko; Hirayama, Ryoichi; Furusawa, Yoshiya; Koike, Sachiko; Sakurai, Yoshinori; Nagata, Kenji; Suzuki, Minoru; Kashino, Genro; Kinashi, Yuko; Tanaka, Hiroki; Maruhashi, Akira; Ono, Koji
2008-01-01
To clarify the radiosensitivity of intratumor quiescent cells in vivo to accelerated carbon ion beams and reactor neutron beams. Squamous cell carcinoma VII tumor-bearing mice were continuously given 5-bromo-2'-deoxyuridine to label all intratumor proliferating cells. Next, they received accelerated carbon ion or gamma-ray high-dose-rate (HDR) or reduced-dose-rate (RDR) irradiation. Other tumor-bearing mice received reactor thermal or epithermal neutrons with RDR irradiation. Immediately after HDR and RDR irradiation or 12 h after HDR irradiation, the response of quiescent cells was assessed in terms of the micronucleus frequency using immunofluorescence staining for 5-bromo-2'-deoxyuridine. The response of the total (proliferating plus quiescent) tumor cells was determined from the 5-bromo-2'-deoxyuridine nontreated tumors. The difference in radiosensitivity between the total and quiescent cell populations after gamma-ray irradiation was markedly reduced with reactor neutron beams or accelerated carbon ion beams, especially with a greater linear energy transfer (LET) value. Clearer repair in quiescent cells than in total cells through delayed assay or a decrease in the dose rate with gamma-ray irradiation was efficiently inhibited with carbon ion beams, especially with a greater LET. With RDR irradiation, the radiosensitivity to accelerated carbon ion beams with a greater LET was almost similar to that to reactor thermal and epithermal neutron beams. In terms of tumor cell-killing effect as a whole, including quiescent cells, accelerated carbon ion beams, especially with greater LET values, are very useful for suppressing the dependency on the heterogeneity within solid tumors, as well as depositing the radiation dose precisely.
Hashimoto, Yoko; Mori, Mayumi; Kobayashi, Shuichiro; Hanya, Akira; Watanabe, Shin-Ichi; Ohara, Naoki; Noguchi, Toshihide; Kawai, Tatsushi; Okuyama, Harumi
2014-01-01
Canola oil (Can) and hydrogenated soybean oil (H2-Soy) are commonly used edible oils. However, in contrast to soybean oil (Soy), they shorten the survival of stroke-prone spontaneously hypertensive (SHRSP) rats. It has been proposed that the adverse effects of these oils on the kidney and testis are caused at least in part by dihydro-vitamin K (VK) 1 in H2-Soy and unidentified component(s) in Can. Increased intake of dihydro-VK1 is associated with decreased tissue VK2 levels and bone mineral density in rats and humans, respectively. The aim of the present study was to determine the effects of these oils on bone morphogenetic protein (BMP)-induced ectopic bone formation, which is promoted by VK2 deficiency, in relation to the role of VK in the γ-carboxylation of osteocalcin and matrix Gla protein. A crude extract of BMPs was implanted into a gap in the fascia of the femoral muscle in 5-week-old mice maintained on a Soy, Can, or H2-Soy diet. Newly formed bone volume, assessed by three-dimensional X-ray micro-computed tomography and three-dimensional reconstruction imaging for bone, was 4-fold greater in the Can and H2-Soy groups than in the Soy group. The plasma carboxylated osteocalcin (Gla-OC) and total OC (Gla-OC plus undercarboxylated osteocalcin [Glu-OC]) levels were significantly lower in the Can group than in the Soy group ( p < 0.05). However, these levels did not significantly differ between the H2-Soy and Soy groups. The plasma Gla-OC/Glu-OC ratio in the Can and H2-Soy groups was significantly lower (in Can; p = 0.044) or was almost significantly lower (in H2-Soy; p = 0.053) than that in the Soy group. In conclusion, Can and H2-Soy accelerated BMP-induced bone formation in mice to a greater extent than Soy. Further research is required to evaluate whether the difference in accelerated ectopic bone formation is associated with altered levels of VK2 and VK-dependent protein(s) among the three dietary groups.
Monahan, Pamela; Himes, Ashley D.; Parfieniuk, Agata; Raetzman, Lori T.
2011-01-01
A delicate balance between proliferation and differentiation must be maintained in the developing pituitary to ensure the formation of the appropriate number of hormone producing cells. In the adult, proliferation is actively restrained to prevent tumor formation. The cyclin dependent kinase inhibitors (CDKIs) of the CIP/KIP family, p21, p27 and p57, mediate cell cycle inhibition. Although p21 is induced in the pituitary upon loss of Notch signaling or initiation of tumor formation to halt cell cycle progression, its role in normal pituitary organogenesis has not been explored. In wildtype pituitaries, expression of p21 is limited to a subset of cells embryonically as well as during the postnatal proliferative phase. Mice lacking p21 do not have altered cell proliferation during early embryogenesis, but do show a slight delay in separation of proliferating progenitors from the oral ectoderm. By embryonic day 16.5, p21 mutants have an alteration in the spatial distribution of proliferating pituitary progenitors, however there is no overall change in proliferation. At postnatal day 21, there appears to be no change in proliferation, as assessed by cells expressing Ki67 protein. However, p21 mutant pituitaries have significantly less mRNA of Myc and the cyclins Ccnb1, Ccnd1, Ccnd2 and Ccne1 than wildtype pituitaries. Interestingly, unlike the redundant role in cell cycle inhibition uncovered in p27/p57 double mutants, the pituitary of p21/p27 double mutants has a similar proliferation profile to p27 single mutants at the time points examined. Taken together, these studies demonstrate that unlike p27 or p57, p21 does not play a major role in control of progenitor proliferation in the developing pituitary. However, p21 may be required to maintain normal levels of cell cycle components. PMID:22154697
Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases
Robey, Ian F.; Baggett, Brenda K.; Kirkpatrick, Nathaniel D.; Roe, Denise J.; Dosescu, Julie; Sloane, Bonnie F.; Hashim, Arig Ibrahim; Morse, David L.; Raghunand, Natarajan; Gatenby, Robert A.; Gillies, Robert J.
2010-01-01
The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO3 selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by 31P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO3 therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO3 therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease. PMID:19276390
Rasnick, David
2002-07-01
The autocatalyzed progression of aneuploidy accounts for all cancer-specific phenotypes, the Hayflick limit of cultured cells, carcinogen-induced tumors in mice, the age distribution of human cancer, and multidrug-resistance. Here aneuploidy theory addresses tumor formation. The logistic equation, phi(n)(+1) = rphi(n) (1 - phi(n)), models the autocatalyzed progression of aneuploidy in vivo and in vitro. The variable phi(n)(+1) is the average aneuploid fraction of a population of cells at the n+1 cell division and is determined by the value at the nth cell division. The value r is the growth control parameter. The logistic equation was used to compute the probability distribution for values of phi after numerous divisions of aneuploid cells. The autocatalyzed progression of aneuploidy follows the laws of deterministic chaos, which means that certain values of phi are more probable than others. The probability map of the logistic equation shows that: 1) an aneuploid fraction of at least 0.30 is necessary to sustain a population of cancer cells; and 2) the most likely aneuploid fraction after many population doublings is 0.70, which is equivalent to a DNA(index)=1.7, the point of maximum disorder of the genome that still sustains life. Aneuploidy theory also explains the lack of immune surveillance and the failure of chemotherapy.
The LILIA experiment: Energy selection and post-acceleration of laser generated protons
NASA Astrophysics Data System (ADS)
Turchetti, Giorgio; Sinigardi, Stefano; Londrillo, Pasquale; Rossi, Francesco; Sumini, Marco; Giove, Dario; De Martinis, Carlo
2012-12-01
The LILIA experiment is planned at the SPARCLAB facility of the Frascati INFN laboratories. We have simulated the laser acceleration of protons, the transport and energy selection with collimators and a pulsed solenoid and the post-acceleration with a compact high field linac. For the highest achievable intensity corresponding to a = 30 over 108 protons at 30 MeV with a 3% spread are selected, and at least107 protons are post-accelerated up to 60 MeV. If a 10 Hz repetition rated can be achieved the delivered dose would be suitable for the treatment of small superficial tumors.
Deregulation of tumor angiogenesis and blockade of tumor growth in PPARβ-deficient mice
Müller-Brüsselbach, Sabine; Kömhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jürgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Müller, Rolf
2007-01-01
The peroxisome proliferator-activated receptor-β (PPARβ) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb−/− mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb−/− mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57Kip2 as a PPARβ target gene and a mediator of the PPARβ-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb−/− mice. Our data point to an unexpected essential role for PPARβ in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels. PMID:17641685
Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice.
Müller-Brüsselbach, Sabine; Kömhoff, Martin; Rieck, Markus; Meissner, Wolfgang; Kaddatz, Kerstin; Adamkiewicz, Jürgen; Keil, Boris; Klose, Klaus J; Moll, Roland; Burdick, Andrew D; Peters, Jeffrey M; Müller, Rolf
2007-08-08
The peroxisome proliferator-activated receptor-beta (PPARbeta) has been implicated in tumorigenesis, but its precise role remains unclear. Here, we show that the growth of syngeneic Pparb wild-type tumors is impaired in Pparb(-/-) mice, concomitant with a diminished blood flow and an abundance of hyperplastic microvascular structures. Matrigel plugs containing pro-angiogenic growth factors harbor increased numbers of morphologically immature, proliferating endothelial cells in Pparb(-/-) mice, and retroviral transduction of Pparb triggers microvessel maturation. We have identified the Cdkn1c gene encoding the cell cycle inhibitor p57(Kip2) as a PPARbeta target gene and a mediator of the PPARbeta-mediated inhibition of cell proliferation, which provides a possible mechanistic explanation for the observed tumor endothelial hyperplasia and deregulation of tumor angiogenesis in Pparb(-/-) mice. Our data point to an unexpected essential role for PPARbeta in constraining tumor endothelial cell proliferation to allow for the formation of functional tumor microvessels.
Dey, Sanjib; Ghosh, Nillu; Saha, Debjit; Kesh, Kousik; Gupta, Arnab; Swarnakar, Snehasikta
2014-01-01
Expression of matrix metalloproteinase-1 (MMP-1), an interstitial collagenase, plays a major role in cellular invasion during development of gastric cancer, a leading cause of death worldwide. A single-nucleotide polymorphism (SNP) −1607 1G/2G site of the MMP-1 gene promoter has been reported to alter transcription level. While the importance’s of other SNPs in the MMP-1 promoter have not yet been studied in gastric cancer, our aim was to investigate MMP-1 gene promoter polymorphisms and gastric cancer susceptibility in eastern Indian population. A total of 145 gastric cancer patients and 145 healthy controls were genotyped for MMP-1 −1607 1G/2G (rs1799750) by PCR-restriction fragment length polymorphism (RFLP), while MMP-1 −519 A/G (rs1144393), MMP-1 −422 T/A (rs475007), MMP-1 −340 T/C (rs514921) and MMP-1 −320 T/C (rs494379) were genotyped by DNA sequencing. A positive association was found with MMP-1 −422 T/A SNP that showed significant risk for regional lymph node metastasis (P = 0.021, Odd’s ratio (OR) = 3.044, Confidence intervals (CI) = 1.187–7.807). In addition, we found a significant association with lower stomach tumor formation among gastric cancer patients for three adjacent polymorphisms near the transcriptional start sites of [MMP-1 −422 T/A (P = 0.043, OR = 2.182, CI = 1.03–4.643), MMP-1 −340 T/C (P = 0.075, OR = 1.97, CI = 0.94–4.158) and MMP-1 −320 T/C (P = 0.034, OR = 2.224, CI = 1.064–40731)]. MMP-1 level in patients’ serum was correlated with MMP-1 promoter haplotypes conferring these three SNPs to evaluate the functional importance of these polymorphisms in lower stomach tumor formation and significant correlation was observed. Furthermore, MMP-1 −519 A/G polymorphism displayed poor cellular differentiation (P = 0.024, OR = 3.8, CI = 1.69–8.56) attributing a higher risk of cancer progression. In conclusion, MMP-1 proximal promoter SNPs are
Zhang, Xinheng; Yan, Yiming; Lei, Xiaoya; Li, Aijun; Zhang, Huanmin; Dai, Zhenkai; Li, Xinjian; Chen, Weiguo; Lin, Wencheng; Chen, Feng; Ma, Jingyun; Xie, Qingmei
2017-05-23
Avian leukosis virus subgroup (ALV-J) is an oncogenic neoplasm-inducing retrovirus that causes significant economic losses in the poultry industry. Recent studies have demonstrated circular RNAs (circRNAs) are implicated in pathogenic processes; however, no research has indicated circRNAs are involved in resistance to disease. In this study, over 1800 circRNAs were detected by circRNA sequencing of liver tissues from ALV-J-resistant (n = 3) and ALV-J-susceptible chickens (n = 3). 32 differentially expressed circRNAs were selected for analyzing including 12 upregulated in ALV-J-resistant chickens and 20 upregulated in ALV-J-susceptible chickens, besides, the top five microRNAs (miRNAs) for 12 upregulated circRNAs in ALV-J-resistant chickens were analyzed. Gene ontology and KEGG pathway analyses were performed for miRNA target genes, the predicted genes were mainly involved in immune pathways. This study provides the first evidence that circRNA alterations are involved in resistance to ALV-J-induced tumor formation. We propose circRNAs may help to mediate tumor induction and development in chickens.
Beam shaping assembly optimization for (7)Li(p,n)(7)Be accelerator based BNCT.
Minsky, D M; Kreiner, A J
2014-06-01
Within the framework of accelerator-based BNCT, a project to develop a folded Tandem-ElectroStatic-Quadrupole accelerator is under way at the Atomic Energy Commission of Argentina. The proposed accelerator is conceived to deliver a proton beam of 30mA at about 2.5MeV. In this work we explore a Beam Shaping Assembly (BSA) design based on the (7)Li(p,n)(7)Be neutron production reaction to obtain neutron beams to treat deep seated tumors. © 2013 Elsevier Ltd. All rights reserved.
Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping
2017-03-01
Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
Electron acceleration by turbulent plasmoid reconnection
NASA Astrophysics Data System (ADS)
Zhou, X.; Büchner, J.; Widmer, F.; Muñoz, P. A.
2018-04-01
In space and astrophysical plasmas, like in planetary magnetospheres, as that of Mercury, energetic electrons are often found near current sheets, which hint at electron acceleration by magnetic reconnection. Unfortunately, electron acceleration by reconnection is not well understood yet, in particular, acceleration by turbulent plasmoid reconnection. We have investigated electron acceleration by turbulent plasmoid reconnection, described by MHD simulations, via test particle calculations. In order to avoid resolving all relevant turbulence scales down to the dissipation scales, a mean-field turbulence model is used to describe the turbulence of sub-grid scales and their effects via a turbulent electromotive force (EMF). The mean-field model describes the turbulent EMF as a function of the mean values of current density, vorticity, magnetic field as well as of the energy, cross-helicity, and residual helicity of the turbulence. We found that, mainly around X-points of turbulent reconnection, strongly enhanced localized EMFs most efficiently accelerated electrons and caused the formation of power-law spectra. Magnetic-field-aligned EMFs, caused by the turbulence, dominate the electron acceleration process. Scaling the acceleration processes to parameters of the Hermean magnetotail, electron energies up to 60 keV can be reached by turbulent plasmoid reconnection through the thermal plasma.
Mast cells mediate malignant pleural effusion formation.
Giannou, Anastasios D; Marazioti, Antonia; Spella, Magda; Kanellakis, Nikolaos I; Apostolopoulou, Hara; Psallidas, Ioannis; Prijovich, Zeljko M; Vreka, Malamati; Zazara, Dimitra E; Lilis, Ioannis; Papaleonidopoulos, Vassilios; Kairi, Chrysoula A; Patmanidi, Alexandra L; Giopanou, Ioanna; Spiropoulou, Nikolitsa; Harokopos, Vaggelis; Aidinis, Vassilis; Spyratos, Dionisios; Teliousi, Stamatia; Papadaki, Helen; Taraviras, Stavros; Snyder, Linda A; Eickelberg, Oliver; Kardamakis, Dimitrios; Iwakura, Yoichiro; Feyerabend, Thorsten B; Rodewald, Hans-Reimer; Kalomenidis, Ioannis; Blackwell, Timothy S; Agalioti, Theodora; Stathopoulos, Georgios T
2015-06-01
Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1β, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable.
Mast cells mediate malignant pleural effusion formation
Giannou, Anastasios D.; Marazioti, Antonia; Spella, Magda; Kanellakis, Nikolaos I.; Apostolopoulou, Hara; Psallidas, Ioannis; Prijovich, Zeljko M.; Vreka, Malamati; Zazara, Dimitra E.; Lilis, Ioannis; Papaleonidopoulos, Vassilios; Kairi, Chrysoula A.; Patmanidi, Alexandra L.; Giopanou, Ioanna; Spiropoulou, Nikolitsa; Harokopos, Vaggelis; Aidinis, Vassilis; Spyratos, Dionisios; Teliousi, Stamatia; Papadaki, Helen; Taraviras, Stavros; Snyder, Linda A.; Eickelberg, Oliver; Kardamakis, Dimitrios; Iwakura, Yoichiro; Feyerabend, Thorsten B.; Rodewald, Hans-Reimer; Kalomenidis, Ioannis; Blackwell, Timothy S.; Agalioti, Theodora; Stathopoulos, Georgios T.
2015-01-01
Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1β, which in turn induced pleural vasculature leakiness and triggered NF-κB activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell–induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable. PMID:25915587
Tai, Kuo-Feng; Chen, Ding-Shinn; Hwang, Lih-Hwa
2004-01-01
In preclinical studies, tumor cells genetically engineered to secrete cytokines, hereafter referred to as tumor cell vaccines, can often generate systemic antitumor immunity. This study investigated the therapeutic effects of live or irradiated tumor cell vaccines that secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) on established orthotopic liver tumors. Experimental results indicated that two doses (3 x 10(7) cells per dose) of irradiated tumor cell vaccines were therapeutically ineffective, whereas one dose (3 x 10(6) cells) of live tumor cell vaccines caused complete tumor regression. In vivo depletion of CD8+ T cells, but not natural killer cells, restored tumor formation in the live vaccine-treated animals. Additionally, the treatment of cells with live vaccine induced markedly higher levels of cytotoxic T lymphocyte activity than the irradiated vaccines in the draining lymph nodes. The higher levels of cytokine and antigen loads could partly explain the superior antitumor activity of live tumor cell vaccines, but other unidentified mechanisms could also play a role in the early T cell activation in the lymph nodes. A protocol using multiple and higher dosages of irradiated tumor cell vaccines also caused significant regression of liver tumors. These results suggest that the GM-CSF-secreting tumor cell vaccines are highly promising for orthotopic liver tumors if higher levels of immune responses are elicited during early tumor development. Copyright 2004 National Science Council, ROC and S. Karger AG, Basel
DOE Office of Scientific and Technical Information (OSTI.GOV)
Dieckmann, M.E.; Shukla, P.K.; Eliasson, B.
2006-06-15
The ever increasing performance of supercomputers is now enabling kinetic simulations of extreme astrophysical and laser produced plasmas. Three-dimensional particle-in-cell (PIC) simulations of relativistic shocks have revealed highly filamented spatial structures and their ability to accelerate particles to ultrarelativistic speeds. However, these PIC simulations have not yet revealed mechanisms that could produce particles with tera-electron volt energies and beyond. In this work, PIC simulations in one dimension (1D) of the foreshock region of an internal shock in a gamma ray burst are performed to address this issue. The large spatiotemporal range accessible to a 1D simulation enables the self-consistent evolutionmore » of proton phase space structures that can accelerate particles to giga-electron volt energies in the jet frame of reference, and to tens of tera-electron volt in the Earth's frame of reference. One potential source of ultrahigh energy cosmic rays may thus be the thermalization of relativistically moving plasma.« less
Ma, Kun; Kwon, Sun Hyung; Padmanabhan, Jagannath; Duscher, Dominik; Trotsyuk, Artem A; Dong, Yixiao; Inayathullah, Mohammed; Rajadas, Jayakumar; Gurtner, Geoffrey C
2018-05-15
Formation of scars following wounding or trauma represents a significant healthcare burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model. Clinical translation of FAKI therapy has been challenging, however, due to the lack of an effective drug delivery system for extensive burn injuries, blast injuries, and large excisional injuries. To address this issue, we have developed a pullulan collagen-based hydrogel to deliver FAKI to excisional and burn wounds in mice. Specifically, two distinct drug-laden hydrogels were developed for rapid or sustained release of FAKI for treatment of burn wounds and excisional wounds, respectively. Controlled delivery of FAKI via pullulan collagen hydrogels accelerated wound healing, reduced collagen deposition and activation of scar forming myofibroblasts in both wound healing models. Our study highlights a biomaterial-based drug delivery approach for wound and scar management that has significant translational implications. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Dominant negative retinoic acid receptor initiates tumor formation in mice.
Kupumbati, Tara S; Cattoretti, Giorgio; Marzan, Christine; Farias, Eduardo F; Taneja, Reshma; Mira-y-Lopez, Rafael
2006-03-24
Retinoic acid suppresses cell growth and promotes cell differentiation, and pharmacological retinoic acid receptor (RAR) activation is anti-tumorigenic. This begs the question of whether chronic physiological RAR activation by endogenous retinoids is likewise anti-tumorigenic. To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARalpha (RARalphaG303E) was under the control of the mouse mammary tumor virus (MMTV) promoter. The transgene was expressed in the lymphoid compartment and in the mammary epithelium. Observation of aging mice revealed that transgenic mice, unlike their wild type littermates, developed B cell lymphomas at high penetrance, with a median latency of 40 weeks. MMTV-RARalphaG303E lymphomas were high grade Pax-5+, surface H+L Ig negative, CD69+ and BCL6- and cytologically and phenotypically resembled human adult high grade (Burkitt's or lymphoblastic) lymphomas. We postulated that mammary tumors might arise after a long latency period as seen in other transgenic models of breast cancer. We tested this idea by transplanting transgenic epithelium into the cleared fat pads of wild type hosts, thus bypassing lymphomagenesis. At 17 months post-transplantation, a metastatic mammary adenocarcinoma developed in one of four transplanted glands whereas no tumors developed in sixteen of sixteen endogenous glands with wild type epithelium. These findings suggest that physiological RAR activity may normally suppress B lymphocyte and mammary epithelial cell growth and that global RAR inactivation is sufficient to initiate a stochastic process of tumor development requiring multiple transforming events. Our work makes available to the research community a new animal resource that should prove useful as an experimental model of aggressive sporadic lymphoma in immunologically uncompromised hosts. We anticipate that it may also prove useful as a model of breast cancer.
NASA Astrophysics Data System (ADS)
Hwu, Derrick; Boutrus, Steven; Greiner, Cherry; Dimeo, Theresa; Kuperwasser, Charlotte; Georgakoudi, Irene
2011-04-01
The identification of breast cancer patients who will ultimately progress to metastatic disease is of significant clinical importance. The quantification and assessment of circulating tumor cells (CTCs) has been proposed as one strategy to monitor treatment effectiveness and disease prognosis. However, CTCs have been an elusive population of cells to study because of their small number and difficulties associated with isolation protocols. In vivo flow cytometry (IVFC) can overcome these limitations and provide insights in the role these cells play during primary and metastatic tumor growth. In this study, we used two-color IVFC to examine, for up to ten weeks following orthotopic implantation, changes in the number of circulating human breast cells expressing GFP and a population of circulating hematopoietic cells with strong autofluorescence. We found that the number of detected CTCs in combination with the number of red autofluorescent cells (650 to 690 nm) during the first seven days following implantation was predictive in development of tumor formation and metastasis eight weeks later. These results suggest that the combined detection of these two cell populations could offer a novel approach in the monitoring and prognosis of breast cancer progression, which in turn could aid significantly in their effective treatment.
Application of Plasma Waveguides to High Energy Accelerators
DOE Office of Scientific and Technical Information (OSTI.GOV)
Milchberg, Howard M
2013-03-30
The eventual success of laser-plasma based acceleration schemes for high-energy particle physics will require the focusing and stable guiding of short intense laser pulses in reproducible plasma channels. For this goal to be realized, many scientific issues need to be addressed. These issues include an understanding of the basic physics of, and an exploration of various schemes for, plasma channel formation. In addition, the coupling of intense laser pulses to these channels and the stable propagation of pulses in the channels require study. Finally, new theoretical and computational tools need to be developed to aid in the design and analysismore » of experiments and future accelerators. Here we propose a 3-year renewal of our combined theoretical and experimental program on the applications of plasma waveguides to high-energy accelerators. During the past grant period we have made a number of significant advances in the science of laser-plasma based acceleration. We pioneered the development of clustered gases as a new highly efficient medium for plasma channel formation. Our contributions here include theoretical and experimental studies of the physics of cluster ionization, heating, explosion, and channel formation. We have demonstrated for the first time the generation of and guiding in a corrugated plasma waveguide. The fine structure demonstrated in these guides is only possible with cluster jet heating by lasers. The corrugated guide is a slow wave structure operable at arbitrarily high laser intensities, allowing direct laser acceleration, a process we have explored in detail with simulations. The development of these guides opens the possibility of direct laser acceleration, a true miniature analogue of the SLAC RF-based accelerator. Our theoretical studies during this period have also contributed to the further development of the simulation codes, Wake and QuickPIC, which can be used for both laser driven and beam driven plasma based acceleration
Modeling the Spatiotemporal Evolution of the Melanoma Tumor Microenvironment
NASA Astrophysics Data System (ADS)
Signoriello, Alexandra; Bosenberg, Marcus; Shattuck, Mark; O'Hern, Corey
The tumor microenvironment, which includes tumor cells, tumor-associated macrophages (TAM), cancer-associated fibroblasts, and endothelial cells, drives the formation and progression of melanoma tumors. Using quantitative analysis of in vivo confocal images of melanoma tumors in three spatial dimensions, we examine the physical properties of the melanoma tumor microenvironment, including the numbers of different cells types, cell size, and morphology. We also compute the nearest neighbor statistics and measure intermediate range spatial correlations between different cell types. We also calculate the step size distribution, mean-square displacement, and non-Gaussian parameter from the spatial trajectories of different cell types in the tumor microenvironment.
Accelerated cure of phenol-formaldehyde resins : studies with model compounds
Anthony H. Conner; Linda F. Lorenz; Kolby C. Hirth
2002-01-01
2-Hydroxymethylphenol (2-HMP) and 4-hydroxymethylphenol (4-HMP) were used as model compounds to study the reactions that occur during cure of phenol-formaldehyde (PF) resin to which cure accelerators (ethyl formate, propylene carbonate, g-butyrolactone, and triacetin) have been added. The addition of cure accelerators significantly increased the rate of condensation...
Malishev, Ravit; Nandi, Sukhendu; Kolusheva, Sofiya; Shaham-Niv, Shira; Gazit, Ehud; Jelinek, Raz
2016-09-01
Bacosides, class of compounds extracted from the Bacopa monniera plant, exhibit interesting therapeutic properties, particularly enhancing cognitive functions and putative anti-amyloid activity. We show that bacoside-A exerted significant effects upon fibrillation and membrane interactions of the amyloidogenic fragment of the prion protein [PrP(106-126)]. Specifically, when co-incubated with PrP(106-126), bacoside-A accelerated fibril formation in the presence of lipid bilayers and in parallel inhibited bilayer interactions of the peptide aggregates formed in solution. These interesting phenomena were studied by spectroscopic and microscopic techniques, which suggest that bacoside A-promoted fibrillation reduced the concentration of membrane-active pre-fibrillar species of the prion fragment. This study suggests that induction of fibril formation and corresponding inhibition of membrane interactions are likely the underlying factors for ameliorating amyloid protein toxicity by bacoside-A. Copyright © 2016 Elsevier B.V. All rights reserved.
Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo
2014-01-01
Purpose Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy. The expansion of tumor-reactive CD8+ T cells with IL-2 in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8+ T cells recently found to constitute the majority of tumor-specific T cells. Experimental Design We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB co-stimulation. Results We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8+ TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL-2 responsiveness, in the CD8+ T cells in the fragments and emerging from the fragments. Early provision of 4-1BB co-stimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8+ T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8+ TIL outgrowth. Conclusions Our results highlight a previously unrecognized concept in TIL adoptive cell therapy that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. PMID:25472998
Chacon, Jessica Ann; Sarnaik, Amod A; Chen, Jie Qing; Creasy, Caitlin; Kale, Charuta; Robinson, John; Weber, Jeffrey; Hwu, Patrick; Pilon-Thomas, Shari; Radvanyi, Laszlo
2015-02-01
Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics. ©2014 American Association for Cancer Research.
Baysan, Mehmet; Woolard, Kevin; Cam, Margaret C; Zhang, Wei; Song, Hua; Kotliarova, Svetlana; Balamatsias, Demosthenes; Linkous, Amanda; Ahn, Susie; Walling, Jennifer; Belova, Galina I; Fine, Howard A
2017-11-15
Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets. © 2017 UICC.
Zhao, Fu-Jun; Han, Bang-Min; Yu, Sheng-Qiang; Xia, Shu-Jie
2009-01-01
This study was designed to investigate the different involvements of prostatic stromal cells from the normal transitional zone (TZ) or peripheral zone (PZ) in the carcinogenesis of prostate cancer (PCa) epithelial cells (PC-3) in vitro and in vivo co-culture models. Ultra-structures and gene expression profiles of primary cultures of human prostatic stromal cells from the normal TZ or PZ were analyzed by electron microscopy and microarray analysis. In vitro and in vivo co-culture models composed of normal TZ or PZ stromal cells and human PCa PC-3 cells were established. We assessed tumor growth and weight in the in vivo nude mice model. There are morphological and ultra-structural differences in stromal cells from TZ and PZ of the normal prostate. In all, 514 differentially expressed genes were selected by microarray analysis; 483 genes were more highly expressed in stromal cells from TZ and 31 were more highly expressed in those from PZ. Co-culture with PZ stromal cells and transforming growth factor-β1 (TGF-β1) increased the tumor growth of PC-3 cells in vitro and in vivo, as well as Bcl-2 expression. On the other hand, stromal cells of TZ suppressed PC-3 cell tumor growth in the mouse model. We conclude that ultra-structures and gene expression differ between the stromal cells from TZ or PZ of the normal prostate, and stroma–epithelium interactions from TZ or PZ might be responsible for the distinct zonal localization of prostate tumor formation. PMID:19122679
Tandem-ESQ for Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kreiner, A. J.; Escuela de Ciencia y Tecnologia, Universidad de Gral San Martin; CONICET,
2007-02-12
A folded tandem, with 1.25 MV terminal voltage, combined with an ElectroStatic Quadrupole (ESQ) chain is being proposed as a machine for Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT). The machine is shown to be capable of accelerating a 30 mA proton beam to 2.5 MeV. These are the specifications needed to produce sufficiently intense and clean epithermal neutron beams, based on the on the 7Li(p,n)7Be reaction, to perform BNCT treatment for deep seated tumors in less than an hour.
Angiogenesis in Spontaneous Tumors and Implications for Comparative Tumor Biology
Benazzi, C.; Al-Dissi, A.; Chau, C. H.; Figg, W. D.; Sarli, G.; de Oliveira, J. T.; Gärtner, F.
2014-01-01
Blood supply is essential for development and growth of tumors and angiogenesis is the fundamental process of new blood vessel formation from preexisting ones. Angiogenesis is a prognostic indicator for a variety of tumors, and it coincides with increased shedding of neoplastic cells into the circulation and metastasis. Several molecules such as cell surface receptors, growth factors, and enzymes are involved in this process. While antiangiogenic therapy for cancer has been proposed over 20 years ago, it has garnered much controversy in recent years within the scientific community. The complex relationships between the angiogenic signaling cascade and antiangiogenic substances have indicated the angiogenic pathway as a valid target for anticancer drug development and VEGF has become the primary antiangiogenic drug target. This review discusses the basic and clinical perspectives of angiogenesis highlighting the importance of comparative biology in understanding tumor angiogenesis and the integration of these model systems for future drug development. PMID:24563633
Modified model of VX2 tumor overexpressing vascular endothelial growth factor.
Pascale, Florentina; Ghegediban, Saida-Homayra; Bonneau, Michel; Bedouet, Laurent; Namur, Julien; Verret, Valentin; Schwartz-Cornil, Isabelle; Wassef, Michel; Laurent, Alexandre
2012-06-01
To determine whether upregulated expression of vascular endothelial growth factor (VEGF) in VX2 cells can increase vessel density (VD) and reduce tumor necrosis. The VX2 cell line was transfected with expression vectors containing cDNA for rabbit VEGF. Stable clones producing rabbit VEGF (VEGF-VX2) were selected. VEGF-VX2 cells (n = 5 rabbits) or nontransfected VX2 cells (controls; n = 5 rabbits) were implanted into leg muscle of 10 rabbits. The animals were sacrificed at day 21. Tumor volume, percentage of necrosis, VD, and VEGF concentration in tumor protein extract were quantified. Overexpression of VEGF by VX2 cells augmented tumor implantation efficiency 100% and favored cyst formation. The tumor volume was significantly larger for VEGF-VX2 transfected tumors versus controls (P = .0143). Overexpression of VEGF in VX2 cells significantly increased the VD of the tumors (P = .0138). The percentage of necrosis was reduced in VEGF-VX2 tumors versus controls (19.5% vs 38.5 %; P = .002). VEGF concentration in VEGF-VX2 tumors was significantly higher than in control tumors (P = .041) and was correlated with tumor volume (ρ = .883, P = .012). The overexpression of VEGF increased tumor growth and vascularization, favored cyst formation, and reduced tumor necrosis. This new phenotype of the VX2 tumor may offer some advantages over classic models of VX2 tumor for evaluating anticancer therapies. Copyright © 2012 SIR. Published by Elsevier Inc. All rights reserved.
Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe–S Assembly Complex
Fox, Nicholas G.; Das, Deepika; Chakrabarti, Mrinmoy; Lindahl, Paul A.; Barondeau, David P.
2015-01-01
Iron–sulfur (Fe–S) clusters function as protein cofactors for a wide variety of critical cellular reactions. In human mitochondria, a core Fe–S assembly complex [called SDUF and composed of NFS1, ISD11, ISCU2, and frataxin (FXN) proteins] synthesizes Fe–S clusters from iron, cysteine sulfur, and reducing equivalents and then transfers these intact clusters to target proteins. In vitro assays have relied on reducing the complexity of this complicated Fe–S assembly process by using surrogate electron donor molecules and monitoring simplified reactions. Recent studies have concluded that FXN promotes the synthesis of [4Fe-4S] clusters on the mammalian Fe–S assembly complex. Here the kinetics of Fe–S synthesis reactions were determined using different electron donation systems and by monitoring the products with circular dichroism and absorbance spectroscopies. We discovered that common surrogate electron donor molecules intercepted Fe–S cluster intermediates and formed high-molecular weight species (HMWS). The HMWS are associated with iron, sulfide, and thiol-containing proteins and have properties of a heterogeneous solubilized mineral with spectroscopic properties remarkably reminiscent of those of [4Fe-4S] clusters. In contrast, reactions using physiological reagents revealed that FXN accelerates the formation of [2Fe-2S] clusters rather than [4Fe-4S] clusters as previously reported. In the preceding paper [Fox, N. G., et al. (2015) Biochemistry 54, DOI: 10.1021/bi5014485], [2Fe-2S] intermediates on the SDUF complex were shown to readily transfer to uncomplexed ISCU2 or apo acceptor proteins, depending on the reaction conditions. Our results indicate that FXN accelerates a rate-limiting sulfur transfer step in the synthesis of [2Fe-2S] clusters on the human Fe–S assembly complex. PMID:26016518
Frataxin Accelerates [2Fe-2S] Cluster Formation on the Human Fe-S Assembly Complex.
Fox, Nicholas G; Das, Deepika; Chakrabarti, Mrinmoy; Lindahl, Paul A; Barondeau, David P
2015-06-30
Iron-sulfur (Fe-S) clusters function as protein cofactors for a wide variety of critical cellular reactions. In human mitochondria, a core Fe-S assembly complex [called SDUF and composed of NFS1, ISD11, ISCU2, and frataxin (FXN) proteins] synthesizes Fe-S clusters from iron, cysteine sulfur, and reducing equivalents and then transfers these intact clusters to target proteins. In vitro assays have relied on reducing the complexity of this complicated Fe-S assembly process by using surrogate electron donor molecules and monitoring simplified reactions. Recent studies have concluded that FXN promotes the synthesis of [4Fe-4S] clusters on the mammalian Fe-S assembly complex. Here the kinetics of Fe-S synthesis reactions were determined using different electron donation systems and by monitoring the products with circular dichroism and absorbance spectroscopies. We discovered that common surrogate electron donor molecules intercepted Fe-S cluster intermediates and formed high-molecular weight species (HMWS). The HMWS are associated with iron, sulfide, and thiol-containing proteins and have properties of a heterogeneous solubilized mineral with spectroscopic properties remarkably reminiscent of those of [4Fe-4S] clusters. In contrast, reactions using physiological reagents revealed that FXN accelerates the formation of [2Fe-2S] clusters rather than [4Fe-4S] clusters as previously reported. In the preceding paper [Fox, N. G., et al. (2015) Biochemistry 54, DOI: 10.1021/bi5014485], [2Fe-2S] intermediates on the SDUF complex were shown to readily transfer to uncomplexed ISCU2 or apo acceptor proteins, depending on the reaction conditions. Our results indicate that FXN accelerates a rate-limiting sulfur transfer step in the synthesis of [2Fe-2S] clusters on the human Fe-S assembly complex.
Deregulated proliferation and differentiation in brain tumors
Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I
2014-01-01
Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506
A 1.1mm AzTEC Survey Tracing Accelerated Galaxy Formation Towards a Protocluster at z 3.8
NASA Astrophysics Data System (ADS)
Hughes, David H.; Montana, A.; Aretxaga, I.; Plionis, M.; Porras, A.; Wagg, J.; Gaztanaga, E.; Huang, J.; Fazio, G.; Wilson, G.; Yun, M.; Lowenthal, J.; Perera, T.; Austermann, J.; Scott, K.; Dunlop, J.; Ivison, R.; Stevens, J.; Smail, I.; Appleton, P.
2006-12-01
Aztec has recently conducted a sensitive, wide-area (300 sq. Armin's) continuum survey at 1.1mm using the 15-m James Clerk Maxwell Telescope towards 4C41.17, a powerful high-redshift (z 3.8) radio galaxy. These Aztec data, which cover an area >40 times larger than our previous SCUBA survey, reveal a significant over-density of luminous, massive dust-enshrouded galaxies, compared to the results from lower-redshift blank-field sub-mm surveys. One natural interpretation of these new AzTEC data is that the over-density is tracing a large (5 x 5 Mpc) "proto-cluster" structure at z 3.8 associated with the environment of 4C41.17, within which the formation of ultra-luminous starburst galaxies (with rest-frame FIR luminosities >5 x 1012 Lsun or SFRs > 500 Msun/yr) is taking place at an accelerated rate. Proving the physical association of these massive optically-faint starbursts with the environment of this high-z AGN, and not with the blank-field sub-mm population, for which 50% of the population lies at 1.9 < z < 2.9, remains an outstanding problem. In this presentation we will describe the AzTEC survey, the empirical evidence for this protocluster structure in the early universe, and the planned multi-wavelength follow-up observations of the brightest AzTEC sources towards 4C41.17 that may demonstrate that we are witnessing accelerated galaxy formation, via an increased rate of merging gas-rich galaxies within a rapidly-developing gravitational potential. AzTEC is one of the suite of instruments destined for the 50-m Large Millimeter Telescope (LMT). We will conclude this presentation with a summary of future LMT observations that will trace the evolution of obscured starformation in the dynamic environments towards a significant sample of intermediate and high-z powerful AGN with greater sensitivity and spatial resolution.
First experimental results from 2 MeV proton tandem accelerator for neutron production.
Kudryavtsev, A; Belchenko, Yu; Burdakov, A; Davydenko, V; Ivanov, A; Khilchenko, A; Konstantinov, S; Krivenko, A; Kuznetsov, A; Mekler, K; Sanin, A; Shirokov, V; Sorokin, I; Sulyaev, Yu; Tiunov, M
2008-02-01
A 2 MeV proton tandem accelerator with vacuum insulation was developed and first experiments are carried out in the Budker Institute of Nuclear Physics (Novosibirsk). The accelerator is designed for neutron production via reaction (7)Li(p,n)(7)Be for the boron neutron-capture therapy of the brain tumors, and for explosive detection based on 9.1724 MeV resonance gamma, which are produced via reaction (13)C(p,gamma)(14)N, absorption in nitrogen.
Experimental evidence of space charge driven resonances in high intensity linear accelerators
Jeon, Dong -O
2016-01-12
In the construction of high intensity accelerators, it is the utmost goal to minimize the beam loss by avoiding or minimizing contributions of various halo formation mechanisms. As a halo formation mechanism, space charge driven resonances are well known for circular accelerators. However, the recent finding showed that even in linear accelerators the space charge potential can excite the 4σ = 360° fourth order resonance [D. Jeon et al., Phys. Rev. ST Accel. Beams 12, 054204 (2009)]. This study increased the interests in space charge driven resonances of linear accelerators. Experimental studies of the space charge driven resonances of highmore » intensity linear accelerators are rare as opposed to the multitude of simulation studies. This paper presents an experimental evidence of the space charge driven 4σ ¼ 360° resonance and the 2σ x(y) – 2σ z = 0 resonance of a high intensity linear accelerator through beam profile measurements from multiple wire-scanners. Moreover, measured beam profiles agree well with the characteristics of the space charge driven 4σ = 360° resonance and the 2σ x(y) – 2σ z = 0 resonance that are predicted by the simulation.« less
In Vitro Model of Tumor Cell Extravasation
Jeon, Jessie S.; Zervantonakis, Ioannis K.; Chung, Seok; Kamm, Roger D.; Charest, Joseph L.
2013-01-01
Tumor cells that disseminate from the primary tumor and survive the vascular system can eventually extravasate across the endothelium to metastasize at a secondary site. In this study, we developed a microfluidic system to mimic tumor cell extravasation where cancer cells can transmigrate across an endothelial monolayer into a hydrogel that models the extracellular space. The experimental protocol is optimized to ensure the formation of an intact endothelium prior to the introduction of tumor cells and also to observe tumor cell extravasation by having a suitable tumor seeding density. Extravasation is observed for 38.8% of the tumor cells in contact with the endothelium within 1 day after their introduction. Permeability of the EC monolayer as measured by the diffusion of fluorescently-labeled dextran across the monolayer increased 3.8 fold 24 hours after introducing tumor cells, suggesting that the presence of tumor cells increases endothelial permeability. The percent of tumor cells extravasated remained nearly constant from1 to 3 days after tumor seeding, indicating extravasation in our system generally occurs within the first 24 hours of tumor cell contact with the endothelium. PMID:23437268
Towards ion beam therapy based on laser plasma accelerators.
Karsch, Leonhard; Beyreuther, Elke; Enghardt, Wolfgang; Gotz, Malte; Masood, Umar; Schramm, Ulrich; Zeil, Karl; Pawelke, Jörg
2017-11-01
Only few ten radiotherapy facilities worldwide provide ion beams, in spite of their physical advantage of better achievable tumor conformity of the dose compared to conventional photon beams. Since, mainly the large size and high costs hinder their wider spread, great efforts are ongoing to develop more compact ion therapy facilities. One promising approach for smaller facilities is the acceleration of ions on micrometre scale by high intensity lasers. Laser accelerators deliver pulsed beams with a low pulse repetition rate, but a high number of ions per pulse, broad energy spectra and high divergences. A clinical use of a laser based ion beam facility requires not only a laser accelerator providing beams of therapeutic quality, but also new approaches for beam transport, dosimetric control and tumor conformal dose delivery procedure together with the knowledge of the radiobiological effectiveness of laser-driven beams. Over the last decade research was mainly focused on protons and progress was achieved in all important challenges. Although currently the maximum proton energy is not yet high enough for patient irradiation, suggestions and solutions have been reported for compact beam transport and dose delivery procedures, respectively, as well as for precise dosimetric control. Radiobiological in vitro and in vivo studies show no indications of an altered biological effectiveness of laser-driven beams. Laser based facilities will hardly improve the availability of ion beams for patient treatment in the next decade. Nevertheless, there are possibilities for a need of laser based therapy facilities in future.
Clustering of brain tumor cells: a first step for understanding tumor recurrence
NASA Astrophysics Data System (ADS)
Khain, Evgeniy; Nowicki, M. O.; Chiocca, E. A.; Lawler, S. E.; Schneider-Mizell, C. M.; Sander, L. M.
2012-02-01
Glioblastoma tumors are highly invasive; therefore the overall prognosis of patients remains poor, despite major improvements in treatment techniques. Cancer cells detach from the inner tumor core and actively migrate away [1]; eventually these invasive cells might form clusters, which can develop to recurrent tumors. In vitro experiments in collagen gel [1] followed the clustering dynamics of different glioma cell lines. Based on the experimental data, we formulated a stochastic model for cell dynamics, which identified two mechanisms of clustering. First, there is a critical value of the strength of adhesion; above the threshold, large clusters grow from a homogeneous suspension of cells; below it, the system remains homogeneous, similarly to the ordinary phase separation. Second, when cells form a cluster, there is evidence that their proliferation rate increases. We confirmed the theoretical predictions in a separate cell migration experiment on a substrate and found that both mechanisms are crucial for cluster formation and growth [2]. In addition to their medical importance, these phenomena present exciting examples of pattern formation and collective cell behavior in intrinsically non-equilibrium systems [3]. [4pt] [1] A. M. Stein et al, Biophys. J., 92, 356 (2007). [0pt] [2] E. Khain et al, EPL 88, 28006 (2009). [0pt] [3] E. Khain et al, Phys. Rev. E. 83, 031920 (2011).
Diesel engine exhaust accelerates plaque formation in a mouse model of Alzheimer's disease.
Hullmann, Maja; Albrecht, Catrin; van Berlo, Damiën; Gerlofs-Nijland, Miriam E; Wahle, Tina; Boots, Agnes W; Krutmann, Jean; Cassee, Flemming R; Bayer, Thomas A; Schins, Roel P F
2017-08-30
Increasing evidence from toxicological and epidemiological studies indicates that the central nervous system is an important target for ambient air pollutants. We have investigated whether long-term inhalation exposure to diesel engine exhaust (DEE), a dominant contributor to particulate air pollution in urban environments, can aggravate Alzheimer's Disease (AD)-like effects in female 5X Familial AD (5XFAD) mice and their wild-type female littermates. Following 3 and 13 weeks exposures to diluted DEE (0.95 mg/m 3 , 6 h/day, 5 days/week) or clean air (controls) behaviour tests were performed and amyloid-β (Aβ) plaque formation, pulmonary histopathology and systemic inflammation were evaluated. In a string suspension task, assessing for grip strength and motor coordination, 13 weeks exposed 5XFAD mice performed significantly less than the 5XFAD controls. Spatial working memory deficits, assessed by Y-maze and X-maze tasks, were not observed in association with the DEE exposures. Brains of the 3 weeks DEE-exposed 5XFAD mice showed significantly higher cortical Aβ plaque load and higher whole brain homogenate Aβ42 levels than the clean air-exposed 5XFAD littermate controls. After the 13 weeks exposures, with increasing age and progression of the AD-phenotype of the 5XFAD mice, DEE-related differences in amyloid pathology were no longer present. Immunohistochemical evaluation of lungs of the mice revealed no obvious genetic background-related differences in tissue structure, and the DEE exposure did not cause histopathological changes in the mice of both backgrounds. Luminex analysis of plasma cytokines demonstrated absence of sustained systemic inflammation upon DEE exposure. Inhalation exposure to DEE causes accelerated plaque formation and motor function impairment in 5XFAD transgenic mice. Our study provides further support that the brain is a relevant target for the effects of inhaled DEE and suggests that long-term exposure to this ubiquitous air
Progress In Plasma Accelerator Development for Dynamic Formation of Plasma Liners
NASA Technical Reports Server (NTRS)
Thio, Y. C. Francis; Eskridge, Richard; Martin, Adam; Smith, James; Lee, Michael; Cassibry, Jason T.; Griffin, Steven; Rodgers, Stephen L. (Technical Monitor)
2002-01-01
An experimental plasma accelerator for magnetic target fusion (MTF) applications under development at the NASA Marshall Space Flight Center is described. The accelerator is a coaxial pulsed plasma thruster (Figure 1). It has been tested experimentally and plasma jet velocities of approx.50 km/sec have been obtained. The plasma jet has been photographed with 10-ns exposure times to reveal a stable and repeatable plasma structure (Figure 2). Data for velocity profile information has been obtained using light pipes and magnetic probes embedded in the gun walls to record the plasma and current transit respectively at various barrel locations. Preliminary spatially resolved spectral data and magnetic field probe data are also presented. A high speed triggering system has been developed and tested as a means of reducing the gun "jitter". This jitter is being characterized and future work for second generation "ultra-low jitter" gun development is being identified.
Kato, Shumei; Goodman, Aaron; Walavalkar, Vighnesh; Barkauskas, Donald A; Sharabi, Andrew; Kurzrock, Razelle
2017-08-01
Purpose: Checkpoint inhibitors demonstrate salutary anticancer effects, including long-term remissions. PD-L1 expression/amplification, high mutational burden, and mismatch repair deficiency correlate with response. We have, however, observed a subset of patients who appear to be "hyperprogressors," with a greatly accelerated rate of tumor growth and clinical deterioration compared with pretherapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with "hyperprogression" after immunotherapy. Experimental Design: Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed ( N = 155). We defined hyperprogression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared with preimmunotherapy imaging, and >2-fold increase in progression pace. Results: Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared with the 2 months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF <2 months. Two of 10 patients with EGFR alterations were also hyperprogressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). Conclusions: Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for hyperprogression on immunotherapy. Further investigation is urgently needed. Clin Cancer Res; 23(15); 4242-50. ©2017 AACR .
Biochemomechanical poroelastic theory of avascular tumor growth
NASA Astrophysics Data System (ADS)
Xue, Shi-Lei; Li, Bo; Feng, Xi-Qiao; Gao, Huajian
2016-09-01
Tumor growth is a complex process involving genetic mutations, biochemical regulations, and mechanical deformations. In this paper, a thermodynamics-based nonlinear poroelastic theory is established to model the coupling among the mechanical, chemical, and biological mechanisms governing avascular tumor growth. A volumetric growth law accounting for mechano-chemo-biological coupled effects is proposed to describe the development of solid tumors. The regulating roles of stresses and nutrient transport in the tumor growth are revealed under different environmental constraints. We show that the mechano-chemo-biological coupling triggers anisotropic and heterogeneous growth, leading to the formation of layered structures in a growing tumor. There exists a steady state in which tumor growth is balanced by resorption. The influence of external confinements on tumor growth is also examined. A phase diagram is constructed to illustrate how the elastic modulus and thickness of the confinements jointly dictate the steady state of tumor volume. Qualitative and quantitative agreements with experimental observations indicate the developed model is capable of capturing the essential features of avascular tumor growth in various environments.
The effect of stochastic re-acceleration on the energy spectrum of shock-accelerated protons
DOE Office of Scientific and Technical Information (OSTI.GOV)
Afanasiev, Alexandr; Vainio, Rami; Kocharov, Leon
2014-07-20
The energy spectra of particles in gradual solar energetic particle (SEP) events do not always have a power-law form attributed to the diffusive shock acceleration mechanism. In particular, the observed spectra in major SEP events can take the form of a broken (double) power law. In this paper, we study the effect of a process that can modify the power-law spectral form produced by the diffusive shock acceleration: the stochastic re-acceleration of energetic protons by enhanced Alfvénic turbulence in the downstream region of a shock wave. There are arguments suggesting that this process can be important when the shock propagatesmore » in the corona. We consider a coronal magnetic loop traversed by a shock and perform Monte Carlo simulations of interactions of shock-accelerated protons with Alfvén waves in the loop. The wave-particle interactions are treated self-consistently, so the finiteness of the available turbulent energy is taken into account. The initial energy spectrum of particles is taken to be a power law. The simulations reveal that the stochastic re-acceleration leads either to the formation of a spectrum that is described in a wide energy range by a power law (although the resulting power-law index is different from the initial one) or to a broken power-law spectrum. The resulting spectral form is determined by the ratio of the energy density of shock-accelerated protons to the wave energy density in the shock's downstream region.« less
Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2
2015-05-01
Award Number: W81XWH-13-1-0093 TITLE: Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2 PRINCIPAL INVESTIGATOR: James F...Genetic and Functional Heterogeneity of Tumors in Neurofibromatosis 2 5a. CONTRACT NUMBER W81XWH-13-1-0093 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...confirm genes and processes that contribute to NF2 tumor formation and assess their effects on cellular phenotypes. 15. SUBJECT TERMS Neurofibromatosis
Preferential tumor cellular uptake and retention of indocyanine green for in vivo tumor imaging.
Onda, Nobuhiko; Kimura, Masayuki; Yoshida, Toshinori; Shibutani, Makoto
2016-08-01
Indocyanine green (ICG) is a fluorescent agent approved for clinical applications by the Food and Drug Administration and European Medicines Agency. This study examined the mechanism of tumor imaging using intravenously administered ICG. The in vivo kinetics of intravenously administered ICG were determined in tumor xenografts using microscopic approaches that enabled both spatio-temporal and high-magnification analyses. The mechanism of ICG-based tumor imaging was examined at the cellular level in six phenotypically different human colon cancer cell lines exhibiting different grades of epithelioid organization. ICG fluorescence imaging detected xenograft tumors, even those < 1 mm in size, based on their preferential cellular uptake and retention of the dye following its rapid tissue-non-specific delivery, in contrast to its rapid clearance by normal tissue. Live-cell imaging revealed that cellular ICG uptake is temperature-dependent and occurs after ICG binding to the cellular membrane, a pattern suggesting endocytic uptake as the mechanism. Cellular ICG uptake correlated inversely with the formation of tight junctions. Intracellular ICG was entrapped in the membrane traffic system, resulting in its slow turnover and prolonged retention by tumor cells. Our results suggest that tumor-specific imaging by ICG involves non-specific delivery of the dye to tissues followed by preferential tumor cellular uptake and retention. The tumor cell-preference of ICG is driven by passive tumor cell-targeting, the inherent ability of ICG to bind to cell membranes, and the high endocytic activity of tumor cells in association with the disruption of their tight junctions. © 2016 UICC.
Xu, X; Ehdaie, B; Ohara, N; Yoshino, T; Deng, C-X
2010-02-04
Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.
Gao, Zhiqiang; Zheng, Junfeng; Chen, Lian
2017-01-01
Ultrasonic accelerated the asparagine-glucose non-enzymatic browning reaction with significant decrease of glucose and asparagine concentrations, and marked increase of intermediate products (UV-absorbance value at 294nm, Abs 294 ), melanoidins (UV-absorbance value at 420nm, Abs 420 ) and in vitro antioxidant activity (DPPH free radical scavenging activity). As the ultrasonic intensity was 17.83W/cm 2 , the asparagine-glucose solution's Abs 294 , Abs 420 and antioxidant activity increased from 0 to 1.26, 0.88 and 21.56%, respectively, and the glucose and asparagine concentrations of the asparagine-glucose solution reduced 58.97 and 12.57%, respectively. The high performance liquid chromatography (HPLC)-Diode Array Detector (DAD) analyses showed that no acrylamide was detected after 50-min ultrasonic reaction. This study suggested that ultrasonic at higher intensity was a potential method to accelerate the non-enzymatic browning reaction in the asparagine-glucose solution without acrylamide production. Copyright © 2016 Elsevier B.V. All rights reserved.
Heme oxygenase-1 system and gastrointestinal tumors
Zhu, Xiao; Fan, Wen-Guo; Li, Dong-Pei; Lin, Marie CM; Kung, Hsiangfu
2010-01-01
Heme oxygenase-1 (HO-1) system catabolizes heme into three products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in many physiological and pathophysiological processes. A great deal of data has demonstrated the roles of HO-1 in the formation, growth and metastasis of tumors. The interest in this system by investigators involved in gastrointestinal tumors is fairly recent, and few papers on HO-1 have touched upon this subject. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal tumors studied to date. The implications for possible therapeutic manipulation of HO-1 in gastrointestinal tumors are also discussed. PMID:20518085
Cell biological mechanisms of multidrug resistance in tumors.
Simon, S M; Schindler, M
1994-04-26
Multidrug resistance (MDR) is a generic term for the variety of strategies tumor cells use to evade the cytotoxic effects of anticancer drugs. MDR is characterized by a decreased sensitivity of tumor cells not only to the drug employed for chemotherapy but also to a broad spectrum of drugs with neither obvious structural homology nor common targets. This pleiotropic resistance is one of the major obstacles to the successful treatment of tumors. MDR may result from structural or functional changes at the plasma membrane or within the cytoplasm, cellular compartments, or nucleus. Molecular mechanisms of MDR are discussed in terms of modifications in detoxification and DNA repair pathways, changes in cellular sites of drug sequestration, decreases in drug-target affinity, synthesis of specific drug inhibitors within cells, altered or inappropriate targeting of proteins, and accelerated removal or secretion of drugs.
Anisimov, V N; Khavinsov, V Kh; Alimova, I N; Provintsiali, M; Manchini, R; Francheski, K
2002-02-01
Female transgenic FVB mice carrying breast cancer gene HER-2/neu were monthly injected with Vilon or Epithalon (1 microgram subcutaneously for 5 consecutive days) starting from the 2nd month of life. Epithalon markedly inhibited neoplasm development: the maximum size of breast adenocarcinomas was 33% lower than in the control (p < 0.05). The intensity of HER-2/neu mRNA expression in breast tumors of Epithalon-treated mice was 3.7 times lower than in control animals. These results indicate that Epithalon inhibits breast tumor development in transgenic mice, which is probably related to suppression of HER-2/neu expression.
Kim, MunJu; Reed, Damon; Rejniak, Katarzyna A.
2014-01-01
Cyclin-dependent kinases (CDKs) are vital in regulating cell cycle progression, and, thus, in highly proliferating tumor cells CDK inhibitors are gaining interest as potential anticancer agents. Clonogenic assay experiments are frequently used to determine drug efficacy against the survival and proliferation of cancer cells. While the anticancer mechanisms of drugs are usually described at the intracellular single-cell level, the experimental measurements are sampled from the entire cancer cell population. This approach may lead to discrepancies between the experimental observations and theoretical explanations of anticipated drug mechanisms. To determine how individual cell responses to drugs that inhibit CDKs affect the growth of cancer cell populations, we developed a spatially explicit hybrid agent-based model. In this model, each cell is equipped with internal cell cycle regulation mechanisms, but it is also able to interact physically with its neighbors. We model cell cycle progression, focusing on the G1 and G2/M cell cycle checkpoints, as well as on related essential components, such as CDK1, CDK2, cell size, and DNA damage. We present detailed studies of how the emergent properties (e.g., cluster formation) of an entire cell population depend on altered physical and physiological parameters. We analyze the effects of CDK1 and CKD2 inhibitors on population growth, time-dependent changes in cell cycle distributions, and the dynamic evolution of spatial cell patterns. We show that cell cycle inhibitors that cause cell arrest at different cell cycle phases are not necessarily synergistically super-additive. Finally, we demonstrate that the physical aspects of cell population growth, such as the formation of tight cell clusters versus dispersed colonies, alter the efficacy of cell cycle inhibitors, both in 2D and 3D simulations. This finding may have implications for interpreting the treatment efficacy results of in vitro experiments, in which treatment is
CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling.
Kang, J M; Park, S; Kim, S J; Hong, H Y; Jeong, J; Kim, H-S; Kim, S-J
2012-12-13
Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-β (TGF-β) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-β target genes, PAI-I and CDK inhibitors such as p15(INK4b) and p21(Cip1). Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-β transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-β tumor suppressor activity.
The Significance of Epithelial-to-Mesenchymal Transition for Circulating Tumor Cells
Kölbl, Alexandra C.; Jeschke, Udo; Andergassen, Ulrich
2016-01-01
Epithelial to mesenchymal transition (EMT) is a process involved in embryonic development, but it also plays a role in remote metastasis formation in tumor diseases. During this process cells lose their epithelial features and adopt characteristics of mesenchymal cells. Thereby single tumor cells, which dissolve from the primary tumor, are enabled to invade the blood vessels and travel throughout the body as so called “circulating tumor cells” (CTCs). After leaving the blood stream the reverse process of EMT, the mesenchymal to epithelial transition (MET) helps the cells to seed in different tissues, thereby generating the bud of metastasis formation. As metastasis is the main reason for tumor-associated death, CTCs and the EMT process are in the focus of research in recent years. This review summarizes what was already found out about the molecular mechanisms driving EMT, the consequences of EMT for tumor cell detection, and suitable markers for the detection of CTCs which underwent EMT. The research work done in this field could open new roads towards combating cancer. PMID:27529216
Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue.
Ho, Yi-Ju; Yeh, Chih-Kuang
2017-01-01
Solid tumors with poorly perfused regions reveal some of the treatment limitations that restrict drug delivery and therapeutic efficacy. Acoustic droplet vaporization (ADV) has been applied to directly disrupt vessels and release nanodroplets, ADV-generated bubbles (ADV-Bs), and drugs into tumor tissue. In this study, we investigated the in vivo behavior of ADV-Bs stimulated by US, and evaluated the possibility of moving intertissue ADV-Bs into the poorly perfused regions of solid tumors. Intravital imaging revealed intertissue ADV-B formation, movement, and cavitation triggered by US, where the distance of intertissue ADV-B movement was 33-99 µm per pulse. When ADV-Bs were applied to tumor cells, the cell membrane was damaged, increasing cellular permeability or inducing cell death. The poorly perfused regions within solid tumors show enhancement due to ADV-B accumulation after application of US-triggered ADV-B. The intratumoral nanodroplet or ADV-B distribution around the poorly perfused regions with tumor necrosis or hypoxia were demonstrated by histological assessment. ADV-B formation, movement and cavitation could induce cell membrane damage by mechanical force providing a mechanism to overcome treatment limitations in poorly perfused regions of tumors.
Theranostic Performance of Acoustic Nanodroplet Vaporization-Generated Bubbles in Tumor Intertissue
Ho, Yi-Ju; Yeh, Chih-Kuang
2017-01-01
Solid tumors with poorly perfused regions reveal some of the treatment limitations that restrict drug delivery and therapeutic efficacy. Acoustic droplet vaporization (ADV) has been applied to directly disrupt vessels and release nanodroplets, ADV-generated bubbles (ADV-Bs), and drugs into tumor tissue. In this study, we investigated the in vivo behavior of ADV-Bs stimulated by US, and evaluated the possibility of moving intertissue ADV-Bs into the poorly perfused regions of solid tumors. Intravital imaging revealed intertissue ADV-B formation, movement, and cavitation triggered by US, where the distance of intertissue ADV-B movement was 33-99 µm per pulse. When ADV-Bs were applied to tumor cells, the cell membrane was damaged, increasing cellular permeability or inducing cell death. The poorly perfused regions within solid tumors show enhancement due to ADV-B accumulation after application of US-triggered ADV-B. The intratumoral nanodroplet or ADV-B distribution around the poorly perfused regions with tumor necrosis or hypoxia were demonstrated by histological assessment. ADV-B formation, movement and cavitation could induce cell membrane damage by mechanical force providing a mechanism to overcome treatment limitations in poorly perfused regions of tumors. PMID:28529631
Velmurugan, Ramraj; Ramakrishnan, Sreevidhya; Kim, Mingin
2018-01-01
Despite the rapidly expanding use of antibody‐based therapeutics to treat cancer, knowledge of the cellular processes following phagocytosis of antibody‐opsonized tumor cells is limited. Here we report the formation of a phagosome‐associated vacuole that is observed in macrophages as these degradative compartments mature following phagocytosis of HER2‐positive cancer cells in the presence of the HER2‐specific antibody, trastuzumab. We demonstrate that this vacuole is a distinct organelle that is closely apposed to the phagosome. Furthermore, the size of the phagosome‐associated vacuole is increased by inhibition of the mTOR pathway. Collectively, the identification of this vacuolar compartment has implications for understanding the subcellular trafficking processes leading to the destruction of phagocytosed, antibody‐opsonized cancer cells by macrophages. PMID:29437282
Li, Yan; Liu, Ruiyuan; Shi, Yuanjie; Zhang, Zhenzhong; Zhang, Xin
2015-01-01
For efficient delivery of small interfering RNA (siRNA) to the target diseased site in vivo, it is important to design suitable vehicles to control the blood circulation of siRNA. It has been shown that surface modification of cationic liposome/siRNA complexes (lipoplexes) with polyethylene glycol (PEG) could enhance the circulation time of lipoplexes. However, the first injection of PEGylated lipoplexes in vivo induces accelerated blood clearance and enhances hepatic accumulation of the following injected PEGylated lipoplexes, which is known as the accelerated blood clearance (ABC) phenomenon. Herein, we developed zwitterionic poly(carboxybetaine) (PCB) modified lipoplexes for the delivery of siRNA therapeutics, which could avoid protein adsorption and enhance the stability of lipoplexes as that for PEG. Quite different from the PEGylation, the PCBylated lipoplexes could avoid ABC phenomenon, which extended the blood circulation time and enhanced the tumor accumulation of lipoplexes in vivo. After accumulation in tumor site, the PCBylation could promote the cellular uptake and endosomal/lysosomal escape of lipoplexes due to its unique chemical structure and pH-sensitive ability. With excellent tumor accumulation, cellular uptake and endosomal/lysosomal escape abilities, the PCBylated lipoplexes significantly inhibited tumor growth and induced tumor cell apoptosis.
Omori, Keisuke; Morikawa, Teppei; Kunita, Akiko; Nakamura, Tatsuro; Aritake, Kosuke; Urade, Yoshihiro; Fukayama, Masashi; Murata, Takahisa
2018-01-01
Endothelial cells (ECs) are a key component of the tumor microenvironment. They have abnormal characteristics compared to the ECs in normal tissues. Here, we found a marked increase in lipocalin-type prostaglandin D synthase (L-PGDS) mRNA (Ptgds) expression in ECs isolated from mouse melanoma. Immunostaining of mouse melanoma revealed expression of L-PGDS protein in the ECs. In situ hybridization also showed L-PGDS (PTGDS) mRNA expression in the ECs of human melanoma and oral squamous cell carcinoma. In vitro experiments showed that stimulation with tumor cell-derived IL-1 and TNF-α increased L-PGDS mRNA expression and its product prostaglandin D 2 (PGD 2 ) in human normal ECs. We also investigated the contribution of L-PGDS-PGD 2 to tumor growth and vascularization. Systemic or EC-specific deficiency of L-PGDS accelerated the growth of melanoma in mice, whereas treatment with an agonist of the PGD 2 receptor, DP1 (BW245C, 0.1 mg/kg, injected intraperitoneally twice daily), attenuated it. Morphological and in vivo studies showed that endothelial L-PGDS deficiency resulted in functional changes of tumor ECs such as accelerated vascular hyperpermeability, angiogenesis, and endothelial-to-mesenchymal transition (EndMT) in tumors, which in turn reduced tumor cell apoptosis. These observations suggest that tumor cell-derived inflammatory cytokines increase L-PGDS expression and subsequent PGD 2 production in the tumor ECs. This PGD 2 acts as a negative regulator of the tumorigenic changes in tumor ECs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The perivascular niche regulates breast tumor dormancy
Peinado, Héctor; Mori, Hidetoshi; Matei, Irina R.; Evason, Kimberley J.; Brazier, Hélène; Almeida, Dena; Koller, Antonius; Hajjar, Katherine A.; Stainier, Didier Y.R.; Chen, Emily I.; Lyden, David
2013-01-01
In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant, and what ‘wakes them up’, are fundamental problems in tumor biology. To address these questions, we utilized metastasis assays in mice to show that dormant DTCs reside upon microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-β1 and periostin as tumor-promoting, endothelial tip cell-derived factors. Our work reveals that stable microvasculature constitutes a ‘dormant niche,’ whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID:23728425
[Tumor-like bone lesions of the forearm after karate training].
Steckel, H; Oldenburg, M; Klinger, H M; Schultz, W
2005-03-01
Differentiation between malignant bone tumors and tumor-like lesions after repetitive microtrauma following sport activities can be difficult just using radiographic methods. We present the case of a fifteen year old karate fighter, who was examined by imaging diagnostics because of a progressive swelling and pain in the distal right forearm. A tumor-like appearance with bone mass formation in the x-ray, an enhancement in the surrounding tissue shown in the MRI and an increased activity in the bone scintigraphy made the diagnosis of an osteosarcoma very likely. Blood tests were not helpful. Only the evaluation of a bone biopsy could demonstrate hypertrophic reparative bone formation after multiple osseous microtrauma. Cast immobilisation reduced the osseous alteration. With the start of the training the swelling reappeared again but then finally vanished after modifying the training technique. The case demonstrates that even modern imaging techniques cannot always distinguish between tumor and tumor-like lesions caused by sports. It also stresses the importance of a correct technique in sports like karate.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Suzuki, Yuka; Tada-Oikawa, Saeko; Ichihara, Gaku
Metal oxide nanoparticles are widely used in industry, cosmetics, and biomedicine. However, the effects of exposure to these nanoparticles on the cardiovascular system remain unknown. The present study investigated the effects of nanosized TiO{sub 2} and ZnO particles on the migration and adhesion of monocytes, which are essential processes in atherosclerogenesis, using an in vitro set-up of human umbilical vein endothelial cells (HUVECs) and human monocytic leukemia cells (THP-1). We also examined the effects of exposure to nanosized metal oxide particles on macrophage cholesterol uptake and foam cell formation. The 16-hour exposure to ZnO particles increased the level of monocytemore » chemotactic protein-1 (MCP-1) and induced the migration of THP-1 monocyte mediated by increased MCP-1. Exposure to ZnO particles also induced adhesion of THP-1 cells to HUVECs. Moreover, exposure to ZnO particles, but not TiO{sub 2} particles, upregulated the expression of membrane scavenger receptors of modified LDL and increased cholesterol uptake in THP-1 monocytes/macrophages. In the present study, we found that exposure to ZnO particles increased macrophage cholesterol uptake, which was mediated by an upregulation of membrane scavenger receptors of modified LDL. These results suggest that nanosized ZnO particles could potentially enhance atherosclerogenesis and accelerate foam cell formation. - Highlights: • Effects of metal oxide nanoparticles on foam cell formation were investigated. • Exposure to ZnO nanoparticles induced migration and adhesion of monocytes. • Exposure to ZnO nanoparticles increased macrophage cholesterol uptake. • Expression of membrane scavenger receptors of modified LDL was also increased. • These effects were not observed after exposure to TiO{sub 2} nanoparticles.« less
Naked singularities as particle accelerators
DOE Office of Scientific and Technical Information (OSTI.GOV)
Patil, Mandar; Joshi, Pankaj S.
We investigate here the particle acceleration by naked singularities to arbitrarily high center of mass energies. Recently it has been suggested that black holes could be used as particle accelerators to probe the Planck scale physics. We show that the naked singularities serve the same purpose and probably would do better than their black hole counterparts. We focus on the scenario of a self-similar gravitational collapse starting from a regular initial data, leading to the formation of a globally naked singularity. It is seen that when particles moving along timelike geodesics interact and collide near the Cauchy horizon, the energymore » of collision in the center of mass frame will be arbitrarily high, thus offering a window to Planck scale physics.« less
Cui, Nan; Yang, Wen-Ting; Zheng, Peng-Sheng
2016-01-01
Slug (Snai2) has been demonstrated to act as an oncogene or tumor suppressor in different human cancers, but the function of Slug in cervical cancer remains poorly understood. In this study, we demonstrated that Slug could suppress the proliferation of cervical cancer cells in vitro and tumor formation in vivo. Further experiments found that Slug could trans-suppress the expression of Akt1/p-Akt1 by binding to E-box motifs in the promoter of the Akt1 gene and then inhibit the cell proliferation and tumor formation of cervical cancer cells by up-regulating p21/p27 and/or down-regulating the activity of the Wnt/β-catenin signaling pathway. Therefore, Slug acts as a tumor suppressor during cervical carcinogenesis. PMID:27036045
Accelerated Threshold Fatigue Crack Growth Effect-Powder Metallurgy Aluminum Alloy
NASA Technical Reports Server (NTRS)
Piascik, R. S.; Newman, J. A.
2002-01-01
Fatigue crack growth (FCG) research conducted in the near threshold regime has identified a room temperature creep crack growth damage mechanism for a fine grain powder metallurgy (PM) aluminum alloy (8009). At very low (Delta) K, an abrupt acceleration in room temperature FCG rate occurs at high stress ratio (R = K(sub min)/K(sub max)). The near threshold accelerated FCG rates are exacerbated by increased levels of K(sub max) (K(sub max) = 0.4 K(sub IC)). Detailed fractographic analysis correlates accelerated FCG with the formation of crack-tip process zone micro-void damage. Experimental results show that the near threshold and K(sub max) influenced accelerated crack growth is time and temperature dependent.
Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis
Ortiz, Berenice; White, Julie R.; Wu, Wei H.; Chan, Timothy A.
2014-01-01
PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly, heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss. PMID:25138050
The Student Course Experience among Online, Accelerated, and Traditional Courses
ERIC Educational Resources Information Center
Bielitz, Colleen L.
2016-01-01
The demand by the public for a wider variety of course formats has led to complexity in determining a course's optimal delivery format as many faculty members still believe that online and accelerated courses do not offer students an equivalent experience to traditional face to face instruction. The purpose of this quantitative, comparative study…
Jablonska, Jadwiga; Leschner, Sara; Westphal, Kathrin; Lienenklaus, Stefan; Weiss, Siegfried
2010-04-01
Angiogenesis is a hallmark of malignant neoplasias, as the formation of new blood vessels is required for tumors to acquire oxygen and nutrients essential for their continued growth and metastasis. However, the signaling pathways leading to tumor vascularization are not fully understood. Here, using a transplantable mouse tumor model, we have demonstrated that endogenous IFN-beta inhibits tumor angiogenesis through repression of genes encoding proangiogenic and homing factors in tumor-infiltrating neutrophils. We determined that IFN-beta-deficient mice injected with B16F10 melanoma or MCA205 fibrosarcoma cells developed faster-growing tumors with better-developed blood vessels than did syngeneic control mice. These tumors displayed enhanced infiltration by CD11b+Gr1+ neutrophils expressing elevated levels of the genes encoding the proangiogenic factors VEGF and MMP9 and the homing receptor CXCR4. They also expressed higher levels of the transcription factors c-myc and STAT3, known regulators of VEGF, MMP9, and CXCR4. In vitro, treatment of these tumor-infiltrating neutrophils with low levels of IFN-beta restored expression of proangiogenic factors to control levels. Moreover, depletion of these neutrophils inhibited tumor growth in both control and IFN-beta-deficient mice. We therefore suggest that constitutively produced endogenous IFN-beta is an important mediator of innate tumor surveillance. Further, we believe our data help to explain the therapeutic effect of IFN treatment during the early stages of cancer development.
Efficient coarse simulation of a growing avascular tumor
Kavousanakis, Michail E.; Liu, Ping; Boudouvis, Andreas G.; Lowengrub, John; Kevrekidis, Ioannis G.
2013-01-01
The subject of this work is the development and implementation of algorithms which accelerate the simulation of early stage tumor growth models. Among the different computational approaches used for the simulation of tumor progression, discrete stochastic models (e.g., cellular automata) have been widely used to describe processes occurring at the cell and subcell scales (e.g., cell-cell interactions and signaling processes). To describe macroscopic characteristics (e.g., morphology) of growing tumors, large numbers of interacting cells must be simulated. However, the high computational demands of stochastic models make the simulation of large-scale systems impractical. Alternatively, continuum models, which can describe behavior at the tumor scale, often rely on phenomenological assumptions in place of rigorous upscaling of microscopic models. This limits their predictive power. In this work, we circumvent the derivation of closed macroscopic equations for the growing cancer cell populations; instead, we construct, based on the so-called “equation-free” framework, a computational superstructure, which wraps around the individual-based cell-level simulator and accelerates the computations required for the study of the long-time behavior of systems involving many interacting cells. The microscopic model, e.g., a cellular automaton, which simulates the evolution of cancer cell populations, is executed for relatively short time intervals, at the end of which coarse-scale information is obtained. These coarse variables evolve on slower time scales than each individual cell in the population, enabling the application of forward projection schemes, which extrapolate their values at later times. This technique is referred to as coarse projective integration. Increasing the ratio of projection times to microscopic simulator execution times enhances the computational savings. Crucial accuracy issues arising for growing tumors with radial symmetry are addressed by
FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal.
Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L; Choi, Hyun-Jin; Hansen, Jean M; Dalton, Heather J; Stone, Rebecca L; Cho, Min Soon; Nick, Alpa M; Nagaraja, Archana S; Gutschner, Tony; Gharpure, Kshipra M; Mangala, Lingegowda S; Rupaimoole, Rajesha; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N; Wu, Sherry Y; Pecot, Chad V; Burns, Alan R; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K
2016-05-02
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management.
FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal
Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L.; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.
2016-01-01
Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283
Parlo, R A; Coleman, P S
1986-04-29
Viable tissue slices from rat liver and Morris hepatoma 3924A were compared as to their ability to incorporate carbons from [U-14 C]pyruvate into newly synthesized cholesterol versus CO2. By 4 h, the tumor slice incubation had incorporated over 6-fold more pyruvate carbons into the sterol than into CO2, relative to the normal liver slice incubation, per g tissue protein. However, the presence of the mitochondrial citrate exchange carrier inhibitor 1,2,3-benzenetricarboxylate in the incubation inhibited the formation of [14C]cholesterol, while simultaneously leading to an increase in the rate of 14CO2 production in the tumor. In the normal liver system by contrast, benzenetricarboxylate also inhibited [14C]cholesterol formation, but had hardly any effect on the already high rate of 14CO2 production. The ability of benzenetricarboxylate to inhibit the rapid carbon flux from pyruvate to cholesterol, and to steer the metabolic flow of carbons toward oxidative decarboxylation via the Krebs cycle in whole, viable tumor tissue, indirectly emphasizes the importance of the mitochondrial citrate exchange carrier in supporting the decontrol of cholesterogenesis de novo in tumors by accelerating the supply of lipogenic precursor carbons to the tumor cytosol. These studies may be therefore interpreted as extensions, to the level of whole-cell metabolism, of the concept of a persistent 'truncated' Krebs cycle in the mitochondria of metastatic cancer tissue. This concept states, in part, that a rapid efflux of mitochondrially generated citrate would operate preferentially in tumors, and thus provide carbons continuously to the cytoplasmic compartment where the well-established deregulated pathway of cholesterogenesis occurs (Parlo, R.A. and Coleman, P.S. (1984) J. Biol. Chem. 259, 9997-10003; Coleman, P.S. and Lavietes, B.B. (1981) CRC Crit. Rev. Biochem. 11, 341-393).
HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
Aits, Sonja; Gustafsson, Lotta; Hallgren, Oskar; Brest, Patrick; Gustafsson, Mattias; Trulsson, Maria; Mossberg, Ann-Kristin; Simon, Hans-Uwe; Mograbi, Baharia; Svanborg, Catharina
2009-03-01
HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
Acceleration modules in linear induction accelerators
NASA Astrophysics Data System (ADS)
Wang, Shao-Heng; Deng, Jian-Jun
2014-05-01
The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.
Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines.
Kishimoto, Takuya Evan; Yashima, Shoko; Nakahira, Rei; Onozawa, Eri; Azakami, Daigo; Ujike, Makoto; Ochiai, Kazuhiko; Ishiwata, Toshiyuki; Takahashi, Kimimasa; Michishita, Masaki
2017-07-07
Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 10 3 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis.
Human Uterine Leiomyoma Stem/Progenitor Cells Expressing CD34 and CD49b Initiate Tumors In Vivo
Ono, Masanori; Moravek, Molly B.; Coon, John S.; Navarro, Antonia; Monsivais, Diana; Dyson, Matthew T.; Druschitz, Stacy A.; Malpani, Saurabh S.; Serna, Vanida A.; Qiang, Wenan; Chakravarti, Debabrata; Kim, J. Julie; Bulun, Serdar E.
2015-01-01
Context: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Using a dye-exclusion technique, we previously identified a side population of leiomyoma cells exhibiting stem cell characteristics. However, unless mixed with mature myometrial cells, these leiomyoma side population cells did not survive or grow well in vitro or in vivo. Objective: The objective of this study was to identify cell surface markers to isolate leiomyoma stem/progenitor cells. Design: Real-time PCR screening was used to identify cell surface markers preferentially expressed in leiomyoma side population cells. In vitro colony-formation assay and in vivo tumor-regeneration assay were used to demonstrate functions of leiomyoma stem/progenitor cells. Results: We found significantly elevated CD49b and CD34 gene expression in side population cells compared with main population cells. Leiomyoma cells were sorted into three populations based on the expression of CD34 and CD49b: CD34+/CD49b+, CD34+/CD49b−, and CD34−/CD49b− cells, with the majority of the side population cells residing in the CD34+/CD49b+ fraction. Of these populations, CD34+/CD49b+ cells expressed the lowest levels of estrogen receptor-α, progesterone receptor, and α-smooth muscle actin, but the highest levels of KLF4, NANOG, SOX2, and OCT4, confirming their more undifferentiated status. The stemness of CD34+/CD49b+ cells was also demonstrated by their strongest in vitro colony-formation capacity and in vivo tumor-regeneration ability. Conclusions: CD34 and CD49b are cell surface markers that can be used to enrich a subpopulation of leiomyoma cells possessing stem/progenitor cell properties; this technique will accelerate efforts to develop new therapies for uterine leiomyoma. PMID:25658015
A Mouse Ependymoma Model Provides Molecular Insights into Tumor Formation.
Pajtler, Kristian W; Pfister, Stefan M
2018-06-26
Ozawa et al. present a murine tumor model resembling the most frequent molecular group of human supratentorial ependymoma, ST-EPN-RELA. Their model shows RELA-fusion-based de novo ependymoma tumorigenesis in the forebrain derived from neural stem cells. Copyright © 2018. Published by Elsevier Inc.
Formation of solid tumors by a single multinucleated cancer cel
Weihua, Zhang; Lin, Qingtang; Ramoth, Asa J.; Fan, Dominic; Fidler, Isaiah J.
2011-01-01
BACKGROUND Large multinucleated cells (MNC) commonly exist in tumorigenic cancer cell lines widely used in research, but their contributions to tumorigenesis are unknown. METHODS In this study, we characterized MNCs in the murine fibrosarcoma cell line UV-2237 in vitro and in vivo at a single cell level. RESULTS We observed that MNCs originated from a rare subpopulation of mononuclear cells; MNCs were positive for a senescent marker, β-galacosidase (SA-β-Gal); MNCs were responsible for the majority of clonogenic activity when cultured in hard agar; MNCs were more resistant to chemotherapeutic agents than were mononuclear cells; MNCs could undergo asymmetric division (producing mononuclear cells) and self-renewal in vitro and in vivo; and, most importantly a single MNC produced orthotopic subcutaneous tumors (composed mainly of mononuclear cells) that gave rise to spontaneous lung metastases in nude mice. CONCLUSIONS MNCs can be growth-arrested under stress, are highly resistant to chemotherapy, and can generate clonal orthotopic metastatic tumors PMID:21365635
A systematic FPGA acceleration design for applications based on convolutional neural networks
NASA Astrophysics Data System (ADS)
Dong, Hao; Jiang, Li; Li, Tianjian; Liang, Xiaoyao
2018-04-01
Most FPGA accelerators for convolutional neural network are designed to optimize the inner acceleration and are ignored of the optimization for the data path between the inner accelerator and the outer system. This could lead to poor performance in applications like real time video object detection. We propose a brand new systematic FPFA acceleration design to solve this problem. This design takes the data path optimization between the inner accelerator and the outer system into consideration and optimizes the data path using techniques like hardware format transformation, frame compression. It also takes fixed-point, new pipeline technique to optimize the inner accelerator. All these make the final system's performance very good, reaching about 10 times the performance comparing with the original system.
NASA Astrophysics Data System (ADS)
Milshteyn, Eugene; von Morze, Cornelius; Reed, Galen D.; Shang, Hong; Shin, Peter J.; Larson, Peder E. Z.; Vigneron, Daniel B.
2018-05-01
Acceleration of dynamic 2D (T2 Mapping) and 3D hyperpolarized 13C MRI acquisitions using the balanced steady-state free precession sequence was achieved with a specialized reconstruction method, based on the combination of low rank plus sparse and local low rank reconstructions. Methods were validated using both retrospectively and prospectively undersampled in vivo data from normal rats and tumor-bearing mice. Four-fold acceleration of 1-2 mm isotropic 3D dynamic acquisitions with 2-5 s temporal resolution and two-fold acceleration of 0.25-1 mm2 2D dynamic acquisitions was achieved. This enabled visualization of the biodistribution of [2-13C]pyruvate, [1-13C]lactate, [13C, 15N2]urea, and HP001 within heart, kidneys, vasculature, and tumor, as well as calculation of high resolution T2 maps.
Extracellular microvesicles and invadopodia mediate non-overlapping modes of tumor cell invasion
Sedgwick, Alanna E.; Clancy, James W.; Olivia Balmert, M.; D’Souza-Schorey, Crislyn
2015-01-01
Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation. On the other hand, during invasion through compliant and deformable environments, tumor cells adopt an amoeboid phenotype and release microvesicles. Notably, firm matrices do not support microvesicle release, whereas compliant matrices are not conducive to invadopodia biogenesis. Furthermore, Rac1 activation is required for invadopodia function, while its inactivation promotes RhoA activation and actomyosin contractility required for microvesicle shedding. Suppression of RhoA signaling blocks microvesicle formation but enhances the formation of invadopodia. Finally, we describe Rho-mediated pathways involved in microvesicle biogenesis through the regulation of myosin light chain phosphatase. Our findings suggest that the ability of tumor cells to switch between the aforementioned qualitatively distinct modes of invasion may allow for dissemination across different microenvironments. PMID:26458510
Zhang, Yunshu; Jiang, Junqiu; Zhao, Qingliang; Gao, YunZhi; Wang, Kun; Ding, Jing; Yu, Hang; Yao, Yue
2017-10-01
Anodic electron transfer is the predominant electricity generation process of MFCs. To accelerate anodic biofilms formation and electron transfer, 40mg/L, 80mg/L, and 120mg/L of rhamnolipid biosurfactants were added to the anolyte, resulting in an increased abiotic capacitance from 15.12F/m 2 (control) to 16.54F/m 2 , 18.00F/m 2 , and 19.39F/m 2 , respectively. Anodic biofilm formation was facilitated after dosing 40mg/L of rhamnolipids on the 7th day after inoculation, resulting in an increased anodic biofilm coverage from 0.43% to 42.51%, and an increased maximum power density from 6.92±1.18W/m 3 to 9.93±0.88W/m 3 . Furthermore, the adsorption of rhamnolipids on the anode caused the Frumkin effect, leading to a decrease of equilibrium potential from -0.43V to -0.56V, and an increase of exchange current density from 5.09×10 -3 A/m 2 to 8.72×10 -3 A/m 2 . However, electron transfer was blocked when the rhamnolipid concentration was further increased to 80mg/L, and 120mg/L. Analysis of the anodic bacterial communities revealed that rhamnolipids facilitated the enrichment of exoelectrogen, increasing the total proportion from 65% to 81%. Additionally, biosurfactants were found to have significant impacts on the composition of exoelectrogens. Copyright © 2017 Elsevier B.V. All rights reserved.
The leading cause of death from cancer is not a primary tumor but is the metastases, or invasion of tumor cells into other locations in the body, that result from it. A complex and incompletely understood process, metastatic tumor formation is thought to require several steps in which tumor cells invade the tissue surrounding the primary tumor, enter local blood vessels,
Cavitation onset caused by acceleration
Pan, Zhao; Kiyama, Akihito; Tagawa, Yoshiyuki; Daily, David J.; Thomson, Scott L.; Hurd, Randy
2017-01-01
Striking the top of a liquid-filled bottle can shatter the bottom. An intuitive interpretation of this event might label an impulsive force as the culprit in this fracturing phenomenon. However, high-speed photography reveals the formation and collapse of tiny bubbles near the bottom before fracture. This observation indicates that the damaging phenomenon of cavitation is at fault. Cavitation is well known for causing damage in various applications including pipes and ship propellers, making accurate prediction of cavitation onset vital in several industries. However, the conventional cavitation number as a function of velocity incorrectly predicts the cavitation onset caused by acceleration. This unexplained discrepancy leads to the derivation of an alternative dimensionless term from the equation of motion, predicting cavitation as a function of acceleration and fluid depth rather than velocity. Two independent research groups in different countries have tested this theory; separate series of experiments confirm that an alternative cavitation number, presented in this paper, defines the universal criteria for the onset of acceleration-induced cavitation. PMID:28739956
Cavitation onset caused by acceleration.
Pan, Zhao; Kiyama, Akihito; Tagawa, Yoshiyuki; Daily, David J; Thomson, Scott L; Hurd, Randy; Truscott, Tadd T
2017-07-24
Striking the top of a liquid-filled bottle can shatter the bottom. An intuitive interpretation of this event might label an impulsive force as the culprit in this fracturing phenomenon. However, high-speed photography reveals the formation and collapse of tiny bubbles near the bottom before fracture. This observation indicates that the damaging phenomenon of cavitation is at fault. Cavitation is well known for causing damage in various applications including pipes and ship propellers, making accurate prediction of cavitation onset vital in several industries. However, the conventional cavitation number as a function of velocity incorrectly predicts the cavitation onset caused by acceleration. This unexplained discrepancy leads to the derivation of an alternative dimensionless term from the equation of motion, predicting cavitation as a function of acceleration and fluid depth rather than velocity. Two independent research groups in different countries have tested this theory; separate series of experiments confirm that an alternative cavitation number, presented in this paper, defines the universal criteria for the onset of acceleration-induced cavitation.
Cavitation onset caused by acceleration
NASA Astrophysics Data System (ADS)
Pan, Zhao; Kiyama, Akihito; Tagawa, Yoshiyuki; Daily, David J.; Thomson, Scott L.; Hurd, Randy; Truscott, Tadd T.
2017-08-01
Striking the top of a liquid-filled bottle can shatter the bottom. An intuitive interpretation of this event might label an impulsive force as the culprit in this fracturing phenomenon. However, high-speed photography reveals the formation and collapse of tiny bubbles near the bottom before fracture. This observation indicates that the damaging phenomenon of cavitation is at fault. Cavitation is well known for causing damage in various applications including pipes and ship propellers, making accurate prediction of cavitation onset vital in several industries. However, the conventional cavitation number as a function of velocity incorrectly predicts the cavitation onset caused by acceleration. This unexplained discrepancy leads to the derivation of an alternative dimensionless term from the equation of motion, predicting cavitation as a function of acceleration and fluid depth rather than velocity. Two independent research groups in different countries have tested this theory; separate series of experiments confirm that an alternative cavitation number, presented in this paper, defines the universal criteria for the onset of acceleration-induced cavitation.
Tymoszuk, Piotr; Evens, Hanneke; Marzola, Vanessa; Wachowicz, Katarzyna; Wasmer, Marie-Helene; Datta, Sebak; Müller-Holzner, Elisabeth; Fiegl, Heidi; Böck, Günther; van Rooijen, Nico; Theurl, Igor; Doppler, Wolfgang
2014-08-01
Infiltration of a neoplasm with tumor-associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Formation Flying in Earth, Libration, and Distant Retrograde Orbits
NASA Technical Reports Server (NTRS)
Folta, David C.
2004-01-01
This slide presentation examines the current and future state of formation flying, LEO formations, control strategies for flight in the vicinity of the libration points, and distant retrograde orbit formations. This discussion of LEO formations includes background on perturbation theory/accelerations and LEO formation flying. The discussion of strategies for formation flight in the vicinity of the libration points includes libration missions and natural and controlled libration orbit formations. A reference list is included.
Compact torus accelerator as a driver for ICF
DOE Office of Scientific and Technical Information (OSTI.GOV)
Tobin, M.T.; Meier, W.R.; Morse, E.C.
1986-01-01
The authors have carried out further investigations of the technical issues associated with using a compact torus (CT) accelerator as a driver for inertial confinement fusion (ICF). In a CT accelerator, a magnetically confined, torus-shaped plasma is compressed, accelerated, and focused by two concentric electrodes. After its initial formation, the torus shape is maintained for lifetimes exceeding 1 ms by inherent poloidal and toroidal currents. Hartman suggests acceleration and focusing of such a plasma ring will not cause dissolution within certain constraints. In this study, we evaluated a point design based on an available capacitor bank energy of 9.2 MJ.more » This accelerator, which was modeled by a zero-dimensional code, produces a xenon plasma ring with a 0.73-cm radius, a velocity of 4.14 x 10/sup 9/ cm/s, and a mass of 4.42 ..mu..g. The energy of the plasma ring as it leaves the accelerator is 3.8 MJ, or 41% of the capacitor bank energy. Our studies confirm the feasibility of producing a plasma ring with the characteristics required to induce fusion in an ICF target with a gain greater than 50. The low cost and high efficiency of the CT accelerator are particularly attractive. Uncertainties concerning propagation, accelerator lifetime, and power supply must be resolved to establish the viability of the accelerator as an ICF driver.« less
Plasma Accelerator Development for Dynamic Formation of Plasma Liners: A Status Report
NASA Technical Reports Server (NTRS)
Thio, Y. C. Francis; Eskridge, Richard; Martin, Adam; Smith, James; Lee, Michael; Rodgers, Stephen L. (Technical Monitor)
2001-01-01
An experimental plasma accelerator for magnetic target fusion (MTF) applications under development at the NASA Marshall Space Flight Center is described. The accelerator is a pulsed plasma thruster and has been tested experimentally and plasma jet velocities of approximately 50 km/sec have been obtained. The plasma jet structure has been photographed with 10 ns exposure times to reveal a stable and repeatable plasma structure. Data for velocity profile information has been obtained using light pipes embedded in the gun walls to record the plasma transit at various barrel locations. Preliminary spatially resolved spectral data and magnetic field probe data are also presented. A high speed triggering system has been developed and tested as a means of reducing the gun "jitter". This jitter is being characterized and future work for second generation "ultra-low jitter" gun development is being identified.
Accelerated degradation of silicon metallization systems
NASA Technical Reports Server (NTRS)
Lathrop, J. W.
1983-01-01
Clemson University has been engaged for the past five years in a program to determine the reliability attributes of solar cells by means of accelerated test procedures. The cells are electrically measured and visually inspected and then subjected for a period of time to stress in excess of that normally encountered in use, and then they are reinspected. Changes are noted and the process repeated. This testing has thus far involved 23 different unencapsulated cell types from 12 different manufacturers, and 10 different encapsulated cell types from 9 different manufacturers. Reliability attributes of metallization systems can be classified as major or minor, depending on the severity of the effects observed. As a result of the accelerated testing conducted under the Clemson program, major effects have been observed related to contact resistance and to mechanical adherence and solderability. This paper does not attempt a generalized survey of accelerated test results, but rather concentrates on one particular attribute of metallization that has been observed to cause electrical degradation - increased contact resistance due to Schottky barrier formation. In this example basic semiconductor theory was able to provide an understanding of the electrical effects observed during accelerated stress testing.
A review of ion sources for medical accelerators (invited)
DOE Office of Scientific and Technical Information (OSTI.GOV)
Muramatsu, M.; Kitagawa, A.
2012-02-15
There are two major medical applications of ion accelerators. One is a production of short-lived isotopes for radionuclide imaging with positron emission tomography and single photon emission computer tomography. Generally, a combination of a source for negative ions (usually H- and/or D-) and a cyclotron is used; this system is well established and distributed over the world. Other important medical application is charged-particle radiotherapy, where the accelerated ion beam itself is being used for patient treatment. Two distinctly different methods are being applied: either with protons or with heavy-ions (mostly carbon ions). Proton radiotherapy for deep-seated tumors has become widespreadmore » since the 1990s. The energy and intensity are typically over 200 MeV and several 10{sup 10} pps, respectively. Cyclotrons as well as synchrotrons are utilized. The ion source for the cyclotron is generally similar to the type for production of radioisotopes. For a synchrotron, one applies a positive ion source in combination with an injector linac. Carbon ion radiotherapy awakens a worldwide interest. About 6000 cancer patients have already been treated with carbon beams from the Heavy Ion Medical Accelerator in Chiba at the National Institute of Radiological Sciences in Japan. These clinical results have clearly verified the advantages of carbon ions. Heidelberg Ion Therapy Center and Gunma University Heavy Ion Medical Center have been successfully launched. Several new facilities are under commissioning or construction. The beam energy is adjusted to the depth of tumors. It is usually between 140 and 430 MeV/u. Although the beam intensity depends on the irradiation method, it is typically several 10{sup 8} or 10{sup 9} pps. Synchrotrons are only utilized for carbon ion radiotherapy. An ECR ion source supplies multi-charged carbon ions for this requirement. Some other medical applications with ion beams attract developer's interests. For example, the several types of
Tracing accelerated galaxy formation in a proto-cluster at z=3.8 with GMOS
NASA Astrophysics Data System (ADS)
Handel Hughes, David; Lowenthal, James; Wilson, Grant; Yun, Min S.; Fazio, Giovanni G.; Huang, Jiasheng; Aretxaga, Itziar; Porras, Alicia; Smail, Ian; Ivison, Rob J.; Stevens, Jason; Dunlop, James S.
2007-08-01
The 1.1mm AzTEC camera has recently conducted the largest and most sensitive survey at mm-wavelengths towards a powerful high-redshift radio galaxy: 4C41.17 at z 3.8. The 1.1mm map reveals a significant over-density of luminous, massive dust-enshrouded galaxies, a factor of 10 more numerous than the blank-field mm-galaxy population, which statistically is expected to lie at lower-redshifts, z 2.2. The AzTEC sources are expected to trace the bulk of the elliptical galaxy formation within a massive protocluster at z 3.8, over an unprecedentedly large area of 6 x 6 Mpc^2. We propose to acquire multi-object spectroscopic observations over 3 adjacent GMOS fields to provide redshifts for 5 SMA/AzTEC sources, which have sub-arcsec interferometric precisions, identifying unambiguously their optical/IR counterparts, which are inferred to be forming stars at rates in excess of 500 M_sun/yr ( L(FIR) > 10^13 L_sun ). Although these are dusty objects, we expect most of them to have patchy obscuration, and thus be able to detect emission-lines from the star-forming regions, as has been achieved with the mm-selected blank-field population. Additional slitlets in the 3 GMOS masks will also simultaneously measure the redshift of 30 neighbouring (< 20") optical/Spitzer selected galaxies that could be associated with the haloes of these SMA detected AzTEC sources, and 60 additional optical/Spitzer sources that, through photo-z, are likely to be at z 3.8 and be associated with other mm-galaxies that lie within the AzTEC map. These GMOS data will identify whether small groups of dynamically-interacting galaxies in the local environment (dark matter haloes) of the gas-rich, luminous starburst AzTEC sources are stimulating the accelerated levels of galaxy formation observed towards this biased region (protocluster) in the early Universe.
Current Fragmentation and Particle Acceleration in Solar Flares
NASA Astrophysics Data System (ADS)
Cargill, P. J.; Vlahos, L.; Baumann, G.; Drake, J. F.; Nordlund, Å.
2012-11-01
Particle acceleration in solar flares remains an outstanding problem in plasma physics and space science. While the observed particle energies and timescales can perhaps be understood in terms of acceleration at a simple current sheet or turbulence site, the vast number of accelerated particles, and the fraction of flare energy in them, defies any simple explanation. The nature of energy storage and dissipation in the global coronal magnetic field is essential for understanding flare acceleration. Scenarios where the coronal field is stressed by complex photospheric motions lead to the formation of multiple current sheets, rather than the single monolithic current sheet proposed by some. The currents sheets in turn can fragment into multiple, smaller dissipation sites. MHD, kinetic and cellular automata models are used to demonstrate this feature. Particle acceleration in this environment thus involves interaction with many distributed accelerators. A series of examples demonstrate how acceleration works in such an environment. As required, acceleration is fast, and relativistic energies are readily attained. It is also shown that accelerated particles do indeed interact with multiple acceleration sites. Test particle models also demonstrate that a large number of particles can be accelerated, with a significant fraction of the flare energy associated with them. However, in the absence of feedback, and with limited numerical resolution, these results need to be viewed with caution. Particle in cell models can incorporate feedback and in one scenario suggest that acceleration can be limited by the energetic particles reaching the condition for firehose marginal stability. Contemporary issues such as footpoint particle acceleration are also discussed. It is also noted that the idea of a "standard flare model" is ill-conceived when the entire distribution of flare energies is considered.
Identification of tumor-initiating cells derived from two canine rhabdomyosarcoma cell lines
KISHIMOTO, Takuya Evan; YASHIMA, Shoko; NAKAHIRA, Rei; ONOZAWA, Eri; AZAKAMI, Daigo; UJIKE, Makoto; OCHIAI, Kazuhiko; ISHIWATA, Toshiyuki; TAKAHASHI, Kimimasa; MICHISHITA, Masaki
2017-01-01
Cancer stem cells or tumor-initiating cells (TICs) are a small subpopulation of cells that have the capacity to self-renew, differentiate and initiate tumors. These cells may function in tumor initiation, aggression and recurrence. Whether spheres derived from canine rhabdomyosarcoma cells have stem cell-like properties is unclear. We induced sphere formation in the canine rhabdomyosarcoma cell lines, CMS-C and CMS-J, and characterized the spheres in vitro and in vivo. Sphere-forming cells were more resistant to vincristine, mitoxantrone and doxorubicin than adherent cells. Xenograft transplantation demonstrated that 1 × 103 sphere-forming cells derived from CMS-C were sufficient for tumor formation. The sphere assay showed that the sphere-forming cells were present in these tumors. These results suggest that the spheres derived from canine rhabdomyosarcoma cells may possess characteristics of TICs. This study provides the foundation for elucidating the contribution of TICs to rhabdomyosarcoma tumorigenesis. PMID:28529244
Present status of Accelerator-Based BNCT
Kreiner, Andres Juan; Bergueiro, Javier; Cartelli, Daniel; Baldo, Matias; Castell, Walter; Asoia, Javier Gomez; Padulo, Javier; Suárez Sandín, Juan Carlos; Igarzabal, Marcelo; Erhardt, Julian; Mercuri, Daniel; Valda, Alejandro A.; Minsky, Daniel M.; Debray, Mario E.; Somacal, Hector R.; Capoulat, María Eugenia; Herrera, María S.; del Grosso, Mariela F.; Gagetti, Leonardo; Anzorena, Manuel Suarez; Canepa, Nicolas; Real, Nicolas; Gun, Marcelo; Tacca, Hernán
2016-01-01
Aim This work aims at giving an updated report of the worldwide status of Accelerator-Based BNCT (AB-BNCT). Background There is a generalized perception that the availability of accelerators installed in hospitals, as neutron sources, may be crucial for the advancement of BNCT. Accordingly, in recent years a significant effort has started to develop such machines. Materials and methods A variety of possible charged-particle induced nuclear reactions and the characteristics of the resulting neutron spectra are discussed along with the worldwide activity in suitable accelerator development. Results Endothermic 7Li(p,n)7Be and 9Be(p,n)9B and exothermic 9Be(d,n)10B are compared. In addition to having much better thermo-mechanical properties than Li, Be as a target leads to stable products. This is a significant advantage for a hospital-based facility. 9Be(p,n)9B needs at least 4–5 MeV bombarding energy to have a sufficient yield, while 9Be(d,n)10B can be utilized at about 1.4 MeV, implying the smallest possible accelerator. This reaction operating with a thin target can produce a sufficiently soft spectrum to be viable for AB-BNCT. The machines considered are electrostatic single ended or tandem accelerators or radiofrequency quadrupoles plus drift tube Linacs. Conclusions 7Li(p,n)7Be provides one of the best solutions for the production of epithermal neutron beams for deep-seated tumors. However, a Li-based target poses significant technological challenges. Hence, Be has been considered as an alternative target, both in combination with (p,n) and (d,n) reactions. 9Be(d,n)10B at 1.4 MeV, with a thin target has been shown to be a realistic option for the treatment of deep-seated lesions. PMID:26933390
Present status of Accelerator-Based BNCT.
Kreiner, Andres Juan; Bergueiro, Javier; Cartelli, Daniel; Baldo, Matias; Castell, Walter; Asoia, Javier Gomez; Padulo, Javier; Suárez Sandín, Juan Carlos; Igarzabal, Marcelo; Erhardt, Julian; Mercuri, Daniel; Valda, Alejandro A; Minsky, Daniel M; Debray, Mario E; Somacal, Hector R; Capoulat, María Eugenia; Herrera, María S; Del Grosso, Mariela F; Gagetti, Leonardo; Anzorena, Manuel Suarez; Canepa, Nicolas; Real, Nicolas; Gun, Marcelo; Tacca, Hernán
2016-01-01
This work aims at giving an updated report of the worldwide status of Accelerator-Based BNCT (AB-BNCT). There is a generalized perception that the availability of accelerators installed in hospitals, as neutron sources, may be crucial for the advancement of BNCT. Accordingly, in recent years a significant effort has started to develop such machines. A variety of possible charged-particle induced nuclear reactions and the characteristics of the resulting neutron spectra are discussed along with the worldwide activity in suitable accelerator development. Endothermic (7)Li(p,n)(7)Be and (9)Be(p,n)(9)B and exothermic (9)Be(d,n)(10)B are compared. In addition to having much better thermo-mechanical properties than Li, Be as a target leads to stable products. This is a significant advantage for a hospital-based facility. (9)Be(p,n)(9)B needs at least 4-5 MeV bombarding energy to have a sufficient yield, while (9)Be(d,n)(10)B can be utilized at about 1.4 MeV, implying the smallest possible accelerator. This reaction operating with a thin target can produce a sufficiently soft spectrum to be viable for AB-BNCT. The machines considered are electrostatic single ended or tandem accelerators or radiofrequency quadrupoles plus drift tube Linacs. (7)Li(p,n)(7)Be provides one of the best solutions for the production of epithermal neutron beams for deep-seated tumors. However, a Li-based target poses significant technological challenges. Hence, Be has been considered as an alternative target, both in combination with (p,n) and (d,n) reactions. (9)Be(d,n)(10)B at 1.4 MeV, with a thin target has been shown to be a realistic option for the treatment of deep-seated lesions.
Wang, Meili; Zhao, Xiulan; Zhu, Dongwang; Liu, Tieju; Liang, Xiaohui; Liu, Fang; Zhang, Yanhui; Dong, Xueyi; Sun, Baocun
2017-04-27
The incidence and mortality rates of hepatocellular carcinoma (HCC) have steadily increased in recent years. A hypoxic microenvironment is one of the most important characteristics of solid tumors which has been shown to promote tumor metastasis, epithelial-mesenchymal transition and angiogenesis. Epithelial-mesenchymal transition and vasculogenic mimicry have been regarded as crucial contributing factors to cancer progression. HIF-1α functions as a master transcriptional regulator in the adaptive response to hypoxia. Lysyl oxidases like 2 (LOXL2) is a member of the lysyl oxidase family, which main function is to catalyze the covalent cross-linkages of collagen and elastin in the extracellular matrix. Recent work has demonstrated that HIF-1α promotes the expression of LOXL2, which is believed to amplify tumor aggressiveness. LOXL2 has shown to promote metastasis and is correlated with poor prognosis in hepatocellular carcinoma. The purpose of our study is to explore the role of HIF-1α in progression and metastasis of hepatocellular carcinoma by promoting the expression of LOXL2 as well as the potential regulatory mechanism. HIF-1α, LOXL2 expression and CD31/periodic acid-Schiff double staining in HCC patient samples were examined by immunohistochemical staining. shRNA plasmids against HIF-1α was used to determine whether LOXL2 been increased by HIF-1α. We monitored a series of rescue assays to demonstrate our hypothesis that LOXL2 is required and sufficient for HIF-1α induced EMT and VM formation, which mediates cellular transformation and takes effect in cellular invasion. Then we performed GeneChip® Human Transcriptome Array (HTA) 2.0 in HepG2 cells, HepG2 cells overexpressed LOXL2 and HepG2 cells treated with CoCl 2 . In clinical HCC tissues, it confirmed a positive relationship between HIF-1α and LOXL2 protein. Importantly, HIF-1α and LOXL2 high expression and the presence of vasculogenic mimicry were correlated to poor prognosis. HIF-1α was found to
Radiosurgery of Glomus Jugulare Tumors: A Meta-Analysis
DOE Office of Scientific and Technical Information (OSTI.GOV)
Guss, Zachary D.; Batra, Sachin; Limb, Charles J.
2011-11-15
Purpose: During the past two decades, radiosurgery has arisen as a promising approach to the management of glomus jugulare. In the present study, we report on a systematic review and meta-analysis of the available published data on the radiosurgical management of glomus jugulare tumors. Methods and Materials: To identify eligible studies, systematic searches of all glomus jugulare tumors treated with radiosurgery were conducted in major scientific publication databases. The data search yielded 19 studies, which were included in the meta-analysis. The data from 335 glomus jugulare patients were extracted. The fixed effects pooled proportions were calculated from the data whenmore » Cochrane's statistic was statistically insignificant and the inconsistency among studies was <25%. Bias was assessed using the Egger funnel plot test. Results: Across all studies, 97% of patients achieved tumor control, and 95% of patients achieved clinical control. Eight studies reported a mean or median follow-up time of >36 months. In these studies, 95% of patients achieved clinical control and 96% achieved tumor control. The gamma knife, linear accelerator, and CyberKnife technologies all exhibited high rates of tumor and clinical control. Conclusions: The present study reports the results of a meta-analysis for the radiosurgical management of glomus jugulare. Because of its high effectiveness, we suggest considering radiosurgery for the primary management of glomus jugulare tumors.« less
Marinetto, Eugenio; Victores, Juan González; García-Sevilla, Mónica; Muñoz, Mercedes; Calvo, Felipe Ángel; Balaguer, Carlos; Desco, Manuel; Pascau, Javier
2017-10-01
Intraoperative electron radiation therapy (IOERT) involves the delivery of a high radiation dose during tumor resection in a shorter time than other radiation techniques, thus improving local control of tumors. However, a linear accelerator device is needed to produce the beam safely. Mobile linear accelerators have been designed as dedicated units that can be moved into the operating room and deliver radiation in situ. Correct and safe dose delivery is a key concern when using mobile accelerators. The applicator is commonly fixed to the patient's bed to ensure that the dose is delivered to the prescribed location, and the mobile accelerator is moved to dock the applicator to the radiation beam output (gantry). In a typical clinical set-up, this task is time-consuming because of safety requirements and the limited degree of freedom of the gantry. The objective of this study was to present a navigation solution based on optical tracking for guidance of docking to improve safety and reduce procedure time. We used an optical tracker attached to the mobile linear accelerator to track the prescribed localization of the radiation collimator inside the operating room. Using this information, the integrated navigation system developed computes the movements that the mobile linear accelerator needs to perform to align the applicator and the radiation gantry and warns the physician if docking is unrealizable according to the available degrees of freedom of the mobile linear accelerator. Furthermore, we coded a software application that connects all the necessary functioning elements and provides a user interface for the system calibration and the docking guidance. The system could safeguard against the spatial limitations of the operating room, calculate the optimal arrangement of the accelerator and reduce the docking time in computer simulations and experimental setups. The system could be used to guide docking with any commercial linear accelerator. We believe that the
A New Paradigm for Flare Particle Acceleration
NASA Astrophysics Data System (ADS)
Guidoni, Silvina E.; Karpen, Judith T.; DeVore, C. Richard
2017-08-01
The mechanism that accelerates particles to the energies required to produce the observed high-energy impulsive emission and its spectra in solar flares is not well understood. Here, we propose a first-principle-based model of particle acceleration that produces energy spectra that closely resemble those derived from hard X-ray observations. Our mechanism uses contracting magnetic islands formed during fast reconnection in solar flares to accelerate electrons, as first proposed by Drake et al. (2006) for kinetic-scale plasmoids. We apply these ideas to MHD-scale islands formed during fast reconnection in a simulated eruptive flare. A simple analytic model based on the particles’ adiabatic invariants is used to calculate the energy gain of particles orbiting field lines in our ultrahigh-resolution, 2.5D, MHD numerical simulation of a solar eruption (flare + coronal mass ejection). Then, we analytically model electrons visiting multiple contracting islands to account for the observed high-energy flare emission. Our acceleration mechanism inherently produces sporadic emission because island formation is intermittent. Moreover, a large number of particles could be accelerated in each macroscopic island, which may explain the inferred rates of energetic-electron production in flares. We conclude that island contraction in the flare current sheet is a promising candidate for electron acceleration in solar eruptions. This work was supported in part by the NASA LWS and H-SR programs..
Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice.
Ikemura, Mai; Nishikawa, Makiya; Kusamori, Kosuke; Fukuoka, Miho; Yamashita, Fumiyoshi; Hashida, Mitsuru
2013-09-10
Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and the removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes. Copyright © 2013 Elsevier B.V. All rights reserved.
Antiphospholipid antibodies promote tissue factor-dependent angiogenic switch and tumor progression.
Wu, Yuan-Yuan; V Nguyen, Andrew; Wu, Xiao-Xuan; Loh, Mingyu; Vu, Michelle; Zou, Yiyu; Liu, Qiang; Guo, Peng; Wang, Yanhua; Montgomery, Leslie L; Orlofsky, Amos; Rand, Jacob H; Lin, Elaine Y
2014-12-01
Progression to an angiogenic state is a critical event in tumor development, yet few patient characteristics have been identified that can be mechanistically linked to this transition. Antiphospholipid autoantibodies (aPLs) are prevalent in many human cancers and can elicit proangiogenic expression in several cell types, but their role in tumor biology is unknown. Herein, we observed that the elevation of circulating aPLs among breast cancer patients is specifically associated with invasive-stage tumors. By using multiple in vivo models of breast cancer, we demonstrated that aPL-positive IgG from patients with autoimmune disease rapidly accelerates tumor angiogenesis and consequent tumor progression, particularly in slow-growing avascular tumors. The action of aPLs was local to the tumor site and elicited leukocytic infiltration and tumor invasion. Tumor cells treated with aPL-positive IgG expressed multiple proangiogenic genes, including vascular endothelial growth factor, tissue factor (TF), and colony-stimulating factor 1. Knockdown and neutralization studies demonstrated that the effects of aPLs on tumor angiogenesis and growth were dependent on tumor cell-derived TF. Tumor-derived TF was essential for the development of pericyte coverage of tumor microvessels and aPL-induced tumor cell expression of chemokine ligand 2, a mediator of pericyte recruitment. These findings identify antiphospholipid autoantibodies as a potential patient-specific host factor promoting the transition of indolent tumors to an angiogenic malignant state through a TF-mediated pathogenic mechanism. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Roussos, Evanthia T; Wang, Yarong; Wyckoff, Jeffrey B; Sellers, Rani S; Wang, Weigang; Li, Jiufeng; Pollard, Jeffrey W; Gertler, Frank B; Condeelis, John S
2010-01-01
The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development. To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice. Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching. Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena
Moriwaki, Kenta; Shinzaki, Shinichiro; Miyoshi, Eiji
2011-01-01
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis through binding to TRAIL receptors, death receptor 4 (DR4), and DR5. TRAIL has potential therapeutic value against cancer because of its selective cytotoxic effects on several transformed cell types. Fucosylation of proteins and lipids on the cell surface is a very important posttranslational modification that is involved in many cellular events. Recently, we found that a deficiency in GDP-mannose-4,6-dehydratase (GMDS) rendered colon cancer cells resistant to TRAIL-induced apoptosis, resulting in tumor development and metastasis by escape from tumor immune surveillance. GMDS is an indispensable regulator of cellular fucosylation. In this study, we investigated the molecular mechanism of inhibition of TRAIL signaling by GMDS deficiency. DR4, but not DR5, was found to be fucosylated; however, GMDS deficiency inhibited both DR4- and DR5-mediated apoptosis despite the absence of fucosylation on DR5. In addition, GMDS deficiency also inhibited CD95-mediated apoptosis but not the intrinsic apoptosis pathway induced by anti-cancer drugs. Binding of TRAIL and CD95 ligand to their cognate receptors primarily leads to formation of a complex comprising the receptor, FADD, and caspase-8, referred to as the death-inducing signaling complex (DISC). GMDS deficiency did not affect formation of the primary DISC or recruitment to and activation of caspase-8 on the DISC. However, formation of secondary FADD-dependent complex II, comprising caspase-8 and cFLIP, was significantly inhibited by GMDS deficiency. These results indicate that GMDS regulates the formation of secondary complex II from the primary DISC independent of direct fucosylation of death receptors. PMID:22027835
Milshteyn, Eugene; von Morze, Cornelius; Reed, Galen D; Shang, Hong; Shin, Peter J; Larson, Peder E Z; Vigneron, Daniel B
2018-05-01
Acceleration of dynamic 2D (T 2 Mapping) and 3D hyperpolarized 13 C MRI acquisitions using the balanced steady-state free precession sequence was achieved with a specialized reconstruction method, based on the combination of low rank plus sparse and local low rank reconstructions. Methods were validated using both retrospectively and prospectively undersampled in vivo data from normal rats and tumor-bearing mice. Four-fold acceleration of 1-2 mm isotropic 3D dynamic acquisitions with 2-5 s temporal resolution and two-fold acceleration of 0.25-1 mm 2 2D dynamic acquisitions was achieved. This enabled visualization of the biodistribution of [2- 13 C]pyruvate, [1- 13 C]lactate, [ 13 C, 15 N 2 ]urea, and HP001 within heart, kidneys, vasculature, and tumor, as well as calculation of high resolution T 2 maps. Copyright © 2018 Elsevier Inc. All rights reserved.
Design of a Microwave Assisted Discharge Inductive Plasma Accelerator
NASA Technical Reports Server (NTRS)
Hallock, Ashley K.; Polzin, Kurt A.
2010-01-01
The design and construction of a thruster that employs electrodeless plasma preionization and pulsed inductive acceleration is described. Preionization is achieved through an electron cyclotron resonance discharge that produces a weakly-ionized plasma at the face of a conical theta pinch-shaped inductive coil. The presence of the preionized plasma allows for current sheet formation at lower discharge voltages than those employed in other pulsed inductive accelerators that do not employ preionization. The location of the electron cyclotron resonance discharge is controlled through the design of the applied magnetic field in the thruster. Finite element analysis shows that there is an arrangement of permanent magnets that yields a small volume of resonant magnetic field at the coil face. Preionization in the resonant zone leads to current sheet formation at the coil face, which minimizes the initial inductance of the pulse circuit and maximizes the potential electrical efficiency of the accelerator. A magnet assembly was constructed around an inductive coil to provide structural support to the selected arrangement of neodymium magnets. Measured values of the resulting magnetic field compare favorably with the finite element model.
Stable quasi-monoenergetic ion acceleration from the laser-driven shocks in a collisional plasma
NASA Astrophysics Data System (ADS)
Bhadoria, Shikha; Kumar, Naveen; Keitel, Christoph H.
2017-10-01
Effect of collisions on the shock formation and subsequent ion acceleration from the laser-plasma interaction is explored by the means of particle-in-cell simulations. In this setup, the incident laser pushes the laser-plasma interface inside the plasma target through the hole-boring effect and generates hot electrons. The propagation of these hot electrons inside the target excites a return plasma current, leading to filamentary structures caused by the Weibel/filamentation instability. Weakening of the space-charge effects due to collisions results in the shock formation with a higher density jump than in a collisionless plasma. This results in the formation of a stronger shock leading to a stable quasi-monoenergetic acceleration of ions.
Accelerator system and method of accelerating particles
NASA Technical Reports Server (NTRS)
Wirz, Richard E. (Inventor)
2010-01-01
An accelerator system and method that utilize dust as the primary mass flux for generating thrust are provided. The accelerator system can include an accelerator capable of operating in a self-neutralizing mode and having a discharge chamber and at least one ionizer capable of charging dust particles. The system can also include a dust particle feeder that is capable of introducing the dust particles into the accelerator. By applying a pulsed positive and negative charge voltage to the accelerator, the charged dust particles can be accelerated thereby generating thrust and neutralizing the accelerator system.
Ponderomotive Acceleration in Coronal Loops
NASA Astrophysics Data System (ADS)
Dahlburg, Russell B.; Laming, J. Martin; Taylor, Brian; Obenschain, Keith
2017-08-01
Ponderomotive acceleration has been asserted to be a cause of the First Ionization Potential (FIP) effect, the by now well known enhancement in abundance by a factor of 3-4 over photospheric values of elements in the solar corona with FIP less than about 10 eV. It is shown here by means of numerical simulations that ponderomotive acceleration occurs in solar coronal loops, with the appropriate magnitude and direction, as a ``byproduct'' of coronal heating. The numerical simulations are performed with the HYPERION code, which solves the fully compressible three-dimensional magnetohydrodynamic equations including nonlinear thermal conduction and optically thin radiation. Numerical simulations of a coronal loops with an axial magnetic field from 0.005 Teslas to 0.02 Teslas and lengths from 25000 km to 75000 km are presented. In the simulations the footpoints of the axial loop magnetic field are convected by random, large-scale motions. There is a continuous formation and dissipation of field-aligned current sheets which act to heat the loop. As a consequence of coronal magnetic reconnection, small scale, high speed jets form. The familiar vortex quadrupoles form at reconnection sites. Between the magnetic footpoints and the corona the reconnection flow merges with the boundary flow. It is in this region that the ponderomotive acceleration occurs. Mirroring the character of the coronal reconnection, the ponderomotive acceleration is also found to be intermittent.
iPSC-derived cancer stem cells provide a model of tumor vasculature.
Prieto-Vila, Marta; Yan, Ting; Calle, Anna Sanchez; Nair, Neha; Hurley, Laura; Kasai, Tomonari; Kakuta, Hiroki; Masuda, Junko; Murakami, Hiroshi; Mizutani, Akifumi; Seno, Masaharu
2016-01-01
To grow beyond a size of approximately 1-2 mm 3 , tumor cells activate many processes to develop blood vasculature. Growing evidences indicate that the formation of the tumor vascular network is very complex, and is not restricted to angiogenesis. Cancer cell-derived tumor vasculatures have been recently described. Among them, endothelial differentiation of tumor cells have been directly related to cancer stem cells, which are cells within a tumor that possess the capacity to self-renew, and to exhibit multipotential heterogeneous lineages of cancer cells. Vasculogenic mimicry has been described to be formed by cancer cells expressing stemness markers. Thus, cancer stem cells have been proposed to contribute to vasculogenic mimicry, though its relation is yet to be clarified. Here, we analyzed the tumor vasculature by using a model of mouse cancer stem cells, miPS-LLCcm cells, which we have previously established from mouse induced pluripotent stem cells and we introduced the DsRed gene in miPS-LLCcm to trace them in vivo . Various features of vasculature were evaluated in ovo , in vitro , and in vivo . The tumors formed in allograft nude mice exhibited angiogenesis in chick chorioallantoic membrane assay. In those tumors, along with penetrated host endothelial vessels, we detected endothelial differentiation from cancer stem cells and formation of vasculogenic mimicry. The angiogenic factors such as VEGF-A and FGF2 were expressed predominantly in the cancer stem cells subpopulation of miPS-LLCcm cells. Our results suggested that cancer stem cells play key roles in not only the recruitment of host endothelial vessels into tumor, but also in maturation of endothelial linage of cancer stem cell's progenies. Furthermore, the undifferentiated subpopulation of the miPS-LLCcm participates directly in the vasculogenic mimicry formation. Collectively, we show that miPS-LLCcm cells have advantages to further study tumor vasculature and to develop novel targeting strategies
iPSC-derived cancer stem cells provide a model of tumor vasculature
Prieto-Vila, Marta; Yan, Ting; Calle, Anna Sanchez; Nair, Neha; Hurley, Laura; Kasai, Tomonari; Kakuta, Hiroki; Masuda, Junko; Murakami, Hiroshi; Mizutani, Akifumi; Seno, Masaharu
2016-01-01
To grow beyond a size of approximately 1-2 mm3, tumor cells activate many processes to develop blood vasculature. Growing evidences indicate that the formation of the tumor vascular network is very complex, and is not restricted to angiogenesis. Cancer cell-derived tumor vasculatures have been recently described. Among them, endothelial differentiation of tumor cells have been directly related to cancer stem cells, which are cells within a tumor that possess the capacity to self-renew, and to exhibit multipotential heterogeneous lineages of cancer cells. Vasculogenic mimicry has been described to be formed by cancer cells expressing stemness markers. Thus, cancer stem cells have been proposed to contribute to vasculogenic mimicry, though its relation is yet to be clarified. Here, we analyzed the tumor vasculature by using a model of mouse cancer stem cells, miPS-LLCcm cells, which we have previously established from mouse induced pluripotent stem cells and we introduced the DsRed gene in miPS-LLCcm to trace them in vivo. Various features of vasculature were evaluated in ovo, in vitro, and in vivo. The tumors formed in allograft nude mice exhibited angiogenesis in chick chorioallantoic membrane assay. In those tumors, along with penetrated host endothelial vessels, we detected endothelial differentiation from cancer stem cells and formation of vasculogenic mimicry. The angiogenic factors such as VEGF-A and FGF2 were expressed predominantly in the cancer stem cells subpopulation of miPS-LLCcm cells. Our results suggested that cancer stem cells play key roles in not only the recruitment of host endothelial vessels into tumor, but also in maturation of endothelial linage of cancer stem cell’s progenies. Furthermore, the undifferentiated subpopulation of the miPS-LLCcm participates directly in the vasculogenic mimicry formation. Collectively, we show that miPS-LLCcm cells have advantages to further study tumor vasculature and to develop novel targeting strategies in
Real-time tracking of respiratory-induced tumor motion by dose-rate regulation
NASA Astrophysics Data System (ADS)
Han-Oh, Yeonju Sarah
We have developed a novel real-time tumor-tracking technology, called Dose-Rate-Regulated Tracking (DRRT), to compensate for tumor motion caused by breathing. Unlike other previously proposed tumor-tracking methods, this new method uses a preprogrammed dynamic multileaf collimator (MLC) sequence in combination with real-time dose-rate control. This new scheme circumvents the technical challenge in MLC-based tumor tracking, that is to control the MLC motion in real time, based on real-time detected tumor motion. The preprogrammed MLC sequence describes the movement of the tumor, as a function of breathing phase, amplitude, or tidal volume. The irregularity of tumor motion during treatment is handled by real-time regulation of the dose rate, which effectively speeds up or slows down the delivery of radiation as needed. This method is based on the fact that all of the parameters in dynamic radiation delivery, including MLC motion, are enslaved to the cumulative dose, which, in turn, can be accelerated or decelerated by varying the dose rate. Because commercially available MLC systems do not allow the MLC delivery sequence to be modified in real time based on the patient's breathing signal, previously proposed tumor-tracking techniques using a MLC cannot be readily implemented in the clinic today. By using a preprogrammed MLC sequence to handle the required motion, the task for real-time control is greatly simplified. We have developed and tested the pre- programmed MLC sequence and the dose-rate regulation algorithm using lung-cancer patients breathing signals. It has been shown that DRRT can track the tumor with an accuracy of less than 2 mm for a latency of the DRRT system of less than 0.35 s. We also have evaluated the usefulness of guided breathing for DRRT. Since DRRT by its very nature can compensate for breathing-period changes, guided breathing was shown to be unnecessary for real-time tracking when using DRRT. Finally, DRRT uses the existing dose-rate control
Targeting Autophagy in the Tumor Stroma to Eradicate Breast Cancer
2013-09-01
initiated. One potential caveat that has arisen is that fibroblast specific protein (FSP) may be expressed at low levels in late stage PyMT tumor...digestion solution per 5g of tumor tissue) 1.5 mg/ml Collagenase (from 100X stock solution) 125 U/ml Hyaluronidase (from 100X stock solution) MMF media...g. Determine the latency period to the onset of primary tumor formation and metastasis for recipient mice generated in subtask 1f. At selected
The Auroral Field-aligned Acceleration - Cluster Results
NASA Astrophysics Data System (ADS)
Vaivads, A.; Cluster Auroral Team
The four Cluster satellites cross the auroral field lines at altitudes well above most of acceleration region. Thus, the orbit is appropriate for studies of the generator side of this region. We consider the energy transport towards the acceleration region and different mechanisms for generating the potential drop. Using data from Cluster we can also for the first time study the dynamics of the generator on a minute scale. We present data from a few auroral field crossings where Cluster are in conjunction with DMSP satellites. We use electric and magnetic field data to estimate electrostatic po- tential along the satellite orbit, Poynting flux as well as the presence of plasma waves. These we can compare with data from particle and wave instruments on Cluster and on low latitude satellites to try to make a consistent picture of the acceleration region formation in these cases. Preliminary results show close agreement both between in- tegrated potential values at Cluster and electron peak energies at DMSP as well as close agreement between the integrated Poynting flux values at Cluster and the elec- tron energy flux at DMSP. At the end we draw a parallels between auroral electron acceleration and electron acceleration at the magnetopause.
Oxidation and formation of deposit precursors in hydrocarbon fuels
NASA Technical Reports Server (NTRS)
Mayo, F. R.; Lan, B.; Cotts, D. B.; Buttrill, S. E., Jr.; St.john, G. A.
1983-01-01
The oxidation of two jet turbine fuels and some pure hydrocarbons was studied at 130 C with and without the presence of small amounts of N-methyl pyrrole (NMP) or indene. Tendency to form solid-deposit precursors was studied by measuring soluble gum formation as well as dimer and trimer formation using field ionization mass spectrometry. Pure n-dodecane oxidized fastest and gave the smallest amount of procursors. An unstable fuel oil oxidized much slower but formed large amounts of precursors. Stable Jet A fuel oxidized slowest and gave little precursors. Indene either retarded or accelerated the oxidation of n-dodecane, depending on its concentration, but always caused more gum formation. The NMP greatly retarded n-dodecane oxidation but accelerated Jet A oxidation and greatly increased the latter's gum formation. In general, the additive reacted faster and formed most of the gum. Results are interpreted in terms of classical cooxidation theory. The effect of oxygen pressure on gum formation is also reported.
Extracorporeal irradiation for malignant bone tumors.
Hong, A; Stevens, G; Stalley, P; Pendlebury, S; Ahern, V; Ralston, A; Estoesta, E; Barrett, I
2001-06-01
Extracorporeal irradiation (ECI) has been used selectively in the management of primary malignant bone tumors since 1996. We report our techniques for ECI and the short-term oncologic and orthopedic outcomes. Sixteen patients with primary malignant bone tumors were treated with ECI from 1996 to 2000. The median age was 14 years. The histologic diagnoses were Ewing's sarcoma (11), osteosarcoma (4) and chondrosarcoma (1). The treated sites were femur (7), tibia (4), humerus (2), ilium (2), and sacrum (1). Following induction chemotherapy in Ewing's sarcomas and osteosarcoma, en bloc resection of the tumor and tumor-bearing bone was performed. A single dose of 50 Gy was delivered to the bone extracorporeally using either a linear accelerator (9 cases) or a blood product irradiator (7 cases). The orthopedic outcome was recorded using a standard functional scale. At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis. For the 10 patients with follow-up greater than 18 months, the functional outcomes were graded good to excellent. The short-term oncologic and orthopedic results are encouraging and suggest that ECI provides a good alternative for reconstruction in limb conservative surgery in selected patients. This technique should only be used in a multidisciplinary setting, where careful follow-up is available to assess the long-term outcomes.
[Growth suppression of transplantable tumors in experimental animals given soya proteins].
Kireev, G V; Asserova, Iu Iu; Iusupova, A A; Koloiarova, I E; Ibragimov, F A
2006-01-01
The development of a malignant process and antitumor treatment leads to the occurrence of a variety of complications. It is expedient to use biological regulators of natural origin to eliminate the side effect of chemical drugs and to improve the outcomes of antitumor therapy. The antitumor effect of soya proteins and their influence on antibody formation and oxidative processes in the sera of tumor-bearing animals were investigated. Soya proteins are shown to retard the development of a tumorous process, modulate the therapeutic effect of 5-fluorouracil, enhance antibody formation, and normalize serum oxidative processes.
Role of HIF-1α and CASPASE-3 in cystogenesis of odontogenic cysts and tumors.
da Costa, Natacha M M; de Siqueira, Adriane S; Ribeiro, André L R; da Silva Kataoka, Maria S; Jaeger, Ruy G; de Alves-Júnior, Sérgio M; Smith, Andrew M; de Jesus Viana Pinheiro, João
2018-01-01
Odontogenic cysts and tumors are the most relevant lesions that affect the gnathic bones. These lesions have in common the formation of cystic areas and this common feature may suggest involvement of similar mechanisms. The hypoxia inducible factor 1 alpha (HIF-1α), a responsive protein to hypoxia and caspase-3, an irreversible apoptosis marker, may contribute to cyst formation. Thus, this study aimed to investigate the immunoexpression of these proteins in odontogenic cysts and tumors. Twenty cases of ameloblastoma, keratocystic odontogenic tumor (KOT) (n = 20), radicular cyst (RC) (n = 18), dentigerous cyst (DC) (n = 11), calcifying cystic odontogenic tumor (n = 8), and dental follicle (DF) (n = 10) were used to investigate HIF-1α and caspase-3 expression in sequential serial cuts by immunohistochemistry. HIF-1α was overexpressed in RC, DC, and ameloblastoma when compared with DF. The basal and sometimes the lower suprabasal layer showed no or very low expression in DC, KOT, and ameloblastoma, the last also showing strong expression in solid epithelial areas and initial cystic formation regions. Caspase-3 was found to be overexpressed in all lesions, with the highest expression in odontogenic cysts compared to tumors. HIF-1α and caspase-3 were localized in similar areas of the same lesions, especially in the epithelium surrounding cystic formations. This study showed distinct immunoexpression of HIF-1α and caspase-3 in odontogenic cyst and tumors, with higher expression observed in odontogenic cysts. These findings suggest a possible correlation between hypoxia, apoptosis, and cystogenesis, leading to understand the mechanisms responsible to cystic formation in odontogenic lesions.
Polymeric micelle for tumor pH and folate-mediated targeting.
Lee, Eun Seong; Na, Kun; Bae, You Han
2003-08-28
Novel pH-sensitive polymeric mixed micelles composed of poly(L-histidine) (polyHis; M(w) 5000)/PEG (M(n) 2000) and poly(L-lactic acid) (PLLA) (M(n) 3000)/PEG (M(n) 2000) block copolymers with or without folate conjugation were prepared by diafiltration. The micelles were investigated for pH-dependent drug release, folate receptor-mediated internalization and cytotoxicity using MCF-7 cells in vitro. The polyHis/PEG micelles showed accelerated adriamycin release as the pH decreased from 8.0. When the cumulative release for 24 h was plotted as a function of pH, the gradual transition in release rate appeared in a pH range from 8.0 to 6.8. In order to tailor the triggering pH of the polymeric micelles to the more acidic extracellular pH of tumors, while improving the micelle stability at pH 7.4, the PLLA/PEG block copolymer was blended with polyHis/PEG to form mixed micelles. Blending shifted the triggering pH to a lower value. Depending on the amount of PLLA/PEG, the mixed micelles were destabilized in the pH range of 7.2-6.6 (triggering pH for adriamycin release). When the mixed micelles were conjugated with folic acid, the in vitro results demonstrated that the micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake. In addition, after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity. This approach is expected to be useful for treatment of solid tumors in vivo.
NASA Technical Reports Server (NTRS)
Lathrop, J. W.
1983-01-01
Results of an ongoing research program into the reliability of terrestrial solar cells are presented. Laboratory accelerated testing procedures are used to identify failure/degradation modes which are then related to basic physical, chemical, and metallurgical phenomena. In the most recent tests, ten different types of production cells, both with and without encapsulation, from eight different manufacturers were subjected to a variety of accelerated tests. Results indicated the presence of a number of hitherto undetected failure mechanisms, including Schottky barrier formation at back contacts and loss of adhesion of grid metallization. The mechanism of Schottky barrier formation is explained by hydrogen, formed by the dissociation of water molecules at the contact surface, diffusing to the metal semiconductor interface. This same mechanism accounts for the surprising increase in sensitivity to accelerated stress conditions that was observed in some cells when encapsulated.
Fully Implict Magneto-hydrodynamics Simulations of Coaxial Plasma Accelerators
Subramaniam, Vivek; Raja, Laxminarayan L.
2017-01-05
The resistive Magneto-Hydrodynamic (MHD) model describes the behavior of a strongly ionized plasma in the presence of external electric and magnetic fields. We developed a fully implicit MHD simulation tool to solve the resistive MHD governing equations in the context of a cell-centered finite-volume scheme. The primary objective of this study is to use the fully-implicit algorithm to obtain insights into the plasma acceleration and jet formation processes in Coaxial Plasma accelerators; electromagnetic acceleration devices that utilize self-induced magnetic fields to accelerate thermal plasmas to large velocities. We also carry out plasma-surface simulations in order to study the impact interactionsmore » when these high velocity plasma jets impinge on target material surfaces. Scaling studies are carried out to establish some basic functional relationships between the target-stagnation conditions and the current discharged between the coaxial electrodes.« less
Prognostic Significance of Tumor Necrosis in Hilar Cholangiocarcinoma.
Atanasov, Georgi; Schierle, Katrin; Hau, Hans-Michael; Dietel, Corinna; Krenzien, Felix; Brandl, Andreas; Wiltberger, Georg; Englisch, Julianna Paulina; Robson, Simon C; Reutzel-Selke, Anja; Pascher, Andreas; Jonas, Sven; Pratschke, Johann; Benzing, Christian; Schmelzle, Moritz
2017-02-01
Tumor necrosis and peritumoral fibrosis have both been suggested to have a prognostic value in selected solid tumors. However, little is known regarding their influence on tumor progression and prognosis in hilar cholangiocarcinoma (HC). Surgically resected tumor specimens of HC (n = 47) were analyzed for formation of necrosis and extent of peritumoral fibrosis. Tumor necrosis and grade of fibrosis were assessed histologically and correlated with clinicopathological characteristics, tumor recurrence, and patients' survival. Univariate Kaplan-Meier analysis and a stepwise multivariable Cox regression model were applied. Mild peritumoral fibrosis was evident in 12 tumor samples, moderate peritumoral fibrosis in 20, and high-grade fibrosis in 15. Necrosis was evident in 19 of 47 tumor samples. Patients with tumors characterized by necrosis showed a significantly decreased 5-year recurrence-free survival (37.9 vs. 25.7 %; p < .05) and a significantly decreased 5-year overall survival (42.6 vs. 12.4 %; p < .05), when compared with patients with tumors showing no necrosis. R status, tumor recurrence, and tumor necrosis were of prognostic value in the univariate analysis (all p < .05). Multivariate survival analysis confirmed tumor necrosis (p = .038) as the only independent prognostic variable. The assessment of tumor necrosis appears as a valuable additional prognostic tool in routine histopathological evaluation of HC. These observations might have implications for monitoring and more individualized multimodal therapeutic strategies.
Glioblastoma: A Pathogenic Crosstalk between Tumor Cells and Pericytes
Redondo-Garcia, Carolina; Martinez, Salvador
2014-01-01
Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co-option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co-option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion-hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor-suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and
Heavy ion acceleration in the radiation pressure acceleration and breakout afterburner regimes
NASA Astrophysics Data System (ADS)
Petrov, G. M.; McGuffey, C.; Thomas, A. G. R.; Krushelnick, K.; Beg, F. N.
2017-07-01
We present a theoretical study of heavy ion acceleration from ultrathin (20 nm) gold foil irradiated by high-intensity sub-picosecond lasers. Using two-dimensional particle-in-cell simulations, three laser systems are modeled that cover the range between femtosecond and picosecond pulses. By varying the laser pulse duration we observe a transition from radiation pressure acceleration (RPA) to the relativistic induced transparency (RIT) regime for heavy ions akin to light ions. The underlying physics of beam formation and acceleration is similar for light and heavy ions, however, nuances of the acceleration process make the heavy ions more challenging. A more detailed study involving variation of peak laser intensity I 0 and pulse duration τFWHM revealed that the transition point from RPA to RIT regime depends on the peak laser intensity on target and occurs for pulse duration {τ }{{F}{{W}}{{H}}{{M}}}{{R}{{P}}{{A}}\\to {{R}}{{I}}{{T}}}[{{f}}{{s}}]\\cong 210/\\sqrt{{I}0[{{W}} {{{cm}}}-2]/{10}21}. The most abundant gold ion and charge-to-mass ratio are Au51+ and q/M ≈ 1/4, respectively, half that of light ions. For ultrathin foils, on the order of one skin depth, we established a linear scaling of the maximum energy per nucleon (E/M)max with (q/M)max, which is more favorable than the quadratic one found previously. The numerical simulations predict heavy ion beams with very attractive properties for applications: high directionality (<10° half-angle), high fluxes (>1011 ions sr-1) and energy (>20 MeV/nucleon) from laser systems delivering >20 J of energy on target.
NASA Astrophysics Data System (ADS)
Ishida, Hiroki; Hachiga, Tadashi; Andoh, Tsugunobu; Akiguchi, Shunsuke
2012-11-01
We demonstrate that using micro multipoint laser Doppler velocimetry (μ-MLDV) for noninvasive in-vivo imaging of blood vessels is useful for diagnosing malignant melanomas by comparison with visual diagnosis by dermoscopy. The blood flow velocity in microvessels varied during growth of melanomas transplanted in mouse ears. Mouse ears were observed by μ-MLDV up to 16 days after transplantation. The blood flow velocity in the tumor increased with increasing time and reached maximum of 4.5 mm/s at 9 days, which is more than twice that prior to transplantation. After 12 days, when the lesion had grown to an area of 6.6 mm2, we observed the formation of new blood vessels in the tumor. Finally, when the lesion had an area of 18 mm2 after 16 days, the flow velocity in the tumor decreased to approximately 3.2 mm/s.
Rosenkrantz, Andrew B; Pujara, Akshat C; Taneja, Samir S
2016-05-01
The purpose of this article is to evaluate the utility of a quality improvement (QI) initiative in achieving long-term adherence to an evolving structured format for reporting the level of suspicion for tumor on prostate MRI examinations. The original QI initiative occurred over a 4-month period in 2010, before which prostate MRI was reported using free text. The initiative consisted of development of a section-wide macro, an initial group training session, ordering physician input regarding the structured report's value, subsequent weekly sessions for ongoing review, and timely individualized feedback in instances of nonuse. The initial structured report included pick lists for describing the level of suspicion for tumor as negative, low, medium, or high. Pick lists were modified in 2011 to incorporate a 5-point Likert scale and again in 2015 to incorporate Prostate Imaging Data and Reporting System (PI-RADS) version 2. These refinements were implemented after accelerated training periods. The frequency of reports providing an MRI-based suspicion level during these periods was assessed. Fifty-five percent of reports provided an MRI-based level of suspicion for tumor before the initiative. For various cohorts evaluated after the initiative (using structured reports based on the low, medium, or high scheme; a numeric Likert scale; or PI-RADS), this frequency improved to 95-100% (p < 0.001). Among reports without a suspicion level, potential confounding factors included marked artifact from hip prosthesis and overt diffuse tumor. The QI initiative achieved excellent adherence in reporting a suspicion level for tumor on prostate MRI examinations. The described components of the initiative were useful for maintaining long-term adherence that persisted after serial modifications to the report lexicon.
Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels
NASA Astrophysics Data System (ADS)
Yan, Le-Ping; Silva-Correia, Joana; Ribeiro, Viviana P.; Miranda-Gonçalves, Vera; Correia, Cristina; da Silva Morais, Alain; Sousa, Rui A.; Reis, Rui M.; Oliveira, Ana L.; Oliveira, Joaquim M.; Reis, Rui L.
2016-08-01
Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to β-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become β-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent β-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials.
Rottiers, P; Verfaillie, T; Contreras, R; Revets, H; Desmedt, M; Dooms, H; Fiers, W; Grooten, J
1998-11-09
Progression to malignancy of transformed cells involves complex genetic alterations and aberrant gene expression patterns. While aberrant gene expression is often caused by alterations in individual genes, the contribution of the tumoral environment to the triggering of this gene expression is less well established. The stable but heterogeneous expression in cultured EL4/13 cells of a novel tumor-associated antigen, designated as HTgp-175, was chosen for the investigation of gene expression during tumor formation. Homogeneously HTgp-175-negative EL4/13 cells, isolated by cell sorting or obtained by subcloning, acquired HTgp-175 expression as a result of tumor formation. The tumorigenicity of HTgp-175-negative vs. HTgp-175-positive EL4 variants was identical, indicating that induction but not selection accounted for the phenotypic switch from HTgp-175-negative to HTgp-175-positive. Although mutagenesis experiments showed that the protein was not essential for tumor establishment, tumor-derived cells showed increased malignancy, linking HTgp-175 expression with genetic changes accompanying tumor progression. This novel gene expression was not an isolated event, since it was accompanied by ectopic expression of the large chondroitin sulfate proteoglycan PG-M and of normal differentiation antigens. We conclude that signals derived from the tumoral microenvironment contribute significantly to the aberrant gene expression pattern of malignant cells, apparently by fortuitous activation of differentiation processes and cause expression of novel differentiation antigens as well as of inappropriate tumor-associated and ectopic antigens.
Tumor-induced osteomalacia (TIO): atypical presentation.
Khaliq, Waseem; Cheripalli, Praveen; Tangella, Krishnarao
2011-05-01
Tumor-induced osteomalacia is a rare acquired condition characterized by phosphaturia, hypophosphatemia and osteomalacia. We report an unusual presentation in a 15-year-old healthy male with a two-week history of cough and chest pain. The chest radiograph showed right middle lobe opacity and chest CT revealed a mass in the extra pleural space. A biopsy showed chondro-myxoidstroma with osteoid formation. Diagnosis was confirmed with the above findings and hypophosphatemia. The patient's symptoms resolved after complete surgical excision of the mass. Tumor-induced osteomalacia, although a rare disorder, can be a diagnostic challenge, especially in patients presenting with atypical symptoms.
Collaborative and Defensive Fibroblasts in Tumor Progression and Therapy Resistance.
Chiavarina, Barbara; Turtoi, Andrei
2017-01-01
Tumor microenvironment is a complex network of epithelial cancer cells and non-transformed stromal cells. Of the many stromal cell types, fibroblasts are the most numerous ones and are traditionally viewed as supportive elements of cancer progression. Many studies show that cancer cells engage in active crosstalk with associated fibroblasts in order to obtain key resources, such as growth factors and nutrients. The facets of fibroblast "complicity to murder" in cancer are multiple. However, recent therapeutic attempts aiming at depleting fibroblasts from tumors, perturbed rather simplistic picture. Contrary to the expectations, tumors devoid of fibroblasts accelerated their progression while patients faced poorer outcomes. These studies remind us of the physiologic roles fibroblasts have in maintaining tissue homeostasis even in the presence of cancer. It is becoming increasingly clear that our research focus on advanced tumors has biased our understanding of fibroblast role in tumor biology. The numerous events where the fibroblasts protect the tissue from malignant transformation remain largely unacknowledged, as the tumors are invisible. The present review has the ambition to offer a more balanced view of fibroblasts functions in cancer progression and therapy resistance. We will address the question whether it is possible to synergize the efforts with fibroblasts as the therapeutic concept against tumor progression and therapy resistance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Autophagy Sustains Mitochondrial Glutamine Metabolism and Growth of BRAFV600E–Driven Lung Tumors
Strohecker, Anne M.; Guo, Jessie Yanxiang; Karsli-Uzunbas, Gizem; Price, Sandy M.; Chen, Guanghua Jim; Mathew, Robin; McMahon, Martin; White, Eileen
2013-01-01
Autophagic elimination of defective mitochondria suppresses oxidative stress and preserves mitochondrial function. Here, the essential autophagy gene Atg7 was deleted in a mouse model of BRAFV600E-induced lung cancer in the presence or absence of the tumor suppressor TRP53. Atg7 deletion initially induced oxidative stress and accelerated tumor cell proliferation in a manner indistinguishable from Nrf2 ablation. Compound deletion of Atg7 and Nrf2 had no additive effect suggesting that both genes modulate tumorigenesis by regulating oxidative stress, revealing a potential mechanism of autophagy-mediated tumor suppression. At later stages of tumorigenesis, Atg7 deficiency resulted in an accumulation of defective mitochondria, proliferative defects, reduced tumor burden, conversion of adenomas and adenocarcinomas to oncocytomas, and increased mouse lifespan. Autophagy-defective tumor-derived cell lines were impaired in their ability to respire, survive starvation and were glutamine-dependent, suggesting that autophagy-supplied substrates from protein degradation sustains BRAFV600E-tumor growth and metabolism. PMID:23965987
Senna and the formation of aberrant crypt foci and tumors in rats treated with azoxymethane.
Borrelli, F; Capasso, R; Aviello, G; Di Carlo, G; Izzo, A A; Mascolo, N; Capasso, F
2005-06-01
Chronic use of anthraquinone laxatives has been blamed for the induction of habituation and the development of colonic cancer, but there are no definitive studies which have demonstrated this. To evaluate the carcinogenic potential of anthraquinones, the effect of long-term senna pod extract (SE) treatment on either healthy rats or rats treated with an initiating tumor agent (azoxymethane--AOM) has been studied. SE (30 and 60mg/kg), administered for 110 weeks, did not induce the development of aberrant crypt foci (ACF) and tumors in healthy rats. The development of ACF and tumors in rats treated with AOM were significantly reduced by SE (30 and 60 mg/kg). These results suggest that a chronic SE use does not predispose to colon cancer. By contrast, SE might exert an anti-tumoral activity on rat colon carcinogenesis.
Accelerators for charged particle therapy: PAMELA and related issues
NASA Astrophysics Data System (ADS)
Peach, Ken
2014-05-01
Cancer is a dreadful disease that will affect one in three people at some point in their life; radiotherapy is used in more than half of all cancer treatment, and contributes about 40% to the successful treatment of cancer. Charged Particle Therapy uses protons and other light ions to deliver the lethal dose to the tumor while being relatively sparing of healthy tissue and, because of the finite range of the particles, is able to avoid giving any dose to vital organs. While there are adequate technologies currently available to deliver the required energies and fluxes, the two main technologies (cyclotrons and synchrotrons) have limitations. PAMELA (the Particle Accelerator for MEdicaLApplications) uses the newly-developed non-scaling Fixed Field Alternating Gradient accelerator concepts to deliver therapeutically relevant beams. The status of the development of the PAMELA conceptual design is discussed.
Radiation Therapy Induces Macrophages to Suppress Immune Responses Against Pancreatic Tumors in Mice
Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Ly, Nancy Ngoc Giao; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R.; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George
2016-01-01
Background & Aims The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcome, compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of pre-invasive foci. Methods We investigated the effects of radiation in p48Cre;LSL-KrasG12D (KC) and p48Cre;LSLKrasG12D;LSL-Trp53R172H (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2–12 Gy and analyzed by flow cytometry. Results Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from invasive and pre-invasive pancreatic tumors had an immune-suppressive, M2-like phenotype, compared with control mice. Pancreata from mice exposed to radiation had fewer CD8+ T cells than controls and greater numbers of CD4+ T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. An antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Conclusions Radiation exposure causes macrophages in PDAs
Alanbay, I; Aktürk, E; Coksuer, H; Ercan, C M; Karaşahin, E; Dede, M; Yenen, M C; Ozan, H; Dilek, S
2012-01-01
The aim of this study was to assess tumor markers and clinicopathological findings of patients with serous and mucinous borderline ovarian tumor (BOT) features. The study consisted of 50 patients that were diagnosed with and treated for BOT between 2005-2010 in three centers. CA125, CA19-9, and CA125+CA19-9 levels and clinicopathological features were compared in serous and mucinous histotypes. In serous and mucinous BOTs, correlations between tumor markers and demographics such as age, menopausal status, parity, clinical findings (stage, relapse, adjuvant chemotherapy, cytology, lymph node involvement and tumoral morphology (cystic-solid content, papilla, septation) were evaluated. There were no significant differences between serous and mucinous tumors in the clinicopathological features such as stage, tumor markers, age, menopausal status, or cytology. In serous BOTs we found a significant relation between elevated CA125+ CA19-9, CA19-9 and recurrence (p < 0.05). Also there was a significant relation between elevated CA125+ CA19-9, CA19-9 and cytology positivity (p < 0.05). We found a significant relation in serous BOTs between elevated CA125+CA19-9, adjuvant chemotherapy and lymph node metastases (p < 0.05). Also In mucinous BOTs with papilla formation we found a significant relation between elevated CA125 and CA125+ CA19-9 (p < 0.05). There was significant relation between cytology positivity and elevated CA19-9 in mucinous BOTs (p < 0.05). Serum tumor markers of serous and mucinous BOTs were different in relation to their clinicopathological features. This may reflect differences of serous and mucinous BOTs.
Targeting Tumor Oct4 to Deplete Prostate Tumor- and Metastasis-Initiating Cells
2015-10-01
and stem cell To investigate whether POU5F1B overrxpression can induce cancer stem cell -related genes expression, we did cancer stem cell ...future 15. SUBJECT TERMS OCT4, cancer stem cells , prostate cancer, metastasis, tumor formation 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT...described in last report. Here we describe some findings previously not reported. 1.1 POU5F1B expression in prostatic tissue As cancer stem cell marker
Malignant tumors of the liver in children.
Aronson, Daniel C; Meyers, Rebecka L
2016-10-01
This article aims to give an overview of pediatric liver tumors; in particular of the two most frequently occurring groups of hepatoblastomas and hepatocellular carcinomas. Focus lays on achievements gained through worldwide collaboration. We present recent advances in insight, treatment results, and future questions to be asked. Increasing international collaboration between the four major Pediatric Liver Tumor Study Groups (SIOPEL/GPOH, COG, and JPLT) may serve as a paradigm to approach rare tumors. This international effort has been catalyzed by the Children's Hepatic tumor International Collaboration (CHIC) formation of a large collaborative database. Interrogation of this database has led to a new universal risk stratification system for hepatoblastoma using PRETEXT/POSTTEXT staging as a backbone. Pathologists in this international collaboration have established a new histopathological consensus classification for pediatric liver tumors. Concomitantly there have been advances in chemotherapy options, an increased role of liver transplantation for unresectable tumors, and a web portal system developed at www.siopel.org for international education, consultation, and collaboration. These achievements will be further tested and validated in the upcoming Paediatric Hepatic International Tumour Trial (PHITT). Copyright © 2016 Elsevier Inc. All rights reserved.
Accelerated Near-Threshold Fatigue Crack Growth Behavior of an Aluminum Powder Metallurgy Alloy
NASA Technical Reports Server (NTRS)
Piascik, Robert S.; Newman, John A.
2002-01-01
Fatigue crack growth (FCG) research conducted in the near threshold regime has identified a room temperature creep crack growth damage mechanism for a fine grain powder metallurgy (PM) aluminum alloy (8009). At very low DK, an abrupt acceleration in room temperature FCG rate occurs at high stress ratio (R = Kmin/Kmax). The near threshold accelerated FCG rates are exacerbated by increased levels of Kmax (Kmax less than 0.4 KIC). Detailed fractographic analysis correlates accelerated FCG with the formation of crack-tip process zone micro-void damage. Experimental results show that the near threshold and Kmax influenced accelerated crack growth is time and temperature dependent.
Ovarian mature cystic teratoma with fistula formation into the rectum: a case report.
Kizaki, Yuichiro; Nagai, Tomonori; Ohara, Ken; Gomi, Yosuke; Akahori, Taichi; Ono, Yoshihisa; Matsunaga, Shigetaka; Takai, Yasushi; Saito, Masahiro; Baba, Kazunori; Seki, Hiroyuki
2016-01-01
While ovarian mature cystic teratomas are benign ovarian germ-cell tumors and the most common type of all ovarian tumors, the formation of fistulas into surrounding organs such as the bladder and the intestinal tract is extremely rare. This report documents a case of ovarian mature cystic teratoma with a rectal fistula, thought to be caused by local inflammation. A pelvic mass was diagnosed as an ovarian mature cystic teratoma of approximately 10 cm in diameter on transvaginal ultrasound and magnetic resonance examinations. Endoscopic examination of the lower gastrointestinal tract to investigate diarrhea revealed an ulcerative lesion with hair in the rectal wall adjacent to the ovarian cyst, and formation of a fistula from the ovarian teratoma into the rectum was suspected. Laparotomy revealed extensive inflammatory adhesions between a left ovarian tumor and the rectum. Left salpingo-oophorectomy and upper anterior resection of the rectum were performed. The final pathological diagnosis was ovarian mature cystic teratoma with no malignant findings, together with severe rectal inflammation and fistula formation with no structural disorders such as diverticulitis of the colon or malignant signs. The formation of fistulas and invasion into the neighboring organs are extremely rare complications for ovarian mature cystic teratomas. The invasion of malignant cells into neighboring organs due to malignant transformation of the tumor is reported as the cause of fistula formation into the neighboring organs. A review of 17 cases including the present case revealed that fistula formation due to malignant transformation comprised only 4 cases (23.5 %), with inflammation as the actual cause in the majority of cases (13 cases, 76.5 %). Although malignancy is the first consideration when fistula formation is observed between ovarian tumors and surrounding organs, in mature cystic teratoma, local inflammation is more likely than malignant transformation.
Orbit selection of nanosatellite formation in term of fuel consumption
NASA Astrophysics Data System (ADS)
Pimnoo, Ammarin; Hiraki, Koju
In nanosatellite formation mission design, orbit selection is a necessary factor. Fuel consumption is also necessary to maintain the orbit. Therefore, the best orbit should be the one of minimum fuel consumption for nanosatellite formation. The purpose of this paper is to provide a convenient way to estimate fuel consumption for a nanosatellite to keep formation flying. The formation is disturbed by J _{2} perturbation and other perturbing accelerations. Firstly, the Hill-Clohessy-Wiltshire equations are used in the analysis. Gaussian variation of parameters is included into the Hill’s equation to analyze the variation of Kaplerian orbital elements. The J _{2} perturbation and other perturbing accelerations such as atmospheric drag, solar-radiation pressure and third-body perturbations are considered. Thus, a linear model based on Hill’s equation is established to estimate fuel consumption. Finally, an example of the best orbit for formation flying with minimum fuel consumption shall be presented.
Tanaka, Kiyoko; Kondo, Keiichi; Kitajima, Kenji; Muraoka, Masatoshi; Nozawa, Akinori; Hara, Takahiko
2013-08-16
Protein-tyrosine phosphatase non-receptor type 23 (PTPN23) is a candidate tumor suppressor involved in the tumorigenesis of various organs. However, its physiological role(s) and detailed expression profile(s) have not yet been elucidated. We investigated the function and regulation of PTPN23 in the formation of testicular germ cell tumors (TGCTs). Expression of PTPN23 in human TGCT cell lines was significantly lower than that in spermatogonial stem cells in mice. Overexpression of PTPN23 in NEC8, a human TGCT cell line, suppressed soft agar colony formation in vitro and tumor formation in nude mice in vivo. These data indicate that PTPN23 functions as a tumor suppressor in TGCTs. Multiple computational algorithms predicted that the 3' UTR of human PTPN23 is a target for miR-142-3p. A luciferase reporter assay confirmed that miR-142-3p bound directly to the 3' UTR of PTPN23. Introduction of pre-miR-142 in the PTPN23 transfectant of NEC8 led to suppressed expression of PTPN23 and increased soft agar colony formation. Quantitative RT-PCR data revealed a significantly higher expression of miR-142-3p in human seminomas compared with normal testes. No difference in mRNA expression between seminoma and non-seminoma samples was detected by in situ hybridization. Both quantitative RT-PCR and immunohistochemical analyses revealed that PTPN23 expression was significantly lower in TGCTs than in normal testicular tissues. Finally, a lack of PTPN23 protein expression in human TGCTs correlated with a relatively higher miR-142-3p expression. These data suggest that PTPN23 is a tumor suppressor and that repression of PTPN23 expression by miR-142-3p plays an important role in the pathogenesis of TGCTs.
The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium
Grego-Bessa, Joaquim; Bloomekatz, Joshua; Castel, Pau; Omelchenko, Tatiana; Baselga, José; Anderson, Kathryn V
2016-01-01
Epithelial morphogenesis and stability are essential for normal development and organ homeostasis. The mouse neural plate is a cuboidal epithelium that remodels into a columnar pseudostratified epithelium over the course of 24 hr. Here we show that the transition to a columnar epithelium fails in mutant embryos that lack the tumor suppressor PTEN, although proliferation, patterning and apical-basal polarity markers are normal in the mutants. The Pten phenotype is mimicked by constitutive activation of PI3 kinase and is rescued by the removal of PDK1 (PDPK1), but does not depend on the downstream kinases AKT and mTORC1. High resolution imaging shows that PTEN is required for stabilization of planar cell packing in the neural plate and for the formation of stable apical-basal microtubule arrays. The data suggest that appropriate levels of membrane-associated PDPK1 are required for stabilization of apical junctions, which promotes cell elongation, during epithelial morphogenesis. DOI: http://dx.doi.org/10.7554/eLife.12034.001 PMID:26809587
Akhmetzyanova, Ilseyar; Zelinskyy, Gennadiy; Schimmer, Simone; Brandau, Sven; Altenhoff, Petra; Sparwasser, Tim; Dittmer, Ulf
2013-02-01
The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.
Reduced Contact Hour Accelerated Courses and Student Learning
ERIC Educational Resources Information Center
Thornton, Barry; Demps, Julius; Jadav, Arpita
2017-01-01
Undergraduate instruction in the Davis College of Business at Jacksonville University utilizes two course delivery methods. Traditional daytime classes are 15 weeks long and have approximately 40 contact hours, while evening courses are offered in the Accelerated Degree program in a compressed 8-week format with 24 contact hours. The curriculum is…
Svanborg, Catharina; Agerstam, Helena; Aronson, Annika; Bjerkvig, Rolf; Düringer, Caroline; Fischer, Walter; Gustafsson, Lotta; Hallgren, Oskar; Leijonhuvud, Irene; Linse, Sara; Mossberg, Ann-Kristin; Nilsson, Hanna; Pettersson, Jenny; Svensson, Malin
2003-01-01
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of alpha-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET. This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.
End-to-end workflow for finite element analysis of tumor treating fields in glioblastomas
NASA Astrophysics Data System (ADS)
Timmons, Joshua J.; Lok, Edwin; San, Pyay; Bui, Kevin; Wong, Eric T.
2017-11-01
Tumor Treating Fields (TTFields) therapy is an approved modality of treatment for glioblastoma. Patient anatomy-based finite element analysis (FEA) has the potential to reveal not only how these fields affect tumor control but also how to improve efficacy. While the automated tools for segmentation speed up the generation of FEA models, multi-step manual corrections are required, including removal of disconnected voxels, incorporation of unsegmented structures and the addition of 36 electrodes plus gel layers matching the TTFields transducers. Existing approaches are also not scalable for the high throughput analysis of large patient volumes. A semi-automated workflow was developed to prepare FEA models for TTFields mapping in the human brain. Magnetic resonance imaging (MRI) pre-processing, segmentation, electrode and gel placement, and post-processing were all automated. The material properties of each tissue were applied to their corresponding mask in silico using COMSOL Multiphysics (COMSOL, Burlington, MA, USA). The fidelity of the segmentations with and without post-processing was compared against the full semi-automated segmentation workflow approach using Dice coefficient analysis. The average relative differences for the electric fields generated by COMSOL were calculated in addition to observed differences in electric field-volume histograms. Furthermore, the mesh file formats in MPHTXT and NASTRAN were also compared using the differences in the electric field-volume histogram. The Dice coefficient was less for auto-segmentation without versus auto-segmentation with post-processing, indicating convergence on a manually corrected model. An existent but marginal relative difference of electric field maps from models with manual correction versus those without was identified, and a clear advantage of using the NASTRAN mesh file format was found. The software and workflow outlined in this article may be used to accelerate the investigation of TTFields in
Ludlow, Aaron D; Benítez-Llambay, Alejandro; Schaller, Matthieu; Theuns, Tom; Frenk, Carlos S; Bower, Richard; Schaye, Joop; Crain, Robert A; Navarro, Julio F; Fattahi, Azadeh; Oman, Kyle A
2017-04-21
We analyze the total and baryonic acceleration profiles of a set of well-resolved galaxies identified in the eagle suite of hydrodynamic simulations. Our runs start from the same initial conditions but adopt different prescriptions for unresolved stellar and active galactic nuclei feedback, resulting in diverse populations of galaxies by the present day. Some of them reproduce observed galaxy scaling relations, while others do not. However, regardless of the feedback implementation, all of our galaxies follow closely a simple relationship between the total and baryonic acceleration profiles, consistent with recent observations of rotationally supported galaxies. The relation has small scatter: Different feedback implementations-which produce different galaxy populations-mainly shift galaxies along the relation rather than perpendicular to it. Furthermore, galaxies exhibit a characteristic acceleration g_{†}, above which baryons dominate the mass budget, as observed. These observations, consistent with simple modified Newtonian dynamics, can be accommodated within the standard cold dark matter paradigm.
Li, Wenjuan; Zhang, Chunjing; Du, Hongyan; Huang, Vincent; Sun, Brandi; Harris, John P; Richardson, Quitin; Shen, Xinggui; Jin, Rong; Li, Guohong; Kevil, Christopher G; Gu, Xin; Shi, Runhua; Zhao, Yunfeng
2016-11-01
Withaferin A (WA), a natural product derived from Withania somnifera, has been used in traditional oriental medicines to treat neurological disorders. Recent studies have demonstrated that this compound may have a potential for cancer treatment and a clinical trial has been launched to test WA in treating melanoma. Herein, WA's chemopreventive potential was tested in a chemically-induced skin carcinogenesis mouse model. Pathological examinations revealed that WA significantly suppressed skin tumor formation. Morphological observations of the skin tissues suggest that WA suppressed cell proliferation rather than inducing apoptosis during skin carcinogenesis. Antibody Micro array analysis demonstrated that WA blocked carcinogen-induced up-regulation of acetyl-CoA carboxylase 1 (ACC1), which was further confirmed in a skin cell transformation model. Overexpression of ACC1 promoted whereas knockdown of ACC1 suppressed anchorage-independent growth and oncogene activation of transformable skin cells. Further studies demonstrated that WA inhibited tumor promotor-induced ACC1 gene transcription by suppressing the activation of activator protein 1. In melanoma cells, WA was also able to suppress the expression levels of ACC1. Finally, results using human skin cancer tissues confirmed the up-regulation of ACC1 in tumors than adjacent normal tissues. In summary, our results suggest that withaferin A may have a potential in chemoprevention and ACC1 may serve as a critical target of WA. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
Targeting Vasculature in Urologic Tumors: Mechanistic and Therapeutic Significance
Sakamoto, Shinichi; Ryan, A. Jacqueline; Kyprianou, Natasha
2008-01-01
Recent advances toward understanding the molecular mechanisms regulating cancer initiation and progression provide new insights into the therapeutic value of targeting tumor vascularity by interfering with angiogenic signaling pathways. The functional contribution of key angiogenic factors toward increased vascularity characterizing metastatic tumors and their therapeutic exploitation is considered in three major urologic malignancies, renal, bladder, and prostate cancer. With the realization that the success of the therapeutic efficacy of the various anti-angiogenic approaches for the treatment of urologic tumors has yet to be proven clinically, the challenge remains to select critical angiogenesis pathways that can be targeted for an individual tumor. Here we discuss the major mechanisms that support formation of vasculature in renal, bladder, and prostate tumors and the current results of targeting of specific molecules/regulators for therapeutic intervention against metastastic disease. PMID:17668426
Solar Energetic Particle Events and CME Accelerations in the Low Corona: MLSO Observations
NASA Astrophysics Data System (ADS)
St Cyr, O. C.; Kahler, S. W.; Richardson, I. G.; Cane, H. V.; Xie, H.; Burkepile, J.
2016-12-01
The low solar corona (< 2.5 Rs) is the region in which maximum coronal mass ejection (CME) acceleration occurs and where Type II radio observations suggest that shock formation occurs (Mäkelä et al., 2015). It is therefore a key region for investigations of solar energetic particle (SEP) acceleration by CME-driven shocks. Observations very low in the corona are necessary to detect the rapid CME accelerations leading to shock formation and to assess the speeds of CMEs through the middle corona. However, these observations cannot be made by space borne coronagraphs in which CME trajectories above the occulting disk are usually characterized by a single (constant) speed: e.g., 80% of the speeds in the compilation of SMM CMEs (Burkepile and St. Cyr, 1993) and SOHO LASCO CMEs (St. Cyr et al., 2000). The Mk3/Mk4/K-Cor coronameters at the Mauna Loa Solar Observatory are able to measure the initial accelerations of CMEs low in the corona (i.e., < 2 Rs). We examine a subset of CMEs that were associated with SEP events between 1980-present. The subset is based on the CME launch occurring between 16 UT - 01 UT - the MLSO observing window. In most cases, the CME accelerations are significantly larger than those measured by spaceborne coronagraphs (e.g., SMM, Solwind, LASCO, SECCHI). We will present the preliminary results of a comparison of the SEP parameters with initial CME accelerations in the MLSO coronagraph field of view.
Intratumor Heterogeneity in Evolutionary Models of Tumor Progression
Durrett, Rick; Foo, Jasmine; Leder, Kevin; Mayberry, John; Michor, Franziska
2011-01-01
With rare exceptions, human tumors arise from single cells that have accumulated the necessary number and types of heritable alterations. Each such cell leads to dysregulated growth and eventually the formation of a tumor. Despite their monoclonal origin, at the time of diagnosis most tumors show a striking amount of intratumor heterogeneity in all measurable phenotypes; such heterogeneity has implications for diagnosis, treatment efficacy, and the identification of drug targets. An understanding of the extent and evolution of intratumor heterogeneity is therefore of direct clinical importance. In this article, we investigate the evolutionary dynamics of heterogeneity arising during exponential expansion of a tumor cell population, in which heritable alterations confer random fitness changes to cells. We obtain analytical estimates for the extent of heterogeneity and quantify the effects of system parameters on this tumor trait. Our work contributes to a mathematical understanding of intratumor heterogeneity and is also applicable to organisms like bacteria, agricultural pests, and other microbes. PMID:21406679
Schönberger, Tanja; Jürgens, Tobias; Müller, Julia; Armbruster, Nicole; Niermann, Christina; Gorressen, Simone; Sommer, Jan; Tian, Huasong; di Paolo, Gilbert; Scheller, Jürgen; Fischer, Jens W; Gawaz, Meinrad; Elvers, Margitta
2014-09-01
Myocardial inflammation is critical for ventricular remodeling after ischemia. Phospholipid mediators play an important role in inflammatory processes. In the plasma membrane they are degraded by phospholipase D1 (PLD1). PLD1 was shown to be critically involved in ischemic cardiovascular events. Moreover, PLD1 is coupled to tumor necrosis factor-α signaling and inflammatory processes. However, the impact of PLD1 in inflammatory cardiovascular disease remains elusive. Here, we analyzed the impact of PLD1 in tumor necrosis factor-α-mediated activation of monocytes after myocardial ischemia and reperfusion using a mouse model of myocardial infarction. PLD1 expression was highly up-regulated in the myocardium after ischemia/reperfusion. Genetic ablation of PLD1 led to defective cell adhesion and migration of inflammatory cells into the infarct border zone 24 hours after ischemia/reperfusion injury, likely owing to reduced tumor necrosis factor-α expression and release, followed by impaired nuclear factor-κB activation and interleukin-1 release. Moreover, PLD1 was found to be important for transforming growth factor-β secretion and smooth muscle α-actin expression of cardiac fibroblasts because myofibroblast differentiation and interstitial collagen deposition were altered in Pld1(-/-) mice. Consequently, infarct size was increased and left ventricular function was impaired 28 days after myocardial infarction in Pld1(-/-) mice. Our results indicate that PLD1 is crucial for tumor necrosis factor-α-mediated inflammation and transforming growth factor-β-mediated collagen scar formation, thereby augmenting cardiac left ventricular function after ischemia/reperfusion. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kasten-Pisula, Ulla; Saker, Jarob; Eicheler, Wolfgang
2011-07-15
Purpose: There is conflicting evidence for whether the expression of epidermal growth factor receptor in human tumors can be used as a marker of radioresponse. Therefore, this association was studied in a systematic manner using squamous cell carcinoma (SCC) cell lines grown as cell cultures and xenografts. Methods and Materials: The study was performed with 24 tumor cell lines of different tumor types, including 10 SCC lines, which were also investigated as xenografts on nude mice. Egfr gene dose and the length of CA-repeats in intron 1 were determined by polymerase chain reaction, protein expression in vitro by Western blotmore » and in vivo by enzyme-linked immunosorbent assay, and radiosensitivity in vitro by colony formation. Data were correlated with previously published tumor control dose 50% data after fractionated irradiation of xenografts of the 10 SCC. Results: EGFR protein expression varies considerably, with most tumor cell lines showing moderate and only few showing pronounced upregulation. EGFR upregulation could only be attributed to massive gene amplification in the latter. In the case of little or no amplification, in vitro EGFR expression correlated with both cellular and tumor radioresponse. In vivo EGFR expression did not show this correlation. Conclusions: Local tumor control after the fractionated irradiation of tumors with little or no gene amplification seems to be dependent on in vitro EGFR via its effect on cellular radiosensitivity.« less
Gravitomagnetic Acceleration of Black Hole Accretion Disk Matter to Polar Jets
NASA Astrophysics Data System (ADS)
Poirier, John; Mathews, Grant
2015-04-01
It is shown that the motion of the neutral masses in an accretion disk orbiting a black hole creates a magnetic-like (gravitomagnetic) field that vertically accelerates neutral particles near the accretion disk away from the disk and then inward toward the axis of the accretion disk. Moreover, as the accelerated material nears the axis, a frame-dragging effect twists the trajectories around the axis thus contributing to the formation of a narrow polar jet emanating from the poles.
Induction of parotitis by fine-needle aspiration in parotid Warthin's tumor.
Suzuki, Kensuke; Iwai, Hiroshi; Kaneko, Toshihiko; Sakaguchi, Mariko; Hoshino, Shoichi; Inaba, Muneo
2009-08-01
To estimate parotitis caused by fine-needle aspiration (FNA) in parotid Warthin tumor. Case series with chart review. Hospital records were reviewed for 104 parotid tumors (103 patients) including 35 Warthin tumors, which underwent FNA within our department. Three patients with four Warthin tumors among them noticed parotid pain, swelling, and abscess formation as a consequence of acute parotitis after FNA. Examinations of the materials obtained from tumor puncture or drainage before the start of antibiotic therapy showed no bacterial association in any patient. Two of the patients with Warthin tumor underwent parotidectomy, and the surgical specimens indicated histopathological changes with necrosis, abscess, granuloma, and the infiltration of inflammatory cells including Langhans-type multinucleated giant cells. It is conceivable that Warthin tumor bears the characteristics of inflammation induced by the FNA procedure without any relation to infection. Therefore, it may be better to avoid routine FNA and give priority to diagnostic imagings over FNA in the diagnosis of tumors strongly suspected as Warthin tumor.
Lu, Jui-Hua; Wei, Hong-Jian; Peng, Bou-Yue; Chou, Hsin-Hua; Chen, Wei-Hong; Liu, Hen-Yu; Deng, Win-Ping
2016-12-01
Adipose-derived stem cells (ADSCs) are multipotent cells that have attracted much recent attention and emerged as therapeutic approaches in several medical fields. Although current knowledge of the biological impacts of ADSCs in cancer research is greatly improved, the underlying effects of ADSCs in tumor development remain controversial and cause the safety concerns in clinical utilization. Hence, we isolated primary ADSCs from the abdominal fat of mice and conducted interaction of ADSCs with Lewis lung carcinoma cells in culture and in mice to investigate the impacts of ADSCs on tumor development. Cytokine array and neutralizing antibody were further utilized to identify the key regulator and downstream signaling pathway. In this study, we demonstrated that ADSCs enhance the malignant characteristics of LLC1 cells, including cell growth ability and especially cancer stem cell property. ADSCs were then identified to promote tumor formation and growth in mice. We further determined that ADSC interaction with LLC1 cells stimulates increased secretion of interleukin-6 mainly from ADSCs, which then act in a paracrine manner on LLC1 cells to enhance their malignant characteristics. Interleukin-6 was also identified to regulate genes related to cell proliferation and cancer stem cell, as well as to activate JAK2/STAT3, a predominant interleukin-6-activated pathway, in LLC1 cells. Collectively, we demonstrated that ADSCs play a pro-malignant role in tumor development of Lewis lung carcinoma cells by particularly promoting cancer stem cell property through interleukin-6 paracrine circuit, which is important for safety considerations regarding the clinical application of ADSCs.
An Improved Binary Differential Evolution Algorithm to Infer Tumor Phylogenetic Trees.
Liang, Ying; Liao, Bo; Zhu, Wen
2017-01-01
Tumourigenesis is a mutation accumulation process, which is likely to start with a mutated founder cell. The evolutionary nature of tumor development makes phylogenetic models suitable for inferring tumor evolution through genetic variation data. Copy number variation (CNV) is the major genetic marker of the genome with more genes, disease loci, and functional elements involved. Fluorescence in situ hybridization (FISH) accurately measures multiple gene copy number of hundreds of single cells. We propose an improved binary differential evolution algorithm, BDEP, to infer tumor phylogenetic tree based on FISH platform. The topology analysis of tumor progression tree shows that the pathway of tumor subcell expansion varies greatly during different stages of tumor formation. And the classification experiment shows that tree-based features are better than data-based features in distinguishing tumor. The constructed phylogenetic trees have great performance in characterizing tumor development process, which outperforms other similar algorithms.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Galloway, Thomas J.; University of Florida Proton Therapy Institute, Jacksonville, FL; Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org
Purpose: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. Methods and Materials: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal tomore » the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). Results: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). Conclusions: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy.« less
Katoh, Hiroshi; Hosono, Kanako; Ito, Yoshiya; Suzuki, Tatsunori; Ogawa, Yasufumi; Kubo, Hidefumi; Kamata, Hiroki; Mishima, Toshiaki; Tamaki, Hideaki; Sakagami, Hiroyuki; Sugimoto, Yukihiko; Narumiya, Shuh; Watanabe, Masahiko; Majima, Masataka
2010-01-01
Bone marrow (BM)–derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)−2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. In this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E2 enhanced stromal formation and CXCL12/CXCR4 expression. In addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3−/− mice and EP4−/− mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EP4 knockout suppressed S100A4+ fibroblasts, CXCL12+, and/or CXCR4+ stromal cells as well. Immunofluorescent analyses revealed that CXCL12+CXCR4+S100A4+ fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE2-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under the control of prostaglandins. PMID:20110411
A tumor profile in Patau syndrome (trisomy 13).
Satgé, Daniel; Nishi, Motoi; Sirvent, Nicolas; Vekemans, Michel; Chenard, Marie-Pierre; Barnes, Ann
2017-08-01
Individuals with trisomic conditions like Down syndrome and Edwards syndrome are prone to certain types of malignancy. However, for Patau syndrome (constitutional trisomy 13), which occurs in 1/10,000-1/20,000 live births, the tumor profile has not been well characterized. An awareness of susceptibility to malignancies can improve care of affected individuals, as well as further our understanding of the contribution of trisomy to carcinogenesis. Therefore, we conducted an extensive review of the literature; we found 17 malignancies reported in individuals with Patau syndrome. These comprised eight embryonic tumors, three leukemias, two malignant germ cell tumors, two carcinomas, a malignant brain tumor, and a sarcoma. Benign tumors were mainly extragonadal teratomas. The small number of reported malignant tumors suggests that there is not an increased risk of cancer in the context of trisomy 13. The tumor profile in Patau syndrome differs from that observed in Edwards syndrome (trisomy 18) and Down syndrome (trisomy 21), suggesting that the supernumerary chromosome 13 could promote particular tumor formations as it does particular malformations. No general and direct relationships of tumor occurrence with organ weight, congenital malformations, histological changes, or presence of tumor suppressor genes on chromosome 13 were observed. However, some tumors were found in tissues whose growth and development are controlled by genes mapping to chromosome 13. Recent reports of successful outcomes following surgical treatment and adapted chemotherapy indicate that treatment of cancer is possible in Patau syndrome. © 2017 Wiley Periodicals, Inc.
Hirakawa, Yuko; Jimbo, Ryo; Shibata, Yasuaki; Watanabe, Ikuya; Wennerberg, Ann; Sawase, Takashi
2013-08-01
The purpose of this study was to investigate the effect of photo-induced hydrophilic titanium dioxide (TiO₂) on serum fibronectin (sFN) attachment, and further to evaluate initial osseointegration responses in the dog mandibles. To apply the anatase TiO₂ film, plasma source ion implantation (PSII) method followed by annealing was employed for the titanium disks and implants, which were then illuminated with UV-A for 24 h for the experimental groups. Non-deposited titanium disks and implants were prepared for the control group. Surface characterization was performed using the interferometer and contact angle analyzer. The attachments of sFN were evaluated using fluorescence emission analysis. Thereafter both groups of implants were placed in the mandible of six beagle dogs. Bone response was investigated with histological and histomorphometrical analyses after periods of 2 and 4 weeks. The experimental groups exhibited strong hydrophilicity under UV-A illumination and showed significant improvement in sFN attachment. And further, the experimental implants enhanced the bone formation with the bone-to-implant contact of 42.7% after 2 weeks of healing (control: 28.4%). The combined applications of plasma fibronectin and PSII to produce hydrophilic titanium surfaces could accelerate early osseointegration. © 2012 John Wiley & Sons A/S.
Bioavailability and efficacy of a gap junction enhancer (PQ7) in a mouse mammary tumor model.
Shishido, Stephanie N; Prasain, Keshar; Beck, Amanda; Nguyen, Thi D T; Hua, Duy H; Nguyen, Thu Annelise
2013-01-01
The loss of gap junctional intercellular communication is characteristic of neoplastic cells, suggesting that the restoration with a gap junction enhancer may be a new therapeutic treatment option with less detrimental effects than traditional antineoplastic drugs. A gap junction enhancer, 6-methoxy-8-[(2-furanylmethyl) amino]-4-methyl-5-(3-trifluoromethylphenyloxy) quinoline (PQ7), on the normal tissue was evaluated in healthy C57BL/6J mice in a systemic drug distribution study. Immunoblot analysis of the vital organs indicates a reduction in Cx43 expression in PQ7-treated animals with no observable change in morphology. Next the transgenic strain FVB/N-Tg(MMTV-PyVT) 634Mul/J (also known as PyVT) was used as a spontaneous mammary tumor mouse model to determine the biological and histological effects of PQ7 on tumorigenesis and metastasis at three stages of development: Pre tumor, Early tumor, and Late tumor formation. PQ7 was assessed to have a low toxicity through intraperitoneal administration, with the majority of the compound being detected in the heart, liver, and lungs six hours post injection. The treatment of tumor bearing animals with PQ7 had a 98% reduction in tumor growth, while also decreasing the total tumor burden compared to control mice during the Pre stage of development. PQ7 treatment increased Cx43 expression in the neoplastic tissue during Pre-tumor formation; however, this effect was not observed in Late stage tumor formation. This study shows that the gap junction enhancer, PQ7, has low toxicity to normal tissue in healthy C57BL/6J mice, while having clinical efficacy in the treatment of spontaneous mammary tumors of PyVT mice. Additionally, gap junctional intercellular communication and neoplastic cellular growth are shown to be inversely related, while treatment with PQ7 inhibits tumor growth through targeting gap junction expression.
An investigation on some of the tumor treatment cases using x-rays and electron beams
NASA Astrophysics Data System (ADS)
Ucar, Burcu; Yigitoglu, Ibrahim; Arslan Kabalay, Ipek; Altiparmak, Duygu; Kilicaslan, Sinem
2015-07-01
In this work, we discussed some of the applications which X-rays and electron beam used in radiotherapy for tumor treatments. This study has been performed at Radiation Oncology Department, Medicine Faculty in Gaziosmanpasa University by using the VARIAN CLINICA DHX linear accelerator which is operated in the range of 6 MeV - 15 MeV. Processes for the treatments that X-rays used for pancreas, bladder and prostate tumors and the processes that the electron beam used for some of the derm tumors are studied. Effects of X-rays and electron beams to treatments process are examined and the obtained results are presented comparatively.
Lobos-González, L; Aguilar, L; Diaz, J; Diaz, N; Urra, H; Torres, V; Silva, V; Fitzpatrick, C; Lladser, A; Hoek, K.S.; Leyton, L; Quest, AFG
2013-01-01
SUMMARY The role of caveolin-1 (CAV1) in cancer is highly controversial. CAV1 suppresses genes that favor tumor development, yet also promotes focal adhesion turnover and migration of metastatic cells. How these contrasting observations relate to CAV1 function in vivo is unclear. Our previous studies implicate E-cadherin in CAV1-dependent tumor suppression. Here we use murine melanoma B16F10 cells, with low levels of endogenous CAV1 and E-cadherin, to unravel how CAV1 affects tumor growth and metastasis, and to assess how co-expression of E-cadherin modulates CAV1 function in vivo in C57BL/6 mice. We find that overexpression of CAV1 in B16F10(cav-1) cells reduces subcutaneous tumor formation, but enhances metastasis relative to control cells. Furthermore, E-cadherin expression in B16F10(E-cad) cells reduces subcutaneous tumor formation, and lung metastasis when intravenously injected. Importantly, co-expression of CAV1 and E-cadherin in B16F10(cav1/E-cad) cells abolishes tumor formation, lung metastasis, increased Rac-1 activity and cell migration observed with B16F10(cav-1) cells. Finally, consistent with the notion that CAV1 participates in switching human melanomas to a more malignant phenotype, elevated levels of CAV1 expression correlated with enhanced migration and Rac-1 activation in these cells. PMID:23470013
The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression.
Schramek, Daniel; Kotsinas, Athanassios; Meixner, Arabella; Wada, Teiji; Elling, Ulrich; Pospisilik, J Andrew; Neely, G Gregory; Zwick, Ralf-Harun; Sigl, Verena; Forni, Guido; Serrano, Manuel; Gorgoulis, Vassilis G; Penninger, Josef M
2011-03-01
Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.
NASA Astrophysics Data System (ADS)
Lopatin, V. S.; Remnev, G. E.; Martynenko, A. A.
2017-05-01
We have studied the collective acceleration of protons and deuterons in an electron beam emitted from plasma formed at the surface of a dielectric anode insert. The experiments were performed with a pulsed electron accelerator operating at an accelerating voltage up to 1 MV, current amplitude up to 40 kA, and pulse duration of 50 ns. Reduction of the accelerating voltage pulse front width and optimization of the diode unit and drift region ensured the formation of several annular structures in the electron beam. As a result, up to 50% of the radioactivity induced in a copper target was concentrated in a ring with 4.5-cm diameter and 0.2-cm width. The formation of high energy density in these circular traces and the appearance of an axial component of the self-generated magnetic field of the electron beam are related with the increasing efficiency of acceleration of the most intense group of ions.
Primary yolk sac tumor of the urachus.
Romero-Rojas, Alfredo Ernesto; Messa-Botero, Oscar Alberto; Melo-Uribe, Mario Alexander; Díaz-Pérez, Julio Alexander; Chinchilla-Olaya, Sandra Isabel
2011-10-01
Neoplasms originating from the urachus are rare. The most common urachal malignancy is adenocarcinoma, whereas extragonadal germ cell tumors, primarily of the urachus, are an extremely rare finding. To describe a primary yolk sac tumor (YST) of the urachus in an adult. A 44-year-old woman presented with 6 months of pelvic pain associated with a sensation of progressive mass growth. At the time of tumor resection, the tumor was found to be attached by a pedicle to the dome of the bladder, with no injury to the adjacent organs. Pathological study showed a neoplasm with epithelioid cells, pseudocysts, a myxomatous background, and Schiller-Duval body formations. Immunohistochemistry stains showed positivity to AE1/AE3, α-1-fetoprotein, and α-1-antitrypsin and negativity to other markers. An unusual case of a YST in the urachus is presented. This is the first reported adult case based on the authors' bibliographic search.
Locomotor proteins in tissues of primary tumors and metastases of ovarian and breast cancer
NASA Astrophysics Data System (ADS)
Kondakova, I. V.; Yunusova, N. V.; Spirina, L. V.; Shashova, E. E.; Kolegova, E. S.; Kolomiets, L. A.; Slonimskaya, E. M.; Villert, A. B.
2016-08-01
The paper discusses the capability for active movement in an extracellular matrix, wherein remodeling of the cytoskeleton by actin binding proteins plays a significant role in metastases formation. We studied the expression of actin binding proteins and β-catenin in tissues of primary tumors and metastases of ovarian and breast cancer. Contents of p45 Ser β-catenin and the actin severing protein gelsolin were decreased in metastases of ovarian cancer relative to primary tumors. The level of the cofilin, functionally similar to gelsolin, was significantly higher in metastases compared to primary ovarian and breast tumor tissue. In breast cancer, significant increase in the number of an actin monomer binder protein thymosin-β4 was observed in metastases as compared to primary tumors. The data obtained suggest the involvement of locomotor proteins in metastases formation in ovarian and breast cancer.
Towards Resolving the Pro- and Anti-Tumor Effects of the Aryl Hydrocarbon Receptor.
Narasimhan, Supraja; Stanford Zulick, Elizabeth; Novikov, Olga; Parks, Ashley J; Schlezinger, Jennifer J; Wang, Zhongyan; Laroche, Fabrice; Feng, Hui; Mulas, Francesca; Monti, Stefano; Sherr, David H
2018-05-07
We have postulated that the aryl hydrocarbon receptor (AHR) drives the later, more lethal stages of some cancers when chronically activated by endogenous ligands. However, other studies have suggested that, under some circumstances, the AHR can oppose tumor aggression. Resolving this apparent contradiction is critical to the design of AHR-targeted cancer therapeutics. Molecular (siRNA, shRNA, AHR repressor, CRISPR-Cas9) and pharmacological (AHR inhibitors) approaches were used to confirm the hypothesis that AHR inhibition reduces human cancer cell invasion (irregular colony growth in 3D Matrigel cultures and Boyden chambers), migration (scratch wound assay) and metastasis (human cancer cell xenografts in zebrafish). Furthermore, these assays were used for a head-to-head comparison between AHR antagonists and agonists. AHR inhibition or knockdown/knockout consistently reduced human ER − /PR − /Her2 − and inflammatory breast cancer cell invasion, migration, and metastasis. This was associated with a decrease in invasion-associated genes (e.g., Fibronectin , VCAM1 , Thrombospondin, MMP1 ) and an increase in CDH1/E-cadherin , previously associated with decreased tumor aggression. Paradoxically, AHR agonists (2,3,7,8-tetrachlorodibenzo- p -dioxin and/or 3,3′-diindolylmethane) similarly inhibited irregular colony formation in Matrigel and blocked metastasis in vivo but accelerated migration. These data demonstrate the complexity of modulating AHR activity in cancer while suggesting that AHR inhibitors, and, under some circumstances, AHR agonists, may be useful as cancer therapeutics.
Formation Flying for Distributed InSAR
NASA Technical Reports Server (NTRS)
Scharf, Daniel P.; Murray, Emmanuell A.; Ploen, Scott R.; Gromov, Konstantin G.; Chen, Curtis W.
2006-01-01
We consider two spacecraft flying in formation to create interferometric synthetic aperture radar (InSAR). Several candidate orbits for such in InSar formation have been previously determined based on radar performance and Keplerian orbital dynamics. However, with out active control, disturbance-induced drift can degrade radar performance and (in the worst case) cause a collision. This study evaluates the feasibility of operating the InSAR spacecraft as a formation, that is, with inner-spacecraft sensing and control. We describe the candidate InSAR orbits, design formation guidance and control architectures and algorithms, and report the (Delta)(nu) and control acceleration requirements for the candidate orbits for several tracking performance levels. As part of determining formation requirements, a formation guidance algorithm called Command Virtual Structure is introduced that can reduce the (Delta)(nu) requirements compared to standard Leader/Follower formation approaches.
Behavioral stress accelerates prostate cancer development in mice
Hassan, Sazzad; Karpova, Yelena; Baiz, Daniele; Yancey, Dana; Pullikuth, Ashok; Flores, Anabel; Register, Thomas; Cline, J. Mark; D’Agostino, Ralph; Danial, Nika; Datta, Sandeep Robert; Kulik, George
2013-01-01
Prostate cancer patients have increased levels of stress and anxiety. Conversely, men who take beta blockers, which interfere with signaling from the stress hormones adrenaline and noradrenaline, have a lower incidence of prostate cancer; however, the mechanisms underlying stress–prostate cancer interactions are unknown. Here, we report that stress promotes prostate carcinogenesis in mice in an adrenaline-dependent manner. Behavioral stress inhibited apoptosis and delayed prostate tumor involution both in phosphatase and tensin homolog–deficient (PTEN-deficient) prostate cancer xenografts treated with PI3K inhibitor and in prostate tumors of mice with prostate-restricted expression of c-MYC (Hi-Myc mice) subjected to androgen ablation therapy with bicalutamide. Additionally, stress accelerated prostate cancer development in Hi-Myc mice. The effects of stress were prevented by treatment with the selective β2-adrenergic receptor (ADRB2) antagonist ICI118,551 or by inducible expression of PKA inhibitor (PKI) or of BCL2-associated death promoter (BAD) with a mutated PKA phosphorylation site (BADS112A) in xenograft tumors. Effects of stress were also blocked in Hi-Myc mice expressing phosphorylation-deficient BAD (BAD3SA). These results demonstrate interactions between prostate tumors and the psychosocial environment mediated by activation of an adrenaline/ADRB2/PKA/BAD antiapoptotic signaling pathway. Our findings could be used to identify prostate cancer patients who could benefit from stress reduction or from pharmacological inhibition of stress-induced signaling. PMID:23348742
Development of a tandem-electrostatic-quadrupole accelerator facility for BNCT.
Kreiner, A J; Thatar Vento, V; Levinas, P; Bergueiro, J; Di Paolo, H; Burlon, A A; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Minsky, D M; Estrada, L; Hazarabedian, A; Johann, F; Suarez Sandin, J C; Castell, W; Davidson, J; Davidson, M; Giboudot, Y; Repetto, M; Obligado, M; Nery, J P; Huck, H; Igarzabal, M; Fernandez Salares, A
2009-07-01
In this work we describe the present status of an ongoing project to develop a tandem-electrostatic-quadrupole (TESQ) accelerator facility for accelerator-based (AB) BNCT at the Atomic Energy Commission of Argentina in Buenos Aires. The project final goal is a machine capable of delivering 30 mA of 2.4 MeV protons to be used in conjunction with a neutron production target based on the (7)Li(p,n)(7)Be reaction slightly beyond its resonance at 2.25 MeV. These are the specifications needed to produce sufficiently intense and clean epithermal neutron beams, based on the (7)Li(p,n)(7)Be reaction, to perform BNCT treatment for deep-seated tumors in less than an hour. An electrostatic machine is the technologically simplest and cheapest solution for optimized AB-BNCT. The machine being designed and constructed is a folded TESQ with a high-voltage terminal at 1.2 MV intended to work in air. Such a machine is conceptually shown to be capable of transporting and accelerating a 30 mA proton beam to 2.4 MeV. The general geometric layout, its associated electrostatic fields, and the acceleration tube are simulated using a 3D finite element procedure. The design and construction of the ESQ modules is discussed and their electrostatic fields are investigated. Beam transport calculations through the accelerator are briefly mentioned. Likewise, work related to neutron production targets, strippers, beam shaping assembly and patient treatment room is briefly described.
Radiobiological research at JINR's accelerators
NASA Astrophysics Data System (ADS)
Krasavin, E. A.
2016-04-01
The half-a-century development of radiobiological studies at the Joint Institute for Nuclear Research (JINR) is reviewed on a stage-by-stage basis. With the use of the institute's accelerators, some key aspects of radiation biology have been settled, including the relative biological effectiveness (RBE) of various types of ionizing radiation with different physical characteristics; radiation-induced mutagenesis mechanisms, and the formation and repair of genetic structure damage. Practical space radiobiology problems that can be solved using high-energy charged particles are discussed.
Seifert, Lena; Werba, Gregor; Tiwari, Shaun; Giao Ly, Nancy Ngoc; Nguy, Susanna; Alothman, Sara; Alqunaibit, Dalia; Avanzi, Antonina; Daley, Donnele; Barilla, Rocky; Tippens, Daniel; Torres-Hernandez, Alejandro; Hundeyin, Mautin; Mani, Vishnu R; Hajdu, Cristina; Pellicciotta, Ilenia; Oh, Philmo; Du, Kevin; Miller, George
2016-06-01
The role of radiation therapy in the treatment of patients with pancreatic ductal adenocarcinoma (PDA) is controversial. Randomized controlled trials investigating the efficacy of radiation therapy in patients with locally advanced unresectable PDA have reported mixed results, with effects ranging from modest benefit to worse outcomes compared with control therapies. We investigated whether radiation causes inflammatory cells to acquire an immune-suppressive phenotype that limits the therapeutic effects of radiation on invasive PDAs and accelerates progression of preinvasive foci. We investigated the effects of radiation therapy in p48(Cre);LSL-Kras(G12D) (KC) and p48(Cre);LSLKras(G12D);LSL-Trp53(R172H) (KPC) mice, as well as in C57BL/6 mice with orthotopic tumors grown from FC1242 cells derived from KPC mice. Some mice were given neutralizing antibodies against macrophage colony-stimulating factor 1 (CSF1 or MCSF) or F4/80. Pancreata were exposed to doses of radiation ranging from 2 to 12 Gy and analyzed by flow cytometry. Pancreata of KC mice exposed to radiation had a higher frequency of advanced pancreatic intraepithelial lesions and more foci of invasive cancer than pancreata of unexposed mice (controls); radiation reduced survival time by more than 6 months. A greater proportion of macrophages from radiation treated invasive and preinvasive pancreatic tumors had an immune-suppressive, M2-like phenotype compared with control mice. Pancreata from mice exposed to radiation had fewer CD8(+) T cells than controls, and greater numbers of CD4(+) T cells of T-helper 2 and T-regulatory cell phenotypes. Adoptive transfer of T cells from irradiated PDA to tumors of control mice accelerated tumor growth. Radiation induced production of MCSF by PDA cells. A neutralizing antibody against MCSF prevented radiation from altering the phenotype of macrophages in tumors, increasing the anti-tumor T-cell response and slowing tumor growth. Radiation treatment causes macrophages
The leading cause of death from cancer is not a primary tumor but is the metastases, or invasion of tumor cells into other locations in the body, that result from it. A complex and incompletely understood process, metastatic tumor formation is thought to require several steps in which tumor cells invade the tissue surrounding the primary tumor, enter local blood vessels, navigate the circulation, exit the vasculature, and colonize a new site. Tumor cells do not, however, operate independently, and the role that the immune system plays in this metastatic process is beginning to be appreciated.
Reyes, Ricardo; Rodríguez, Jose Antonio; Orbe, Josune; Arnau, María Rosa; Évora, Carmen; Delgado, Araceli
2018-11-01
The effect of dual delivery of bone morphogenetic protein-2 (BMP-2) and matrix metalloproteinase 10 (MMP10) on bone regeneration was investigated in a murine model of calvarial critical-size defect, hypothesizing that it would result in an enhanced bone formation. Critical-size calvarial defects (4 mm diameter) were created in mice and PLGA microspheres preloaded with either BMP-2, MMP10 or a microsphere combination of both were transplanted into defect sites at different doses. Empty microspheres were used as the negative control. Encapsulation efficiency was assessed and in vivo release kinetics of BMP-2 and MMP10 were examined over 14 days. Histological analyses were used to analyze bone formation after four and eight weeks. Combination with MMP10 (30 ng) significantly enhanced BMP-2 (600 ng)-mediated osteogenesis, as confirmed by the increase in percentage of bone fill (p < .05) at four weeks. Moreover, it also increased mineral apposition rate (p < .05), measured by double labeling with tetracycline and calceine. MMP10 accelerates bone repair by enhancing BMP-2-promoted bone healing and improving the mineralization rate. In conclusion combination of MMP10 and BMP-2 may become a promising strategy for repair and regeneration of bone defects.
Memon, Muhammad Ali; Ahmed, Usman; Saleem, Muhammad Abid; Bhatti, Amer Iqtidar; Ahmed, Naveed; Hashim, Abdul Sattar M.
2012-01-01
Objective To evaluate the clinical outcome of linear accelerator based multisession stereotactic radiosurgery (SRS) for large benign brain tumors of >3cm. Methods Between June 2009 and May 2011, 35 patients having large benign brain tumors of >3cm (≥15 cm3) were treated by multisession stereotactic radiosurgery. This retrospective study was carried out at Neurospinal & Medical Institute Karachi. There were 17 (48.6 %) males and 18(51.4 %) females. Median age was 36 years (range: 13-65 years). Median target volume was 49.4 cm3 (range: 15-184 cm3). The median marginal dose was 25 Gy (range: 20–27.5Gy) prescribed to a median 75% isodose line (range: 65-100 %). Median number of 5 fractions were used ranging 3-5 fractions. Results All the patients tolerated treatment very well. 21 (58.3%) patients had remarkable clinical improvement of neurological symptoms, 14 (38.9%) patients had stable symptoms, and only one patient had transient worsening of symptoms. No permanent neurological damage or radiation injury was seen. Radiologically, 9 (25.7%) patients achieved reduction in size of the tumor, 26(74.3 %) patients were having stable disease, and overall control rate was found to be 100 %. Median follow-up time from the end of SRS was 6.4 months (range: 1-22.5months). Conclusion Linear accelerator based multisession stereotactic radiosurgery for large benign brain tumors of >3cm is effective and well tolerated. PMID:29296340
Özdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L; Zheng, Xiaofeng; Wu, Chia-Chin; Simpson, Tyler R; Laklai, Hanane; Sugimoto, Hikaru; Kahlert, Christoph; Novitskiy, Sergey V; De Jesus-Acosta, Ana; Sharma, Padmanee; Heidari, Pedram; Mahmood, Umar; Chin, Lynda; Moses, Harold L; Weaver, Valerie M; Maitra, Anirban; Allison, James P; LeBleu, Valerie S; Kalluri, Raghu
2014-06-16
Pancreatic ductal adenocarcinoma (PDAC) is associated with marked fibrosis and stromal myofibroblasts, but their functional contribution remains unknown. Transgenic mice with the ability to delete αSMA(+) myofibroblasts in pancreatic cancer were generated. Depletion starting at either noninvasive precursor (pancreatic intraepithelial neoplasia) or the PDAC stage led to invasive, undifferentiated tumors with enhanced hypoxia, epithelial-to-mesenchymal transition, and cancer stem cells, with diminished animal survival. In PDAC patients, fewer myofibroblasts in their tumors also correlated with reduced survival. Suppressed immune surveillance with increased CD4(+)Foxp3(+) Tregs was observed in myofibroblast-depleted mouse tumors. Although myofibroblast-depleted tumors did not respond to gemcitabine, anti-CTLA4 immunotherapy reversed disease acceleration and prolonged animal survival. This study underscores the need for caution in targeting carcinoma-associated fibroblasts in PDAC. Copyright © 2014 Elsevier Inc. All rights reserved.
ONCOGENIC DRIVER GENES AND THE INFLAMMATORY MICROENVIRONMENT DICTATE LIVER TUMOR PHENOTYPE
Matter, Matthias S.; Marquardt, Jens U.; Andersen, Jesper B.; Quintavalle, Cristina; Korokhov, Nikolay; Stauffer, Jim K.; Kaji, Kosuke; Decaens, Thomas; Quagliata, Luca; Elloumi, Fathi; Hoang, Tanya; Molinolo, Alfredo; Conner, Elizabeth A.; Weber, Achim; Heikenwalder, Mathias; Factor, Valentina M.; Thorgeirsson, Snorri S.
2016-01-01
The majority of hepatocellular carcinoma (HCC) develops in the background of chronic liver inflammation caused by viral hepatitis and alcoholic or non-alcoholic steatohepatitis. However, the impact of different types of chronic inflammatory microenvironments on the phenotypes of tumors generated by distinct oncogenes is largely unresolved. To address this issue, we generated murine liver tumors by constitutively active AKT-1 (AKT) and β-catenin (CAT) followed by induction of chronic liver inflammation by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4). Also, the impact of DDC-induced chronic liver inflammation was compared between two liver tumor models using a combination of AKT-CAT or AKT-NRASG12V. Treatment with DDC and CCl4 significantly facilitated the adenoma-to-carcinoma conversion and accelerated the growth of AKT-CAT tumors. Furthermore, DDC treatment altered the morphology of AKT-CAT tumors and caused loss of lipid droplets. Transcriptome analysis of AKT-CAT tumors revealed that cellular growth and proliferation was mainly affected by chronic inflammation and caused upregulated of Cxcl16, Galectin-3 and Nedd9 among others. Integration with transcriptome profiles from human HCCs further demonstrated that AKT-CAT tumors generated in the context of chronic liver inflammation showed enrichment of poor prognosis gene sets or decrease of good prognosis gene sets. In contrast, DDC had a more subtle effect on AKT-NRASG12V tumors and primarily enhanced already existent tumor characteristics as supported by transcriptome analysis. However, it also reduced lipid droplets in AKT-NRASG12V tumors. Conclusion Our study suggests that liver tumor phenotype is defined by a combination of driving oncogenes but also the nature of chronic liver inflammation. PMID:26844528
Chemically-induced mouse lung tumors: applications to ...
A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to discuss issues related to the use of mouse lung tumor data in human health assessments. Naphthalene, styrene, and ethylbenzene were chosen for the analysis due to the commonality of mouse lung tumors in all these three environmental chemicals. The goals of the workshop were to: identify the evidence, from multiple scientific disciplines, regarding formation of chemically-induced lung tumors in mice; discuss analysis and interpretation of the evidence; discuss how such evidence informs human health assessments; and identify commonalities, linkages, or differences between the evidence from various disciplines and across the chemicals. Evidence informing the association between occupational exposure to styrene, ethylbenzene, or naphthalene and lung cancer; comparative biology of mouse lung tumors, associated pathologic effects, issues related to tissue and species concordance; mode of action analysis and biological mechanisms including pharmacokinetics and pharmacodynamics; and evidence from cellular, genetic and molecular toxicity was discussed. In summary, although consensus was not sought, the panelists agreed that data showing mouse lung tumors with chemical exposures can be relevant for human health risk evaluation on an individual chemical basis. Key data gaps were identified that would assist in further understanding the mechanism
Chemically-induced Mouse Lung Tumors: Applications to ...
A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbenzene were chosen for the analysis due to the commonality of mouse lung tumors in all three chemicals. The goals of the workshop were to: identify the evidence, from multiple scientific disciplines, regarding formation of chemically-induced lung tumors in mice; discuss analysis and interpretation of the evidence; discuss how such evidence informs human health assessments; and identify commonalities, linkages, or differences between the evidence from various disciplines and across the chemicals. Evidence informing the association between occupational exposure to styrene, ethylbenzene, or naphthalene and lung cancer; comparative biology of mouse lung tumors, associated pathologic effects, issues related to tissue and species concordance; mode of action analysis and biological mechanisms including pharmacokinetics and pharmacodynamics; and evidence from cellular, genetic and molecular toxicity was discussed. In summary, although consensus was not sought, the panelists agreed that available mouse lung tumor data should be considered for human health risk evaluation on an individual chemical basis. Key data gaps were identified that would assist in further understanding the mechanism and relevan
Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression
Karp, Cristina M.; Tan, Ting Ting; Mathew, Robin; Nelson, Deidre; Mukherjee, Chandreyee; Degenhardt, Kurt; Karantza-Wadsworth, Vassiliki; White, Eileen
2009-01-01
Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial (iBMK) cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity and contact inhibition, while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. PMID:18519669
Wefers, Annika K; Lindner, Sven; Schulte, Johannes H; Schüller, Ulrich
2017-02-01
LIN28B is a homologue of the RNA-binding protein LIN28A and regulates gene expression during development and carcinogenesis. It is strongly upregulated in a variety of brain tumors, such as medulloblastoma, embryonal tumor with multilayered rosettes (ETMR), atypical teratoid/rhabdoid tumor (AT/RT), or glioblastoma, but the effect of an in vivo overexpression of LIN28B on the developing central nervous system is unknown. We generated transgenic mice that either overexpressed Lin28b in Math1-positive cerebellar granule neuron precursors or in a broad range of Nestin-positive neural precursors. Sections of the cerebellar vermis from adult Math1-Cre::lsl-Lin28b mice had an additional subfissure in lobule IV. Vermes from p0 and p7 Nestin-Cre::lsl-Lin28b mice appeared normal, but we found a pronounced vermal hypersublobulation at p15 and p21 in these mice. Also, the external granule cell layer (EGL) was thicker at p15 than in controls, contained more proliferating cells, and persisted up to p21. Consistently, some Pax6- and NeuN-positive cells were present in the EGL of Nestin-Cre::lsl-Lin28b mice even at p21, and we detected more NeuN-positive granule neuron precursors in the molecular layer (ML) as compared to control. Finally, we found some residual Pax2-positive precursors of inhibitory interneurons in the ML of Nestin-Cre::lsl-Lin28b mice at p21, which have already disappeared in controls. We conclude that while overexpression of LIN28B in Nestin-positive cells does not lead to tumor formation, it results in a protracted development of granule cells and inhibitory interneurons and leads to a hypersublobulation of the cerebellar vermis.
First muon acceleration using a radio-frequency accelerator
NASA Astrophysics Data System (ADS)
Bae, S.; Choi, H.; Choi, S.; Fukao, Y.; Futatsukawa, K.; Hasegawa, K.; Iijima, T.; Iinuma, H.; Ishida, K.; Kawamura, N.; Kim, B.; Kitamura, R.; Ko, H. S.; Kondo, Y.; Li, S.; Mibe, T.; Miyake, Y.; Morishita, T.; Nakazawa, Y.; Otani, M.; Razuvaev, G. P.; Saito, N.; Shimomura, K.; Sue, Y.; Won, E.; Yamazaki, T.
2018-05-01
Muons have been accelerated by using a radio-frequency accelerator for the first time. Negative muonium atoms (Mu- ), which are bound states of positive muons (μ+) and two electrons, are generated from μ+'s through the electron capture process in an aluminum degrader. The generated Mu- 's are initially electrostatically accelerated and injected into a radio-frequency quadrupole linac (RFQ). In the RFQ, the Mu- 's are accelerated to 89 keV. The accelerated Mu- 's are identified by momentum measurement and time of flight. This compact muon linac opens the door to various muon accelerator applications including particle physics measurements and the construction of a transmission muon microscope.
The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts.
Peinado, Héctor; Lavotshkin, Simon; Lyden, David
2011-04-01
Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis. Copyright © 2011 Elsevier Ltd. All rights reserved.
Tandem accelerators in Romania: Multi-tools for science, education and technology
NASA Astrophysics Data System (ADS)
Burducea, I.; GhiÅ£ǎ, D. G.; Sava, T. B.; Straticiuc, M.
2017-06-01
An educated selection of the main beam parameters - particle type, velocity and intensity, can result in a cutting-edge scalpel to remove tumors, sanitize sewage, act as a nuclear forensics detective, date an artefact, clean up air, improve a microprocessor, transmute nuclear waste, detect a counterfeit or even look into the stars. Nowadays more than particle accelerators operate worldwide in medicine, industry and basic research. For example the proton therapy market is expected to attain 1 billion US per year in 2019 with almost 330 proton therapy rooms, while the annual market for the ion implantation industry already reached 1.5 G in revenue [1,2]. A brief history of the Tandem Accelerators Complex at IFIN-HH [3] emphasizing on their applications and the physics behind the scenes, is also presented [4-6].
P-selectin deficiency attenuates tumor growth and metastasis
Kim, Young J.; Borsig, Lubor; Varki, Nissi M.; Varki, Ajit
1998-01-01
Selectins are adhesion receptors that normally recognize certain vascular mucin-type glycoproteins bearing the carbohydrate structure sialyl-Lewisx. The clinical prognosis and metastatic progression of many epithelial carcinomas has been correlated independently with production of tumor mucins and with enhanced expression of sialyl-Lewisx. Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. We provide a link between these observations by showing that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient mice showed significantly slower growth of subcutaneously implanted human colon carcinoma cells and generated fewer lung metastases from intravenously injected cells. Three potential pathophysiological mechanisms are demonstrated: first, intravenously injected tumor cells home to the lungs of P-selectin deficient mice at a lower rate; second, P-selectin-deficient mouse platelets fail to adhere to tumor cell-surface mucins; and third, tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin-deficient animals. PMID:9689079
Electrostatic Steering Accelerates C3d:CR2 Association
2016-01-01
Electrostatic effects are ubiquitous in protein interactions and are found to be pervasive in the complement system as well. The interaction between complement fragment C3d and complement receptor 2 (CR2) has evolved to become a link between innate and adaptive immunity. Electrostatic interactions have been suggested to be the driving factor for the association of the C3d:CR2 complex. In this study, we investigate the effects of ionic strength and mutagenesis on the association of C3d:CR2 through Brownian dynamics simulations. We demonstrate that the formation of the C3d:CR2 complex is ionic strength-dependent, suggesting the presence of long-range electrostatic steering that accelerates the complex formation. Electrostatic steering occurs through the interaction of an acidic surface patch in C3d and the positively charged CR2 and is supported by the effects of mutations within the acidic patch of C3d that slow or diminish association. Our data are in agreement with previous experimental mutagenesis and binding studies and computational studies. Although the C3d acidic patch may be locally destabilizing because of unfavorable Coulombic interactions of like charges, it contributes to the acceleration of association. Therefore, acceleration of function through electrostatic steering takes precedence to stability. The site of interaction between C3d and CR2 has been the target for delivery of CR2-bound nanoparticle, antibody, and small molecule biomarkers, as well as potential therapeutics. A detailed knowledge of the physicochemical basis of C3d:CR2 association may be necessary to accelerate biomarker and drug discovery efforts. PMID:27092816
Electrostatic Steering Accelerates C3d:CR2 Association.
Mohan, Rohith R; Huber, Gary A; Morikis, Dimitrios
2016-08-25
Electrostatic effects are ubiquitous in protein interactions and are found to be pervasive in the complement system as well. The interaction between complement fragment C3d and complement receptor 2 (CR2) has evolved to become a link between innate and adaptive immunity. Electrostatic interactions have been suggested to be the driving factor for the association of the C3d:CR2 complex. In this study, we investigate the effects of ionic strength and mutagenesis on the association of C3d:CR2 through Brownian dynamics simulations. We demonstrate that the formation of the C3d:CR2 complex is ionic strength-dependent, suggesting the presence of long-range electrostatic steering that accelerates the complex formation. Electrostatic steering occurs through the interaction of an acidic surface patch in C3d and the positively charged CR2 and is supported by the effects of mutations within the acidic patch of C3d that slow or diminish association. Our data are in agreement with previous experimental mutagenesis and binding studies and computational studies. Although the C3d acidic patch may be locally destabilizing because of unfavorable Coulombic interactions of like charges, it contributes to the acceleration of association. Therefore, acceleration of function through electrostatic steering takes precedence to stability. The site of interaction between C3d and CR2 has been the target for delivery of CR2-bound nanoparticle, antibody, and small molecule biomarkers, as well as potential therapeutics. A detailed knowledge of the physicochemical basis of C3d:CR2 association may be necessary to accelerate biomarker and drug discovery efforts.
A Model of RHIC Using the Unified Accelerator Libraries
DOE Office of Scientific and Technical Information (OSTI.GOV)
Pilat, F.; Tepikian, S.; Trahern, C. G.
1998-01-01
The Unified Accelerator Library (UAL) is an object oriented and modular software environment for accelerator physics which comprises an accelerator object model for the description of the machine (SMF, for Standard Machine Format), a collection of Physics Libraries, and a Perl inte,face that provides a homogeneous shell for integrating and managing these components. Currently available physics libraries include TEAPOT++, a collection of C++ physics modules conceptually derived from TEAPOT, and DNZLIB, a differential algebra package for map generation. This software environment has been used to build a flat model of RHIC which retains the hierarchical lattice description while assigning specificmore » characteristics to individual elements, such as measured field harmonics. A first application of the model and of the simulation capabilities of UAL has been the study of RHIC stability in the presence of siberian snakes and spin rotators. The building blocks of RHIC snakes and rotators are helical dipoles, unconventional devices that can not be modeled by traditional accelerator physics codes and have been implemented in UAL as Taylor maps. Section 2 describes the RHIC data stores, Section 3 the RHIC SMF format and Section 4 the RHIC specific Perl interface (RHIC Shell). Section 5 explains how the RHIC SMF and UAL have been used to study the RHIC dynamic behavior and presents detuning and dynamic aperture results. If the reader is not familiar with the motivation and characteristics of UAL, we include in the Appendix an useful overview paper. An example of a complete set of Perl Scripts for RHIC simulation can also be found in the Appendix.« less
Tikoo, Anjali; Roh, Vincent; Montgomery, Karen G.; Ivetac, Ivan; Waring, Paul; Pelzer, Rebecca; Hare, Lauren; Shackleton, Mark; Humbert, Patrick; Phillips, Wayne A.
2012-01-01
PIK3CA, the gene coding for the p110α subunit of phosphoinositide 3-kinase, is frequently mutated in a variety of human tumors including breast cancers. To better understand the role of mutant PIK3CA in the initiation and/or progression of breast cancer, we have generated mice with a conditional knock-in of the common activating mutation, Pik3caH1047R, into one allele of the endogenous gene in the mammary gland. These mice developed a ductal anaplasia and hyperplasia by 6 weeks of age characterized by multi-layering of the epithelial lining of the mammary ducts and expansion of the luminal progenitor (Lin−; CD29lo; CD24+; CD61+) cell population. The Pik3caH1047R expressing mice eventually develop mammary tumors with 100% penetrance but with a long latency (>12 months). This is significantly longer than has been reported for transgenic models where expression of the mutant Pik3ca is driven by an exogenous promoter. Histological analysis of the tumors formed revealed predominantly ERα-positive fibroadenomas, carcinosarcomas and sarcomas. In vitro induction of Pik3caH1047R in immortalized mammary epithelial cells also resulted in tumor formation when injected into the mammary fat pad of immunodeficient recipient mice. This novel model, which reproduces the scenario of a heterozygous somatic mutation occurring in the endogenous PIK3CA gene, will thus be a valuable tool for investigating the role of Pik3caH1047R mutation in mammary tumorigenesis both in vivo and in vitro. PMID:22666336
Kiyono, Kunihiko; Suzuki, Hiroshi I; Morishita, Yasuyuki; Komuro, Akiyoshi; Iwata, Caname; Yashiro, Masakazu; Hirakawa, Kosei; Kano, Mitsunobu R; Miyazono, Kohei
2009-10-01
c-Ski, originally identified as a proto-oncogene product, is an important negative regulator of transforming growth factor (TGF)-beta family signaling through interaction with Smad2, Smad3, and Smad4. High expression of c-Ski has been found in some cancers, including gastric cancer. We previously showed that disruption of TGF-beta signaling by dominant-negative TGF-beta type II receptor in a diffuse-type gastric carcinoma model accelerated tumor growth through induction of tumor angiogenesis by decreased expression of the anti-angiogenic factor thrombospondin (TSP)-1. Here, we examined the function of c-Ski in human diffuse-type gastric carcinoma OCUM-2MLN cells. Overexpression of c-Ski inhibited TGF-beta signaling in OCUM-2MLN cells. Interestingly, c-Ski overexpression resulted in extensive acceleration of the growth of subcutaneous xenografts in BALB/c nu/nu female mice (6 weeks of age). Similar to tumors expressing dominant-negative TGF-beta type II receptor, histochemical studies revealed less fibrosis and increased angiogenesis in xenografted tumors expressing c-Ski compared to control tumors. Induction of TSP-1 mRNA by TGF-beta was attenuated by c-Ski in vitro, and expression of TSP-1 mRNA was decreased in tumors expressing c-Ski in vivo. These findings suggest that c-Ski overexpression promotes the growth of diffuse-type gastric carcinoma through induction of angiogenesis.
Teng, L.C.
1960-01-19
ABS>A combination of two accelerators, a cyclotron and a ring-shaped accelerator which has a portion disposed tangentially to the cyclotron, is described. Means are provided to transfer particles from the cyclotron to the ring accelerator including a magnetic deflector within the cyclotron, a magnetic shield between the ring accelerator and the cyclotron, and a magnetic inflector within the ring accelerator.
Lisanti, Michael P; Martinez-Outschoorn, Ubaldo E; Chiavarina, Barbara; Pavlides, Stephanos; Whitaker-Menezes, Diana; Tsirigos, Aristotelis; Witkiewicz, Agnieszka; Lin, Zhao; Balliet, Renee; Howell, Anthony; Sotgia, Federica
2010-09-15
We have recently proposed a new model for understanding how tumors evolve. To achieve successful "Tumor-Stroma Co-Evolution", cancer cells induce oxidative stress in adjacent fibroblasts and possibly other stromal cells. Oxidative stress in the tumor stroma mimics the effects of hypoxia, under aerobic conditions, resulting in an excess production of reactive oxygen species (ROS). Excess stromal production of ROS drives the onset of an anti-oxidant defense in adjacent cancer cells, protecting them from apoptosis. Moreover, excess stromal ROS production has a "Bystander-Effect", leading to DNA damage and aneuploidy in adjacent cancer cells, both hallmarks of genomic instability. Finally, ROS-driven oxidative stress induces autophagy and mitophagy in the tumor micro-environment, leading to the stromal over-production of recycled nutrients (including energy-rich metabolites, such as ketones and L-lactate). These recycled nutrients or chemical building blocks then help drive mitochondrial biogenesis in cancer cells, thereby promoting the anabolic growth of cancer cells (via an energy imbalance). We also show that ketones and lactate help "fuel" tumor growth and cancer cell metastasis and can act as chemo-attractants for cancer cells. We have termed this new paradigm for accelerating tumor-stroma co-evolution, "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism". Heterotypic signaling in cancer-associated fibroblasts activates the transcription factors HIF1alpha and NFκB, potentiating the onset of hypoxic and inflammatory response(s), which further upregulates the autophagic program in the stromal compartment. Via stromal autophagy, this hypoxic/inflammatory response may provide a new escape mechanism for cancer cells during anti-angiogenic therapy, further exacerbating tumor recurrence and metastasis.
O'Neill, Ann Marie; Burrington, Christine M; Gillaspie, Erin A; Lynch, Darin T; Horsman, Melissa J; Greene, Michael W
2016-12-01
Strong epidemiologic evidence links colon cancer to obesity. The increasing worldwide incidence of colon cancer has been linked to the spread of the Western lifestyle, and in particular consumption of a high-fat Western diet. In this study, our objectives were to establish mouse models to examine the effects of high-fat Western diet-induced obesity on the growth of human colon cancer tumor xenografts, and to examine potential mechanisms driving obesity-linked human colon cancer tumor growth. We hypothesize that mice rendered insulin resistant due to consumption of a high-fat Western diet will show increased and accelerated tumor growth. Homozygous Rag1 tm1Mom mice were fed either a low-fat Western diet or a high-fat Western diet (HFWD), then human colon cancer xenografts were implanted subcutaneously or orthotopically. Tumors were analyzed to detect changes in receptor tyrosine kinase-mediated signaling and expression of inflammatory-associated genes in epididymal white adipose tissue. In both models, mice fed an HFWD weighed more and had increased intra-abdominal fat, and tumor weight was greater compared with in the low-fat Western diet-fed mice. They also displayed significantly higher levels of leptin; however, there was a negative correlation between leptin levels and tumor size. In the orthotopic model, tumors and adipose tissue from the HFWD group displayed significant increases in both c-Jun N-terminal kinase activation and monocyte chemoattractant protein 1 expression, respectively. In conclusion, this study suggests that human colon cancer growth is accelerated in animals that are obese and insulin resistant due to the consumption of an HFWD. Copyright © 2016 Elsevier Inc. All rights reserved.
Chromosomal instability affects the tumorigenicity of glioblastoma tumor-initiating cells
Godek, Kristina M.; Venere, Monica; Wu, Quilian; Mills, Kevin D.; Hickey, William F.; Rich, Jeremy N.; Compton, Duane A.
2016-01-01
Tumors are dynamic organs that evolve during disease progression with genetic, epigenetic, and environmental differences among tumor cells serving as the foundation for selection and evolution in tumors. Tumor-initiating cells (TICs) that are responsible for tumorigenesis are a source of functional cellular heterogeneity while chromosomal instability (CIN) is a source of karyotypic genetic diversity. However, the extent that CIN contributes to TIC genetic diversity and its relationship to TIC function remains unclear. Here we demonstrate that glioblastoma TICs display chromosomal instability with lagging chromosomes at anaphase and extensive non-clonal chromosome copy number variations. Elevating the basal chromosome mis-segregation rate in TICs both decreases proliferation and the stem-like phenotype of TICs in vitro. Consequently tumor formation is abolished in an orthotopic mouse model. These results demonstrate that TICs generate genetic heterogeneity within tumors but that TIC function is impaired if the rate of genetic change is elevated above a tolerable threshold. PMID:27001151
3D brain tumor localization and parameter estimation using thermographic approach on GPU.
Bousselham, Abdelmajid; Bouattane, Omar; Youssfi, Mohamed; Raihani, Abdelhadi
2018-01-01
The aim of this paper is to present a GPU parallel algorithm for brain tumor detection to estimate its size and location from surface temperature distribution obtained by thermography. The normal brain tissue is modeled as a rectangular cube including spherical tumor. The temperature distribution is calculated using forward three dimensional Pennes bioheat transfer equation, it's solved using massively parallel Finite Difference Method (FDM) and implemented on Graphics Processing Unit (GPU). Genetic Algorithm (GA) was used to solve the inverse problem and estimate the tumor size and location by minimizing an objective function involving measured temperature on the surface to those obtained by numerical simulation. The parallel implementation of Finite Difference Method reduces significantly the time of bioheat transfer and greatly accelerates the inverse identification of brain tumor thermophysical and geometrical properties. Experimental results show significant gains in the computational speed on GPU and achieve a speedup of around 41 compared to the CPU. The analysis performance of the estimation based on tumor size inside brain tissue also presented. Copyright © 2017 Elsevier Ltd. All rights reserved.
Qi, Shuhong; Li, Hui; Lu, Lisen; Qi, Zhongyang; Liu, Lei; Chen, Lu; Shen, Guanxin; Fu, Ling; Luo, Qingming; Zhang, Zhihong
2016-01-01
The combined-immunotherapy of adoptive cell therapy (ACT) and cyclophosphamide (CTX) is one of the most efficient treatments for melanoma patients. However, no synergistic effects of CTX and ACT on the spatio-temporal dynamics of immunocytes in vivo have been described. Here, we visualized key cell events in immunotherapy-elicited immunoreactions in a multicolor-coded tumor microenvironment, and then established an optimal strategy of metronomic combined-immunotherapy to enhance anti-tumor efficacy. Intravital imaging data indicated that regulatory T cells formed an 'immunosuppressive ring' around a solid tumor. The CTX-ACT combined-treatment elicited synergistic immunoreactions in tumor areas, which included relieving the immune suppression, triggering the transient activation of endogenous tumor-infiltrating immunocytes, increasing the accumulation of adoptive cytotoxic T lymphocytes, and accelerating the infiltration of dendritic cells. These insights into the spatio-temporal dynamics of immunocytes are beneficial for optimizing immunotherapy and provide new approaches for elucidating the mechanisms underlying the involvement of immunocytes in cancer immunotherapy. DOI: http://dx.doi.org/10.7554/eLife.14756.001 PMID:27855783
Acceleration Modes and Transitions in Pulsed Plasma Accelerators
NASA Technical Reports Server (NTRS)
Polzin, Kurt A.; Greve, Christine M.
2018-01-01
Pulsed plasma accelerators typically operate by storing energy in a capacitor bank and then discharging this energy through a gas, ionizing and accelerating it through the Lorentz body force. Two plasma accelerator types employing this general scheme have typically been studied: the gas-fed pulsed plasma thruster and the quasi-steady magnetoplasmadynamic (MPD) accelerator. The gas-fed pulsed plasma accelerator is generally represented as a completely transient device discharging in approximately 1-10 microseconds. When the capacitor bank is discharged through the gas, a current sheet forms at the breech of the thruster and propagates forward under a j (current density) by B (magnetic field) body force, entraining propellant it encounters. This process is sometimes referred to as detonation-mode acceleration because the current sheet representation approximates that of a strong shock propagating through the gas. Acceleration of the initial current sheet ceases when either the current sheet reaches the end of the device and is ejected or when the current in the circuit reverses, striking a new current sheet at the breech and depriving the initial sheet of additional acceleration. In the quasi-steady MPD accelerator, the pulse is lengthened to approximately 1 millisecond or longer and maintained at an approximately constant level during discharge. The time over which the transient phenomena experienced during startup typically occur is short relative to the overall discharge time, which is now long enough for the plasma to assume a relatively steady-state configuration. The ionized gas flows through a stationary current channel in a manner that is sometimes referred to as the deflagration-mode of operation. The plasma experiences electromagnetic acceleration as it flows through the current channel towards the exit of the device. A device that had a short pulse length but appeared to operate in a plasma acceleration regime different from the gas-fed pulsed plasma
Enhanced dimethyl phthalate biodegradation by accelerating phthalic acid di-oxygenation.
Tang, Yingxia; Zhang, Yongming; Jiang, Ling; Yang, Chao; Rittmann, Bruce E
2017-12-01
The aerobic biodegradation of dimethyl phthalate (DMP) is initiated with two hydrolysis reactions that generate an intermediate, phthalic acid (PA), that is further biodegraded through a two-step di-oxygenation reaction. DMP biodegradation is inhibited when PA accumulates, but DMP's biodegradation can be enhanced by adding an exogenous electron donor. We evaluated the effect of adding succinate, acetate, or formate as an exogenous electron donor. PA removal rates were increased by 15 and 30% for initial PA concentrations of 0.3 and 0.6 mM when 0.15 and 0.30 mM succinate, respectively, were added as exogenous electron donor. The same electron-equivalent additions of acetate and formate had the same acceleration impacts on PA removal. Consequently, the DMP-removal rate, even PA coexisting with DMP simultaneously, was accelerated by 37% by simultaneous addition of 0.3 mM succinate. Thus, lowering the accumulation of PA by addition of an electron increased the rate of DMP biodegradation.
Temporal evolution of the electric field accelerating electrons away from the auroral ionosphere.
Marklund, G T; Ivchenko, N; Karlsson, T; Fazakerley, A; Dunlop, M; Lindqvist, P A; Buchert, S; Owen, C; Taylor, M; Vaivalds, A; Carter, P; André, M; Balogh, A
2001-12-13
The bright night-time aurorae that are visible to the unaided eye are caused by electrons accelerated towards Earth by an upward-pointing electric field. On adjacent geomagnetic field lines the reverse process occurs: a downward-pointing electric field accelerates electrons away from Earth. Such magnetic-field-aligned electric fields in the collisionless plasma above the auroral ionosphere have been predicted, but how they could be maintained is still a matter for debate. The spatial and temporal behaviour of the electric fields-a knowledge of which is crucial to an understanding of their nature-cannot be resolved uniquely by single satellite measurements. Here we report on the first observations by a formation of identically instrumented satellites crossing a beam of upward-accelerated electrons. The structure of the electric potential accelerating the beam grew in magnitude and width for about 200 s, accompanied by a widening of the downward-current sheet, with the total current remaining constant. The 200-s timescale suggests that the evacuation of the electrons from the ionosphere contributes to the formation of the downward-pointing magnetic-field-aligned electric fields. This evolution implies a growing load in the downward leg of the current circuit, which may affect the visible discrete aurorae.
DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis.
Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu
2016-04-19
Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer.
BENIGN TUMORS AND TUMOR-LIKE LESIONS OF THE PANCREAS
Basturk, Olca; Askan, Gokce
2017-01-01
Synopsis The pancreas is a complex organ that may give rise to large number of neoplasms and non-neoplastic lesions. This article will focus on benign neoplasms such as serous neoplasms as well as tumor-like (pseudotumoral) lesions that may be mistaken for neoplasm not only by clinicians and radiologists, but also by pathologists. The family of pancreatic pseudotumors, by a loosely defined conception of that term, includes a variety of lesions including heterotopia, hamartoma, and lipomatous pseudohypertrophy. Autoimmue pancreatitis (covered in chronic pancreatitis chapter) and paraduodenal (“groove”) pancreatitis may also lead to pseudotumor formation. Knowledge of these entities will help in making an accurate diagnosis. PMID:27926363
Jacobson, Orit
2013-01-01
Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [18F]fluorodeoxyglucose ([18F]FDG), which measures glucose metabolism. However, [18F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[18F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications. PMID:24064460
Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype
Passaro, Nunzia; Zannetti, Antonella
2017-01-01
Multipotent mesenchymal stem cells (MSCs) are recruited into tumor microenvironment in response to multiple signals produced by cancer cells. Molecules involved in their homing to tumors are the same inflammatory mediators produced by injured tissues: chemokines, cytokines and growth factors. When MSCs arrive into the tumor microenvironment these are “educated” to have pro-metastatic behaviour. Firstly, they promote cancer immunosuppression modulating both innate and adaptive immune systems. Moreover, tumor associated-MSCs trans-differentiating into cancer-associated fibroblasts can induce epithelial-mesenchymal-transition program in tumor cells. This process determinates a more aggressive phenotype of cancer cells by increasing their motility and invasiveness and favoring their dissemination to distant sites. In addition, MSCs are involved in the formation and modelling of pre-metastatic niches creating a supportive environment for colonization of circulating tumor cells. The development of novel therapeutic approaches targeting the different functions of MSCs in promoting tumor progression as well as the mechanisms underlying their activities could enhance the efficacy of conventional and immune anti-cancer therapies. Furthermore, many studies report the use of MSCs engineered to express different genes or as vehicle to specifically deliver novel drugs to tumors exploiting their strong tropism. Importantly, this approach can enhance local therapeutic efficacy and reduce the risk of systemic side effects. PMID:29069870
[Clinical experience of carbon ion radiotherapy for malignant tumors].
Ishikawa, Hitoshi; Tsuji, Hiroshi; Tsujii, Hirohiko
2006-04-01
The carbon ion (C-ion) beams provide unique advantageous biological and physical properties in radiotherapy (RT) for malignant tumors. C-ion beams have a high relative biological effectiveness (RBE) resulting from the high linear energy transfer (LET). In terms of their physical characteristics, C-ion beams exhibit a spread-out Bragg peak (SOBP) and make for a better dose distribution of the target volume by specified beam modulations. Between June 1994 and August 2005, a total of 2,371 patients with malignant tumors were registered in phase I/II dose-escalation studies and clinical phase II trials using C-ion beams generated at Heavy Ion Medical Accelerator in Chiba (HIMAC). In the initial dose-escalation studies, grade 3 or more late rectal complications had developed in some patients. However, the adverse effects were resolved because of the use of appropriate dose levels and modification of the radiation technique. C-ion beams can carry out hypofractionated radiotherapy with a large fraction dose and reduce the overall treatment times compared with conventional radiotherapy. They can also achieve better local tumor control even for radio-resistant tumors such as malignant melanoma, hepatocellular carcinoma and bone and soft tissue sarcomas with minimal morbidity to the normal surrounding tissues.
Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4
Brigatte, Patrícia; Faiad, Odair Jorge; Ferreira Nocelli, Roberta Cornélio; Landgraf, Richardt G.; Palma, Mario Sergio; Cury, Yara; Curi, Rui; Sampaio, Sandra Coccuzzo
2016-01-01
We investigated the effects of Crotoxin (CTX), the main toxin of South American rattlesnake (Crotalus durissus terrificus) venom, on Walker 256 tumor growth, the pain symptoms associated (hyperalgesia and allodynia), and participation of endogenous lipoxin A4. Treatment with CTX (s.c.), daily, for 5 days reduced tumor growth at the 5th day after injection of Walker 256 carcinoma cells into the plantar surface of adult rat hind paw. This observation was associated with inhibition of new blood vessel formation and decrease in blood vessel diameter. The treatment with CTX raised plasma concentrations of lipoxin A4 and its natural analogue 15-epi-LXA4, an effect mediated by formyl peptide receptors (FPRs). In fact, the treatment with Boc-2, an inhibitor of FPRs, abolished the increase in plasma levels of these mediators triggered by CTX. The blockage of these receptors also abolished the inhibitory action of CTX on tumor growth and blood vessel formation and the decrease in blood vessel diameter. Together, the results herein presented demonstrate that CTX increases plasma concentrations of lipoxin A4 and 15-epi-LXA4, which might inhibit both tumor growth and formation of new vessels via FPRs. PMID:27190493
Knips, Jill; Czech-Sioli, Manja; Spohn, Michael; Heiland, Max; Moll, Ingrid; Grundhoff, Adam; Schumacher, Udo; Fischer, Nicole
2017-07-01
Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC-derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV-positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signalling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation. © 2017 UICC.
CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity
Zhang, Yang; Gao, Jing; Wang, Xia; Deng, Shaorong; Ye, Hao; Guan, Wen; Wu, Mingyuan; Zhu, Shunying; Yu, Yan; Han, Wei
2015-01-01
The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor-regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-γ and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy. PMID:26479470
CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity.
Zhang, Yang; Gao, Jing; Wang, Xia; Deng, Shaorong; Ye, Hao; Guan, Wen; Wu, Mingyuan; Zhu, Shunying; Yu, Yan; Han, Wei
2015-01-01
The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor-regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-γ and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy.
Gacerez, Albert T; Hua, Casey K; Ackerman, Margaret E; Sentman, Charles L
2018-05-01
B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display. In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development.
Boron Neutron Capture Therapy for Malignant Brain Tumors
MIYATAKE, Shin-Ichi; KAWABATA, Shinji; HIRAMATSU, Ryo; KUROIWA, Toshihiko; SUZUKI, Minoru; KONDO, Natsuko; ONO, Koji
2016-01-01
Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting. PMID:27250576
Boron Neutron Capture Therapy for Malignant Brain Tumors.
Miyatake, Shin-Ichi; Kawabata, Shinji; Hiramatsu, Ryo; Kuroiwa, Toshihiko; Suzuki, Minoru; Kondo, Natsuko; Ono, Koji
2016-07-15
Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Therefore, BNCT enables the application of a high dose of particle radiation selectively to tumor cells in which boron-10 compound has been accumulated. We applied BNCT using nuclear reactors for 167 cases of malignant brain tumors, including recurrent malignant gliomas, newly diagnosed malignant gliomas, and recurrent high-grade meningiomas from January 2002 to May 2014. Here, we review the principle and history of BNCT. In addition, we introduce fluoride-18-labeled boronophenylalanine positron emission tomography and the clinical results of BNCT for the above-mentioned malignant brain tumors. Finally, we discuss the recent development of accelerators producing epithermal neutron beams. This development could provide an alternative to the current use of specially modified nuclear reactors as a neutron source, and could allow BNCT to be performed in a hospital setting.
JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.
Langiewicz, Magda; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A
2018-04-28
To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (associating liver partition and portal vein ligation for staged hepatectomy [coined ALPPS]) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. c-Jun N-terminal kinase (JNK1 [Mapk8]) activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK1 diminution to substantiate their relationship during accelerated liver regeneration. Transcriptomic analysis linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in alpha-smooth muscle actin-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. JNK1-mediated induction of IHH paracrine signaling from hepatic stellate cells is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. Associating liver partition and portal vein ligation for staged hepatectomy (so called ALPPS), is a new two-staged approach to hepatectomy, which induces an unprecedented acceleration of liver
Gps mutations in Chilean patients harboring growth hormone-secreting pituitary tumors.
Johnson, M C; Codner, E; Eggers, M; Mosso, L; Rodriguez, J A; Cassorla, F
1999-01-01
Hypersecretion of GH is usually caused by a pituitary adenoma and about 40% of these tumors exhibit missense gsp mutations in Arg201 or Gln227 of the Gs, gene. We studied 20 pituitary tumors obtained from patients with GH hypersecretion. One tumor was resected from an 11 year-old boy with a 3 year history of accelerated growth, associated with increased concentrations of serum GH and IGF-I, which were not suppressed by glucose administration. The remaining 19 tumors were obtained from adult acromegalic patients, who had elevated baseline serum GH levels that did not show evidence of suppression after administration of glucose. The gsp mutations were studied by enzymatic digestion of the amplified PCR fragment of exon 8 (Arg201) and exon 9 (Gln227) with the enzymes NlaIII and NgoAIV, respectively. The tumors obtained from the boy and from nine of the 19 patients with acromegaly exhibited the gsp mutation R201H. None of the tumors had the Gln227 mutation. The gsp positive patients tended to be older, had smaller tumors, and had preoperative basal serum GH levels which were significantly lower (21 +/- 6 vs 56 +/- 16 microg/l, p<0.05) than the gsp negative patients. In this study, we documented the presence of a gsp mutation in Arg201 in a boy with gigantism and in approximately half of 19 Chilean adult patients with acromegaly, similar to other populations.
Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H
2014-04-01
Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve
Negative regulatory role of PI3-kinase in TNF-induced tumor necrosis.
Matschurat, Susanne; Blum, Sabine; Mitnacht-Kraus, Rita; Dijkman, Henry B P M; Kanal, Levent; De Waal, Robert M W; Clauss, Matthias
2003-10-20
Tissue factor is the prime initiator of blood coagulation. Expression of tissue factor in tumor endothelial cells leads to thrombus formation, occlusion of vessels and development of hemorrhagic infarctions in the tumor tissue, often followed by regression of the tumor. Tumor cells produce endogenous vascular endothelial growth factor (VEGF), which sensitizes endothelial cells for systemically administered tumor necrosis factor alpha (TNF alpha) and synergistically enhances the TNF-induced expression of tissue factor. We have analyzed the pathways involved in the induction of tissue factor in human umbilical cord vein endothelial cells (HUVECs) after combined stimulation with TNF and VEGF. By using specific low molecular weight inhibitors, we demonstrated that protein kinase C (PKC), p44/42 and p38 mitogen-activated protein (MAP) kinases, and stress-activated protein kinase (JNK) are essentially involved in the induction of tissue factor. In contrast, the application of wortmannin, an inhibitor of phosphatidylinositol 3 (PI3)-kinase, led to strongly enhanced expression of tissue factor in TNF- and VEGF-treated cells, implicating a negative regulatory role for PI3-kinase. In vivo, the application of wortmannin promoted the formation of TNF-induced hemorrhages and intratumoral necroses in murine meth A tumors. The co-injection of wortmannin lowered the effective dose of applied TNF. Therefore, it is conceivable that the treatment of TNF-sensitive tumors with a combination of TNF and wortmannin will ensure the selective damage of the tumor endothelium and minimize the risk of systemic toxicity of TNF. TNF-treatment in combination with specific inhibition of PI3-kinase is a novel concept in anti-cancer therapy. Copyright 2003 Wiley-Liss, Inc.
SH003 represses tumor angiogenesis by blocking VEGF binding to VEGFR2
Choi, Hyeong Sim; Kim, Min Kyoung; Lee, Kangwook; Lee, Kang Min; Choi, Youn Kyung; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu
2016-01-01
Tumor angiogenesis is a key feature of cancer progression, because a tumor requires abundant oxygen and nutrition to grow. Here, we demonstrate that SH003, a mixed herbal extract containing Astragalus membranaceus (Am), Angelica gigas (Ag) and Trichosanthes Kirilowii Maximowicz (Tk), represses VEGF-induced tumor angiogenesis both in vitro and in vivo. SH003 inhibited VEGF-induced migration, invasion and tube formation in human umbilical vein endothelial cells (HUVEC) with no effect on the proliferation. SH003 reduced CD31-positive vessel numbers in tumor tissues and retarded tumor growth in our xenograft mouse tumor model, while SH003 did not affect pancreatic tumor cell viability. Consistently, SH003 inhibited VEGF-stimulated vascular permeability in ears and back skins. Moreover, SH003 inhibited VEGF-induced VEGFR2-dependent signaling by blocking VEGF binding to VEGFR2. Therefore, our data conclude that SH003 represses tumor angiogenesis by inhibiting VEGF-induced VEGFR2 activation, and suggest that SH003 may be useful for treating cancer. PMID:27105528
Long non-coding RNA CRNDE promotes tumor growth in medulloblastoma.
Song, H; Han, L-M; Gao, Q; Sun, Y
2016-06-01
Medulloblastoma is the most common malignant brain tumor in children. Despite remarkable advances over the past decades, a novel therapeutic strategy is urgently required to increase long-term survival. This study aimed to understand the role of a long non-coding RNA (lncRNA), colorectal neoplasia differentially expressed (CRNDE), in medulloblastoma tumor growth. The transcript level of CRNDE was initially examined in dissected clinical tissues and cultured cancerous cells. Effects of CRNDE knockdown on cell viability and colony formation in vitro were assessed using the CCK-8 and colony formation assays, respectively. Cell cycle progression and survival were also determined after CRNDE knockdown. A xenograft mouse model of human medulloblastoma was established by injecting nude mice with medulloblastoma cells stably depleted of CRNDE expression. Our data suggest that transcript levels of CRNDE are elevated in clinical medulloblastoma tissues instead of in adjacent non-cancerous tissues. Knockdown of CRNDE significantly slowed cell proliferation rates and inhibited colony formation in Daoy and D341 cells. Tumor growth in vivo was also inhibited after CRNDE knockdown. Moreover, after knockdown of CRNDE, cell cycle progression was arrested in S phase and apoptosis was promoted by 15-20% in Daoy and D341 cells. In vivo data further showed that proliferating cell nuclei antigen (PCNA) was decreased, whereas the apoptosis initiator cleaved-caspase-3 was increased upon CRNDE knockdown in cancerous tissues from the mouse model. All these data suggest that CRNDE promotes tumor growth both in vitro and in vivo. This growth-promotion effect might be achieved via arresting cell cycle progression and inhibiting apoptosis. Therapeutics against CRNDE may be a novel strategy for the treatment of medulloblastoma.
Formation and role of exosomes in cancer.
Brinton, Lindsey T; Sloane, Hillary S; Kester, Mark; Kelly, Kimberly A
2015-02-01
Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.
Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar
2014-02-01
F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.
Sung, Da-Young; Gunjakar, Jayavant L; Kim, Tae Woo; Kim, In Young; Lee, Yu Ri; Hwang, Seong-Ju
2013-05-27
A new prompt room temperature synthetic route to 2D nanostructured metal oxide-graphene-hybrid electrode materials can be developed by the application of colloidal reduced graphene oxide (RGO) nanosheets as an efficient reaction accelerator for the synthesis of δ-MnO2 2D nanoplates. Whereas the synthesis of the 2D nanostructured δ-MnO2 at room temperature requires treating divalent manganese compounds with persulfate ions for at least 24 h, the addition of RGO nanosheet causes a dramatic shortening of synthesis time to 1 h, underscoring its effectiveness for the promotion of the formation of 2D nanostructured metal oxide. To the best of our knowledge, this is the first example of the accelerated synthesis of 2D nanostructured hybrid material induced by the RGO nanosheets. The observed acceleration of nanoplate formation upon the addition of RGO nanosheets is attributable to the enhancement of the oxidizing power of persulfate ions, the increase of the solubility of precursor MnCO3, and the promoted crystal growth of δ-MnO2 2D nanoplates. The resulting hybridization between RGO nanosheets and δ-MnO2 nanoplates is quite powerful not only in increasing the surface area of manganese oxide nanoplate but also in enhancing its electrochemical activity. Of prime importance is that the present δ-MnO2 -RGO nanocomposites show much superior electrode performance over most of 2D nanostructured manganate systems including a similar porous assembly of RGO and layered MnO2 nanosheets. This result underscores that the present RGO-assisted solution-based synthesis can provide a prompt and scalable method to produce nanostructured hybrid electrode materials. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua
2013-07-01
The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.
Teng, Yan; Sun, An-Na; Pan, Xiao-Chen; Yang, Guan; Yang, Lei-Lei; Wang, Ming-Rong; Yang, Xiao
2006-07-15
The genetic bases underlying esophageal tumorigenesis are poorly understood. Our previous studies have shown that coordinated deletion of the Smad4 and PTEN genes results in accelerated hair loss and skin tumor formation in mice. Herein, we exemplify that the concomitant inactivation of Smad4 and PTEN accelerates spontaneous forestomach carcinogenesis at complete penetrance during the first 2 months of age. All of the forestomach tumors were invasive squamous cell carcinomas (SCCs), which recapitulated the natural history and pathologic features of human esophageal SCCs. A small population of the SCC lesions was accompanied by adenocarcinomas at the adjacent submucosa region in the double mutant mice. The rapid progression of forestomach tumor formation in the Smad4 and PTEN double knockout mice corresponded to a dramatic increase in esophageal and forestomach epithelial proliferation. The decreased expression of p27, p21, and p16 together with the overexpression of cyclin D1 contributed cooperatively to the accelerated forestomach tumorigenesis in the double mutant mice. Our results point strongly to the crucial relevance of synergy between Smad4 and PTEN to suppress forestomach tumorigenesis through the cooperative induction of cell cycle inhibitors.
Epigenetic changes in solid and hematopoietic tumors.
Toyota, Minoru; Issa, Jean-Pierre J
2005-10-01
There are three connected molecular mechanisms of epigenetic cellular memory in mammalian cells: DNA methylation, histone modifications, and RNA interference. The first two have now been firmly linked to neoplastic transformation. Hypermethylation of CpG-rich promoters triggers local histone code modifications resulting in a cellular camouflage mechanism that sequesters gene promoters away from transcription factors and results in stable silencing. This normally restricted mechanism is ubiquitously used in cancer to silence hundreds of genes, among which some critically contribute to the neoplastic phenotype. Virtually every pathway important to cancer formation is affected by this process. Methylation profiling of human cancers reveals tissue-specific epigenetic signatures, as well as tumor-specific signatures, reflecting in particular the presence of epigenetic instability in a subset of cancers affected by the CpG island methylator phenotype. Generally, methylation patterns can be traced to a tissue-specific, proliferation-dependent accumulation of aberrant promoter methylation in aging tissues, a process that can be accelerated by chronic inflammation and less well-defined mechanisms including, possibly, diet and genetic predisposition. The epigenetic machinery can also be altered in cancer by specific lesions in epigenetic effector genes, or by aberrant recruitment of these genes by mutant transcription factors and coactivators. Epigenetic patterns are proving clinically useful in human oncology via risk assessment, early detection, and prognostic classification. Pharmacologic manipulation of these patterns-epigenetic therapy-is also poised to change the way we treat cancer in the clinic.
Covariant Uniform Acceleration
NASA Astrophysics Data System (ADS)
Friedman, Yaakov; Scarr, Tzvi
2013-04-01
We derive a 4D covariant Relativistic Dynamics Equation. This equation canonically extends the 3D relativistic dynamics equation , where F is the 3D force and p = m0γv is the 3D relativistic momentum. The standard 4D equation is only partially covariant. To achieve full Lorentz covariance, we replace the four-force F by a rank 2 antisymmetric tensor acting on the four-velocity. By taking this tensor to be constant, we obtain a covariant definition of uniformly accelerated motion. This solves a problem of Einstein and Planck. We compute explicit solutions for uniformly accelerated motion. The solutions are divided into four Lorentz-invariant types: null, linear, rotational, and general. For null acceleration, the worldline is cubic in the time. Linear acceleration covariantly extends 1D hyperbolic motion, while rotational acceleration covariantly extends pure rotational motion. We use Generalized Fermi-Walker transport to construct a uniformly accelerated family of inertial frames which are instantaneously comoving to a uniformly accelerated observer. We explain the connection between our approach and that of Mashhoon. We show that our solutions of uniformly accelerated motion have constant acceleration in the comoving frame. Assuming the Weak Hypothesis of Locality, we obtain local spacetime transformations from a uniformly accelerated frame K' to an inertial frame K. The spacetime transformations between two uniformly accelerated frames with the same acceleration are Lorentz. We compute the metric at an arbitrary point of a uniformly accelerated frame. We obtain velocity and acceleration transformations from a uniformly accelerated system K' to an inertial frame K. We introduce the 4D velocity, an adaptation of Horwitz and Piron s notion of "off-shell." We derive the general formula for the time dilation between accelerated clocks. We obtain a formula for the angular velocity of a uniformly accelerated object. Every rest point of K' is uniformly accelerated, and
Bone formation is not impaired by hibernation (disuse) in black bears Ursus americanus
Donahue, S.W.; Vaughan, M.R.; Demers, L.M.; Donahue, H.J.
2003-01-01
Disuse by bed rest, limb immobilization or space flight causes rapid bone loss by arresting bone formation and accelerating bone resorption. This net bone loss increases the risk of fracture upon remobilization. Bone loss also occurs in hibernating ground squirrels, golden hamsters, and little brown bats by arresting bone formation and accelerating bone resorption. There is some histological evidence to suggest that black bears Ursus americanus do not lose bone mass during hibernation (i.e. disuse). There is also evidence suggesting that muscle mass and strength are preserved in black bears during hibernation. The question of whether bears can prevent bone loss during hibernation has not been conclusively answered. The goal of the current study was to further assess bone metabolism in hibernating black bears. Using the same serum markers of bone remodeling used to evaluate human patients with osteoporosis, we assayed serum from five black bears, collected every 10 days over a 196-day period, for bone resorption and formation markers. Here we show that bone resorption remains elevated over the entire hibernation period compared to the pre-hibernation period, but osteoblastic bone formation is not impaired by hibernation and is rapidly accelerated during remobilization following hibernation.
Augmented lymphocyte expansion from solid tumors with engineered cells for costimulatory enhancement
Friedman, Kevin M; DeVillier, Laura E; Feldman, Steven A; Rosenberg, Steven A; Dudley, Mark E
2011-01-01
Treatment of patients with adoptive T cell therapy requires expansion of unique tumor-infiltrating lymphocyte (TIL) cultures from single cell suspensions processed from melanoma biopsies. Strategies which increase the expansion and reliability of TIL generation from tumor digests are necessary to improve access to TIL therapy. Prior work evaluated artificial antigen presenting cells (aAPCs) for their antigen-specific and costimulatory properties. We investigated engineered cells for co-stimulatory enhancement (ECCE) consisting of K562 cells which express 4-1BBL in the absence of artificial antigen stimulation. ECCE accelerated TIL expansion and significantly improved TIL numbers (p=0.001) from single cell melanoma suspensions. TIL generated with ECCE contain significantly more CD8+CD62L+ and CD8+CD27+ T cells then comparable IL-2-expanded TIL and maintained anti-tumor reactivity. Moreover, ECCE improved TIL expansion from non-melanoma cell suspensions similar to that seen with melanoma tumors. These data demonstrate that ECCE addition to TIL production will enable treatment of patients ineligible using current methods. PMID:21989413
Chiarella, Paula; Vermeulen, Mónica; Montagna, Daniela R; Vallecorsa, Pablo; Strazza, Ariel Ramiro; Meiss, Roberto P; Bustuoabad, Oscar D; Ruggiero, Raúl A; Prehn, Richmond T
2018-01-01
Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth.
Chiarella, Paula; Vermeulen, Mónica; Montagna, Daniela R.; Vallecorsa, Pablo; Strazza, Ariel Ramiro; Meiss, Roberto P.; Bustuoabad, Oscar D.; Ruggiero, Raúl A.; Prehn, Richmond T.
2018-01-01
Immune-checkpoint inhibitors and antitumor vaccines may produce both tumor-inhibitory and tumor-stimulatory effects on growing tumors depending on the stage of tumor growth at which treatment is initiated. These paradoxical results are not necessarily incompatible with current tumor immunology but they might better be explained assuming the involvement of the phenomenon of tumor immunostimulation. This phenomenon was originally postulated on the basis that the immune response (IR) evoked in Winn tests by strong chemical murine tumors was not linear but biphasic, with strong IR producing inhibition and weak IR inducing stimulation of tumor growth. Herein, we extended those former observations to weak spontaneous murine tumors growing in pre-immunized, immune-competent and immune-depressed mice. Furthermore, we demonstrated that the interaction of specifical T cells and target tumor cells at low stimulatory ratios enhanced the production of chemokines aimed to recruit macrophages at the tumor site, which, upon activation of toll-like receptor 4 and p38 signaling pathways, would recruit and activate more macrophages and other inflammatory cells which would produce growth-stimulating signals leading to an accelerated tumor growth. On this basis, the paradoxical effects achieved by immunological therapies on growing tumors could be explained depending upon where the therapy-induced IR stands on the biphasic IR curve at each stage of tumor growth. At stages where tumor growth was enhanced (medium and large-sized tumors), counteraction of the tumor-immunostimulatory effect with anti-inflammatory strategies or, more efficiently, with selective inhibitors of p38 signaling pathways enabled the otherwise tumor-promoting immunological strategies to produce significant inhibition of tumor growth. PMID:29435437
Analyzing radial acceleration with a smartphone acceleration sensor
NASA Astrophysics Data System (ADS)
Vogt, Patrik; Kuhn, Jochen
2013-03-01
This paper continues the sequence of experiments using the acceleration sensor of smartphones (for description of the function and the use of the acceleration sensor, see Ref. 1) within this column, in this case for analyzing the radial acceleration.
Yoshihara, Kazuki; Takagi, Kohei; Son, Aoi; Kurihara, Ryohsuke; Tanabe, Kazuhito
2017-08-17
The use of DNA aggregates could be a promising strategy for the molecular imaging of biological functions. Herein, phosphorescent oligodeoxynucleotides were designed with the aim of visualizing oxygen fluctuation in tumor cells. DNA-ruthenium conjugates (DRCs) that consisted of oligodeoxynucleotides, a phosphorescent ruthenium complex, a pyrene unit for high oxygen responsiveness, and a nitroimidazole unit as a tumor-targeting unit were prepared. In general, oligonucleotides have low cell permeability because of their own negative charges; however, the DRC formed aggregates in aqueous solution due to the hydrophobic pyrene and nitroimidazole groups, and smoothly penetrated the cellular membrane to accumulate in tumor cells in a hypoxia-selective manner. The oxygen-dependent phosphorescence of DRC in cells was also observed. In vivo experiments revealed that aggregates of DRC accumulated in hypoxic tumor tissue that was transplanted into the left leg of mice, and showed that oxygen fluctuations in tumor tissue could be monitored by tracking of the phosphorescence emission of DRC. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Russo, Debora; Poggi, Alessandro; Villa, Federico; Brizzolara, Antonella; Canale, Claudio; Mescola, Andrea; Daga, Antonio; Russo, Claudio; Nizzari, Mario; Florio, Tullio; Menichini, Paola; Pagano, Aldo
2017-01-01
We recently reported the in vitro over-expression of 45A, a RNA polymerase III-transcribed non-coding (nc)RNA, that perturbs the intracellular content of FE65L1 affecting cell proliferation rate, short-term response to genotoxic stress, substrate adhesion capacity and, ultimately, increasing the tumorigenic potential of human neuroblastoma cells. In this work, to deeply explore the mechanism by which 45A ncRNA contributes to cancer development, we targeted in vitro and in vivo 45A levels by the stable overexpression of antisense 45A RNA. 45A downregulation leads to deep modifications of cytoskeleton organization, adhesion and migration of neuroblastoma cells. These effects are correlated with alterations in the expression of several genes including GTSE1 (G2 and S phase-expressed-1), a crucial regulator of tumor cell migration and metastatic potential. Interestingly, the downregulation of 45A ncRNA strongly affects the in vivo tumorigenic potential of SKNBE2 neuroblastoma cells, increasing tumor nodule compactness and reducing GTSE1 protein expression in a subcutaneous neuroblastoma mouse model. Moreover, intracardiac injection of neuroblastoma cells showed that downregulation of 45A ncRNA also influences tumor metastatic ability. In conclusion, our data highlight a key role of 45A ncRNA in cancer development and suggest that its modulation might represent a possible novel anticancer therapeutic approach. PMID:28029658
Penna, Ilaria; Gigoni, Arianna; Costa, Delfina; Vella, Serena; Russo, Debora; Poggi, Alessandro; Villa, Federico; Brizzolara, Antonella; Canale, Claudio; Mescola, Andrea; Daga, Antonio; Russo, Claudio; Nizzari, Mario; Florio, Tullio; Menichini, Paola; Pagano, Aldo
2017-01-31
We recently reported the in vitro over-expression of 45A, a RNA polymerase III-transcribed non-coding (nc)RNA, that perturbs the intracellular content of FE65L1 affecting cell proliferation rate, short-term response to genotoxic stress, substrate adhesion capacity and, ultimately, increasing the tumorigenic potential of human neuroblastoma cells. In this work, to deeply explore the mechanism by which 45A ncRNA contributes to cancer development, we targeted in vitro and in vivo 45A levels by the stable overexpression of antisense 45A RNA.45A downregulation leads to deep modifications of cytoskeleton organization, adhesion and migration of neuroblastoma cells. These effects are correlated with alterations in the expression of several genes including GTSE1 (G2 and S phase-expressed-1), a crucial regulator of tumor cell migration and metastatic potential. Interestingly, the downregulation of 45A ncRNA strongly affects the in vivo tumorigenic potential of SKNBE2 neuroblastoma cells, increasing tumor nodule compactness and reducing GTSE1 protein expression in a subcutaneous neuroblastoma mouse model. Moreover, intracardiac injection of neuroblastoma cells showed that downregulation of 45A ncRNA also influences tumor metastatic ability. In conclusion, our data highlight a key role of 45A ncRNA in cancer development and suggest that its modulation might represent a possible novel anticancer therapeutic approach.
ERIC Educational Resources Information Center
Floyd, Anika Z.
2017-01-01
The purpose of this study was to examine the effect of the accelerated course learning format on student achievement in developmental English and math courses offered at a rural community college. Due to a rise in the number of underprepared students who enroll in community college, some college officials implemented the accelerated course…
Boric Acid Reduces the Formation of DNA Double Strand Breaks and Accelerates Wound Healing Process.
Tepedelen, Burcu Erbaykent; Soya, Elif; Korkmaz, Mehmet
2016-12-01
Boron is absorbed by the digestive and respiratory system, and it was considered that it is converted to boric acid (BA), which was distributed to all tissues above 90 %. The biochemical essentiality of boron element is caused by boric acid because it affects the activity of several enzymes involved in the metabolism. DNA damage repair mechanisms and oxidative stress regulation is quite important in the transition stage from normal to cancerous cells; thus, this study was conducted to investigate the protective effect of boric acid on DNA damage and wound healing in human epithelial cell line. For this purpose, the amount of DNA damage occurred with irinotecan (CPT-11), etoposide (ETP), doxorubicin (Doxo), and H 2 O 2 was determined by immunofluorescence through phosphorylation of H2AX (Ser139) and pATM (Ser1981) in the absence and presence of BA. Moreover, the effect of BA on wound healing has been investigated in epithelial cells treated with these agents. Our results demonstrated that H2AX (Ser139) foci numbers were significantly decreased in the presence of BA while wound healing was accelerated by BA compared to that in the control and only drug-treated cells. Eventually, the results indicate that BA reduced the formation of DNA double strand breaks caused by agents as well as improving the wound healing process. Therefore, we suggest that boric acid has important therapeutical effectiveness and may be used in the treatment of inflammatory diseases where oxidative stress and wound healing process plays an important role.
Ion response to relativistic electron bunches in the blowout regime of laser-plasma accelerators.
Popov, K I; Rozmus, W; Bychenkov, V Yu; Naseri, N; Capjack, C E; Brantov, A V
2010-11-05
The ion response to relativistic electron bunches in the so called bubble or blowout regime of a laser-plasma accelerator is discussed. In response to the strong fields of the accelerated electrons the ions form a central filament along the laser axis that can be compressed to densities 2 orders of magnitude higher than the initial particle density. A theory of the filament formation and a model of ion self-compression are proposed. It is also shown that in the case of a sharp rear plasma-vacuum interface the ions can be accelerated by a combination of three basic mechanisms. The long time ion evolution that results from the strong electrostatic fields of an electron bunch provides a unique diagnostic of laser-plasma accelerators.
PIXE analysis of tumors and localization behavior of a lanthanide in nude mice
NASA Astrophysics Data System (ADS)
Chang, Pei-Jiun; Yang, Czau-Siung; Chou, Ming-Ji; Wei, Chau-Chin; Hsu, Chu-Chung; Wang, Chia-Yu
1984-04-01
We have used particle induced X-ray emission (PIXE) to analyze the elemental compositions and uptakes of a lanthanide, yttrium in this report, in tumors and normal tissues of nude mice. A small amount of yttrium nitrate was injected into nude mice with tumors. Samples of normal and malignant tissues taken from these mice were bombarded by the 2 MeV proton beam from a 3 MeV Van de Graaff accelerator with a Ge detector system to determine the relative elemental compositions of tissues and the relative concentrations of yttrium taken up by these tissues. We found that the uptakes of yttrium by tumors were at least five times more than those by normal tissues. Substantial differences were often observed between the trace element weight (or concentration) pattern of the cancerous and normal tissues. The present result is compared with human tissues.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Spentzouris, P.; /Fermilab; Cary, J.
The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessarymore » accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors. ComPASS is in the first year of executing its plan to develop the next-generation HPC accelerator modeling tools. ComPASS aims to develop an integrated simulation environment that will utilize existing and new accelerator physics modules with petascale capabilities, by employing modern computing and solver technologies. The ComPASS vision is to deliver to accelerator scientists a virtual accelerator and virtual prototyping modeling environment, with the necessary multiphysics, multiscale capabilities. The plan for this development includes delivering accelerator modeling applications appropriate for each stage of the ComPASS software evolution. Such applications are already being used to address challenging problems in accelerator design and optimization. The Com
Synergistic Action of FOXP3 and TSC1 Pathways During Tumor Progression
2015-10-01
invasive carcinoma and, ultimately, metastatic disease [1-3]. Mouse models of PIN (mPIN) generated by a single- mutant gene in prostate do not progress...downstream target) is sufficient to significantly reduce the initiation of prostate cancer in the Pten conditional knockout mouse model [19-21...the possibility that these two genetic hits cooperate to promote tumor progression, and mouse models show that this cooperation accelerates
A hierarchy of self-renewing tumor-initiating cell types in glioblastoma.
Chen, Ruihuan; Nishimura, Merry C; Bumbaca, Stephanie M; Kharbanda, Samir; Forrest, William F; Kasman, Ian M; Greve, Joan M; Soriano, Robert H; Gilmour, Laurie L; Rivers, Celina Sanchez; Modrusan, Zora; Nacu, Serban; Guerrero, Steve; Edgar, Kyle A; Wallin, Jeffrey J; Lamszus, Katrin; Westphal, Manfred; Heim, Susanne; James, C David; VandenBerg, Scott R; Costello, Joseph F; Moorefield, Scott; Cowdrey, Cynthia J; Prados, Michael; Phillips, Heidi S
2010-04-13
The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133(-) cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133(+) and CD133(-) self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. Copyright 2010 Elsevier Inc. All rights reserved.
Natural and Chemotherapy-Induced Clonal Evolution of Tumors.
Ibragimova, M K; Tsyganov, M M; Litviakov, N V
2017-04-01
Evolution and natural selection of tumoral clones in the process of transformation and the following carcinogenesis can be called natural clonal evolution. Its main driving factors are internal: genetic instability initiated by driver mutations and microenvironment, which enables selective pressure while forming the environment for cell transformation and their survival. We present our overview of contemporary research dealing with mechanisms of carcinogenesis in different localizations from precancerous pathologies to metastasis and relapse. It shows that natural clonal evolution establishes intratumoral heterogeneity and enables tumor progression. Tumors of monoclonal origin are of low-level intratumoral heterogeneity in the initial stages, and this increases with the size of the tumor. Tumors of polyclonal origin are of extremely high-level intratumoral heterogeneity in the initial stages and become more homogeneous when larger due to clonal expansion. In cases of chemotherapy-induced clonal evolution of a tumor, chemotherapy becomes the leading factor in treatment. The latest research shows that the impact of chemotherapy can radically increase the speed of clonal evolution and lead to new malignant and resistant clones that cause tumor metastasis. Another option of chemotherapy-induced clonal evolution is formation of a new dominant clone from a clone that was minor in the initial tumor and obtained free space due to elimination of sensitive clones by chemotherapy. As a result, in ~20% of cases, chemotherapy can stimulate metastasis and relapse of tumors due to clonal evolution. The conclusion of the overview formulates approaches to tumor treatment based on clonal evolution: in particular, precision therapy, prediction of metastasis stimulation in patients treated with chemotherapy, methods of genetic evaluation of chemotherapy efficiency and clonal-oriented treatment, and approaches to manipulating the clonal evolution of tumors are presented.
Wang, Bin; Ding, Yanping; Zhao, Xiaozheng; Han, Xuexiang; Yang, Na; Zhang, Yinlong; Zhao, Ying; Zhao, Xiao; Taleb, Mohammad; Miao, Qing Robert; Nie, Guangjun
2018-08-01
Nogo-B receptor (NgBR) plays fundamental roles in regulating angiogenesis, vascular development, and the epithelial-mesenchymal transition (EMT) of cancer cells. However, the therapeutic effect of NgBR blockade on tumor vasculature and malignancy is unknown, investigations on which requires an adequate delivery system for small interfering RNA against NgBR (NgBR siRNA). Here a surface charge switchable polymeric nanoparticle that was sensitive to the slightly acidic tumor microenvironment was developed for steady delivery of NgBR siRNA to tumor tissues. The nanoformulation was constructed by conjugating 2, 3-dimethylmaleic anhydride (DMMA) molecules to the surface amines of micelles formed by cationic co-polymer poly(lactic-co-glycolic acid) 2 -poly(ethylenimine) and subsequent absorption of NgBR siRNAs. The nanoparticles remained negatively charged in physiological condition and smartly converted to positive surface charge due to tumor-acidity-activated shedding of DMMA. The charge conversion facilitated cellular uptake of siRNAs and in turn efficiently depleted the expression of NgBR in tumor-bearing tissues. Silencing of NgBR suppressed endothelial cell migration and tubule formation, and reverted the EMT process of breast cancer cells. Delivery of the nanoformulation to mice bearing orthotopic breast carcinoma showed no effect on tumor growth, but led to remarkable decrease of distant metastasis by normalizing tumor vessels and suppressing the EMT of breast cancer cells. This study demonstrated that NgBR is a promising therapeutic target in abnormal tumor vasculature and aggressive cancer cells, and the tumor-responsive nanoparticle with the feature of charge transformation offers great potential for tumor-specific delivery of gene therapeutics. Copyright © 2018 Elsevier Ltd. All rights reserved.
Lin28 sustains early renal progenitors and induces Wilms tumor
Urbach, Achia; Yermalovich, Alena; Zhang, Jin; Spina, Catherine S.; Zhu, Hao; Perez-Atayde, Antonio R.; Shukrun, Rachel; Charlton, Jocelyn; Sebire, Neil; Mifsud, William; Dekel, Benjamin; Pritchard-Jones, Kathy; Daley, George Q.
2014-01-01
Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis. PMID:24732380
The properties of the anti-tumor model with coupling non-Gaussian noise and Gaussian colored noise
NASA Astrophysics Data System (ADS)
Guo, Qin; Sun, Zhongkui; Xu, Wei
2016-05-01
The anti-tumor model with correlation between multiplicative non-Gaussian noise and additive Gaussian-colored noise has been investigated in this paper. The behaviors of the stationary probability distribution demonstrate that the multiplicative non-Gaussian noise plays a dual role in the development of tumor and an appropriate additive Gaussian colored noise can lead to a minimum of the mean value of tumor cell population. The mean first passage time is calculated to quantify the effects of noises on the transition time of tumors between the stable states. An increase in both the non-Gaussian noise intensity and the departure from the Gaussian noise can accelerate the transition from the disease state to the healthy state. On the contrary, an increase in cross-correlated degree will slow down the transition. Moreover, the correlation time can enhance the stability of the disease state.
Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis.
Mahmoud, N N; Carothers, A M; Grunberger, D; Bilinski, R T; Churchill, M R; Martucci, C; Newmark, H L; Bertagnolli, M M
2000-05-01
Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.
Yang, Xiaoliang; Saito, Ryuta; Nakamura, Taigen; Zhang, Rong; Sonoda, Yukihiko; Kumabe, Toshihiro; Forsayeth, John; Bankiewicz, Krystof; Tominaga, Teiji
2016-01-01
In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.
NASA Astrophysics Data System (ADS)
Zhou, Min; Zhao, Jun; Tian, Mei; Song, Shaoli; Zhang, Rui; Gupta, Sanjay; Tan, Dongfeng; Shen, Haifa; Ferrari, Mauro; Li, Chun
2015-11-01
Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress breast tumor metastasis through eradication of TICs. Positron electron tomography (PET) imaging and biodistribution studies showed that more than 90% of [64Cu]CuS NPs was retained in subcutaneously grown BT474 breast tumor 24 h after intratumoral (i.t.) injection, indicating the NPs are suitable for the combination therapy. Combined RT/PTT therapy resulted in significant tumor growth delay in the subcutaneous BT474 breast cancer model. Moreover, RT/PTT treatment significantly prolonged the survival of mice bearing orthotopic 4T1 breast tumors compared to no treatment, RT alone, or PTT alone. The RT/PTT combination therapy significantly reduced the number of tumor nodules in the lung and the formation of tumor mammospheres from treated 4T1 tumors. No obvious side effects of the CuS NPs were noted in the treated mice in a pilot toxicity study. Taken together, our data support the feasibility of a therapeutic approach for the suppression of tumor metastasis through localized RT/PTT therapy.Tumor Initiating Cells (TICs) are resistant to radiotherapy and chemotherapy, and are believed to be responsible for tumor recurrence and metastasis. Combination therapies can overcome the limitation of conventional cancer treatments, and have demonstrated promising application in the clinic. Here, we show that dual modality radiotherapy (RT) and photothermal therapy (PTT) mediated by a single compartment nanosystem copper-64-labeled copper sulfide nanoparticles ([64Cu]CuS NPs) could suppress
Accelerators, Beams And Physical Review Special Topics - Accelerators And Beams
DOE Office of Scientific and Technical Information (OSTI.GOV)
Siemann, R.H.; /SLAC
Accelerator science and technology have evolved as accelerators became larger and important to a broad range of science. Physical Review Special Topics - Accelerators and Beams was established to serve the accelerator community as a timely, widely circulated, international journal covering the full breadth of accelerators and beams. The history of the journal and the innovations associated with it are reviewed.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Spentzouris, Panagiotis; /Fermilab; Cary, John
The design and performance optimization of particle accelerators are essential for the success of the DOE scientific program in the next decade. Particle accelerators are very complex systems whose accurate description involves a large number of degrees of freedom and requires the inclusion of many physics processes. Building on the success of the SciDAC-1 Accelerator Science and Technology project, the SciDAC-2 Community Petascale Project for Accelerator Science and Simulation (ComPASS) is developing a comprehensive set of interoperable components for beam dynamics, electromagnetics, electron cooling, and laser/plasma acceleration modelling. ComPASS is providing accelerator scientists the tools required to enable the necessarymore » accelerator simulation paradigm shift from high-fidelity single physics process modeling (covered under SciDAC1) to high-fidelity multiphysics modeling. Our computational frameworks have been used to model the behavior of a large number of accelerators and accelerator R&D experiments, assisting both their design and performance optimization. As parallel computational applications, the ComPASS codes have been shown to make effective use of thousands of processors.« less
Erbb2 up-regulation of ADAM12 expression accelerates skin cancer progression.
Rao, Velidi H; Vogel, Kristen; Yanagida, Jodi K; Marwaha, Nitin; Kandel, Amrit; Trempus, Carol; Repertinger, Susan K; Hansen, Laura A
2015-10-01
Solar ultraviolet (UV) radiation can cause severe damage to the skin and is the primary cause of most skin cancer. UV radiation causes DNA damage leading to mutations and also activates the Erbb2/HER2 receptor through indirect mechanisms involving reactive oxygen species. We hypothesized that Erbb2 activation accelerates the malignant progression of UV-induced skin cancer. Following the induction of benign squamous papillomas by UV exposure of v-ras(Ha) transgenic Tg.AC mice, mice were treated topically with the Erbb2 inhibitor AG825 and tumor progression monitored. AG825 treatment reduced tumor volume, increased tumor regression, and delayed the development of malignant squamous cell carcinoma (SCC). Progression to malignancy was associated with increased Erbb2 and ADAM12 (A Disintegin And Metalloproteinase 12) transcripts and protein, while inhibition of Erbb2 blocked the increase in ADAM12 message upon malignant progression. Similarly, human SCC and SCC cell lines had increased ADAM12 protein and transcripts when compared to normal controls. To determine whether Erbb2 up-regulation of ADAM12 contributed to malignant progression of skin cancer, Erbb2 expression was modulated in cultured SCC cells using forced over-expression or siRNA targeting, demonstrating up-regulation of ADAM12 by Erbb2. Furthermore, ADAM12 transfection or siRNA targeting revealed that ADAM12 increased both the migration and invasion of cutaneous SCC cells. Collectively, these results suggest Erbb2 up-regulation of ADAM12 as a novel mechanism contributing to the malignant progression of UV-induced skin cancer. Inhibition of Erbb2/HER2 reduced tumor burden, increased tumor regression, and delayed the progression of benign skin tumors to malignant SCC in UV-exposed mice. Inhibition of Erbb2 suppressed the increase in metalloproteinase ADAM12 expression in skin tumors, which in turn increased migration and tumor cell invasiveness. © 2014 Wiley Periodicals, Inc.
Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer
Hillebrand, Larissa E.; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas
2016-01-01
Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45−, showed a high tumorigenicity compared to non-CD24+CD90+CD45− cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45− TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45− cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45− cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas. PMID:27542270
NASA Astrophysics Data System (ADS)
Umezawa, Masumi; Fujimoto, Rintaro; Umekawa, Tooru; Fujii, Yuusuke; Takayanagi, Taisuke; Ebina, Futaro; Aoki, Takamichi; Nagamine, Yoshihiko; Matsuda, Koji; Hiramoto, Kazuo; Matsuura, Taeko; Miyamoto, Naoki; Nihongi, Hideaki; Umegaki, Kikuo; Shirato, Hiroki
2013-04-01
Hokkaido University and Hitachi Ltd. have started joint development of the Gated Spot Scanning Proton Therapy with Real-Time Tumor-Tracking System by integrating real-time tumor tracking technology (RTRT) and the proton therapy system dedicated to discrete spot scanning techniques under the "Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program)". In this development, we have designed the synchrotron-based accelerator system by using the advantages of the spot scanning technique in order to realize a more compact and lower cost proton therapy system than the conventional system. In the gated irradiation, we have focused on the issues to maximize irradiation efficiency and minimize the dose errors caused by organ motion. In order to understand the interplay effect between scanning beam delivery and target motion, we conducted a simulation study. The newly designed system consists of the synchrotron, beam transport system, one compact rotating gantry treatment room with robotic couch, and one experimental room for future research. To improve the irradiation efficiency, the new control function which enables multiple gated irradiations per synchrotron cycle has been applied and its efficacy was confirmed by the irradiation time estimation. As for the interplay effect, we confirmed that the selection of a strict gating width and scan direction enables formation of the uniform dose distribution.
Innovations in the management of Wilms' tumor.
Gleason, Joseph M; Lorenzo, Armando J; Bowlin, Paul R; Koyle, Martin A
2014-08-01
Advances in the management of Wilms' tumor have been dramatic over the past half century, not in small part due to the institution of multimodal therapy and the formation of collaborative study groups. While different opinions exist in the management of Wilms' tumors depending on where one lives and practices, survival rates have surpassed 90% across the board in Western societies. With more children surviving into adulthood, the concerns about morbidity have reached the forefront and now represent as much a consideration as oncologic outcomes these days. Innovations in treatment are on the horizon in the form of potential tumor markers, molecular biological means of testing for chemotherapeutic responsiveness, and advances in the delivery of chemotherapy for recurrent or recalcitrant tumors. Other technological innovations are being applied to childhood renal tumors, such as minimally invasive and nephron-sparing approaches. Risk stratification also allows for children to forego potentially unnecessary treatments and their associated morbidities. Wilms' tumor stands as a great example of the gains that can be made through protocol-driven therapy with strenuous outcomes analyses. These gains continue to spark interest in minimization of morbidity, while avoiding any compromise in oncologic efficacy. While excitement and innovation are important in the advancement of treatment delivery, we must continue to temper this enthusiasm and carefully evaluate options in order to continue to provide the highest standard of care in the management of this now highly curable disease.
A tissue-engineered subcutaneous pancreatic cancer model for antitumor drug evaluation.
He, Qingyi; Wang, Xiaohui; Zhang, Xing; Han, Huifang; Han, Baosan; Xu, Jianzhong; Tang, Kanglai; Fu, Zhiren; Yin, Hao
2013-01-01
The traditional xenograft subcutaneous pancreatic cancer model is notorious for its low incidence of tumor formation, inconsistent results for the chemotherapeutic effects of drug molecules of interest, and a poor predictive capability for the clinical efficacy of novel drugs. These drawbacks are attributed to a variety of factors, including inoculation of heterogeneous tumor cells from patients with different pathological histories, and use of poorly defined Matrigel(®). In this study, we aimed to tissue-engineer a pancreatic cancer model that could readily cultivate a pancreatic tumor derived from highly homogenous CD24(+)CD44(+) pancreatic cancer stem cells delivered by a well defined electrospun scaffold of poly(glycolide-co-trimethylene carbonate) and gelatin. The scaffold supported in vitro tumorigenesis from CD24(+)CD44(+) cancer stem cells for up to 7 days without inducing apoptosis. Moreover, CD24(+)CD44(+) cancer stem cells delivered by the scaffold grew into a native-like mature pancreatic tumor within 8 weeks in vivo and exhibited accelerated tumorigenesis as well as a higher incidence of tumor formation than the traditional model. In the scaffold model, we discovered that oxaliplatin-gemcitabine (OXA-GEM), a chemotherapeutic regimen, induced tumor regression whereas gemcitabine alone only capped tumor growth. The mechanistic study attributed the superior antitumorigenic performance of OXA-GEM to its ability to induce apoptosis of CD24(+)CD44(+) cancer stem cells. Compared with the traditional model, the scaffold model demonstrated a higher incidence of tumor formation and accelerated tumor growth. Use of a tiny population of highly homogenous CD24(+)CD44(+) cancer stem cells delivered by a well defined scaffold greatly reduces the variability associated with the traditional model, which uses a heterogeneous tumor cell population and poorly defined Matrigel. The scaffold model is a robust platform for investigating the antitumorigenesis mechanism of
Redente, Elizabeth F.; Keith, Rebecca C.; Janssen, William; Henson, Peter M.; Ortiz, Luis A.; Downey, Gregory P.; Bratton, Donna L.
2014-01-01
Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α−/− mice by measuring hydroxyproline levels, static compliance, and Masson’s trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α−/− mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α–induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve
Fermilab | Tevatron | Accelerator
Leading accelerator technology Accelerator complex Illinois Accelerator Research Center Fermilab temperature. They were used to transfer particles from one part of the Fermilab accelerator complex to another center ring of Fermilab's accelerator complex. Before the Tevatron shut down, it had three primary
Jin, Lili; Li, Zhou-Fang; Wang, Da-Kui; Sun, Meina; Qi, Wei; Ma, Qiang; Zhang, Li; Chu, Chun; Chan, Elaine Y M; Lee, Susanna S T; Wise, Helen; To, Ka-Fai; Shi, Ying; Zhou, Naiming; Cheung, Wing-Tai
2018-02-01
Previously our lab has created a mouse ovarian xenograft model of copy number variation (CNV)-mediated G protein-coupled receptor (GPCR) MAS-driven tumorigenesis, and RNA profiling identified a putative chemokine tumor-induced factor (Tif). Sequence analysis and chemotactic study suggested that Tif was likely to be a hamster homolog of human GROγ (CXCL3) [IJC 125 (2009): 1316-1327]. In the present study, we report the molecular and functional characterization of the Tif gene. Genomic study of CHO-K1 cells indicated that Tif gene consisted of 4 exons, characterized with an antisense B1 element which is embedded in the fourth exon. Two Tif transcripts were identified which shared identical sequences except that a string of 71-nt derived from the antisense B1 element was deficient in the shorter transcript. Of interests, B1-like RNA ladder was detected in xenografts. Functional studies showed that TIF induced chemotaxis and neovessel formation. Pharmacological studies suggested that TIF activated Gi-coupled CXCR2 and induced both calcium mobilization and ERK1/2 phosphorylation, and suppressed forskolin-stimulated cAMP accumulation. In addition, secreted matured TIF functioned as an autocrine factor and promoted anchorage-independent growth. Unexpectedly, TIF delayed the onset of tumor formation, possibly via suppressing proliferation of stromal fibroblasts. However, TIF did not exert any inhibitory effect on tumor growth. Potentially, TIF could be used for preventing cancer relapse. Copyright © 2017 Elsevier Ltd. All rights reserved.
BATHYMETRIC IRREGULARITIES, JET FORMATION, AND SUBSEQUENT MIXING PROCESSES
It is well known that bathymetric contours influence and steer currents and that irregularities in bathymetry contribute to the formation of aquatic non-buoyant jets and buoyant plumes. For example, bathymetric irregularities can channel flow through canyons or accelerate flow ov...
Piezoelectric particle accelerator
DOE Office of Scientific and Technical Information (OSTI.GOV)
Kemp, Mark A.; Jongewaard, Erik N.; Haase, Andrew A.
2017-08-29
A particle accelerator is provided that includes a piezoelectric accelerator element, where the piezoelectric accelerator element includes a hollow cylindrical shape, and an input transducer, where the input transducer is disposed to provide an input signal to the piezoelectric accelerator element, where the input signal induces a mechanical excitation of the piezoelectric accelerator element, where the mechanical excitation is capable of generating a piezoelectric electric field proximal to an axis of the cylindrical shape, where the piezoelectric accelerator is configured to accelerate a charged particle longitudinally along the axis of the cylindrical shape according to the piezoelectric electric field.
EDITORIAL: Laser and plasma accelerators Laser and plasma accelerators
NASA Astrophysics Data System (ADS)
Bingham, Robert
2009-02-01
This special issue on laser and plasma accelerators illustrates the rapid advancement and diverse applications of laser and plasma accelerators. Plasma is an attractive medium for particle acceleration because of the high electric field it can sustain, with studies of acceleration processes remaining one of the most important areas of research in both laboratory and astrophysical plasmas. The rapid advance in laser and accelerator technology has led to the development of terawatt and petawatt laser systems with ultra-high intensities and short sub-picosecond pulses, which are used to generate wakefields in plasma. Recent successes include the demonstration by several groups in 2004 of quasi-monoenergetic electron beams by wakefields in the bubble regime with the GeV energy barrier being reached in 2006, and the energy doubling of the SLAC high-energy electron beam from 42 to 85 GeV. The electron beams generated by the laser plasma driven wakefields have good spatial quality with energies ranging from MeV to GeV. A unique feature is that they are ultra-short bunches with simulations showing that they can be as short as a few femtoseconds with low-energy spread, making these beams ideal for a variety of applications ranging from novel high-brightness radiation sources for medicine, material science and ultrafast time-resolved radiobiology or chemistry. Laser driven ion acceleration experiments have also made significant advances over the last few years with applications in laser fusion, nuclear physics and medicine. Attention is focused on the possibility of producing quasi-mono-energetic ions with energies ranging from hundreds of MeV to GeV per nucleon. New acceleration mechanisms are being studied, including ion acceleration from ultra-thin foils and direct laser acceleration. The application of wakefields or beat waves in other areas of science such as astrophysics and particle physics is beginning to take off, such as the study of cosmic accelerators considered
Tumor cell-derived microparticles polarize M2 tumor-associated macrophages for tumor progression.
Ma, Ruihua; Ji, Tiantian; Chen, Degao; Dong, Wenqian; Zhang, Huafeng; Yin, Xiaonan; Ma, Jingwei; Liang, Xiaoyu; Zhang, Yi; Shen, Guanxin; Qin, Xiaofeng; Huang, Bo
2016-04-01
Despite identification of macrophages in tumors (tumor-associated macrophages, TAM) as potential targets for cancer therapy, the origin and function of TAM in the context of malignancy remain poorly characterized. Here, we show that microparticles (MPs), as a by-product, released by tumor cells act as a general mechanism to mediate M2 polarization of TAM. Taking up tumor MPs by macrophages is a very efficient process, which in turn results in the polarization of macrophages into M2 type, not only leading to promoting tumor growth and metastasis but also facilitating cancer stem cell development. Moreover, we demonstrate that the underlying mechanism involves the activation of the cGAS/STING/TBK1/STAT6 pathway by tumor MPs. Finally, in addition to murine tumor MPs, we show that human counterparts also possess consistent effect on human M2 polarization. These findings provide new insights into a critical role of tumor MPs in remodeling of tumor microenvironment and better understanding of the communications between tumors and macrophages.
Hasegawa, Sumitaka; Maruyama, Kouichi; Takenaka, Hikaru; Furukawa, Takako; Saga, Tsuneo
2009-08-18
The recent success with small fish as an animal model of cancer with the aid of fluorescence technique has attracted cancer modelers' attention because it would be possible to directly visualize tumor cells in vivo in real time. Here, we report a medaka model capable of allowing the observation of various cell behaviors of transplanted tumor cells, such as cell proliferation and metastasis, which were visualized easily in vivo. We established medaka melanoma (MM) cells stably expressing GFP and transplanted them into nonirradiated and irradiated medaka. The tumor cells were grown at the injection sites in medaka, and the spatiotemporal changes were visualized under a fluorescence stereoscopic microscope at a cellular-level resolution, and even at a single-cell level. Tumor dormancy and metastasis were also observed. Interestingly, in irradiated medaka, accelerated tumor growth and metastasis of the transplanted tumor cells were directly visualized. Our medaka model provides an opportunity to visualize in vivo tumor cells "as seen in a culture dish" and would be useful for in vivo tumor cell biology.
Kuwahara, Yoshikazu; Mori, Miyuki; Kitahara, Shuji; Fukumoto, Motoi; Ezaki, Taichi; Mori, Shiro; Echigo, Seishi; Ohkubo, Yasuhito; Fukumoto, Manabu
2014-01-01
Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS-R, from SAS cells. SAS-R cells continue to proliferate when exposed to fractionated radiation (FR) of 2 Gy/day for more than 30 days in vitro. A xenograft tumor model of SAS-R was also resistant to 2 Gy/day of X-rays for 30 days. The density of blood vessels in SAS-R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS-R cells in vitro. Everolimus with FR markedly reduced SAS and SAS-R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS-R tumor tissues when both Everolimus and radiation were administered. Both CD34-positive and tomato lectin-positive blood vessel densities in SAS-R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus-induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs. PMID:24464839
Mutagenic effect of accelerated heavy ions on bacterial cells
NASA Astrophysics Data System (ADS)
Boreyko, A. V.; Krasavin, E. A.
2011-11-01
The heavy ion accelerators of the Joint Institute for Nuclear Research were used to study the regularities and mechanisms of formation of different types of mutations in prokaryote cells. The induction of direct (lac-, ton B-, col B) mutations for Esherichia coli cells and reverse his- → His+ mutations of Salmonella typhimurium, Bacillus subtilis cells under the action of radiation in a wide range of linear energy transfer (LET) was studied. The regularities of formation of gene and structural (tonB trp-) mutations for Esherichia coli bacteria under the action of accelerated heavy ions were studied. It was demonstrated that the rate of gene mutations as a function of the dose under the action of Γ rays and accelerated heavy ions is described by linear-quadratic functions. For structural mutations, linear "dose-effect" dependences are typical. The quadratic character of mutagenesis dose curves is determined by the "interaction" of two independent "hitting" events in the course of SOS repair of genetic structures. The conclusion made was that gene mutations under the action of accelerated heavy ions are induced by δ electron regions of charged particle tracks. The methods of SOS chromotest, SOS lux test, and λ prophage induction were used to study the regularities of SOS response of cells under the action of radiations in a wide LET range. The following proposition was substantiated: the molecular basis for formation of gene mutations are cluster single-strand DNA breaks, and that for structural mutations, double-strand DNA breaks. It was found out that the LET dependence of the relative biological efficiency of accelerated ions is described by curves with a local maximum. It was demonstrated that the biological efficiency of ionizing radiations with different physical characteristics on cells with different genotype, estimated by the lethal action, induction of gene and deletion mutations, precision excision of transposons, is determined by the specific
Zhong, Nianxin; Ward, Jerrold M.; Perella, Christine M.; Hoffmann, Victoria J.; Rogers, Keith; Combs, Gerald F.; Schweizer, Ulrich; Merlino, Glenn; Gladyshev, Vadim N.; Hatfield, Dolph L.
2013-01-01
Changes in dietary selenium and selenoprotein status may influence both anti- and pro-cancer pathways, making the outcome of interventions different from one study to another. To characterize such outcomes in a defined setting, we undertook a controlled hepatocarcinogenesis study involving varying levels of dietary selenium and altered selenoprotein status using mice carrying a mutant (A37G) selenocysteine tRNA transgene (TrsptG37) and/or a cancer driver TGFα transgene. The use of TrsptG37 altered selenoprotein expression in a selenoprotein and tissue specific manner and, at sufficient dietary selenium levels, separate the effect of diet and selenoprotein status. Mice were maintained on diets deficient in selenium (0.02 ppm selenium) or supplemented with 0.1, 0.4 or 2.25 ppm selenium or 30 ppm triphenylselenonium chloride (TPSC), a non-metabolized selenium compound. TrsptG37 transgenic and TGFα/TrsptG37 bi-transgenic mice subjected to selenium-deficient or TPSC diets developed a neurological phenotype associated with early morbidity and mortality prior to hepatocarcinoma development. Pathology analyses revealed widespread disseminated pyogranulomatous inflammation. Pyogranulomas occurred in liver, lungs, heart, spleen, small and large intestine, and mesenteric lymph nodes in these transgenic and bi-transgenic mice. The incidence of liver tumors was significantly increased in mice carrying the TGFα transgene, while dietary selenium and selenoprotein status did not affect tumor number and multiplicity. However, adenoma and carcinoma size and area were smaller in TGFα transgenic mice that were fed 0.4 and 2.25 versus 0.1 ppm of selenium. Thus, selenium and selenoprotein deficiencies led to widespread pyogranuloma formation, while high selenium levels inhibited the size of TGFα–induced liver tumors. PMID:23460847
Cong, Menglin; Li, Jianmin; Jing, Rui; Li, Zhenzhong
2016-07-01
Osteosarcoma is the most common malignant tumor of bone. Recent studies have proven long non-coding RNAs (lncRNAs) play important roles in the tumorigenesis and progression of cancer. However, few lncRNAs have been investigated in osteosarcoma. Here, we reported a novel lncRNA, tumor suppressor candidate 7 (TUSC7), was significantly downregulated in osteosarcoma tissues compared with paired non-tumor tissues and low expression of TUSC7 indicated poor survival (HR = 0.313, 95 % confidence interval (CI) 0.092-0.867) of osteosarcoma patients. Further analysis revealed that loss copy number of TUSC7 was correlated with low expression of TUSC7, and additionally, loss of TUSC7 copy number also indicated poor prognosis (HR = 3.994, 95 % CI 1.147-13.91) of osteosarcoma patients. Two osteosarcoma cell lines, HOS and MG63, were utilized to investigate biological function of TUSC7. Cell counting kit 8 (CCK-8) assay revealed that after silence of TUSC7, cell proliferation ability increased and the colony formation ability also increased. Further results showed that cell cycle was not affected by treatment of si-TUSC7, while the percentage of apoptotic cells decreased. Western blot showed that after silence of TUSC7, the proapoptotic Bcl2 expression was downregulated. Finally, we established xenograft tumor models in nude mice with MG63 cells. Compared with negative control group, silence of TUSC7 significantly promoted tumor growth in vivo. Thus, we demonstrated that TUSC7 could be a potential tumor suppressor in osteosarcoma.
Tumor-associated myeloid cells as guiding forces of cancer cell stemness.
Sica, Antonio; Porta, Chiara; Amadori, Alberto; Pastò, Anna
2017-08-01
Due to their ability to differentiate into various cell types and to support tissue regeneration, stem cells simultaneously became the holy grail of regenerative medicine and the evil obstacle in cancer therapy. Several studies have investigated niche-related conditions that favor stemness properties and increasingly emphasized their association with an inflammatory environment. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are major orchestrators of cancer-related inflammation, able to dynamically express different polarized inflammatory programs that promote tumor outgrowth, including tumor angiogenesis, immunosuppression, tissue remodeling and metastasis formation. In addition, these myeloid populations support cancer cell stemness, favoring tumor maintenance and progression, as well as resistance to anticancer treatments. Here, we discuss inflammatory circuits and molecules expressed by TAMs and MDSCs as guiding forces of cancer cell stemness.
Single particles accelerate final stages of capillary break-up
NASA Astrophysics Data System (ADS)
Lindner, Anke; Fiscina, Jorge Eduardo; Wagner, Christian
2015-06-01
Droplet formation of suspensions is present in many industrial and technological processes such as coating and food engineering. Whilst the finite-time singularity of the minimum neck diameter in capillary break-up of simple liquids can be described by well-known self-similarity solutions, the pinching of non-Brownian suspension depends in a complex way on the particle dynamics in the thinning thread. Here we focus on the very dilute regime where the filament contains only isolated beads to identify the physical mechanisms leading to the pronounced acceleration of the filament thinning observed. This accelerated regime is characterized by an asymmetric shape of the filament with an enhanced curvature that depends on the size and the spatial distribution of the particles within the capillary thread.
Significance of biological resource collection and tumor tissue bank creation.
Yu, Ying-Yan; Zhu, Zheng-Gang
2010-01-15
Progress in the molecular oncology of gastrointestinal carcinomas depends on high quality cancer tissues for research. Recent acceleration on new technological platforms as well as the "omics" revolution increases the demands on tissues and peripheral blood for research at the DNA, mRNA and protein levels. Tissue bank creation emerges as a priority. Tumor tissue banks are facilities that are organized to collect, store and distribute samples of tumor and normal tissue for further use in basic and translational cancer research. The samples are generally obtained immediately after excision, prior to fixation, to ensure optimal preservation of proteins and nucleic acids. It is possible for surgeons or pathologists to collect fresh tissue prospectively during their routine dissection procedures. Most tissue banks are "project-driven" tumor banks, which are specialized collections of tumor samples on which their research is based. Systematic collection of all available tumor tissue is much rarer. High quality tissue banks need the collaboration of clinicians and basic scientists, but also the informed consent of patients and ethical approval. Through the standard operation procedure, snap frozen fresh tissue collection, storage and quality control for cryopreserved tissues are the pivotal factors on tissue bank construction and maintaining. The purpose of the tissue bank creation is enhancing the quality and speed on both the basic and translational research on gastrointestinal cancer. The quality assurance and quality control are handled based on reviewing HE staining slides or touch imprint cytology by pathologists.
Increased formate overflow is a hallmark of oxidative cancer.
Meiser, Johannes; Schuster, Anne; Pietzke, Matthias; Vande Voorde, Johan; Athineos, Dimitris; Oizel, Kristell; Burgos-Barragan, Guillermo; Wit, Niek; Dhayade, Sandeep; Morton, Jennifer P; Dornier, Emmanuel; Sumpton, David; Mackay, Gillian M; Blyth, Karen; Patel, Ketan J; Niclou, Simone P; Vazquez, Alexei
2018-04-10
Formate overflow coupled to mitochondrial oxidative metabolism\\ has been observed in cancer cell lines, but whether that takes place in the tumor microenvironment is not known. Here we report the observation of serine catabolism to formate in normal murine tissues, with a relative rate correlating with serine levels and the tissue oxidative state. Yet, serine catabolism to formate is increased in the transformed tissue of in vivo models of intestinal adenomas and mammary carcinomas. The increased serine catabolism to formate is associated with increased serum formate levels. Finally, we show that inhibition of formate production by genetic interference reduces cancer cell invasion and this phenotype can be rescued by exogenous formate. We conclude that increased formate overflow is a hallmark of oxidative cancers and that high formate levels promote invasion via a yet unknown mechanism.
Source-to-accelerator quadrupole matching section for a compact linear accelerator
NASA Astrophysics Data System (ADS)
Seidl, P. A.; Persaud, A.; Ghiorso, W.; Ji, Q.; Waldron, W. L.; Lal, A.; Vinayakumar, K. B.; Schenkel, T.
2018-05-01
Recently, we presented a new approach for a compact radio-frequency (RF) accelerator structure and demonstrated the functionality of the individual components: acceleration units and focusing elements. In this paper, we combine these units to form a working accelerator structure: a matching section between the ion source extraction grids and the RF-acceleration unit and electrostatic focusing quadrupoles between successive acceleration units. The matching section consists of six electrostatic quadrupoles (ESQs) fabricated using 3D-printing techniques. The matching section enables us to capture more beam current and to match the beam envelope to conditions for stable transport in an acceleration lattice. We present data from an integrated accelerator consisting of the source, matching section, and an ESQ doublet sandwiched between two RF-acceleration units.
Radiolabeled Nanoparticles for Multimodality Tumor Imaging
Xing, Yan; Zhao, Jinhua; Conti, Peter S.; Chen, Kai
2014-01-01
Each imaging modality has its own unique strengths. Multimodality imaging, taking advantages of strengths from two or more imaging modalities, can provide overall structural, functional, and molecular information, offering the prospect of improved diagnostic and therapeutic monitoring abilities. The devices of molecular imaging with multimodality and multifunction are of great value for cancer diagnosis and treatment, and greatly accelerate the development of radionuclide-based multimodal molecular imaging. Radiolabeled nanoparticles bearing intrinsic properties have gained great interest in multimodality tumor imaging over the past decade. Significant breakthrough has been made toward the development of various radiolabeled nanoparticles, which can be used as novel cancer diagnostic tools in multimodality imaging systems. It is expected that quantitative multimodality imaging with multifunctional radiolabeled nanoparticles will afford accurate and precise assessment of biological signatures in cancer in a real-time manner and thus, pave the path towards personalized cancer medicine. This review addresses advantages and challenges in developing multimodality imaging probes by using different types of nanoparticles, and summarizes the recent advances in the applications of radiolabeled nanoparticles for multimodal imaging of tumor. The key issues involved in the translation of radiolabeled nanoparticles to the clinic are also discussed. PMID:24505237
Nonlocal Models of Cosmic Acceleration
NASA Astrophysics Data System (ADS)
Woodard, R. P.
2014-02-01
I review a class of nonlocally modified gravity models which were proposed to explain the current phase of cosmic acceleration without dark energy. Among the topics considered are deriving causal and conserved field equations, adjusting the model to make it support a given expansion history, why these models do not require an elaborate screening mechanism to evade solar system tests, degrees of freedom and kinetic stability, and the negative verdict of structure formation. Although these simple models are not consistent with data on the growth of cosmic structures many of their features are likely to carry over to more complicated models which are in better agreement with the data.
IL-33 activates tumor stroma to promote intestinal polyposis.
Maywald, Rebecca L; Doerner, Stephanie K; Pastorelli, Luca; De Salvo, Carlo; Benton, Susan M; Dawson, Emily P; Lanza, Denise G; Berger, Nathan A; Markowitz, Sanford D; Lenz, Heinz-Josef; Nadeau, Joseph H; Pizarro, Theresa T; Heaney, Jason D
2015-05-12
Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.
A Secreted Effector Protein of Ustilago maydis Guides Maize Leaf Cells to Form Tumors
Redkar, Amey; Hoser, Rafal; Schilling, Lena; Zechmann, Bernd; Krzymowska, Magdalena; Walbot, Virginia; Doehlemann, Gunther
2015-01-01
The biotrophic smut fungus Ustilago maydis infects all aerial organs of maize (Zea mays) and induces tumors in the plant tissues. U. maydis deploys many effector proteins to manipulate its host. Previously, deletion analysis demonstrated that several effectors have important functions in inducing tumor expansion specifically in maize leaves. Here, we present the functional characterization of the effector See1 (Seedling efficient effector1). See1 is required for the reactivation of plant DNA synthesis, which is crucial for tumor progression in leaf cells. By contrast, See1 does not affect tumor formation in immature tassel floral tissues, where maize cell proliferation occurs independent of fungal infection. See1 interacts with a maize homolog of SGT1 (Suppressor of G2 allele of skp1), a factor acting in cell cycle progression in yeast (Saccharomyces cerevisiae) and an important component of plant and human innate immunity. See1 interferes with the MAPK-triggered phosphorylation of maize SGT1 at a monocot-specific phosphorylation site. We propose that See1 interferes with SGT1 activity, resulting in both modulation of immune responses and reactivation of DNA synthesis in leaf cells. This identifies See1 as a fungal effector that directly and specifically contributes to the formation of leaf tumors in maize. PMID:25888589
Lin, Yi-Hsin; Yang, Ming-Chieh; Tseng, Ssu-Hsueh; Jiang, Rosie; Yang, Andrew; Farmer, Emily; Peng, Shiwen; Henkle, Talia; Chang, Yung-Nien; Hung, Chien-Fu; Wu, T-C
2018-01-23
Human papillomavirus type 16 (HPV16) is the etiologic factor for cervical cancer and a subset of oropharyngeal cancers. Although several prophylactic HPV vaccines are available, no effective therapeutic strategies to control active HPV diseases exist. Tumor implantation models are traditionally used to study HPV-associated buccal tumors. However, they fail to address precancerous phases of disease progression and display tumor microenvironments distinct from those observed in patients. Previously, K14-E6/E7 transgenic mouse models have been used to generate spontaneous tumors. However, the rate of tumor formation is inconsistent, and the host often develops immune tolerance to the viral oncoproteins. We developed a preclinical, spontaneous, HPV16 + buccal tumor model using submucosal injection of oncogenic plasmids expressing HPV16-E6/E7, NRas G12V , luciferase, and sleeping beauty (SB) transposase, followed by electroporation in the buccal mucosa. We evaluated responses to immunization with a pNGVL4a-CRT/E7(detox) therapeutic HPV DNA vaccine and tumor cell migration to distant locations. Mice transfected with plasmids encoding HPV16-E6/E7, NRas G12V , luciferase, and SB transposase developed tumors within 3 weeks. We also found transient anti-CD3 administration is required to generate tumors in immunocompetent mice. Bioluminescence signals from luciferase correlated strongly with tumor growth, and tumors expressed HPV16-associated markers. We showed that pNGVL4a-CRT/E7(detox) administration resulted in antitumor immunity in tumor-bearing mice. Lastly, we demonstrated that the generated tumor could migrate to tumor-draining lymph nodes. Our model provides an efficient method to induce spontaneous HPV + tumor formation, which can be used to identify effective therapeutic interventions, analyze tumor migration, and conduct tumor biology research. Cancer Immunol Res; 6(3); 1-15. ©2018 AACR. ©2018 American Association for Cancer Research.
Generation and acceleration of neutral atoms in intense laser plasma experiments
NASA Astrophysics Data System (ADS)
Tata, Sheroy; Mondal, Angana; Sarkar, Shobhik; Ved, Yash; Lad, Amit D.; Pasley, John; Colgan, James; Krishnamurthy, M.
2017-10-01
The interaction of a high intensity (>=1018 W/cm2), high contrast (>=109), ultra-short (30fs) laser with solid targets generates a highly dense hot plasma. The quasi-static electric fields in such plasmas are well known for ion acceleration via the target normal sheath acceleration process. Under such conditions charge reduction to generate fast neutral atoms is almost inhibited. Improvised Thomson parabola spectrometry with improved signal to noise ratio has enabled us to measure the signals of fast neutral atoms and negative ions having energies in excess of tens of keV. A study on the neutralization of accelerated protons in plasma shows that the neutral atom to all particle ratio rises sharply from a few percent at the highest detectable energy to 50 % at 15 keV. Using usual charge transfer reactions the generation of neutral atoms can not be explained, thus we conjecture that the neutralization of the accelerated ions is not from the hot dense region of the plasma but neutral atom formation takes place by co-propagating ions with low energy electrons enhancing the effective neutral ratio.
Circulating Microparticles Alter Formation, Structure, and Properties of Fibrin Clots.
Zubairova, Laily D; Nabiullina, Roza M; Nagaswami, Chandrasekaran; Zuev, Yuriy F; Mustafin, Ilshat G; Litvinov, Rustem I; Weisel, John W
2015-12-04
Despite the importance of circulating microparticles in haemostasis and thrombosis, there is limited evidence for potential causative effects of naturally produced cell-derived microparticles on fibrin clot formation and its properties. We studied the significance of blood microparticles for fibrin formation, structure, and susceptibility to fibrinolysis by removing them from platelet-free plasma using filtration. Clots made in platelet-free and microparticle-depleted plasma samples from the same healthy donors were analyzed in parallel. Microparticles accelerate fibrin polymerisation and support formation of more compact clots that resist internal and external fibrinolysis. These variations correlate with faster thrombin generation, suggesting thrombin-mediated kinetic effects of microparticles on fibrin formation, structure, and properties. In addition, clots formed in the presence of microparticles, unlike clots from the microparticle-depleted plasma, contain 0.1-0.5-μm size granular and CD61-positive material on fibres, suggesting that platelet-derived microparticles attach to fibrin. Therefore, the blood of healthy individuals contains functional microparticles at the levels that have a procoagulant potential. They affect the structure and stability of fibrin clots indirectly through acceleration of thrombin generation and through direct physical incorporation into the fibrin network. Both mechanisms underlie a potential role of microparticles in haemostasis and thrombosis as modulators of fibrin formation, structure, and resistance to fibrinolysis.
The hormone prolactin (PRL) plays a critical role in normal breast development by stimulating the proliferation of mammary cells, the production of milk proteins, and the formation of new mammary blood vessels. Unfortunately, the same cell and vessel growth pathways controlled by PRL in normal cells also operate in breast cancer cells, and elevated plasma PRL is a risk factor
Energy dissipation on ion-accelerator grids during high-voltage breakdown
DOE Office of Scientific and Technical Information (OSTI.GOV)
Menon, M.M.; Ponte, N.S.
1981-01-01
The effects of stored energy in the system capacitance across the accelerator grids during high voltage vacuum breakdown are examined. Measurements were made of the current flow and the energy deposition on the grids during breakdown. It is shown that only a portion (less than or equal to 40 J) of the total stored energy (congruent to 100 J) is actually dissipated on the grids. Most of the energy is released during the formation phase of the vacuum arc and is deposited primarily on the most positive grid. Certain abnormal situations led to energy depositions of about 200 J onmore » the grid, but the ion accelerator endured them without exhibiting any deterioration in performance.« less
Regulation of hematogenous tumor metastasis by acid sphingomyelinase
Carpinteiro, Alexander; Becker, Katrin Anne; Japtok, Lukasz; Hessler, Gabriele; Keitsch, Simone; Požgajovà, Miroslava; Schmid, Kurt W; Adams, Constantin; Müller, Stefan; Kleuser, Burkhard; Edwards, Michael J; Grassmé, Heike; Helfrich, Iris; Gulbins, Erich
2015-01-01
Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1−/− mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. PMID:25851537
NASA Astrophysics Data System (ADS)
Orlova, A. G.; Kirillin, M. Yu; Volovetsky, A. B.; Shilyagina, N. Yu; Sergeeva, E. A.; Golubiatnikov, G. Yu; Turchin, I. V.
2017-01-01
Tumor oxygenation and hemoglobin content are the key indicators of the tumor status which can be efficiently employed for prognosis of tumor development and choice of treatment strategy. We report on monitoring of these parameters in SKBR-3 (human breast adenocarcinoma) tumors established as subcutaneous tumor xenografts in athymic nude mice by diffuse optical spectroscopy (DOS). A simple continuous wave fiber probe DOS system is employed. Optical properties extraction approach is based on diffusion approximation. Statistically significant difference between measured values of normal tissue and tumor are demonstrated. Hemoglobin content in tumor increases from 7.0 ± 4.2 μM to 30.1 ± 16.1 μM with tumor growth from 150 ± 80 mm3 to 1300 ± 650 mm3 which is determined by gradual increase of deoxyhemoglobin content while measured oxyhemoglobin content does not demonstrate any statistically significant variations. Oxygenation in tumor falls quickly from 52.8 ± 24.7% to 20.2 ± 4.8% preceding acceleration of tumor growth. Statistical analysis indicated dependence of oxy-, deoxy- and total hemoglobin on tumor volume (p < 0.01). DOS measurements of oxygen saturation are in agreement with independent measurements of oxygen partial pressure by polarography (Pearson’s correlation coefficient equals 0.8).
Can Accelerators Accelerate Learning?
NASA Astrophysics Data System (ADS)
Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.
2009-03-01
The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ) [1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.
Sustained acceleration on perception of relative position and motion.
McKinley, R Andrew; Tripp, Lloyd D; Fullerton, Kathy L; Goodyear, Chuck
2013-03-01
Air-to-air refueling, formation flying, and projectile countermeasures all rely on a pilot's ability to be aware of his position and motion relative to another object. Eight subjects participated in the study, all members of the sustained acceleration stress panel at Wright-Patterson AFB, OH. The task consisted of the subject performing a two-dimensional join up task between a KC-135 tanker and an F-16. The objective was to guide the nose of the F-16 to the posterior end of the boom extended from the tanker, and hold this position for 2 s. If the F-16 went past the tanker, or misaligned with the tanker, it would be recorded as an error. These tasks were performed during four G(z) acceleration profiles starting from a baseline acceleration of 1.5 G(z). The plateaus were 3, 5, and 7 G(z). The final acceleration exposure was a simulated aerial combat maneuver (SACM). One subject was an outlier and therefore omitted from analysis. The mean capture time and percent error data were recorded and compared separately. There was a significant difference in error percentage change from baseline among the G(z) profiles, but not capture time. Mean errors were approximately 15% higher in the 7 G profile and 10% higher during the SACM. This experiment suggests that the ability to accurately perceive the motion of objects relative to other objects is impeded at acceleration levels of 7 G(z) or higher.
A statistical investigation of the mass discrepancy-acceleration relation
NASA Astrophysics Data System (ADS)
Desmond, Harry
2017-02-01
We use the mass discrepancy-acceleration relation (the correlation between the ratio of total-to-visible mass and acceleration in galaxies; MDAR) to test the galaxy-halo connection. We analyse the MDAR using a set of 16 statistics that quantify its four most important features: shape, scatter, the presence of a `characteristic acceleration scale', and the correlation of its residuals with other galaxy properties. We construct an empirical framework for the galaxy-halo connection in LCDM to generate predictions for these statistics, starting with conventional correlations (halo abundance matching; AM) and introducing more where required. Comparing to the SPARC data, we find that: (1) the approximate shape of the MDAR is readily reproduced by AM, and there is no evidence that the acceleration at which dark matter becomes negligible has less spread in the data than in AM mocks; (2) even under conservative assumptions, AM significantly overpredicts the scatter in the relation and its normalization at low acceleration, and furthermore positions dark matter too close to galaxies' centres on average; (3) the MDAR affords 2σ evidence for an anticorrelation of galaxy size and Hubble type with halo mass or concentration at fixed stellar mass. Our analysis lays the groundwork for a bottom-up determination of the galaxy-halo connection from relations such as the MDAR, provides concrete statistical tests for specific galaxy formation models, and brings into sharper focus the relative evidence accorded by galaxy kinematics to LCDM and modified gravity alternatives.
NASA Astrophysics Data System (ADS)
McGrady, John; Scenini, Fabio; Duff, Jonathan; Stevens, Nicholas; Cassineri, Stefano; Curioni, Michele; Banks, Andrew
2017-09-01
The deposition of CRUD (Chalk River Unidentified Deposit) in the primary circuit of a Pressurised Water Reactor (PWR) is known to preferentially occur in regions of the circuit where flow acceleration of coolant occurs. A micro-fluidic flow cell was used to recreate accelerated flow under simulated PWR conditions, by flowing water through a disc with a central micro-orifice. CRUD deposition was reproduced on the disc, and CRUD Build-Up Rates (BUR) in various regions of the disc were analysed. The effect of the local environment on BUR was investigated. In particular, the effect of flow velocity, specimen material and Fe concentration were considered. The morphology and composition of the deposits were analysed with respect to experimental conditions. The BUR of CRUD was found to be sensitive to flow velocity and Fe concentration, suggesting that mass transfer is an important factor. The morphology of the deposit was affected by the specimen material indicating a dependence on surface/particle electrostatics meaning surface chemistry plays an important role in deposition. The preferential deposition of CRUD in accelerated flow regions due to electrokinetic effects was observed and it was shown that higher Fe concentrations in solution increased BURs within the orifice whereas increased flow velocity reduced BURs.
M1-like macrophages change tumor blood vessels and microenvironment in murine melanoma
Kamińska, Natalia; Matuszczak, Sybilla; Cichoń, Tomasz; Pamuła-Piłat, Jolanta; Czapla, Justyna; Smolarczyk, Ryszard; Skwarzyńska, Daria; Kulik, Klaudia; Szala, Stanisław
2018-01-01
Tumor-associated macrophages (TAMs) play a significant role in at least two key processes underlying neoplastic progression: angiogenesis and immune surveillance. TAMs phenotypic changes play important role in tumor vessel abnormalization/ normalization. M2-like TAMs stimulate immunosuppression and formation of defective tumor blood vessels leading to tumor progression. In contrast M1-like TAMs trigger immune response and normalize irregular tumor vascular network which should sensitize cancer cells to chemo- and radiotherapy and lead to tumor growth regression. Here, we demonstrated that combination of endoglin-based DNA vaccine with interleukin 12 repolarizes TAMs from tumor growth-promoting M2-like phenotype to tumor growth-inhibiting M1-like phenotype. Combined therapy enhances tumor infiltration by CD4+, CD8+ lymphocytes and NK cells. Depletion of TAMs as well as CD8+ lymphocytes and NK cells, but not CD4+ lymphocytes, reduces the effect of combined therapy. Furthermore, combined therapy improves tumor vessel maturation, perfusion and reduces hypoxia. It caused that suboptimal doses of doxorubicin reduced the growth of tumors in mice treated with combined therapy. To summarize, combination of antiangiogenic drug and immunostimulatory agent repolarizes TAMs phenotype from M2-like (pro-tumor) into M1-like (anti-tumor) which affects the structure of tumor blood vessels, improves the effect of chemotherapy and leads to tumor growth regression. PMID:29320562
Optimal Lorentz-augmented spacecraft formation flying in elliptic orbits
NASA Astrophysics Data System (ADS)
Huang, Xu; Yan, Ye; Zhou, Yang
2015-06-01
An electrostatically charged spacecraft accelerates as it moves through the Earth's magnetic field due to the induced Lorentz force, providing a new means of propellantless electromagnetic propulsion for orbital maneuvers. The feasibility of Lorentz-augmented spacecraft formation flying in elliptic orbits is investigated in this paper. Assuming the Earth's magnetic field as a tilted dipole corotating with Earth, a nonlinear dynamical model that characterizes the orbital motion of Lorentz spacecraft in the vicinity of arbitrary elliptic orbits is developed. To establish a predetermined formation configuration at given terminal time, pseudospectral method is used to solve the optimal open-loop trajectories of hybrid control inputs consisted of Lorentz acceleration and thruster-generated control acceleration. A nontilted dipole model is also introduced to analyze the effect of dipole tilt angle via comparisons with the tilted one. Meanwhile, to guarantee finite-time convergence and system robustness against external perturbations, a continuous fast nonsingular terminal sliding mode controller is designed and the closed-loop system stability is proved by Lyapunov theory. Numerical simulations substantiate the validity of proposed open-loop and closed-loop control schemes, and the results indicate that an almost propellantless formation establishment can be achieved by choosing appropriate objective function in the pseudospectral method. Furthermore, compared to the nonsingular terminal sliding mode controller, the closed-loop controller presents superior convergence rate with only a bit more control effort. And the proposed controller can be applied in other Lorentz-augmented relative orbital control problems.
NASA Technical Reports Server (NTRS)
Doolittle, J H
1925-01-01
This work on accelerometry was done at McCook Field for the purpose of continuing the work done by other investigators and obtaining the accelerations which occur when a high-speed pursuit airplane is subjected to the more common maneuvers. The accelerations obtained in suddenly pulling out of a dive with well-balanced elevators are shown to be within 3 or 4 per cent of the theoretically possible accelerations. The maximum acceleration which a pilot can withstand depends upon the length of time the acceleration is continued. It is shown that he experiences no difficulty under the instantaneous accelerations as high as 7.8 G., but when under accelerations in excess of 4.5 G., continued for several seconds, he quickly loses his faculties.
Antibody induction directed against the tumor-associated MUC4 glycoprotein.
Cai, Hui; Palitzsch, Björn; Hartmann, Sebastian; Stergiou, Natascha; Kunz, Horst; Schmitt, Edgar; Westerlind, Ulrika
2015-04-13
Mucin glycoproteins are important diagnostic and therapeutic targets for cancer treatment. Although several strategies have been developed to explore anti-tumor vaccines based on MUC1 glycopeptides, only few studies have focused on vaccines directed against the tumor-associated MUC4 glycoprotein. MUC4 is an important tumor marker overexpressed in lung cancer and uniquely expressed in pancreatic ductual adenocarcinoma. The aberrant glycosylation of MUC4 in tumor cells results in an exposure of its peptide backbone and the formation of tumor-associated glycopeptide antigens. Due to the low immunogenicity of these endogenous structures, their conjugation with immune stimulating peptide or protein carriers are required. In this study, MUC4 tandem-repeat glycopeptides were conjugated to the tetanus toxoid and used for vaccination of mice. Immunological evaluations showed that our MUC4-based vaccines induced very strong antigen-specific immune responses. In addition, antibody binding epitope analysis on glycopeptide microarrays, were demonstrating a clear glycosylation site dependence of the induced antibodies. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hauptman, Jason S., E-mail: jhauptman@mednet.ucla.edu; Barkhoudarian, Garni; Safaee, Michael
2012-06-01
Purpose: Intracranial chordomas and chondrosarcomas are histologically low-grade, locally invasive tumors that infiltrate the skull base. Currently, consensus therapy includes surgical resection and adjuvant radiotherapy. Radiation delivery is typically limited by the proximity of these tumors to critical skull base structures. Methods: This is a retrospective review of 13 cases of chordomas and 2 cases of chondroid chondrosarcomas of the skull based treated with linear accelerator stereotactic radiotherapy (SRT, n = 10) or stereotactic radiosurgery (SRS, n = 5). The average time to the most recent follow-up visit was 4.5 years. The tumor characteristics, treatment details, and outcomes were recorded.more » Each radiation plan was reviewed, and the dosage received by the brainstem, optic apparatus, and pituitary was calculated. Results: Of the 10 patients treated with SRT, 6 were found to have unchanged or decreased tumor size as determined from radiographic follow-up. Of the 5 patients treated with SRS, 3 were found to have stable or unchanged tumors at follow-up. The complications included 1 SRT patient who developed endocrinopathy, 2 patients (1 treated with SRS and the other with SRT), who developed cranial neuropathy, and 1 SRS patient who developed visual deficits. Additionally, 1 patient who received both SRS and SRT within 2 years for recurrence experienced transient medial temporal lobe radiation changes that resolved. Conclusions: Where proton beam therapy is unavailable, linear accelerator-based SRT or radiosurgery remains a safe option for adjuvant therapy of chordomas and chondrosarcomas of the skull base. The exposure of the optic apparatus, pituitary stalk, and brainstem must be considered during planning to minimize complications. If the optic apparatus is included in the 80% isodose line, it might be best to fractionate therapy. Exposure of the pituitary stalk should be kept to <30 Gy to minimize endocrine dysfunction. Brainstem exposure should
Electron dynamics in a plasma focus. [electron acceleration
NASA Technical Reports Server (NTRS)
Hohl, F.; Gary, S. P.; Winters, P. A.
1977-01-01
Results are presented of a numerical integration of the three-dimensional relativistic equations of motion of electrons subject to given electric and magnetic fields deduced from experiments. Fields due to two different models are investigated. For the first model, the fields are those due to a circular distribution of axial current filaments. As the current filaments collapse toward the axis, large azimuthal magnetic and axial electric fields are induced. These fields effectively heat the electrons to a temperature of approximately 8 keV and accelerate electrons within the radius of the filaments to high axial velocities. Similar results are obtained for the current-reduction phase of focus formation. For the second model, the fields are those due to a uniform current distribution. Both the current-reduction and the compression phases were studied. These is little heating or acceleration of electrons during the compression phase because the electrons are tied to the magnetic field. However, during the current-reduction phase, electrons near the axis are accelerated toward the center electrode and reach energies of 100 keV. A criterion is obtained which limits the runaway electron current to about 400 A.
Rainusso, N; Brawley, V S; Ghazi, A; Hicks, M J; Gottschalk, S; Rosen, J M; Ahmed, N
2012-03-01
Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes.
Clearance of phenylalanine ammonia-lyase from normal and tumor-bearing mice.
Shen, R S; Fritz, R R; Abell, C W
1977-04-01
Yeast phenylalanine ammonia-lyase was administered i.p. to normal and tumor-bearing mice, and its clearance from plasma was studied. Single and multiple weekly injections at dosages of 10,20,50 and 100 units/kg were administered to C57BL female, C57BL X DBA/2F1 male, and A/J female mice. L5178Y murine lymphoblastic leukemia, B16 melanoma, BW10232 adenocarcinoma, and 15091A anaplastic carcinoma were implanted 7 to 11 days prior to enzyme injection in the appropriate host. After a single injection, the average plasma half-lives of phenylalanine ammonia-lyase were 18 to 24 hr in all groups studied. While the other tumors had no effect on the plasma level of phenylalanine ammonia-lyase after a single injection, L5178Y murine lymphoblastic leukemia and 15091A anaplastic carcinoma significantly depressed the maximal level of phenylalanine ammonia-lyase attained in the plasma. After repeated injections of phenylalanine ammonia-lyase, the initial plasma enzyme level was significantly reduced when 20 units/kg were administered, and the clearance of the enzyme from the plasma was greatly accelerated regardless of the amount administered. Furthermore, in tumor-bearing mice, the rate of clearance was significantly more rapid than in the appropriate non-tumor-bearing control.
An accelerator-based Boron Neutron Capture Therapy (BNCT) facility based on the 7Li(p,n)7Be
NASA Astrophysics Data System (ADS)
Musacchio González, Elizabeth; Martín Hernández, Guido
2017-09-01
BNCT (Boron Neutron Capture Therapy) is a therapeutic modality used to irradiate tumors cells previously loaded with the stable isotope 10B, with thermal or epithermal neutrons. This technique is capable of delivering a high dose to the tumor cells while the healthy surrounding tissue receive a much lower dose depending on the 10B biodistribution. In this study, therapeutic gain and tumor dose per target power, as parameters to evaluate the treatment quality, were calculated. The common neutron-producing reaction 7Li(p,n)7Be for accelerator-based BNCT, having a reaction threshold of 1880.4 keV, was considered as the primary source of neutrons. Energies near the reaction threshold for deep-seated brain tumors were employed. These calculations were performed with the Monte Carlo N-Particle (MCNP) code. A simple but effective beam shaping assembly (BSA) was calculated producing a high therapeutic gain compared to previously proposed facilities with the same nuclear reaction.
CD34 EXPRESSION BY HAIR FOLLICLE STEM CELLS IS REQUIRED FOR SKIN TUMOR DEVELOPMENT IN MICE
We used knockout mice to show that a cell surface protein called CD34 is required for skin tumor formation in mice. Wild type mice treated with 7-12-Dimethylbenz(a)anthracene (DMBA) and a tumor promoter developed papillomas. When we treated CD34 knockout (KO) mice the same way, n...
Land use, macroalgae, and a tumor-forming disease in marine turtles.
Van Houtan, Kyle S; Hargrove, Stacy K; Balazs, George H
2010-09-29
Wildlife diseases are an increasing concern for endangered species conservation, but their occurrence, causes, and human influences are often unknown. We analyzed 3,939 records of stranded Hawaiian green sea turtles (Chelonia mydas) over 28 years to understand fibropapillomatosis, a tumor-forming disease linked to a herpesvirus. Turtle size is a consistent risk factor and size-standardized models revealed considerable spatial and temporal variability. The disease peaked in some areas in the 1990s, in some regions rates remained constant, and elsewhere rates increased. Land use, onshore of where the turtles feed, may play a role. Elevated disease rates were clustered in watersheds with high nitrogen-footprints; an index of natural and anthropogenic factors that affect coastal eutrophication. Further analysis shows strong epidemiological links between disease rates, nitrogen-footprints, and invasive macroalgae and points to foraging ecology. These turtles now forage on invasive macroalgae, which can dominate nutrient rich waters and sequester environmental N in the amino acid arginine. Arginine is known to regulate immune activity, promote herpesviruses, and contribute to tumor formation. Our results have implications for understanding diseases in aquatic organisms, eutrophication, herpesviruses, and tumor formation.
Land Use, Macroalgae, and a Tumor-Forming Disease in Marine Turtles
Van Houtan, Kyle S.; Hargrove, Stacy K.; Balazs, George H.
2010-01-01
Wildlife diseases are an increasing concern for endangered species conservation, but their occurrence, causes, and human influences are often unknown. We analyzed 3,939 records of stranded Hawaiian green sea turtles (Chelonia mydas) over 28 years to understand fibropapillomatosis, a tumor-forming disease linked to a herpesvirus. Turtle size is a consistent risk factor and size-standardized models revealed considerable spatial and temporal variability. The disease peaked in some areas in the 1990s, in some regions rates remained constant, and elsewhere rates increased. Land use, onshore of where the turtles feed, may play a role. Elevated disease rates were clustered in watersheds with high nitrogen-footprints; an index of natural and anthropogenic factors that affect coastal eutrophication. Further analysis shows strong epidemiological links between disease rates, nitrogen-footprints, and invasive macroalgae and points to foraging ecology. These turtles now forage on invasive macroalgae, which can dominate nutrient rich waters and sequester environmental N in the amino acid arginine. Arginine is known to regulate immune activity, promote herpesviruses, and contribute to tumor formation. Our results have implications for understanding diseases in aquatic organisms, eutrophication, herpesviruses, and tumor formation. PMID:20927370
Stat3-induced S1PR1 expression is critical for persistent Stat3 activation in tumors
Lee, Heehyoung; Deng, Jiehui; Kujawski, Maciej; Yang, Chunmei; Liu, Yong; Herrmann, Andreas; Kortylewski, Marcin; Horne, David; Somlo, George; Forman, Stephen; Jove, Richard; Yu, Hua
2011-01-01
IL-6/Jak2 signaling is viewed critical for persistent Stat3 activation in cancer. However, IL-6-induced Stat3 activity is transient in normal physiology. Here we identify a mechanism important for persistent Stat3 activation in tumor cells and the tumor microenvironment. We show that sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor for lysophospholipid sphingosine-1-phosphate (S1P), is elevated in Stat3-positive tumors. Stat3 is a transcription factor for the S1pr1 gene. Enhanced S1pr1 expression activates Stat3 and upregulates Il6 gene expression, thereby accelerating tumor growth and metastasis. Conversely, silencing S1pr1 in tumor cells or immune cells inhibits tumor Stat3 activity, tumor growth and metastasis. S1P/S1PR1-induced Stat3 activation is persistent, in contrast to transient Stat3 activation by IL-6. S1PR1 activates Stat3 in part by upregulating Jak2 tyrosine kinase activity. We demonstrate that Stat3-induced S1pr1 expression, as well as S1P/S1PR1 pathway, is important for persistent Stat3 activation in cancer cells and the tumor microenvironment and for malignant progression. PMID:21102457
Waugh, Katherine A.; Leach, Sonia M.; Moore, Brandon L.; Bruno, Tullia C.; Buhrman, Jonathan D.; Slansky, Jill E.
2016-01-01
Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first “molecular profile” of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells. PMID:27371726
Grange, Cristina; Tapparo, Marta; Collino, Federica; Vitillo, Loriana; Damasco, Christian; Deregibus, Maria Chiara; Tetta, Ciro; Bussolati, Benedetta; Camussi, Giovanni
2011-08-01
Recent studies suggest that tumor-derived microvesicles (MV) act as a vehicle for exchange of genetic information between tumor and stromal cells, engendering a favorable microenvironment for cancer development. Within the tumor mass, all cell types may contribute to MV shedding, but specific contributions to tumor progression have yet to be established. Here we report that a subset of tumor-initiating cells expressing the mesenchymal stem cell marker CD105 in human renal cell carcinoma releases MVs that trigger angiogenesis and promote the formation of a premetastatic niche. MVs derived only from CD105-positive cancer stem cells conferred an activated angiogenic phenotype to normal human endothelial cells, stimulating their growth and vessel formation after in vivo implantation in immunocompromised severe combined immunodeficient (SCID) mice. Furthermore, treating SCID mice with MVs shed from CD105-positive cells greatly enhanced lung metastases induced by i.v. injection of renal carcinoma cells. Molecular characterization of CD105-positive MVs defines a set of proangiogenic mRNAs and microRNAs implicated in tumor progression and metastases. Our results define a specific source of cancer stem cell-derived MVs that contribute to triggering the angiogenic switch and coordinating metastatic diffusion during tumor progression.
[Disorders of endocrine function after brain tumor therapy in childhood].
Marx, M; Langer, T; Beck, J D; Dörr, H G
1999-07-01
Advances in the therapy of malignant brain tumors in children have led to a significant improvement in survival rates over the last few decades. As a result, the recognition and treatment of late effects have become more important. In addition to secondary tumors and deficiencies in cognitive and intellectual skills, the resulting endocrine disturbances play an important role. Own data and literature review. Deviations from the normal growth hormone secretion are usually recognized first and are most common, and have already been observed after conventional whole brain irradiation with 18 Gy. With some delay, other hypothalamo-pituitary deficiencies may occur, including panhypopituitarism. Puberty may come too early or too late or may not appear at all. Girls in particular, frequently experience an early and rapid pubertal development after brain tumor therapy, which may lead to further reduction in height due to an accelerated bone maturation. Functional disturbances of the thyroid and adrenal glands due to hypothalamic or pituitary deficiency are less common, and usually seen only after a radiation dose of over 40 Gy. Survivors of childhood brain tumors must be considered as long-term survivors, in whom the first therapy-induced long-term side effects appear almost immediately after the end of therapy. Maximum quality of life for the individual patient can only be achieved by long-term care and close cooperation of specialists in the different medical disciplines involved.
The hormone prolactin (PRL) plays a critical role in normal breast development by stimulating the proliferation of mammary cells, the production of milk proteins, and the formation of new mammary blood vessels. Unfortunately, the same cell and vessel growth pathways controlled by PRL in normal cells also operate in breast cancer cells, and elevated plasma PRL is a risk factor for breast cancer, especially in post-menopausal women.
The Krebs cycle is part of the complex process where cells turn food into energy. One of the elements of the Krebs cycle is succinate dehydrogenase (SDH). Loss of SDH activity in cells has been linked to tumor formation. This new trial is studying guadecitabine for tumors associated with Krebs cycle dysfunction. Learn more...
Micro-Bubble Experiments at the Van de Graaff Accelerator
DOE Office of Scientific and Technical Information (OSTI.GOV)
Sun, Z. J.; Wardle, Kent E.; Quigley, K. J.
In order to test and verify the experimental designs at the linear accelerator (LINAC), several micro-scale bubble ("micro-bubble") experiments were conducted with the 3-MeV Van de Graaff (VDG) electron accelerator. The experimental setups included a square quartz tube, sodium bisulfate solution with different concentrations, cooling coils, gas chromatography (GC) system, raster magnets, and two high-resolution cameras that were controlled by a LabVIEW program. Different beam currents were applied in the VDG irradiation. Bubble generation (radiolysis), thermal expansion, thermal convection, and radiation damage were observed in the experiments. Photographs, videos, and gas formation (O 2 + H 2) data were collected.more » The micro-bubble experiments at VDG indicate that the design of the full-scale bubble experiments at the LINAC is reasonable.« less
On the modulation of the Jovian decametric radiation by Io. I - Acceleration of charged particles
NASA Technical Reports Server (NTRS)
Smith, R. A.; Goertz, C. K.
1978-01-01
A steady-state analysis of the current circuit between Io and the Jovian ionosphere is performed, assuming that the current is carried by electrons accelerated through potential double layers in the Io flux tube. The circuit analysis indicates that electrons may be accelerated up to energies of several hundred keV. Several problems associated with the formation of double layers are also discussed. The parallel potential drops decouple the flux tube from the satellite's orbital motion.
NASA Technical Reports Server (NTRS)
Foster, John E.
2004-01-01
A plasma accelerator has been conceived for both material-processing and spacecraft-propulsion applications. This accelerator generates and accelerates ions within a very small volume. Because of its compactness, this accelerator could be nearly ideal for primary or station-keeping propulsion for spacecraft having masses between 1 and 20 kg. Because this accelerator is designed to generate beams of ions having energies between 50 and 200 eV, it could also be used for surface modification or activation of thin films.
Greenaway, James; Henkin, Jack; Lawler, Jack; Moorehead, Roger; Petrik, Jim
2009-01-01
Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.
Microelectromechanical acceleration-sensing apparatus
Lee, Robb M [Albuquerque, NM; Shul, Randy J [Albuquerque, NM; Polosky, Marc A [Albuquerque, NM; Hoke, Darren A [Albuquerque, NM; Vernon, George E [Rio Rancho, NM
2006-12-12
An acceleration-sensing apparatus is disclosed which includes a moveable shuttle (i.e. a suspended mass) and a latch for capturing and holding the shuttle when an acceleration event is sensed above a predetermined threshold level. The acceleration-sensing apparatus provides a switch closure upon sensing the acceleration event and remains latched in place thereafter. Examples of the acceleration-sensing apparatus are provided which are responsive to an acceleration component in a single direction (i.e. a single-sided device) or to two oppositely-directed acceleration components (i.e. a dual-sided device). A two-stage acceleration-sensing apparatus is also disclosed which can sense two acceleration events separated in time. The acceleration-sensing apparatus of the present invention has applications, for example, in an automotive airbag deployment system.
SHORT ACCELERATION TIMES FROM SUPERDIFFUSIVE SHOCK ACCELERATION IN THE HELIOSPHERE
DOE Office of Scientific and Technical Information (OSTI.GOV)
Perri, S.; Zimbardo, G., E-mail: silvia.perri@fis.unical.it
2015-12-10
The analysis of time profiles of particles accelerated at interplanetary shocks allows particle transport properties to be inferred. The frequently observed power-law decay upstream, indeed, implies a superdiffusive particle transport when the level of magnetic field variance does not change as the time interval from the shock front increases. In this context, a superdiffusive shock acceleration (SSA) theory has been developed, allowing us to make predictions of the acceleration times. In this work we estimate for a number of interplanetary shocks, including the solar wind termination shock, the acceleration times for energetic protons in the framework of SSA and wemore » compare the results with the acceleration times predicted by standard diffusive shock acceleration. The acceleration times due to SSA are found to be much shorter than in the classical model, and also shorter than the interplanetary shock lifetimes. This decrease of the acceleration times is due to the scale-free nature of the particle displacements in the framework of superdiffusion. Indeed, very long displacements are possible, increasing the probability for particles far from the front of the shock to return, and short displacements have a high probability of occurrence, increasing the chances for particles close to the front to cross the shock many times.« less
Ovarian Brenner tumors and Walthard nests: a histologic and immunohistochemical study.
Roma, Andres A; Masand, Ramya P
2014-12-01
Brenner tumors are composed of urothelial/transitional-type epithelium and, hence, are morphologically similar to Walthard nests and tubal/mesothelial transitional metaplasia. In this study, we analyzed immunohistochemical markers on Brenner tumors to explore Müllerian as well as Wolffian and germ cell derivation. We also attempted to explore their possible association with tubal/paratubal Walthard nests/transitional metaplasia, using the same immunostains. Thirty-two consecutive cases of Brenner tumors were identified. Thirteen (43%) of the patients had Walthard nests in the tubal/periovarian soft tissue. All Brenner tumors were diffusely positive for GATA3 (strongly positive in 30/32 and weakly positive in the remaining 2) and negative for PAX8, PAX2, and SALL4. Similarly, all Walthard nests were positive for GATA3, whereas only 3 (23%) of 13 showed occasional PAX8 expression; all were negative for PAX2 and SALL4. In our study, more than 40% of Brenner tumors had associated Walthard nests. The similar morphology and immunoprofile of Brenner tumors and Walthard nests suggest a probable link between Brenner tumors and Walthard nests. Two additional cases presented highlight small transitional lesions involving the ovary: a possible precursor lesion or the initial steps of Brenner tumor formation. Brenner tumors and most Walthard nests lacked staining for Müllerian (PAX8 and PAX2) and germ cell tumor markers (SALL4). Copyright © 2014 Elsevier Inc. All rights reserved.
Integrative models of vascular remodeling during tumor growth
Rieger, Heiko; Welter, Michael
2015-01-01
Malignant solid tumors recruit the blood vessel network of the host tissue for nutrient supply, continuous growth, and gain of metastatic potential. Angiogenesis (the formation of new blood vessels), vessel cooption (the integration of existing blood vessels into the tumor vasculature), and vessel regression remodel the healthy vascular network into a tumor-specific vasculature that is in many respects different from the hierarchically organized arterio-venous blood vessel network of the host tissues. Integrative models based on detailed experimental data and physical laws implement in silico the complex interplay of molecular pathways, cell proliferation, migration, and death, tissue microenvironment, mechanical and hydrodynamic forces, and the fine structure of the host tissue vasculature. With the help of computer simulations high-precision information about blood flow patterns, interstitial fluid flow, drug distribution, oxygen and nutrient distribution can be obtained and a plethora of therapeutic protocols can be tested before clinical trials. In this review, we give an overview over the current status of integrative models describing tumor growth, vascular remodeling, blood and interstitial fluid flow, drug delivery, and concomitant transformations of the microenvironment. © 2015 The Authors. WIREs Systems Biology and Medicine published by Wiley Periodicals, Inc. PMID:25808551
Immunoconjugates against solid tumors: mind the gap.
Ricart, A D
2011-04-01
The objective of immunoconjugate development is to combine the specificity of immunoglobulins with the efficacy of cytotoxic molecules. This therapeutic approach has been validated in hematologic malignancies; however, several obstacles to achieving efficacy in treating solid tumors have been identified. These include insufficient specificity of targets and poor antibody delivery, most specifically to the tumor core. Heterogeneous antigen expression, imperfect vascular supply, and elevated interstitial fluid pressure have been suggested as the factors responsible for the poor delivery of antibodies. Promising immunoconjugates are in development: immunoconjugates targeting the prostate-specific membrane antigen, trastuzumab-DM1, lorvotuzumab mertansine, and SS1P. Advances in cancer biology and antibody engineering may overcome some of the challenges. New small antibody formats, such as single-chain Fv, Fab, and diabodies, may improve penetration within tumor masses. Nevertheless, the cost of treatment might require justification in terms of demonstrable improvement in quality of life in addition to efficacy; further economic evaluation might be necessary before this approach can replace the current standards of care in clinical practice.
DOE Office of Scientific and Technical Information (OSTI.GOV)
Hasti, D.E.; Ramirez, J.J.; Coleman, P.D.
1985-01-01
The Megamp Accelerator and Beam Experiment (MABE) was the technology development testbed for the multiple beam, linear induction accelerator approach for Hermes III, a new 20 MeV, 0.8 MA, 40 ns accelerator being developed at Sandia for gamma-ray simulation. Experimental studies of a high-current, single-beam accelerator (8 MeV, 80 kA), and a nine-beam injector (1.4 MeV, 25 kA/beam) have been completed, and experiments on a nine-beam linear induction accelerator are in progress. A two-beam linear induction accelerator is designed and will be built as a gamma-ray simulator to be used in parallel with Hermes III. The MABE pulsed power systemmore » and accelerator for the multiple beam experiments is described. Results from these experiments and the two-beam design are discussed. 11 refs., 6 figs.« less