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Sample records for accelerated tumor formation

  1. [Tumor formation in plants].

    PubMed

    Matveeva, T V; Lutova, L A; Nester, Iu

    2001-09-01

    The data on genetic tumors in plant species and interspecific hybrids, as well as the problems of Agrobacterium-induced tumors are reviewed. The role of the horizontal gene transfer in the induction of genetic tumors is discussed. PMID:11642121

  2. Tumor formations in scleractinian corals

    NASA Astrophysics Data System (ADS)

    Loya, Y.; Bull, G.; Pichon, M.

    1984-03-01

    A highly localized incidence of skeletal malformations (tumors) in the scleractinian corals Platygyra pini and P. sinensis on an inshore fringing reef at Cockle Bay, Magnetic Island within the Great Barrier Reef province is reported. These tumors are typified by a localized area of increased growth rate resulting in roughly circular protuberances extending up to 4.5 cm above the colony's surface. In both species, similar proportions of their populations carried tumors (24.1 % in P. pini and 18.7 % in P. sinensis). Larger colonies (>80 cm in diameter) are at least 7 times more likely to possess tumors than smaller colonies (<40 cm in diameter). X-radiographs of the skeletal malformations indicate a point of origin, presumably from a single budded polyp with subsequent, localized, accelerated growth. The mean radial growth rate of the tumorous area was 29 % greater than that of the surrounding normal regions. In contrast to the normal tissue, the tumorous tissue exhibited proliferation of cells, atrophied gastrodermal cells and mesenterial filaments which were larger and disordered in structure. The environmental conditions at Cockle Bay are relatively extreme with high turbidity, periodic exposure of the reef flat, abrupt changes in salinity during the wet season and mechanical damage to corals caused by unpredictable cyclonic storms. It is suggested that a combination of environmental stresses coupled with an injury inflicted on the corals are possible stimuli that initiate the development of these abnormal growth through either bacterial attack or the development of an aberrant polyp during tissue repair.

  3. Impaired capsule formation of tumors in periostin-null mice

    SciTech Connect

    Shimazaki, Masashi; Kudo, Akira

    2008-03-21

    Being a secreted protein, periostin is a multifunctional matricellular glycoprotein. In vitro, periostin has the ability to promote the proliferation and migration of fibroblasts. Previously, it was demonstrated that periostin is mainly produced by cancer-associated fibroblasts or tumor stromal cells. In the present study, we show that periostin regulates capsule formation in a positive manner and inhibits tumor growth. Consistent with a previous finding, several tumor cell lines did not exhibit expression of periostin in vitro or in vivo; and the growth of tumors that had been allografted into periostin -/- mice was significantly accelerated compared with that of the same kind of tumors grafted into periostin +/+ mice. Immunostaining and biochemical analyses revealed that mature collagen was detected abundantly in the capsules and interstitium of the wild-type-grafted tumors but not in those of the periostin -/- grafted tumors. Moreover, the number of activated tumor stromal cells was decreased significantly in the periostin -/- grafted tumors. Our studies suggest that host-derived periostin negatively regulates tumor growth by promoting capsule formation and by mediating changes in the deposition and organization of the tumor microenvironment coordinated by periostin-producing stromal cells.

  4. Propane Clathrate Hydrate Formation Accelerated by Methanol.

    PubMed

    Amtawong, Jaruwan; Guo, Jin; Hale, Jared S; Sengupta, Suvrajit; Fleischer, Everly B; Martin, Rachel W; Janda, Kenneth C

    2016-07-01

    The role of methanol as both an inhibitor and a catalyst for the formation of clathrate hydrates (CHs) has been a topic of intense study. We report a new quantitative study of the kinetics of propane CH formation at 253 K from the reaction of propane gas with <75 μm ice particles that have been doped with varying amounts of methanol. We find that methanol significantly accelerates the formation reaction with quite small doping quantities. Even for only 1 methanol molecule per 10 000 water molecules, the maximum uptake rate of propane into CHs is enhanced and the initiation pressure is reduced. These results enable more efficient production of CHs for gas storage. This remarkable acceleration of the CH formation reaction by small quantities of methanol may place constraints on the mechanism of the inhibition effect observed under other conditions, usually employing much larger quantities of methanol. PMID:27275862

  5. Carboxylic acid accelerated formation of diesters

    DOEpatents

    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.

  6. Carboxylic acid accelerated formation of diesters

    DOEpatents

    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.

  7. Wnt5a Suppresses Tumor Formation and Redirects Tumor Phenotype in MMTV-Wnt1 Tumors

    PubMed Central

    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. PMID:25401739

  8. Wnt5a suppresses tumor formation and redirects tumor phenotype in MMTV-Wnt1 tumors.

    PubMed

    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.

  9. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

    PubMed

    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.

  10. NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

    PubMed

    Wang, Hui; Liu, Xiufei; Long, Min; Huang, Yi; Zhang, Linlin; Zhang, Rui; Zheng, Yi; Liao, Xiaoyu; Wang, Yuren; Liao, Qian; Li, Wenjie; Tang, Zili; Tong, Qiang; Wang, Xiaocui; Fang, Fang; Rojo de la Vega, Montserrat; Ouyang, Qin; Zhang, Donna D; Yu, Shicang; Zheng, Hongting

    2016-04-13

    Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis. PMID:27075625

  11. Becoming a nurse: role formation among accelerated baccalaureate students.

    PubMed

    Ostrogorsky, Tanya L; Raber, Anjanette M; McKinley Yoder, Claire; Nielsen, Ann E; Lutz, Kristin F; Wros, Peggy L

    2015-01-01

    To understand nursing role formation for students enrolled in an accelerated baccalaureate nursing program, end-of-term narrative reflections from 34 students were analyzed over the course of the 15-month program. Using thematic analysis, 4 major themes were identified: evolving role perception, extending nursing student-patient interaction, engaging with health care team and systems of care, and expanding clinical thinking.

  12. Formation and Acceleration Physics on Plasma Injector 1

    NASA Astrophysics Data System (ADS)

    Howard, Stephen

    2012-10-01

    Plasma Injector 1 (PI-1) is a two stage coaxial Marshal gun with conical accelerator electrodes, similar in shape to the MARAUDER device, with power input of the same topology as the RACE device. The goal of PI-1 research is to produce a self-confined compact toroid with high-flux (200 mWb), high-density (3x10^16 cm-3) and moderate initial temperature (100 eV) to be used as the target plasma in a MTF reactor. PI-1 is 5 meters long and 1.9 m in diameter at the expansion region where a high aspect ratio (4.4) spheromak is formed with a minimum lambda of 9 m-1. The acceleration stage is 4 m long and tapers to an outer diameter of 40 cm. The capacitor banks store 0.5 MJ for formation and 1.13 MJ for acceleration. Power is delivered via 62 independently controlled switch modules. Several geometries for formation bias field, inner electrodes and target chamber have been tested, and trends in accelerator efficiency and target lifetime have been observed. Thomson scattering and ion Doppler spectroscopy show significant heating (>100 eV) as the CT is compressed in the conical accelerator. B-dot probes show magnetic field structure consistent with Grad-Shafranov models and MHD simulations, and CT axial length depends strongly on the lambda profile.

  13. Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors.

    PubMed

    Bondarenko, Gennadiy; Ugolkov, Andrey; Rohan, Stephen; Kulesza, Piotr; Dubrovskyi, Oleksii; Gursel, Demirkan; Mathews, Jeremy; O'Halloran, Thomas V; Wei, Jian J; Mazar, Andrew P

    2015-09-01

    Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients' personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients' samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers. PMID:26476081

  14. Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors1

    PubMed Central

    Bondarenko, Gennadiy; Ugolkov, Andrey; Rohan, Stephen; Kulesza, Piotr; Dubrovskyi, Oleksii; Gursel, Demirkan; Mathews, Jeremy; O’Halloran, Thomas V.; Wei, Jian J.; Mazar, Andrew P.

    2015-01-01

    Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients’ personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients’ samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers. PMID:26476081

  15. Patient-Derived Tumor Xenografts Are Susceptible to Formation of Human Lymphocytic Tumors.

    PubMed

    Bondarenko, Gennadiy; Ugolkov, Andrey; Rohan, Stephen; Kulesza, Piotr; Dubrovskyi, Oleksii; Gursel, Demirkan; Mathews, Jeremy; O'Halloran, Thomas V; Wei, Jian J; Mazar, Andrew P

    2015-09-01

    Patient-derived xenograft (PDX) tumor models have emerged as a new approach to evaluate the effects of cancer drugs on patients' personalized tumor grafts enabling to select the best treatment for the cancer patient and providing a new tool for oncology drug developers. Here, we report that human tumors engrafted in immunodeficient mice are susceptible to formation of B-and T-cell PDX tumors. We xenografted human primary and metastatic tumor samples into immunodeficient mice and found that a fraction of PDX tumors generated from patients' samples of breast, colon, pancreatic, bladder and renal cancer were histologically similar to lymphocytic neoplasms. Moreover, we found that the first passage of breast and pancreatic cancer PDX tumors after initial transplantation of the tumor pieces from the same human tumor graft could grow as a lymphocytic tumor in one mouse and as an adenocarcinoma in another mouse. Whereas subcutaneous PDX tumors resembling human adenocarcinoma histology were slow growing and non-metastatic, we found that subcutaneous PDX lymphocytic tumors were fast growing and formed large metastatic lesions in mouse lymph nodes, liver, lungs, and spleen. PDX lymphocytic tumors were comprised of B-cells which were Epstein-Barr virus positive and expressed CD45 and CD20. Because B-cells are typically present in malignant solid tumors, formation of B-cell tumor may evolve in a wide range of PDX tumor models. Although PDX tumor models show great promise in the development of personalized therapy for cancer patients, our results suggest that confidence in any given PDX tumor model requires careful screening of lymphocytic markers.

  16. Bax-deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation

    PubMed Central

    Garcia, Idoia; Crowther, Andrew J.; Gama, Vivian; Miller, C. Ryan; Deshmukh, Mohanish; Gershon, Timothy R.

    2012-01-01

    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 up-regulation 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. PMID:22710714

  17. Becoming a nurse: role formation among accelerated baccalaureate students.

    PubMed

    Ostrogorsky, Tanya L; Raber, Anjanette M; McKinley Yoder, Claire; Nielsen, Ann E; Lutz, Kristin F; Wros, Peggy L

    2015-01-01

    To understand nursing role formation for students enrolled in an accelerated baccalaureate nursing program, end-of-term narrative reflections from 34 students were analyzed over the course of the 15-month program. Using thematic analysis, 4 major themes were identified: evolving role perception, extending nursing student-patient interaction, engaging with health care team and systems of care, and expanding clinical thinking. PMID:25290964

  18. Air Plasma Formation in MHD Slipstream Accelerator for Mercury Lightcraft

    SciTech Connect

    Myrabo, L.N.; Raizer, Y.P.; Surzhikov, S.

    2004-03-30

    This paper investigates the physics of air plasma formation at the entrance of the MHD slipstream accelerator for the 'tractor-beam' Mercury Lightcraft. Two scenarios are analyzed. The first addresses the needs of the minimum power airspike assuming that all the power required for air plasma formation must come from the remote laser beam. The second case considers the constant-focus airspike and assumes that the breakdown criteria is satisfied by an on-board auxiliary source (e.g., electric discharge, RF source, microwave source, or E-beam)

  19. Air Plasma Formation in MHD Slipstream Accelerator for Mercury Lightcraft

    NASA Astrophysics Data System (ADS)

    Myrabo, L. N.; Raizer, Y. P.; Surzhikov, S.

    2004-03-01

    This paper investigates the physics of air plasma formation at the entrance of the MHD slipstream accelerator for the `tractor-beam' Mercury Lightcraft. Two scenarios are analyzed. The first addresses the needs of the minimum power airspike assuming that all the power required for air plasma formation must come from the remote laser beam. The second case considers the constant-focus airspike and assumes that the breakdown criteria is satisfied by an on-board auxiliary source (e.g., electric discharge, RF source, microwave source, or E-beam).

  20. Enhancement of lung tumor formation in mice

    SciTech Connect

    Witschi, H.P.

    1984-01-01

    There is now a great deal of data available to show that butylated hydroxytoluene (BHT) enhances the development of lung tumors in mice. In many ways BHT functions like a promoting agent. Interestingly, it also has tumor enhancing or promoting properties in organs other than mouse lung such as rat liver, rat bladder, possibly rat GI tract and in in vitro systems. The development of lung tumors by BHT may be influenced by comparatively low exposure regimens; the minimum dose found so far to be effective are 6 intraperitoneal injections of 50 mg/kg or a diet containing 500 ppM of BHT for 2 weeks. While these findings seem to require that the continued use of BHT as a food additive needs to be reevaluated it should be mentioned that other considerations have lead to the conclusion that BHT probably has a large margin of safety. This makes it important to establish the mechanism of action of BHT which remains unknown. 41 references, 1 figure, 3 tables.

  1. Solid-particle jet formation under shock-wave acceleration.

    PubMed

    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. PMID:24483561

  2. Solid-particle jet formation under shock-wave acceleration.

    PubMed

    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.

  3. Three mutant genes cooperatively induce brain tumor formation in Drosophila malignant brain tumor.

    PubMed

    Riede, I

    1996-09-01

    The Drosophila melanogaster strain Malignant Brain Tumor reveals temperature-sensitive transformation of the larval brain tissue. Genetic analysis shows that three gene defects, spzMBT, yetiMBT, and tldMBT, cooperatively induce brain tumor formation. Whereas spz and tld belong to the genes inducing differentiation patterns in the embryo, yeti induces cell overgrowth. spzMBT-, yetiMBT-, and tldMBT-containing animals are larval lethal, whereas Malignant Brain Tumor is kept as a homozygous strain at a permissive temperature. This reveals that this tumor-forming strain is the result of a number of adaptive mutation events.

  4. Learning formative skills of nursing practice in an accelerated program.

    PubMed

    McNiesh, Susan; Benner, Patricia; Chesla, Catherine

    2011-01-01

    The purpose of this qualitative research study was to describe how students in an accelerated master's degree entry program experientially learned the practice of nursing. One research question examined in this study was: What formative experiences did students identify as helping them develop and differentiate their clinical practice? Data from clinical observations and a combination of small group and individual interviews were collected and analyzed using interpretive phenomenological methods. Students identified formative skills learned through the independent care of a patient as pivotal in their identity and agency development. By experiencing the responsibility and action from within the body and from within concrete situations, students developed a new understanding that changed their embodied ways of perceiving and orienting to the situation, as well as their skills and sense of agency.

  5. The mechanisms by which polyamines accelerate tumor spread.

    PubMed

    Soda, Kuniyasu

    2011-10-11

    Increased polyamine concentrations in the blood and urine of cancer patients reflect the enhanced levels of polyamine synthesis in cancer tissues arising from increased activity of enzymes responsible for polyamine synthesis. In addition to their de novo polyamine synthesis, cells can take up polyamines from extracellular sources, such as cancer tissues, food, and intestinal microbiota. Because polyamines are indispensable for cell growth, increased polyamine availability enhances cell growth. However, the malignant potential of cancer is determined by its capability to invade to surrounding tissues and metastasize to distant organs. The mechanisms by which increased polyamine levels enhance the malignant potential of cancer cells and decrease anti-tumor immunity are reviewed. Cancer cells with a greater capability to synthesize polyamines are associated with increased production of proteinases, such as serine proteinase, matrix metalloproteinases, cathepsins, and plasminogen activator, which can degrade surrounding tissues. Although cancer tissues produce vascular growth factors, their deregulated growth induces hypoxia, which in turn enhances polyamine uptake by cancer cells to further augment cell migration and suppress CD44 expression. Increased polyamine uptake by immune cells also results in reduced cytokine production needed for anti-tumor activities and decreases expression of adhesion molecules involved in anti-tumor immunity, such as CD11a and CD56. Immune cells in an environment with increased polyamine levels lose anti-tumor immune functions, such as lymphokine activated killer activities. Recent investigations revealed that increased polyamine availability enhances the capability of cancer cells to invade and metastasize to new tissues while diminishing immune cells' anti-tumor immune functions.

  6. ADAM17 in tumor associated leukocytes regulates inflammatory mediators and promotes mammary tumor formation

    PubMed Central

    Chuntova, Pavlina; Brady, Nicholas J.; Witschen, Patrice M.; Kemp, Sarah E.; Nelson, Andrew C.; Walcheck, Bruce; Schwertfeger, Kathryn L.

    2016-01-01

    The presence of inflammatory cells within the tumor microenvironment has been tightly linked to mammary tumor formation and progression. Specifically, interactions between tumor cells and infiltrating macrophages can contribute to the generation of a pro-tumorigenic microenvironment. Understanding the complex mechanisms that drive tumor cell-macrophage cross-talk will ultimately lead to the development of approaches to prevent or treat early stage breast cancers. As described here, we demonstrate that the cell surface protease a disintegrin and metalloproteinase 17 (ADAM17) is expressed by macrophages in mammary tumors and contributes to regulating the expression of pro-inflammatory mediators, including inflammatory cytokines and the inflammatory mediator cyclooxygenase-2 (Cox-2). Furthermore, we demonstrate that ADAM17 is expressed on leukocytes, including macrophages, within polyoma middle T (PyMT)-derived mammary tumors. Genetic deletion of ADAM17 in leukocytes resulted in decreased onset of mammary tumor growth, which was associated with reduced expression of the Cox-2 within the tumor. These findings demonstrate that ADAM17 regulates key inflammatory mediators in macrophages and that leukocyte-specific ADAM17 is an important promoter of mammary tumor initiation. Understanding the mechanisms associated with early stage tumorigenesis has implications for the development of preventive and/or treatment strategies for early stage breast cancers.

  7. 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.

  8. Retention of Information Taught in Introductory Psychology Courses across Different Accelerated Course Formats

    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…

  9. Characterising the acceleration phase of blast wave formation

    SciTech Connect

    Fox, T. E. Pasley, J.; Robinson, A. P. L.; Schmitz, H.

    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 relation for this measure of the acceleration phase, preceding the establishment of the blast wave, is presented and confirmed using a 1D planar hydrodynamic model.

  10. Caveolin-1 and Accelerated Host Aging in the Breast Tumor Microenvironment

    PubMed Central

    Mercier, Isabelle; Camacho, Jeanette; Titchen, Kanani; Gonzales, Donna M.; Quann, Kevin; Bryant, Kelly G.; Molchansky, Alexander; Milliman, Janet N.; Whitaker-Menezes, Diana; Sotgia, Federica; Jasmin, Jean-François; Schwarting, Roland; Pestell, Richard G.; Blagosklonny, Mikhail V.; Lisanti, Michael P.

    2013-01-01

    Increasing chronological age is the most significant risk factor for human cancer development. To examine the effects of host aging on mammary tumor growth, we used caveolin (Cav)-1 knockout mice as a bona fide model of accelerated host aging. Mammary tumor cells were orthotopically implanted into these distinct microenvironments (Cav-1+/+ versus Cav-1−/− age-matched young female mice). Mammary tumors grown in a Cav-1–deficient tumor microenvironment have an increased stromal content, with vimentin-positive myofibroblasts (a marker associated with oxidative stress) that are also positive for S6-kinase activation (a marker associated with aging). Mammary tumors grown in a Cav-1–deficient tumor microenvironment were more than fivefold larger than tumors grown in a wild-type microenvironment. Thus, a Cav-1–deficient tumor microenvironment provides a fertile soil for breast cancer tumor growth. Interestingly, the mammary tumor-promoting effects of a Cav-1–deficient microenvironment were estrogen and progesterone independent. In this context, chemoprevention was achieved by using the mammalian target of rapamycin (mTOR) inhibitor and anti-aging drug, rapamycin. Systemic rapamycin treatment of mammary tumors grown in a Cav-1–deficient microenvironment significantly inhibited their tumor growth, decreased their stromal content, and reduced the levels of both vimentin and phospho-S6 in Cav-1–deficient cancer-associated fibroblasts. Since stromal loss of Cav-1 is a marker of a lethal tumor microenvironment in breast tumors, these high-risk patients might benefit from treatment with mTOR inhibitors, such as rapamycin or other rapamycin-related compounds (rapalogues). PMID:22698676

  11. Enhanced Tumor Formation in Mice Heterozygous for Blm Mutation

    NASA Astrophysics Data System (ADS)

    Heppner Goss, Kathleen; Risinger, Mary A.; Kordich, Jennifer J.; Sanz, Maureen M.; Straughen, Joel E.; Slovek, Lisa E.; Capobianco, Anthony J.; German, James; Boivin, Gregory P.; Groden, Joanna

    2002-09-01

    Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apctumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.

  12. Drosophila neural stem cells in brain development and tumor formation.

    PubMed

    Jiang, Yanrui; Reichert, Heinrich

    2014-01-01

    Neuroblasts, the neural stem cells in Drosophila, generate the complex neural structure of the central nervous system. Significant progress has been made in understanding the mechanisms regulating the self-renewal, proliferation, and differentiation in Drosophila neuroblast lineages. Deregulation of these mechanisms can lead to severe developmental defects and the formation of malignant brain tumors. Here, the authors review the molecular genetics of Drosophila neuroblasts and discuss some recent advances in stem cell and cancer biology using this model system.

  13. Survivin isoform Delta Ex3 regulates tumor spheroid formation.

    PubMed

    Espinosa, Magali; Ceballos-Cancino, Gisela; Callaghan, Richard; Maldonado, Vilma; Patiño, Nelly; Ruíz, Víctor; Meléndez-Zajgla, Jorge

    2012-05-01

    Survivin is an important member of the Inhibitor of Apoptosis Proteins (IAPs) family and has essential roles in apoptosis and cell cycle progression. This gene is commonly upregulated in human cancer and provides an exciting diagnostic and therapeutic target. Survivin is expressed as several isoforms that are generated by alternative splicing, and some of these present antagonistic activities. Currently, information regarding the regulation of these isoforms is lacking. In this study, we sought to analyze survivin Delta Ex3 expression in a three-dimensional model of avascular tumors and its overexpression effects in processes such as proliferation, clonogenicity and apoptosis. We found a positive correlation between spheroid growth and survivin Delta Ex3 expression during the exponential phase. We demonstrated that this isoform not only decreased apoptosis but also inhibited tumor spheroid formation by decreasing proliferation and clonogenic survival. These results point toward a dual and antagonistic effect of this spliced survivin isoform in cancer development.

  14. Accelerated tumor progression in mice lacking the ATP receptor P2X7.

    PubMed

    Adinolfi, Elena; Capece, Marina; Franceschini, Alessia; Falzoni, Simonetta; Giuliani, Anna L; Rotondo, Alessandra; Sarti, Alba C; Bonora, Massimo; Syberg, Susanne; Corigliano, Domenica; Pinton, Paolo; Jorgensen, Niklas R; Abelli, Luigi; Emionite, Laura; Raffaghello, Lizzia; Pistoia, Vito; Di Virgilio, Francesco

    2015-02-15

    The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma cells. Tumor size and metastatic dissemination were assessed by in vivo calliper and luciferase luminescence emission measurements along with postmortem examination. In P2X7R-deficient mice, tumor growth and metastatic spreading were accelerated strongly, compared with wild-type (wt) mice. Intratumoral IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth and metastatic diffusion. PMID:25542861

  15. Salivary gland anlage tumor. A case with widespread necrosis and large cyst formation.

    PubMed

    Michal, M; Sokol, L; Mukensnabl, P

    1996-05-01

    We describe a case of the salivary gland anlage tumor (congenital pleomorphic adenoma). The tumor arose in the nasopharynx as a pedunculated mass. Microscopically most of the tumor contained large necrotic areas which revealed squamous cell metaplasia resulting in the formation of large cysts. This feature has never been described previously in this tumor and might lead to an erroneous diagnosis.

  16. Tanshinon IIA Injection Accelerates Tissue Expansion by Reducing the Formation of the Fibrous Capsule

    PubMed Central

    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. PMID:25157742

  17. Accelerator-based epithermal neutron sources for boron neutron capture therapy of brain tumors.

    PubMed

    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

  18. Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation

    PubMed Central

    Ricke, Robin M.; Jeganathan, Karthik B.

    2011-01-01

    High expression of the protein kinase Bub1 has been observed in a variety of human tumors and often correlates with poor clinical prognosis, but its molecular and cellular consequences and role in tumorigenesis are unknown. Here, we demonstrate that overexpression of Bub1 in mice leads to near-diploid aneuploidies and tumor formation. We found that chromosome misalignment and lagging are the primary mitotic errors responsible for the observed aneuploidization. High Bub1 levels resulted in aberrant Bub1 kinase activity and hyperactivation of Aurora B kinase. When Aurora B activity is suppressed, pharmacologically or via BubR1 overexpression, chromosome segregation errors caused by Bub1 overexpression are largely corrected. Importantly, Bub1 transgenic mice overexpressing Bub1 developed various kinds of spontaneous tumors and showed accelerated Myc-induced lymphomagenesis. Our results establish that Bub1 has oncogenic properties and suggest that Aurora B is a critical target through which overexpressed Bub1 drives aneuploidization and tumorigenesis. PMID:21646403

  19. CLOUD FORMATION AND ACCELERATION IN A RADIATIVE ENVIRONMENT

    SciTech Connect

    Proga, Daniel; Waters, Tim

    2015-05-10

    In a radiatively heated and cooled medium, thermal instability (TI) is a plausible mechanism for forming clouds, while the radiation force provides a natural acceleration, especially when ions recombine and opacity increases. Here we extend Field’s theory to self-consistently account for a radiation force resulting from bound–free and bound–bound transitions in the optically thin limit. We present physical arguments for clouds to be significantly accelerated by a radiation force due to lines during a nonlinear phase of the instability. To qualitatively illustrate our main points, we perform both one- and two-dimensional (1D/2D) hydrodynamical simulations that allow us to study the nonlinear outcome of the evolution of thermally unstable gas subjected to this radiation force. Our 1D simulations demonstrate that the TI can produce long-lived clouds that reach a thermal equilibrium between radiative processes and thermal conduction, while the radiation force can indeed accelerate the clouds to supersonic velocities. However, our 2D simulations reveal that a single cloud with a simple morphology cannot be maintained due to destructive processes, triggered by the Rayleigh–Taylor instability and followed by the Kelvin–Helmholtz instability. Nevertheless, the resulting cold gas structures are still significantly accelerated before they are ultimately dispersed.

  20. Is IGSF1 involved in human pituitary tumor formation?

    PubMed

    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.

  1. Is IGSF1 involved in human pituitary tumor formation?

    PubMed Central

    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

  2. Is IGSF1 involved in human pituitary tumor formation?

    PubMed

    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. PMID:25527509

  3. Note: Numerical simulation and experimental validation of accelerating voltage formation for a pulsed electron accelerator

    SciTech Connect

    Egorov, I.

    2014-06-15

    This paper describes the development of a computation model of a pulsed voltage generator for a repetitive electron accelerator. The model is based on a principle circuit of the generator, supplemented with the parasitics elements of the construction. Verification of the principle model was achieved by comparison of simulation with experimental results, where reasonable agreement was demonstrated for a wide range of generator load resistance.

  4. Ion acceleration and plasma jet formation in ultra-thin foils undergoing expansion and relativistic transparency

    NASA Astrophysics Data System (ADS)

    King, M.; Gray, R. J.; Powell, H. W.; MacLellan, D. A.; Gonzalez-Izquierdo, B.; Stockhausen, L. C.; Hicks, G. S.; Dover, N. P.; Rusby, D. R.; Carroll, D. C.; Padda, H.; Torres, R.; Kar, S.; Clarke, R. J.; Musgrave, I. O.; Najmudin, Z.; Borghesi, M.; Neely, D.; McKenna, P.

    2016-09-01

    At sufficiently high laser intensities, the rapid heating to relativistic velocities and resulting decompression of plasma electrons in an ultra-thin target foil can result in the target becoming relativistically transparent to the laser light during the interaction. Ion acceleration in this regime is strongly affected by the transition from an opaque to a relativistically transparent plasma. By spatially resolving the laser-accelerated proton beam at near-normal laser incidence and at an incidence angle of 30°, we identify characteristic features both experimentally and in particle-in-cell simulations which are consistent with the onset of three distinct ion acceleration mechanisms: sheath acceleration; radiation pressure acceleration; and transparency-enhanced acceleration. The latter mechanism occurs late in the interaction and is mediated by the formation of a plasma jet extending into the expanding ion population. The effect of laser incident angle on the plasma jet is explored.

  5. Impact of Schedule Duration on Head and Neck Radiotherapy: Accelerated Tumor Repopulation Versus Compensatory Mucosal Proliferation

    SciTech Connect

    Fenwick, John D.; Pardo-Montero, Juan; Nahum, Alan E.; Malik, Zafar I.

    2012-02-01

    Purpose: To determine how modelled maximum tumor control rates, achievable without exceeding mucositis tolerance (tcp{sub max-early}) vary with schedule duration for head and neck squamous cell carcinoma (HNSCC). Methods and materials: Using maximum-likelihood techniques, we have fitted a range of tcp models to two HNSCC datasets (Withers' and British Institute of Radiology [BIR]), characterizing the dependence of tcp on duration and equivalent dose in 2 Gy fractions (EQD{sub 2}). Models likely to best describe future data have been selected using the Akaike information criterion (AIC) and its quasi-AIC extension to overdispersed data. Setting EQD{sub 2}s in the selected tcp models to levels just tolerable for mucositis, we have plotted tcp{sub max-early} against schedule duration. Results: While BIR dataset tcp fits describe dose levels isoeffective for tumor control as rising significantly with schedule protraction, indicative of accelerated tumor repopulation, repopulation terms in fits to Withers' dataset do not reach significance after accounting for overdispersion of the data. The tcp{sub max-early} curves calculated from tcp fits to the overall Withers' and BIR datasets rise by 8% and 0-4%, respectively, between 20 and 50 days duration; likewise, tcp{sub max-early} curves calculated for stage-specific cohorts also generally rise slowly with increasing duration. However none of the increases in tcp{sub max-early} calculated from the overall or stage-specific fits reach significance. Conclusions: Local control rates modeled for treatments which lie just within mucosal tolerance rise slowly but insignificantly with increasing schedule length. This finding suggests that whereas useful gains may be made by accelerating unnecessarily slow schedules until they approach early reaction tolerance, little is achieved by shortening schedules further while reducing doses to remain within mucosal tolerance, an approach that may slightly worsen outcomes.

  6. Milk extracellular vesicles accelerate osteoblastogenesis but impair bone matrix formation.

    PubMed

    Oliveira, Marina C; Arntz, Onno J; Blaney Davidson, Esmeralda N; van Lent, Peter L E M; Koenders, Marije I; van der Kraan, Peter M; van den Berg, Wim B; Ferreira, Adaliene V M; van de Loo, Fons A J

    2016-04-01

    The claimed beneficial effect of milk on bone is still a matter for debate. Recently extracellular vesicles (EVs) that contain proteins and RNA were discovered in milk, but their effect on bone formation has not yet been determined. We demonstrated previously that bovine milk-derived EVs (BMEVs) have immunoregulatory properties. Our aim was to evaluate the effect of BMEVs on osteogenesis by mice and human mesenchymal stem cells (hMSCs). Oral delivery of two concentrations of BMEVs to female DBA/1J mice during 7weeks did not alter the tibia trabecular bone area; however, the osteocytes number increased. In addition, the highest dose of BMEVs markedly increased the woven bone tissue, which is more brittle. The exposure of hMSCs to BMEVs during 21days resulted in less mineralization but higher cell proliferation. Interestingly BMEVs reduced the collagen production, but enhanced the expression of genes characteristic for immature osteoblasts. A kinetic study showed that BMEVs up-regulated many osteogenic genes within the first 4days. However, the production of type I collagen and expression of its genes (COL1A1 and COL1A2) were markedly reduced at days 21 and 28. At day 28, BMEVs again lead to higher proliferation, but mineralization was significantly increased. This was associated with increased expression of sclerostin, a marker for osteocytes, and reduced osteonectin, which is associated to bone matrix formation. Our study adds BMEVs to the list of milk components that can affect bone formation and may shed new light on the contradictory claims of milk on bone formation.

  7. Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

    PubMed Central

    Landis, MD; Seachrist, DD; Abdul-Karim, FW; Keri, RA

    2006-01-01

    Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These

  8. Tumor Interstitial Fluid Formation, Characterization, and Clinical Implications

    PubMed Central

    Wagner, Marek; Wiig, Helge

    2015-01-01

    The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase representing the tissue microenvironment. In the present review, we focus on the interstitial fluid phase of solid tumors, the tumor interstitial fluid (TIF), i.e., the fluid bathing the tumor and stroma cells, also including immune cells. This is a component of the internal milieu of a solid tumor that has attracted regained attention. Access to this space may provide important insight into tumor development and therapy response. TIF is formed by transcapillary filtration, and since this fluid is not readily available we discuss available techniques for TIF isolation, results from subsequent characterization and implications of recent findings with respect to fluid filtration and uptake of macromolecular therapeutic agents. There appear to be local gradients in signaling substances from neoplastic tissue to plasma that may provide new understanding of tumor biology. The development of sensitive proteomic technologies has made TIF a valuable source for tumor specific proteins and biomarker candidates. Potential biomarkers will appear locally in high concentrations in tumors and may eventually be found diluted in the plasma. Access to TIF that reliably reflects the local tumor microenvironment enables identification of substances that can be used in early detection and monitoring of disease. PMID:26075182

  9. Tumor Interstitial Fluid Formation, Characterization, and Clinical Implications.

    PubMed

    Wagner, Marek; Wiig, Helge

    2015-01-01

    The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase representing the tissue microenvironment. In the present review, we focus on the interstitial fluid phase of solid tumors, the tumor interstitial fluid (TIF), i.e., the fluid bathing the tumor and stroma cells, also including immune cells. This is a component of the internal milieu of a solid tumor that has attracted regained attention. Access to this space may provide important insight into tumor development and therapy response. TIF is formed by transcapillary filtration, and since this fluid is not readily available we discuss available techniques for TIF isolation, results from subsequent characterization and implications of recent findings with respect to fluid filtration and uptake of macromolecular therapeutic agents. There appear to be local gradients in signaling substances from neoplastic tissue to plasma that may provide new understanding of tumor biology. The development of sensitive proteomic technologies has made TIF a valuable source for tumor specific proteins and biomarker candidates. Potential biomarkers will appear locally in high concentrations in tumors and may eventually be found diluted in the plasma. Access to TIF that reliably reflects the local tumor microenvironment enables identification of substances that can be used in early detection and monitoring of disease. PMID:26075182

  10. Accelerating procelain formation by incorporating a complex additive

    SciTech Connect

    Maslennikova, G.N.; Dubovitskii, S.A.; Moroz, I.K.

    1986-05-01

    The authors studied the influence of a complex additive consisting of oxides of calcium, zinc, and magnesium on the formaton of porcelain. In order to achieve a more uniform distribution of the complex additive in the porcelain body it was incorporated in the form of water soluble salts-nitrates, which ensured comparability of results and excluded the effect of the different types of anions. The study of the main parameters of sintering (porosity, shrinkage, and mechanical strength) for the test bodies showed that they sinter at lower temperatures and attain zero porosity, maximum shrinkage, and mechanical strength. The most typical bodies indentified in this way were investigated by methods of complex differential thermal analysis and x-ray diffraction. Thus, the introduction of complex additives consisting of calcium, zinc, and magnesium oxides contributes to the earlier formation of porcelain. With the reduction of firing temperatures by 100/sup 0/C the authors observe an improvement in the basic properties of porcelain.

  11. What will it take for laser driven proton accelerators to be applied to tumor therapy?

    NASA Astrophysics Data System (ADS)

    Linz, Ute; Alonso, Jose

    2007-09-01

    After many years on the periphery of cancer therapy, the successes of proton and ion beams in tumor therapy are gradually receiving a higher degree of recognition. The considerable construction and acquisition costs are usually invoked to explain the slow market penetration of this favorable treatment modality. Recently, high-intensity lasers have been suggested as a potential, cost-saving alternative to cyclotrons or synchrotrons for oncology. This article will detail the technical requirements necessary for successful implementation of ion beam therapy (IBT)—the general term for proton and heavier-ion therapy. It will summarize the current state of laser acceleration of protons and will outline the very substantial developments still necessary for this technology to be successfully applied to IBT.

  12. [Succinate dehydrogenase-deficient tumors--a novel mechanism of tumor formation].

    PubMed

    Miettinen, Markku

    2015-01-01

    Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation. These tumors, discovered during the past 15 years, often occur in young patients and include 15% of paragangliomas, 7% of gastric gastrointestinal stromal tumors (GISTs), and <1% of renal cell carcinomas and pituitary adenomas. SDH-deficient tumors have lost SDH complex activity via bi-allelic genomic losses or epigenetic silencing. This deficiency is oncogenic, activating pseudohypoxia signaling. SDH deficiency has to be suspected in the above-cited tumor types presenting at a young age. Immunohistochemical testing of tumor tissue for SDHB loss is diagnostic. PMID:26749909

  13. 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.

  14. Possible mechanism by which stress accelerates growth of virally derived tumors.

    PubMed Central

    Romero, L M; Raley-Susman, K M; Redish, D M; Brooke, S M; Horner, H C; Sapolsky, R M

    1992-01-01

    Stress accelerates the growth of certain types of tumors. Here we report a possible metabolic mechanism underlying this phenomenon. Some early features of transformation include increased number of glucose transporters and greatly enhanced rates of glucose uptake; this adaptation accommodates the vast energy demands needed for neoplastic growth. In contrast, glucocorticoids, a class of steroid hormones secreted during stress, inhibit glucose transport in various tissues; this is one route by which circulating glucose concentrations are raised during stress. We reasoned that should transformed cells become resistant to this inhibitory action of glucocorticoids, such cells would gain preferential access to these elevated concentrations of glucose. In agreement with this, we observed that Fujinami sarcoma virus-transformed fibroblasts became resistant to this glucocorticoid action both in vitro and in the rat. As a result, under conditions where glucocorticoids exerted catabolic effects upon nontransformed fibroblasts (inhibition of metabolism and ATP concentrations), the opposite occurred in the virally transformed cells. We observe that this glucocorticoid resistance upon transformation cannot be explained by depletion of glucocorticoid receptors; previous studies have suggested that transformation causes an alteration in trafficking of such receptors. Because of this resistance of transformed fibroblasts to the inhibitory effects of glucocorticoids upon glucose transport, glucose stores throughout the body are, in effect, preferentially shunted to such tumors during stress. Images PMID:1438318

  15. Effect of single-walled carbon nanotubes on tumor cells viability and formation of multicellular tumor spheroids

    NASA Astrophysics Data System (ADS)

    Yakymchuk, Olena M.; Perepelytsina, Olena M.; Dobrydnev, Alexey V.; Sydorenko, Mychailo V.

    2015-03-01

    This paper describes the impact of different concentrations of single-walled carbon nanotubes (SWCNTs) on cell viability of breast adenocarcinoma, MCF-7 line, and formation of multicellular tumor spheroids (MTS). Chemical composition and purity of nanotubes is controlled by Fourier transform infrared spectroscopy. The strength and direction of the influence of SWCNTs on the tumor cell population was assessed by cell counting and measurement of the volume of multicellular tumor spheroids. Effect of SWCNTs on the formation of multicellular spheroids was compared with the results obtained by culturing tumor cells with ultra dispersed diamonds (UDDs). Our results demonstrated that SWCNTs at concentrations ranging from 12.5 to 50 μg/ml did not have cytotoxic influence on tumor cells; instead, they had weak cytostatic effect. The increasing of SWCNTs concentration to 100 to 200 μg/ml stimulated proliferation of tumor cells, especially in suspension fractions. The result of this influence was in formation of more MTS in cell culture with SWCNTs compared with UDDs and control samples. In result, the median volume of MTS after cultivation with SWCNTs at 100 to 200 μg/ml concentrations is 3 to 5 times greater than that in samples which were incubated with the UDDs and is 2.5 times greater than that in control cultures. So, if SWCNTs reduced cell adhesion to substrate and stimulated formation of tumor cell aggregates volume near 7 · 10-3 mm3, at the same time, UDDs reduced adhesion and cohesive ability of cells and stimulated generation of cell spheroids volume no more than 4 · 10-3 mm3. Our results could be useful for the control of cell growth in three-dimensional culture.

  16. Exploring Teacher Beliefs and Use of Acceleration, Ability Grouping, and Formative Assessment

    ERIC Educational Resources Information Center

    Missett, Tracy C.; Brunner, Marguerite M.; Callahan, Carolyn M.; Moon, Tonya R.; Azano, Amy Price

    2014-01-01

    Few academic interventions for gifted students have generated more empirical support than acceleration and ability grouping, and formative assessment is advocated as a tool that educators can use to appropriately integrate accelerative practices and ability grouping into the classroom. However, the empirical support for accelerative practices,…

  17. Pathophysiological Basis for the Formation of the Tumor Microenvironment

    PubMed Central

    Horsman, Michael R.; Vaupel, Peter

    2016-01-01

    Poor microenvironmental conditions are a characteristic feature of solid tumors. Such conditions occur because the tumor vascular supply, which develops from the normal host vasculature by the process of angiogenesis, is generally inadequate in meeting the oxygen and nutrient demands of the growing tumor mass. Regions of low oxygenation (hypoxia) is believed to be the most critical deficiency, since it has been well documented to play a significant role in influencing the response to conventional radiation and chemotherapy treatments, as well as influencing malignant progression in terms of aggressive growth and recurrence of the primary tumor and its metastatic spread. As a result, significant emphasis has been placed on finding clinically applicable approaches to identify those tumors that contain hypoxia and realistic methods to target this hypoxia. However, most studies consider hypoxia as a single entity, yet we now know that it is multifactorial. Furthermore, hypoxia is often associated with other microenvironmental parameters, such as elevated interstitial fluid pressure, glycolysis, low pH, and reduced bioenergetic status, and these can also influence the effects of hypoxia. Here, we review the various aspects of hypoxia, but also discuss the role of the other microenvironmental parameters associated with hypoxia. PMID:27148472

  18. WIP1 Enhances Tumor Formation in a Sonic Hedgehog–Dependent Model of Medulloblastoma

    PubMed Central

    Doucette, Tiffany A.; Yang, Yuhui; Pedone, Carolyn; Kim, John Y.H.; Dubuc, Adrian; Northcott, Paul D.; Taylor, Michael D.; Fults, Daniel W.; Rao, Ganesh

    2013-01-01

    BACKGROUND A significant number of medulloblastomas (MBs) originate from abnormal activation of the sonic hedgehog/patched (SHH/PTC) signaling pathway. Although p53 deficiency enhances tumor formation in mice, inactivation of the p53 gene is seen in a minority of MBs. Wild-type p53-induced phosphatase 1 (WIP1) downregulates p53 expression and has been shown to be overexpressed in MBs. OBJECTIVE We tested the hypothesis that overexpression of WIP1 enhances tumor formation in an SHH-dependent model of MB. METHODS We used the RCAS/Ntv-a system to study the effect of WIP1 in vitro and in vivo. We transfected A375-TVA cells with RCAS-WIP1 and then exposed these cells to cisplatin to determine the effect on p53 expression. We modeled ectopic WIP1 expression independently and in combination with SHH in the cerebella of newborn mice to assess the effect on tumor formation. Mice were observed for 12 weeks or until neurological symptoms developed. The brains were examined for tumor formation. RESULTS A375-TVA cells infected with RCAS-WIP1 demonstrated reduced p53 expression after exposure to cisplatin compared with controls. We detected tumors in 12 of 35 mice (34%) injected with RCAS-WIP1 and RCAS-SHH. Tumors were detected in 3 of 40 mice (8%) injected with RCAS-SHH alone. The difference in tumor formation rates was significant (×2 test, P = < .01). Tumors did not form in mice injected with RCAS-WIP1 alone. CONCLUSION We show that ectopic expression of WIP1 cooperates with SHH to enhance formation of MB, although it is insufficient to induce tumors independently. Our results verify the role of WIP1 in MB formation and provide a crucial link to the inactivation of p53 in MBs. PMID:22037313

  19. Tumor formation in Hoffa's infrapatellar fat: Case report.

    PubMed

    Mozella, Alan de Paula; da Silveira Moller, João Victor; de Araújo Barros Cobra, Hugo Alexandre

    2015-01-01

    Although tumors or pseudotumoral lesions are rare in the infrapatellar fat, they may affect it. Osteochondroma is the commonest benign bone tumor. However, extraskeletal presentations are rare. There are three extraskeletal variants of osteochondroma: synovial chondromatosis, para-articular chondroma and soft-tissue chondroma. We present a case of a single intra-articular lesion in the area of Hoffa's fat, in a 78-year-old female patient with a complaint of progressive knee pain associated with severe arthrosis. From the clinical and radiological findings, the diagnosis was para-articular osteochondroma. However, the histopathological findings, after excision of the lesion, showed that this was synovial chondromatosis secondary to osteoarthrosis.

  20. Optimal technique of linear accelerator-based stereotactic radiosurgery for tumors adjacent to brainstem.

    PubMed

    Chang, Chiou-Shiung; Hwang, Jing-Min; Tai, Po-An; Chang, You-Kang; Wang, Yu-Nong; Shih, Rompin; Chuang, Keh-Shih

    2016-01-01

    Stereotactic radiosurgery (SRS) is a well-established technique that is replacing whole-brain irradiation in the treatment of intracranial lesions, which leads to better preservation of brain functions, and therefore a better quality of life for the patient. There are several available forms of linear accelerator (LINAC)-based SRS, and the goal of the present study is to identify which of these techniques is best (as evaluated by dosimetric outcomes statistically) when the target is located adjacent to brainstem. We collected the records of 17 patients with lesions close to the brainstem who had previously been treated with single-fraction radiosurgery. In all, 5 different lesion catalogs were collected, and the patients were divided into 2 distance groups-1 consisting of 7 patients with a target-to-brainstem distance of less than 0.5cm, and the other of 10 patients with a target-to-brainstem distance of ≥ 0.5 and < 1cm. Comparison was then made among the following 3 types of LINAC-based radiosurgery: dynamic conformal arcs (DCA), intensity-modulated radiosurgery (IMRS), and volumetric modulated arc radiotherapy (VMAT). All techniques included multiple noncoplanar beams or arcs with or without intensity-modulated delivery. The volume of gross tumor volume (GTV) ranged from 0.2cm(3) to 21.9cm(3). Regarding the dose homogeneity index (HIICRU) and conformity index (CIICRU) were without significant difference between techniques statistically. However, the average CIICRU = 1.09 ± 0.56 achieved by VMAT was the best of the 3 techniques. Moreover, notable improvement in gradient index (GI) was observed when VMAT was used (0.74 ± 0.13), and this result was significantly better than those achieved by the 2 other techniques (p < 0.05). For V4Gy of brainstem, both VMAT (2.5%) and IMRS (2.7%) were significantly lower than DCA (4.9%), both at the p < 0.05 level. Regarding V2Gy of normal brain, VMAT plans had attained 6.4 ± 5%; this was significantly better (p < 0.05) than

  1. Appalachian Mountaintop Mining Particulate Matter Induces Neoplastic Transformation of Human Bronchial Epithelial Cells and Promotes Tumor Formation

    PubMed Central

    2015-01-01

    Epidemiological studies suggest that living near mountaintop coal mining (MTM) activities is one of the contributing factors for high lung cancer incidence. The purpose of this study was to investigate the long-term carcinogenic potential of MTM particulate matter (PMMTM) exposure on human bronchial epithelial cells. Our results show that chronic exposure (3 months) to noncytotoxic, physiological relevant concentration (1 μg/mL) of PMMTM, but not control particle PMCON, induced neoplastic transformation, accelerated cell proliferation, and enhanced cell migration of the exposed lung cells. Xenograft transplantation of the PMMTM-exposed cells in mice caused no apparent tumor formation, but promoted tumor growth of human lung carcinoma H460 cells, suggesting the tumor-promoting effect of PMMTM. Chronic exposure to the main inorganic chemical constituent of PMMTM, molybdenum but not silica, similarly induced cell transformation and tumor promotion, suggesting the contribution of molybdenum, at least in part, in the PMMTM effects. These results provide new evidence for the carcinogenic potential of PMMTM and support further risk assessment and implementation of exposure control for PMMTM. PMID:25347054

  2. Cathepsin S-mediated autophagic flux in tumor-associated macrophages accelerate tumor development by promoting M2 polarization

    PubMed Central

    2014-01-01

    Background Tumor-associated macrophages (TAMs) are the major component of tumor-infiltrating leukocytes. TAMs are heterogeneous, with distinct phenotypes influenced by the microenvironment surrounding tumor tissues, but relatively little is known about the key molecular in these cells that contribute to malignant phenotypes. Autophagic activity is a critical factor in tumor development that contributes to enhancing cellular fitness and survival in the hostile tumor microenvironment. However, the molecular basis and relations between autophagy and TAMs polarization remain unclear. Methods Cathepsin S (Cat S) expression was analyzed in human colon carcinoma and normal colon tissues. In vivo effects were evaluated using PancO2 subcutaneous tumor model and SL4 hepatic metastasis model. Immunofluorescence staining, flow cytometry and real-time PCR were done to examine TAMs polarization. Western blotting assay, transmission electron microscopy, mCherry-GFP-LC3 transfection and DQ-BSA degradation assays were carried out to determine its role in regulating autophagy. Results In the present study, we showed that the enhanced expression of Cat S correlated with the severity of histologic grade as well as clinical stage, metastasis, and recurrence, which are known indicators of a relatively poor prognosis of human colon carcinoma. Cat S knockout led to decreased tumor growth and metastasis. Moreover, Cat S knockout inhibited M2 macrophage polarization during tumor development. We further demonstrated that Cat S was required for not only autophagic flux but also the fusion processes of autophagosomes and lysosomes in TAMs. Importantly, we found that Cat S contributed to tumor development by regulating the M2 phenotype of TAMs through the activation of autophagy. Conclusions These results indicated that Cat S-mediated autophagic flux is an important mechanism for inducing M2-type polarization of TAMs, which leads to tumor development. These data provide strong evidence for a

  3. Endothelial progenitor cells promote tumor growth and progression by enhancing new vessel formation

    PubMed Central

    Zhao, Xin; Liu, Huan-Qiu; Li, Ji; Liu, Xiao-Liang

    2016-01-01

    Tumor growth and progression require new blood vessel formation to deliver nutrients and oxygen for further cell proliferation and to create a neovascular network exit for tumor cell metastasis. Endothelial progenitor cells (EPCs) are a bone marrow (BM)-derived stem cell population that circulates in the peripheral circulation and homes to the tumor bed to participate in new blood vessel formation. In addition to structural support to nascent vessels, these cells can also regulate the angiogenic process by paracrine secretion of a number of proangiogenic growth factors and cytokines, thus playing a crucial role in tumor neovascularization and development. Inhibition of EPC-mediated new vessel formation may be a promising therapeutic strategy in tumor treatment. EPC-mediated neovascularization is a complex process that includes multiple steps and requires a series of cytokines and modulators, thus understanding the underlying mechanisms may provide anti-neovasculogenesis targets that may be blocked for the prevention of tumor development. The present review stresses the process and contribution of EPCs to the formation of new blood vessels in solid tumors, in an attempt to gain an improved understanding of the underlying cellular and molecular mechanisms involved, and to provide a potential effective therapeutic target for cancer treatment. PMID:27446353

  4. CASTLEMAN'S DISEASE PRESENTING AS A TUMOROUS PARACARDIAC FORMATION.

    PubMed

    Vuković, Ivica; Brešković, Toni; Duplancić, Darko; Batinić, Tonci; Štula, Ivana; Bulat, Cristian; Tomić, Snježana

    2016-03-01

    Castleman's disease (in the literature also known as angiofollicular hyperplasia) is a rare benign lymphoproliferative disease. Clinically, it can manifest as unicentric or multicentric disease. Unicentric disease is most often diagnosed by accident or by symptomatology resulting from compression upon the adjoining anatomical structures. Considering its lymphatic origin, tumor mass can theoretically occur in any body region. We present a case of paracardiac localization of unicentric Castleman's disease in a previously healthy 24-year-old woman. In such clinical cases, the specific localization of the tumor and its radiological properties can pose a differential diagnostic dilemma. Correct diagnosis is only possible after complete surgical excision and histopathologic analysis, which is the optimal therapeutic approach in this disease. PMID:27333732

  5. Dominant negative retinoic acid receptor initiates tumor formation in mice

    PubMed Central

    Kupumbati, Tara S; Cattoretti, Giorgio; Marzan, Christine; Farias, Eduardo F; Taneja, Reshma; Mira-y-Lopez, Rafael

    2006-01-01

    Background 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. Results To address this question, we generated transgenic mice in which expression of a ligand binding defective dominant negative RARα (RARαG303E) 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-RARαG303E 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. Conclusion 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. PMID

  6. FTIR spectro-imaging of collagen scaffold formation during glioma tumor development.

    PubMed

    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. PMID:24068168

  7. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies.

    PubMed

    Hanker, Ariella B; Pfefferle, Adam D; Balko, Justin M; Kuba, María Gabriela; Young, Christian D; Sánchez, Violeta; Sutton, Cammie R; Cheng, Hailing; Perou, Charles M; Zhao, Jean J; Cook, Rebecca S; Arteaga, Carlos L

    2013-08-27

    Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-to-mesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies.

  8. 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.

  9. Formation of solid tumors by a single multinucleated cancer cel

    PubMed Central

    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

  10. Current Sheet Formation in a Conical Theta Pinch Faraday Accelerator with Radio-frequency Assisted Discharge

    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.

  11. Mammary gland tumor formation in transgenic mice overexpressing stromelysin-1

    SciTech Connect

    Sympson, Carolyn J; Bissell, Mina J; Werb, Zena

    1995-06-01

    An intact basement membrane (BM) is essential for the proper function, differentiation and morphology of many epithelial cells. The disruption or loss of this BM occurs during normal development as well as in the disease state. To examine the importance of BM during mammary gland development in vivo, we generated transgenic mice that inappropriately express autoactivating isoforms of the matrix metalloproteinase stromelysin-1. The mammary glands from these mice are both functionally and morphologically altered throughout development. We have now documented a dramatic incidence of breast tumors in several independent lines of these mice. These data suggest that overexpression of stromelysin-1 and disruption of the BM may be a key step in the multi-step process of breast cancer.

  12. Apospory appears to accelerate onset of meiosis and sexual embryo sac formation in sorghum ovules

    PubMed Central

    2011-01-01

    Background Genetically unreduced (2n) embryo sacs (ES) form in ovules of gametophytic apomicts, the 2n eggs of which develop into embryos parthenogenetically. In many apomicts, 2n ES form precociously during ovule development. Whether meiosis and sexual ES formation also occur precociously in facultative apomicts (capable of apomictic and sexual reproduction) has not been studied. We determined onset timing of meiosis and sexual ES formation for 569 Sorghum bicolor genotypes, many of which produced 2n ES facultatively. Results Genotype differences for onset timing of meiosis and sexual ES formation, relative to ovule development, were highly significant. A major source of variation in timing of sexual germline development was presence or absence of apomictic ES, which formed from nucellar cells (apospory) in some genotypes. Genotypes that produced these aposporous ES underwent meiosis and sexual ES formation precociously. Aposporous ES formation was most prevalent in subsp. verticilliflorum and in breeding lines of subsp. bicolor. It was uncommon in land races. Conclusions The present study adds meiosis and sexual ES formation to floral induction, apomictic ES formation, and parthenogenesis as processes observed to occur precociously in apomictic plants. The temporally diverse nature of these events suggests that an epigenetic memory of the plants' apomixis status exists throughout its life cycle, which triggers, during multiple life cycle phases, temporally distinct processes that accelerate reproduction. PMID:21223576

  13. MMP7 is required to mediate cell invasion and tumor formation upon Plakophilin3 loss.

    PubMed

    Basu, Srikanta; Thorat, Rahul; Dalal, Sorab N

    2015-01-01

    Plakophilin3 (PKP3) loss results in increased transformation in multiple cell lines in vitro and increased tumor formation in vivo. A microarray analysis performed in the PKP3 knockdown clones, identified an inflammation associated gene signature in cell lines derived from stratified epithelia as opposed to cell lines derived from simple epithelia. However, in contrast to the inflammation associated gene signature, the expression of MMP7 was increased upon PKP3 knockdown in all the cell lines tested. Using vector driven RNA interference, it was demonstrated that MMP7 was required for in-vitro cell migration and invasion and tumor formation in vivo. The increase in MMP7 levels was due to the increase in levels of the Phosphatase of Regenerating Liver3 (PRL3), which is observed upon PKP3 loss. The results suggest that MMP7 over-expression may be one of the mechanisms by which PKP3 loss leads to increased cell invasion and tumor formation.

  14. Food-grade titanium dioxide exposure exacerbates tumor formation in colitis associated cancer model.

    PubMed

    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.

  15. Diaphragm opening effects on shock wave formation and acceleration in a rectangular cross section channel

    NASA Astrophysics Data System (ADS)

    Pakdaman, S. A.; Garcia, M.; Teh, E.; Lincoln, D.; Trivedi, M.; Alves, M.; Johansen, C.

    2016-03-01

    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.

  16. 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.

  17. Acceleration of atherogenesis by COX-1-dependent prostanoid formation in low density lipoprotein receptor knockout mice.

    PubMed

    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.

  18. 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.

  19. Photoacoustic monitoring of clot formation during surgery and tumor surgery

    NASA Astrophysics Data System (ADS)

    Juratli, Mazen A.; Galanzha, Ekaterina I.; Sarimollaoglu, Mustafa; Nedosekin, Dmitry A.; Suen, James Y.; Zharov, Vladimir P.

    2013-03-01

    When a blood vessel is injured, the normal physiological response of the body is to form a clot (thrombus) to prevent blood loss. Alternatively, even without injury to the blood vessel, the pathological condition called thromboembolism may lead to the formation of circulating blood clots (CBCs), also called emboli, which can clog blood vessels throughout the body. Veins of the extremities (venous thromboembolism), lungs (pulmonary embolism ), brain (embolic stroke), heart (myocardial infarction), kidneys, and gastrointestinal tract are often affected. Emboli are also common complications of infection, inflammation, cancer, surgery, radiation and coronary artery bypass grafts. Despite the clear medical significance of CBCs, however, little progress has been made in the development of methods for real-time detection and identification of CBCs. To overcome these limitations, we developed a new modification of in vivo photoacoustic (PA) flow cytometry (PAFC) for real-time detection of white, red, and mixed clots through a transient decrease, increase or fluctuation of PA signal amplitude, respectively. In this work, using PAFC and mouse models, we present for the first time direct evidence that some medical procedures, such as conventional or cancer surgery may initiate the formation of CBCs. In conclusion, the PA diagnostic platform can be used in real-time to define risk factors for cardiovascular diseases, assist in the prognosis and potential prevention of stroke by using a well-timed therapy or as a clot count as a marker of therapy efficacy.

  20. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

    PubMed

    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)

  1. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

    PubMed

    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) PMID:7740497

  2. Granular assembly of alpha-synuclein leading to the accelerated amyloid fibril formation with shear stress.

    PubMed

    Bhak, Ghibom; Lee, Jung-Ho; Hahn, Ji-Sook; Paik, Seung R

    2009-01-01

    alpha-Synuclein participates in the Lewy body formation of Parkinson's disease. Elucidation of the underlying molecular mechanism of the amyloid fibril formation is crucial not only to develop a controlling strategy toward the disease, but also to apply the protein fibrils for future biotechnology. Discernable homogeneous granules of alpha-synuclein composed of approximately 11 monomers in average were isolated in the middle of a lag phase during the in vitro fibrillation process. They were demonstrated to experience almost instantaneous fibrillation during a single 12-min centrifugal membrane-filtration at 14,000 x g. The granular assembly leading to the drastically accelerated fibril formation was demonstrated to be a result of the physical influence of shear force imposed on the preformed granular structures by either centrifugal filtration or rheometer. Structural rearrangement of the preformed oligomomeric structures is attributable for the suprastructure formation in which the granules act as a growing unit for the fibril formation. To parallel the prevailing notion of nucleation-dependent amyloidosis, we propose a double-concerted fibrillation model as one of the mechanisms to explain the in vitro fibrillation of alpha-synuclein, in which two consecutive concerted associations of monomers and subsequent oligomeric granular species are responsible for the eventual amyloid fibril formation. PMID:19137068

  3. Monoallelic Loss of the Imprinted Gene Grb10 Promotes Tumor Formation in Irradiated Nf1+/- Mice

    PubMed Central

    Mroue, Rana; Huang, Brian; Braunstein, Steve; Firestone, Ari J.; Nakamura, Jean L.

    2015-01-01

    Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis. PMID:26000738

  4. Formation of GEMS from shock-accelerated crystalline dust in Superbubbles

    SciTech Connect

    Westphal, A; Bradley, J P

    2004-12-08

    Interplanetary dust particles (IDPs) contain enigmatic sub-micron 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 {micro}m 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, 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 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 galactic cosmic rays. Thus, representatives of the GCR source material may have been awaiting discovery in cosmic dust labs for the last thirty years.

  5. Acceleration of Mouse Mammary Tumor Virus-Induced Murine Mammary Tumorigenesis by a p53172H Transgene

    PubMed Central

    Chatterjee, Gouri; Rosner, Andrea; Han, Yi; Zelazny, Edward T.; Li, Baolin; Cardiff, Robert D.; Perkins, Archibald S.

    2002-01-01

    We previously showed that a mammary-specific dominant-negative p53 transgene (WAP-p53172H) could accelerate ErbB2-induced mammary tumorigenesis in mice, but was not tumorigenic on its own. To identify other genes that cooperate with WAP-p53172H in tumorigenesis, we performed mouse mammary tumor virus (MMTV) proviral mutagenesis. We derived F1, N2, and N4/N5 mice from p53172H transgenic FVB mice backcrossed onto MMTV+ C3H/He mice. Results show the latency of MMTV tumorigenesis is correlated with FVB contribution. F1 tumors had the shortest latency (217 days), had a higher rate of metastasis, and were less differentiated than the N2 and N4/N5 tumors. The latency was 269 days in N2 mice, and lengthened to 346 days in N4/N5 mice. p53172H significantly accelerated MMTV tumorigenesis only in N2 mice, indicating cooperativity between p53172H and MMTV in this cohort. To identify genes that may be causally involved in MMTV-induced mammary tumorigenesis, we identified 60 sites of proviral insertion in the N2 tumors. Among the insertions in p53172H transgenic tumors were 10 genes not previously found as sites of MMTV insertion including genes involved in signaling (Pdgfra, Pde1b, Cnk1), cell adhesion (Cd44), angiogenesis (Galgt1), and transcriptional regulation (Olig1, Olig2, and Uncx4.1). These may represent cellular functions that are likely not deregulated by mutation in p53. PMID:12466138

  6. Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation.

    PubMed

    Garman, Russell; Gaudette, Glenn; Donahue, Leah-Rae; Rubin, Clinton; Judex, Stefan

    2007-06-01

    High-frequency whole body vibrations can be osteogenic, but their efficacy appears limited to skeletal segments that are weight bearing and thus subject to the induced load. To determine the anabolic component of this signal, we investigated whether low-level oscillatory displacements, in the absence of weight bearing, are anabolic to skeletal tissue. A loading apparatus, developed to shake specific segments of the murine skeleton without the direct application of deformations to the tissue, was used to subject the left tibia of eight anesthesized adult female C57BL/6J mice to small (0.3 g or 0.6 g) 45 Hz sinusoidal accelerations for 10 min/day, while the right tibia served as an internal control. Video and strain analysis revealed that motions of the apparatus and tibia were well coupled, inducing dynamic cortical deformations of less than three microstrain. After 3 weeks, trabecular metaphyseal bone formation rates and the percentage of mineralizing surfaces (MS/BS) were 88% and 64% greater (p < 0.05) in tibiae accelerated at 0.3 g than in their contralateral controls. At 0.6 g, bone formation rates and mineral apposition rates were 66% and 22% greater (p < 0.05) in accelerated tibiae. Changes in bone morphology were evident only in the epiphysis, where stimulated tibiae displayed significantly greater cortical area (+8%) and thickness (+8%). These results suggest that tiny acceleratory motions--independent of direct loading of the matrix--can influence bone formation and bone morphology. If confirmed by clinical studies, the unique nature of the signal may ultimately facilitate the stimulation of skeletal regions that are prone to osteoporosis even in patients that are suffering from confinement to wheelchairs, bed rest, or space travel.

  7. Accelerated gravity testing of aquitard core permeability and implications at formation and regional scale

    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.

  8. In Situ Investigation of a Self-Accelerated Cocrystal Formation by Grinding Pyrazinamide with Oxalic Acid.

    PubMed

    Kulla, Hannes; Greiser, Sebastian; Benemann, Sigrid; Rademann, Klaus; Emmerling, Franziska

    2016-01-01

    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. PMID:27428942

  9. Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors

    PubMed Central

    Zhang, Jin; Xu, Enshun; Ren, Cong; Yan, Wensheng; Zhang, Min; Chen, Mingyi; Cardiff, Robert D.; Imai, Denise M.; Wisner, Erik; Chen, Xinbin

    2014-01-01

    RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53-dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression. PMID:25512531

  10. USP10 antagonizes c-Myc transcriptional activation through SIRT6 stabilization to suppress tumor formation.

    PubMed

    Lin, Zhenghong; Yang, Heeyoung; Tan, Can; Li, Jinping; Liu, Zhaojian; Quan, Qiu; Kong, Sinyi; Ye, Junsheng; Gao, Beixue; Fang, Deyu

    2013-12-26

    The reduced protein expression of SIRT6 tumor suppressor is involved in tumorigenesis. The molecular mechanisms underlying SIRT6 protein downregulation in human cancers remain unknown. Using a proteomic approach, we have identified the ubiquitin-specific peptidase USP10, another tumor suppressor, as one of the SIRT6-interacting proteins. USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation. USP10 antagonizes the transcriptional activity of the c-Myc oncogene through SIRT6, as well as p53, to inhibit cell-cycle progression, cancer cell growth, and tumor formation. To support this conclusion, we detected significant reductions in both USP10 and SIRT6 protein expression in human colon cancers. Our study discovered crosstalk between two tumor-suppressive genes in regulating cell-cycle progression and proliferation and showed that dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.

  11. [Role of meristem-specific genes of plants in formation of genetic tumors].

    PubMed

    Lutova, L A; Dodueva, I E

    2007-01-01

    In higher plants, homeobox genes of the KNOX and WOX subfamilies plays a key role in maintenance of the pool of stem cells, regulate proliferation, and prevent cell differentiation. It has been shown that meristem-specific genes are regulated by phytohormones and affect their metabolism, specifically that of cytokinins. Plant tumors are widely used as a model for studying the genetic control of cell division and differentiation. The tumors induced by pathogens and genetic tumors, whose development depends on the plant genotype, are distinguished. The changes in the levels of expression of genes--regulators of cell cycle, meristem-specific genes, and genes controlling metabolism and transmission of the signal of phytohormones were described on tumors of different origin. The mechanisms underlying tumor formation in plants and animals were shown to be similar, specifically as concerns the relationship between the genes--cell cycle regulators and tumorigenesis. In plants, transcriptional factors of the subfamily KNOX have similarity in structure and, supposedly, common origin with transcriptional factors MEIS in animals, which are very active in neoplastic cells. The review presents the characteristics of KNOX and WOX transcriptional factors, their functions in meristem development, and interaction with the plant hormonal system. The role of homeodomain-containing transcriptional factors in tumorigenesis in plants and animals is discussed. The role of meristem-specific genes and phytohormones in tumorigenesis is discussed on the example of genetic tumors obtained by mutagenesis in Arabidopsis thaliana and tumors in the radish inbred lines.

  12. Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica

    PubMed Central

    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

  13. High-intensity ion sources for accelerators with emphasis on H-beam formation and transport

    SciTech Connect

    Keller, Roderich

    2009-01-01

    This paper lays out the fundamental working principles of a variety of high-current ion sources for accelerators in a tutorial manner, and gives examples of specific source types such as d. c. discharge- and rf-driven multicusp sources. Penning-type and ECR-based sources while discussing those principles, pointing out general performance limits as well as the performance parameters of specific sources. Laser-based, two-chamber-. and surface-ionization sources are briefly mentioned. Main aspects of this review are particle feed. ionization mechanism, beam formation and beam transport. Issues seen with beam formation and low-energy transport of negative hydrogen-ion beams are treated in detail.

  14. Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica.

    PubMed

    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

  15. 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.

  16. Mechanisms and control of beam halo formation in intense microwave sources and accelerators

    NASA Astrophysics Data System (ADS)

    Chen, C.; Pakter, R.

    2000-05-01

    Halo formation and control in space-charge-dominated electron and ion beams are investigated in parameter regimes relevant to the development of high-power microwave (HPM) sources and high-intensity electron and ion linear accelerators. In particular, a mechanism for electron beam halo formation is identified in high-power periodic permanent magnet (PPM) focusing klystron amplifiers. It is found in self-consistent simulations that large-amplitude current oscillations induce mismatched beam envelope oscillations and electron beam halo formation. Qualitative agreement is found between simulations and the 50 MW 11.4 GHz PPM focusing klystron experiment at Stanford Linear Accelerator Center (SLAC) (D. Sprehn, G. Caryotakis, E. Jongewaard, and R. M. Phillips, "Periodic permanent magnetic development for linear collider X-band klystrons," Proceedings of the XIXth International Linac Conference, Argonne National Laboratory Report ANL-98/28, 1998, p. 689). Moreover, a new class of cold-fluid corkscrewing elliptic beam equilibria is discovered for ultrahigh-brightness, space-charge dominated electron or ion beam propagation through a linear focusing channel consisting of uniform solenoidal magnetic focusing fields, periodic solenoidal magnetic focusing fields, and/or alternating-gradient quadrupole magnetic focusing fields in an arbitrary arrangement including field tapering. As an important application of such new cold-fluid corkscrewing elliptic beam equilibria, a technique is developed and demonstrated for controlling of halo formation and beam hollowing in a rms-matched ultrahigh-brightness ion beam as it is injected from an axisymmetric Pierce diode into an alternating-gradient magnetic quadrupole focusing channel.

  17. Circadian Disruption Accelerates Tumor Growth and Angio/Stromagenesis through a Wnt Signaling Pathway

    PubMed Central

    Yasuniwa, Yoshihiro; Izumi, Hiroto; Wang, Ke-Yong; Shimajiri, Shohei; Sasaguri, Yasuyuki; Kawai, Kazuaki; Kasai, Hiroshi; Shimada, Takashi; Miyake, Koichi; Kashiwagi, Eiji; Hirano, Gen; Kidani, Akihiko; Akiyama, Masaki; Han, Bin; Wu, Ying; Ieiri, Ichiro; Higuchi, Shun; Kohno, Kimitoshi

    2010-01-01

    Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more “normal” 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway. PMID:21203463

  18. Current sheet Formation in a Conical Theta Pinch Faraday Accelerator with Radio-Frequency Assisted Discharge

    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.

  19. Expression of a Mutant p53 Results in an Age-Related Demographic Shift in Spontaneous Lung Tumor Formation in Transgenic Mice

    PubMed Central

    Duan, Wenrui; Gao, Li; Wu, Xin; Hade, Erinn M.; Gao, Jian-Xin; Ding, Haiming; Barsky, Sanford H.; Otterson, Gregory A.; Villalona-Calero, Miguel A.

    2009-01-01

    Background Mutations in the P53 gene are among the most common genetic abnormalities in human lung cancer. Codon 273 in the sequence-specific DNA binding domain is one of the most frequently mutated sites. Methodology To investigate the role of mutant p53 in lung tumorigenesis, a lung specific p53(273H) transgenic mouse model was developed. Rates of lung cancer formation in the transgenic animals and their littermates were evaluated by necropsy studies performed in progressive age cohorts ranging from 4 to 24 months. In order to establish the influence of other common genetic abnormalities in lung tumor formation in the animals, K-Ras gene mutation and p16INK4a (p16) promoter methylation were evaluated in a total of 281 transgenic mice and 189 non-transgenic littermates. Principal Findings At the age extremes of 4–12 and 22–24 months no differences were observed, with very low prevalence of tumors in animals younger than 12 months, and a relatively high prevalence at age 22 months or older. However, the transgenic mice had a significant higher lung tumor rate than their non-transgenic counterparts during the age of 13–21 months, suggesting an age-related shift in lung tumor formation induced by the lung-specific expression of the human mutant p53. Histopathology suggested a more aggressive nature for the transgenic tumors. Older mice (>13 months) had a significantly higher rate of p16 promoter methylation (17% v 82%). In addition, an age related effect was observed for K-Ras codons 12 or 13 mutations, but not for codon 61 mutations. Conclusions/Significance These results would suggest that the mutant p53(273H) contributes to an acceleration in the development of spontaneous lung tumors in these mice. Combination with other genetic and epigenetic alterations occurring after the age of 13 months is intimately linked to its oncogenic potential. PMID:19440353

  20. Formation and persistence of 8-oxoguanine in rat lung cells as an important determinant for tumor formation following particle exposure.

    PubMed Central

    Nehls, P; Seiler, F; Rehn, B; Greferath, R; Bruch, J

    1997-01-01

    Exposure of rats to quartz (or various other particles) can lead to the development of lung tumors. At the moment, the mechanisms involved in particle-induced tumor formation are not clarified. However, it is suggested that inflammation, in conjunction with the production of reactive oxygen species (ROS) and an enhancement of epithelial cell proliferation, may play a key role in the development of lung tumors. ROS induces 8-oxoguanine (8-oxoGua) and other mutagenic DNA oxidation products, which can be converted to mutations in proliferating cells. Mutation formation in cancer-related genes is a critical event with respect to tumor formation. In this study we investigated the effects of quartz (DQ12) and of the nontumorigenic dust corundum on the induction of 8-oxoGua in the DNA of rat lung cells, as well as on cell proliferation and pulmonary inflammation. Wistar rats were exposed by intratracheal instillation to quartz (2.5 mg/rat) or corundum (2.5 mg/rat) suspended in physiological saline; control animals exposed to physiological saline or left untreated. Measurements were carried out 7, 21, and 90 days after the exposures. 8-oxoGua levels were determined in lung tissue sections at the single cell level by immunocytological assay using a rabbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua levels were significantly increased at all time points of investigation. Additionally, we observed inflammation and an enhanced cell proliferation. Exposure to corundum had no adverse effects on the lung; neither increased 8-oxoGua levels nor enhanced cell proliferation or inflammation were detected. These observations support the suggestion that inflammation associated with increased 8-oxoGua levels in lung cells and increased cell proliferation is an important determinant for particle-induced development of lung tumors in the rat. Images Figure 1. A i Figure 1. A ii Figure 1. A iii Figure 1. B Figure 1. B Figure 1. B Figure 1. C Figure 1. C Figure 1. C PMID

  1. Accelerated gravity testing of aquitard core permeability and implications at formation and regional scale

    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 × 10-9 to 2.0 × 10-9 m s-1. These Kv results were very similar to an independent in situ Kv method based on pore pressure propagation though the sequence. However, there was less certainty at two other core sites due to limited and variable Kv data. Blind standard 1 g column tests underestimated Kv compared to CP and in situ Kv data, possibly due to deionised water interactions with clay, and were more time-consuming than CP tests. Our Kv results were compared with the set-up of a flow model for the region, and considered in the context of heterogeneity and preferential flow paths at site and

  2. Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors

    PubMed Central

    Efimova, Elena V.; Mauceri, Helena J.; Golden, Daniel W.; Labay, Edwardine; Bindokas, Vytautas P.; Darga, Thomas E.; Chakraborty, Chaitali; Andrade, Juan Camilo Barreto; Crawley, Clayton; Sutton, Harold G.; Kron, Stephen J.; Weichselbaum, Ralph R.

    2010-01-01

    Persistent DNA double strand breaks (DSBs) may determine the anti-tumor effects of ionizing radiation (IR) by inducing apoptosis, necrosis, mitotic catastrophe or permanent growth arrest. Ionizing radiation (IR) induces rapid modification of megabase chromatin domains surrounding double strand breaks (DSBs) via poly-ADP-ribosylation, phosphorylation, acetylation, and protein assembly. The dynamics of these ionizing radiation-induced foci (IRIF) have been implicated in DNA damage signaling and DNA repair. As an IRIF reporter, we tracked relocalization of GFP fused to a chromatin binding domain of the checkpoint adapter protein 53BP1 after IR of breast cancer cells and tumors. To block DSB repair in breast cancer cells and tumors, we targeted poly(ADP-ribose) polymerase with ABT-888 (veliparib), one of several PARP inhibitors currently in clinical trials. PARP inhibition markedly enhanced IRIF persistence and increased breast cancer cell senescence both in vitro and in vivo, arguing for targeting IRIF resolution as a novel therapeutic strategy. PMID:20610628

  3. Mathematical modeling of capillary formation and development in tumor angiogenesis: penetration into the stroma.

    PubMed

    Levine, H A; Pamuk, S; Sleeman, B D; Nilsen-Hamilton, M

    2001-09-01

    molecular species in porous media. One consequence of our numerical simulations is that we obtain very good computational agreement with the time of the onset of vascularization and the rate of capillary tip growth observed in rabbit cornea experiments [Ausprunk, D. H. and J. Folkman (1977) Migration and proliferation of endothelial cells in performed and newly formed blood vessels during tumor angiogenesis, Microvasc Res., 14, 73-65; Brem, S., B. A. Preis, ScD. Langer, B. A. Brem and J. Folkman (1997) Inhibition of neovascularization by an extract derived from vitreous Am. J. Opthalmol., 84, 323-328; Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64; Gimbrone, M. A. Jr, R. S. Cotran, S. B. Leapman and J. Folkman (1974) Tumor growth and neovascularization: An experimental model using the rabbit cornea. J. Nat. Cancer Inst., 52, 413-419]. Furthermore, our numerical experiments agree with the observation that the tip of a growing capillary accelerates as it approaches the tumor [Folkman, J. (1976) The vascularization of tumors, Sci. Am., 234, 58-64]. PMID:11565406

  4. Formation of Ultrarelativistic Electron Rings from a Laser-Wakefield Accelerator.

    PubMed

    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.

  5. 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.

  6. p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

    PubMed Central

    Ide, Fumio; Kitada, Munenori; Sakashita, Hideaki; Kusama, Kaoru; Tanaka, Kiyoji; Ishikawa, Takatoshi

    2003-01-01

    Mice lacking the xeroderma pigmentosum group A gene (XPA−/− mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA−/− mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA−/−p53+/− mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA−/−p53+/+ littermates. XPA−/−p53−/− mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA−/−p53+/− mice maintained the p53+/− genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA−/−p53+/+ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency. PMID:14578172

  7. Three-Dimensional Culture Assay to Explore Cancer Cell Invasiveness and Satellite Tumor Formation.

    PubMed

    Côté, Marie-France; Turcotte, Audrey; Doillon, Charles; Gobeil, Stephane

    2016-01-01

    Mammalian cell culture in monolayers is widely used to study various physiological and molecular processes. However, this approach to study growing cells often generates unwanted artifacts. Therefore, cell culture in a three-dimensional (3D) environment, often using extracellular matrix components, emerged as an interesting alternative due to its close similarity to the native in vivo tissue or organ. We developed a 3D cell culture system using two compartments, namely (i) a central compartment containing cancer cells embedded in a collagen gel acting as a pseudo-primary macrospherical tumor and (ii) a peripheral cell-free compartment made of a fibrin gel, i.e. an extracellular matrix component different from that used in the center, in which cancer cells can migrate (invasion front) and/or form microspherical tumors representing secondary or satellite tumors. The formation of satellite tumors in the peripheral compartment is remarkably correlated to the known aggressiveness or metastatic origin of the native tumor cells, which makes this 3D culture system unique. This cell culture approach might be considered to assess cancer cell invasiveness and motility, cell-extracellular matrix interactions and as a method to evaluate anti-cancer drug properties. PMID:27585303

  8. Tumor-Specific Formation of Enzyme-Instructed Supramolecular Self-Assemblies as Cancer Theranostics.

    PubMed

    Huang, Peng; Gao, Yuan; Lin, Jing; Hu, Hao; Liao, Hsien-Shun; Yan, Xuefeng; Tang, Yuxia; Jin, Albert; Song, Jibin; Niu, Gang; Zhang, Guofeng; Horkay, Ferenc; Chen, Xiaoyuan

    2015-10-27

    Despite the effort of developing various nanodelivery systems, most of them suffer from undesired high uptakes by the reticuloendothelial system, such as liver and spleen. Herein we develop an endogenous phosphatase-triggered coassembly strategy to form tumor-specific indocyanine green (ICG)-doped nanofibers (5) for cancer theranostics. Based on coordinated intermolecular interactions, 5 significantly altered near-infrared absorbance of ICG, which improves the critical photoacoustic and photothermal properties. The phosphatase-instructed coassembly process, as well as its theranostic capability, was successfully conducted at different levels ranging from in vitro, living cell, tissue mimic, to in vivo. Specifically, the tumor uptake of ICG was markedly increased to 15.05 ± 3.78%ID/g, which was 25-fold higher than that of free ICG (0.59 ± 0.24%ID/g) at 4 h after intravenous injection. The resulting ultrahigh T/N ratios (>15) clearly differentiated tumors from the surrounding normal tissue. Complete tumor elimination with high therapeutic accuracy has been successfully achieved upon laser irradiation (0.8 W/cm(2), 5 min) within 24-48 h postinjection. As the first example, in vivo formation of tumor-specific ICG-doped nanofiber for PTT theranostics owns the immense potential for clinical translation of personalized nanomedicine with targeted drug delivery as well as for cancer theranostics.

  9. Tumor-Specific Formation of Enzyme-Instructed Supramolecular Self-Assemblies as Cancer Theranostics.

    PubMed

    Huang, Peng; Gao, Yuan; Lin, Jing; Hu, Hao; Liao, Hsien-Shun; Yan, Xuefeng; Tang, Yuxia; Jin, Albert; Song, Jibin; Niu, Gang; Zhang, Guofeng; Horkay, Ferenc; Chen, Xiaoyuan

    2015-10-27

    Despite the effort of developing various nanodelivery systems, most of them suffer from undesired high uptakes by the reticuloendothelial system, such as liver and spleen. Herein we develop an endogenous phosphatase-triggered coassembly strategy to form tumor-specific indocyanine green (ICG)-doped nanofibers (5) for cancer theranostics. Based on coordinated intermolecular interactions, 5 significantly altered near-infrared absorbance of ICG, which improves the critical photoacoustic and photothermal properties. The phosphatase-instructed coassembly process, as well as its theranostic capability, was successfully conducted at different levels ranging from in vitro, living cell, tissue mimic, to in vivo. Specifically, the tumor uptake of ICG was markedly increased to 15.05 ± 3.78%ID/g, which was 25-fold higher than that of free ICG (0.59 ± 0.24%ID/g) at 4 h after intravenous injection. The resulting ultrahigh T/N ratios (>15) clearly differentiated tumors from the surrounding normal tissue. Complete tumor elimination with high therapeutic accuracy has been successfully achieved upon laser irradiation (0.8 W/cm(2), 5 min) within 24-48 h postinjection. As the first example, in vivo formation of tumor-specific ICG-doped nanofiber for PTT theranostics owns the immense potential for clinical translation of personalized nanomedicine with targeted drug delivery as well as for cancer theranostics. PMID:26301492

  10. Guide to LIBXSIF, a Library for Parsing the Extended Standard Input Format of Accelerated Beamlines(LCC-0060)

    SciTech Connect

    Tenenbaum, P

    2003-12-03

    We describe LIBXSIF, a standalone library for parsing the Extended Standard Input Format of accelerator beamlines. Included in the description are: documentation of user commands; full description of permitted accelerator elements and their attributes; the construction of beamline lists; the mechanics of adding LIBXSIF to an existing program; and ''under the hood'' details for users who wish to modify the library or are merely morbidly curious.

  11. Biotic stress accelerates formation of climate-relevant aerosols in boreal forests

    NASA Astrophysics Data System (ADS)

    Joutsensaari, J.; Yli-Pirilä, P.; Korhonen, H.; Arola, A.; Blande, J. D.; Heijari, J.; Kivimäenpää, M.; Mikkonen, S.; Hao, L.; Miettinen, P.; Lyytikäinen-Saarenmaa, P.; Faiola, C. L.; Laaksonen, A.; Holopainen, J. K.

    2015-11-01

    Boreal forests are a major source of climate-relevant biogenic secondary organic aerosols (SOAs) and will be greatly influenced by increasing temperature. Global warming is predicted to not only increase emissions of reactive biogenic volatile organic compounds (BVOCs) from vegetation directly but also induce large-scale insect outbreaks, which significantly increase emissions of reactive BVOCs. Thus, climate change factors could substantially accelerate the formation of biogenic SOAs in the troposphere. In this study, we have combined results from field and laboratory experiments, satellite observations and global-scale modelling in order to evaluate the effects of insect herbivory and large-scale outbreaks on SOA formation and the Earth's climate. Field measurements demonstrated 11-fold and 20-fold increases in monoterpene and sesquiterpene emissions respectively from damaged trees during a pine sawfly (Neodiprion sertifer) outbreak in eastern Finland. Laboratory chamber experiments showed that feeding by pine weevils (Hylobius abietis) increased VOC emissions from Scots pine and Norway spruce seedlings by 10-50 fold, resulting in 200-1000-fold increases in SOA masses formed via ozonolysis. The influence of insect damage on aerosol concentrations in boreal forests was studied with a global chemical transport model GLOMAP and MODIS satellite observations. Global-scale modelling was performed using a 10-fold increase in monoterpene emission rates and assuming 10 % of the boreal forest area was experiencing outbreak. Results showed a clear increase in total particulate mass (local max. 480 %) and cloud condensation nuclei concentrations (45 %). Satellite observations indicated a 2-fold increase in aerosol optical depth over western Canada's pine forests in August during a bark beetle outbreak. These results suggest that more frequent insect outbreaks in a warming climate could result in substantial increase in biogenic SOA formation in the boreal zone and, thus

  12. Biotic stress accelerates formation of climate-relevant aerosols in boreal forests

    NASA Astrophysics Data System (ADS)

    Joutsensaari, J.; Yli-Pirilä, P.; Korhonen, H.; Arola, A.; Blande, J. D.; Heijari, J.; Kivimäenpää, M.; Mikkonen, S.; Hao, L.; Miettinen, P.; Lyytikäinen-Saarenmaa, P.; Faiola, C. L.; Laaksonen, A.; Holopainen, J. K.

    2015-04-01

    Boreal forests are a major source of climate-relevant biogenic secondary organic aerosols (SOA) and will be greatly influenced by increasing temperature. Global warming is predicted to increase emissions of reactive biogenic volatile organic compounds (BVOC) from vegetation directly, but will also induce large-scale insect outbreaks, which significantly increase emissions of reactive BVOC. Thus, climate change factors could substantially accelerate the formation of biogenic SOA in the troposphere. In this study, we have combined results from field and laboratory experiments, satellite observations and global scale modelling in order to evaluate the effects of insect herbivory and large-scale outbreaks on SOA formation and the Earth's climate. Field measurements demonstrated 11-fold and 20-fold increases in monoterpene and sesquiterpene emissions, respectively, from damaged trees during a pine sawfly (Neodiprion sertifer) outbreak in eastern Finland. Laboratory chamber experiments showed that feeding by pine weevils (Hylobius abietis) increased VOC emissions from Scots pine and Norway spruce seedlings by 10-50 fold resulting in 200-1000 fold increases in SOA masses formed via ozonolysis. The influence of insect damage on aerosol concentrations in boreal forests was studied with a global chemical transport model GLOMAP and MODIS satellite observations. Global scale modelling was performed using a 10-fold increase in monoterpene emission rates and assuming 10% of the boreal forest area was experiencing outbreak. Results showed a clear increase in total particulate mass (local max. 480%) and cloud condensation nuclei concentrations (45%). Satellite observations indicated a two-fold increase in aerosol optical depth (AOD) over western Canada's pine forests in August during a bark beetle outbreak. These results suggest that more frequent insect outbreaks in a warming climate could result in substantial increase in biogenic SOA formation in the boreal zone and, thus

  13. MMP7 Is Required to Mediate Cell Invasion and Tumor Formation upon Plakophilin3 Loss

    PubMed Central

    Basu, Srikanta; Thorat, Rahul; Dalal, Sorab N.

    2015-01-01

    Plakophilin3 (PKP3) loss results in increased transformation in multiple cell lines in vitro and increased tumor formation in vivo. A microarray analysis performed in the PKP3 knockdown clones, identified an inflammation associated gene signature in cell lines derived from stratified epithelia as opposed to cell lines derived from simple epithelia. However, in contrast to the inflammation associated gene signature, the expression of MMP7 was increased upon PKP3 knockdown in all the cell lines tested. Using vector driven RNA interference, it was demonstrated that MMP7 was required for in-vitro cell migration and invasion and tumor formation in vivo. The increase in MMP7 levels was due to the increase in levels of the Phosphatase of Regenerating Liver3 (PRL3), which is observed upon PKP3 loss. The results suggest that MMP7 over-expression may be one of the mechanisms by which PKP3 loss leads to increased cell invasion and tumor formation. PMID:25875355

  14. Accelerated Partial Breast Irradiation through Brachytherapy for Ductal Carcinoma in situ: Factors Influencing Utilization and Risks of Second Breast Tumors

    PubMed Central

    Liu, Ying; Schloemann, Derek T.; Lian, Min; Colditz, Graham A.

    2015-01-01

    Purpose To examine influencing factors and outcomes of accelerated partial breast irradiation through brachytherapy (APBIb) versus whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). Patients and Methods From the Surveillance Epidemiology and End Results program, we identified 40749 women who were diagnosed with first primary DCIS between 2002 and 2011 and treated with breast conserving surgery (BCS) and radiotherapy. A multi-level logistic regression analysis was performed to estimate odds ratios of APBIb use. Hazard ratios (HRs) of developing ipsilateral breast tumors (IBTs) and contralateral breast tumors (CBTs) were analyzed in 1962 patients with APBIb and 7203 propensity score-matched patients with WBI, using Cox proportional hazards regression. Results Overall, 2212 (4.5%) of 40749 women (the whole cohort) received APBIb. Factors associated with the increased use of APBIb included older age, non-Hispanic white race/ethnicity, smaller tumor size, hormone receptor positivity, comedo subtypes and urban residence. During the 46-month follow-up, 74 (0.8%) and 131 (1.4%) of 9165 propensity score-matched patients developed IBTs and CBTs, respectively. Compared with WBI, APBIb was associated with a significantly increased risk of IBTs (HR, 1.74; 95% CI, 1.06 to 2.85) but not CBTs (OR, 0.91; 95% CI, 0.59 to 1.41). Conclusion This population-based study suggests that APBIb use for DCIS was influenced by patient and tumor characteristics as well as urbanization of residence. We observed a moderately increased IBT risk associated with APBIb versus WBI, suggesting that APBIb should be used with caution for DCIS before data from randomized controlled trials with long-term followups are available. PMID:25893591

  15. Removal of boron from wastewater by the hydroxyapatite formation reaction using acceleration effect of ammonia.

    PubMed

    Yoshikawa, Eishi; Sasaki, Atsushi; Endo, Masatoshi

    2012-10-30

    The mechanism was discussed for the removal of boron by the hydroxyapatite (HAp) formation reaction using Ca(OH)(2) and (NH(4))(2)HPO(4) in room temperature. Time required to remove boron was 20 min by adding Ca(OH)(2) and (NH(4))(2)HPO(4) for the remaining boron to below 1mg/L. The removal rate of boron was controlled by the HAp precipitate formation and the presence of ammonia. From the XRD patterns and SEM images, HAp could be confirmed in the precipitate product. The reaction between borate ions and calcium hydroxide was accelerated by dehydration with ammonia; the borate-calcium hydroxide compound coprecipitated with resulting HAp. Although the removal of boron decreased in the presence of sulfate, phosphate, and aluminum, these effects could be prevented by adding excess Ca(OH)(2). Interference of fluoride ions was eliminated by adding Al(3+). Sodium alpha-olefin sulfonate was the most effective coagulant for HAp precipitation. The proposed boron removal method has several advantages about treating time and ability of boron removal. The method was successfully applied to the real hot spring wastewater.

  16. Removal of boron from wastewater by the hydroxyapatite formation reaction using acceleration effect of ammonia.

    PubMed

    Yoshikawa, Eishi; Sasaki, Atsushi; Endo, Masatoshi

    2012-10-30

    The mechanism was discussed for the removal of boron by the hydroxyapatite (HAp) formation reaction using Ca(OH)(2) and (NH(4))(2)HPO(4) in room temperature. Time required to remove boron was 20 min by adding Ca(OH)(2) and (NH(4))(2)HPO(4) for the remaining boron to below 1mg/L. The removal rate of boron was controlled by the HAp precipitate formation and the presence of ammonia. From the XRD patterns and SEM images, HAp could be confirmed in the precipitate product. The reaction between borate ions and calcium hydroxide was accelerated by dehydration with ammonia; the borate-calcium hydroxide compound coprecipitated with resulting HAp. Although the removal of boron decreased in the presence of sulfate, phosphate, and aluminum, these effects could be prevented by adding excess Ca(OH)(2). Interference of fluoride ions was eliminated by adding Al(3+). Sodium alpha-olefin sulfonate was the most effective coagulant for HAp precipitation. The proposed boron removal method has several advantages about treating time and ability of boron removal. The method was successfully applied to the real hot spring wastewater. PMID:22981286

  17. Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis

    PubMed Central

    Ito, Hiromitsu; Tanaka, Shinji; Akiyama, Yoshimitsu; Shimada, Shu; Adikrisna, Rama; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Yamaoka, Shoji; Tanabe, Minoru

    2016-01-01

    Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer. PMID:26764906

  18. Phosphoribosylpyrophosphate Synthetase 1 Knockdown Suppresses Tumor Formation of Glioma CD133+ Cells Through Upregulating Cell Apoptosis.

    PubMed

    Li, Chen; Yan, Zhongjie; Cao, Xuhua; Zhang, Xiaowei; Yang, Liang

    2016-10-01

    Relapse is the main cause of mortality in patients with glioblastoma multiforme (GBM). Treatment options involve surgical resection followed by a combination of radiotheraphy and chemotherapy with temozolomide. Several genes and genetic pathways have been identified to contribute to therapeutic resistance, giving rise to recurrence of the malignancy. In the last decades, glioma stem cells (GSCs) with the capacity of self-renewal have been demonstrated to maintain tumor propagation and treatment resistance. Here, we isolated CD133-positive (CD133+) and CD133-negative (CD133-) cells from glioblastoma U98G and U87MG cell lines. The role of phosphoribosylpyrophosphate synthetase 1 (PRPS1), which catalyzes the first step of the synthesis of nucleotide, in proliferation and apoptosis was investigated. We found that PRPS1 had a remarkable effect on cell proliferation and sphere formation in both CD133+ and CD133- cells. Compared to CD133- cells, CD133+ cells exhibited more significant results in cell apoptosis assay. CD133+ T98G and U87MG cells were used in xenograft mouse model of tumor formation. Interestingly, the mice implanted with PRPS1 knockdown T98G or U87MG stem cells exhibited prolonged survival time and reduced tumor volume. By immunostaining caspase-3 in tumor tissues of these mice, we demonstrated that the apoptotic activities in tumor cells were positively correlated to the survival time but negatively correlated to PRPS1 expression. Our results indicate that PRPS1 plays an important role in proliferation and apoptosis in GSCs and provide new clues for potential PRPS1-targeted therapy in GBM treatment. PMID:27343059

  19. Clinical Outcome in Pediatric Glial and Embryonal Brain Tumors Correlates With In Vitro Multi-Passageable Neurosphere Formation

    PubMed Central

    Panosyan, Eduard H.; Laks, Dan R.; Masterman-Smith, Michael; Mottahedeh, Jack; Yong, William H.; Cloughesy, Timothy F.; Lazareff, Jorge A.; Mischel, Paul S.; Moore, Theodore B.; Kornblum, Harley I.

    2014-01-01

    Background Cultured brain tumors can form neurospheres harboring tumorigenic cells with self renewal and differentiation capacities. Renewable neurosphere formation has clinical predictive value in adult malignant gliomas, yet its prognostic role for pediatric brain tumors is unknown. Methods Established neurosphere conditions were used for culturing samples from glial, embryonal and mixed glioneuronal tumors from 56 pediatric patients. Potential associations between neurosphere formation and clinical outcome were analyzed retrospectively. Results Thirty-seven percent of all samples formed renewable neurospheres. Analysis of available clinical outcome data from 51 patients demonstrated significantly increased hazard ratios (HR) for both disease progression (HR=9.9, P < 0.001) and death (HR=16.6, P < 0.01) in the neurosphere forming group. Furthermore, neurosphere formation correlated with adverse progression free survival (PFS) in glial and embryonal tumors, but not in mixed glioneuronal tumors. Overall survival (OS) was significantly worse for neurosphere-forming patients with embryonal tumors, as a group and amongst the subgroup with medulloblastoma, but not in the glial group. Multivariate analysis showed that neurosphere formation was associated with diminished PFS and OS independent of age, gender, or treatment. Neurosphere formation was an independent predictor of diminished PFS of glial tumors after adjusting for grade. Multivariate analysis, adjusting for both Ki67 staining and neurosphere formation, demonstrated that neurosphere formation remained predictive of progression whereas Ki67 did not. Conclusions Neurosphere formation is more predictive of pediatric brain tumor progression than semi-quantitative Ki67 staining. Pediatric brain tumor derived neurospheres may provide a predictive model for preclinical explorations. PMID:20589659

  20. Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy

    SciTech Connect

    Massimino, Maura . E-mail: maura.massimino@istitutotumori.mi.it; Gandola, Lorenza; Spreafico, Filippo; Luksch, Roberto; Collini, Paola; Giangaspero, Felice; Simonetti, Fabio; Casanova, Michela; Cefalo, Graziella; Pignoli, Emanuele; Ferrari, Andrea; Terenziani, Monica; Podda, Marta; Meazza, Cristina; Polastri, Daniela; Poggi, Geraldina; Ravagnani, Fernando; Fossati-Bellani, Franca

    2006-03-15

    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 in 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.

  1. Core-shell hydrogel beads with extracellular matrix for tumor spheroid formation

    PubMed Central

    Yu, L.; Grist, S. M.; Nasseri, S. S.; Ni, C.; Cheung, K. C.

    2015-01-01

    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. PMID:25945144

  2. Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma

    PubMed Central

    Puzio-Kuter, A M; Laddha, S V; Castillo-Martin, M; Sun, Y; Cordon-Cardo, C; Chan, C S; Levine, A J

    2015-01-01

    Liposarcoma (LPS) is a type of soft tissue sarcoma that mostly occurs in adults, and in humans is characterized by amplifications of MDM2 and CDK4. The molecular pathogenesis of this malignancy is still poorly understood and, therefore, we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease. We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS (from well-differentiated LPS to pleomorphic LPS). In addition, progression of the tumors is further characterized by the expression of D cyclins and CDK4/6, which allow for continued cell division. Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS, which could aid in understanding the disease and to unravel potential new therapeutic targets. PMID:25822339

  3. YB-1 regulates stress granule formation and tumor progression by translationally activating G3BP1

    PubMed Central

    Somasekharan, Syam Prakash; El-Naggar, Amal; Leprivier, Gabriel; Cheng, Hongwei; Hajee, Shamil; Grunewald, Thomas G.P.; Zhang, Fan; Ng, Tony; Delattre, Olivier; Evdokimova, Valentina; Wang, Yuzhuo; Gleave, Martin

    2015-01-01

    Under cell stress, global protein synthesis is inhibited to preserve energy. One mechanism is to sequester and silence mRNAs in ribonucleoprotein complexes known as stress granules (SGs), which contain translationally silent mRNAs, preinitiation factors, and RNA-binding proteins. Y-box binding protein 1 (YB-1) localizes to SGs, but its role in SG biology is unknown. We now report that YB-1 directly binds to and translationally activates the 5′ untranslated region (UTR) of G3BP1 mRNAs, thereby controlling the availability of the G3BP1 SG nucleator for SG assembly. YB-1 inactivation in human sarcoma cells dramatically reduces G3BP1 and SG formation in vitro. YB-1 and G3BP1 expression are highly correlated in human sarcomas, and elevated G3BP1 expression correlates with poor survival. Finally, G3BP1 down-regulation in sarcoma xenografts prevents in vivo SG formation and tumor invasion, and completely blocks lung metastasis in mouse models. Together, these findings demonstrate a critical role for YB-1 in SG formation through translational activation of G3BP1, and highlight novel functions for SGs in tumor progression. PMID:25800057

  4. Ghrelin accelerates synapse formation and activity development in cultured cortical networks

    PubMed Central

    2014-01-01

    Background While ghrelin was initially related to appetite stimulation and growth hormone secretion, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of those processes is related to synaptic efficacy and plasticity. Previous studies have shown that ghrelin not only stimulates synapse formation in cultured cortical neurons and hippocampal slices, but also alters some of the electrophysiological properties of neurons in the hypothalamus, amygdala and other subcortical areas. However, direct evidence for ghrelin’s ability to modulate the activity in cortical neurons is not available yet. In this study, we investigated the effect of acylated ghrelin on the development of the activity level and activity patterns in cortical neurons, in relation to its effect on synaptogenesis. Additionally, we quantitatively evaluated the expression of the receptor for acylated ghrelin – growth hormone secretagogue receptor-1a (GHSR-1a) during development. Results We performed electrophysiology and immunohistochemistry on dissociated cortical cultures from neonates, treated chronically with acylated ghrelin. On average 76 ± 4.6% of the cortical neurons expressed GHSR-1a. Synapse density was found to be much higher in ghrelin treated cultures than in controls across all age groups (1, 2 or 3 weeks). In all cultures (control and ghrelin treated), network activity gradually increased until it reached a maximum after approximately 3 weeks, followed by a slight decrease towards a plateau. During early developmental stages (1–2 weeks), the activity was much higher in ghrelin treated cultures and consequently, they reached the plateau value almost a week earlier than controls. Conclusions Acylated ghrelin leads to earlier network formation and activation in cultured cortical neuronal networks, the latter being a possibly consequence of accelerated synaptogenesis. PMID:24742241

  5. Blockage of neddylation modification stimulates tumor sphere formation in vitro and stem cell differentiation and wound healing in vivo

    PubMed Central

    Zhou, Xiaochen; Tan, Mingjia; Nyati, Mukesh K.; Zhao, Yongchao; Wang, Gongxian; Sun, Yi

    2016-01-01

    MLN4924, also known as pevonedistat, is the first-in-class inhibitor of NEDD8-activating enzyme, which blocks the entire neddylation modification of proteins. Previous preclinical studies and current clinical trials have been exclusively focused on its anticancer property. Unexpectedly, we show here, to our knowledge for the first time, that MLN4924, when applied at nanomolar concentrations, significantly stimulates in vitro tumor sphere formation and in vivo tumorigenesis and differentiation of human cancer cells and mouse embryonic stem cells. These stimulatory effects are attributable to (i) c-MYC accumulation via blocking its degradation and (ii) continued activation of EGFR (epidermal growth factor receptor) and its downstream pathways, including PI3K/AKT/mammalian target of rapamycin and RAS/RAF/MEK/ERK, via inducing EGFR dimerization. Finally, MLN4924 accelerates EGF-mediated skin wound healing in mouse and stimulates cell migration in an in vitro culture setting. Taking these data together, our study reveals that neddylation modification could regulate stem cell proliferation and differentiation and that a low dose of MLN4924 might have a therapeutic value for stem cell therapy and tissue regeneration. PMID:27162365

  6. Failure-to-thrive syndrome associated with tumor formation by Madin-Darby canine kidney cells in newborn nude mice.

    PubMed

    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

    2013-08-01

    Tumors that formed in newborn nude mice that were inoculated with 10(7) 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 = 10(2.8) to 10(7.5)); 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

  7. alpha-Lactalbumin species variation, HAMLET formation, and tumor cell death.

    PubMed

    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.

  8. Direct measurement of formation of loops in DNA by a human tumor suppressor protein

    NASA Astrophysics Data System (ADS)

    Migliori, Amy; Kung, Samuel; Wang, Danielle; Smith, Douglas E.

    2013-09-01

    In previous work we developed methods using optical tweezers to measure protein-mediated formation of loops in DNA structures that can play an important role in regulating gene expression. We previously applied this method to study two-site restriction endonucleases, which were convenient model systems for studying this phenomenon. Here we report preliminary work in which we have applied this method to study p53, a human tumor suppressor protein, and show that we can measure formation of loops. Previous biophysical evidence for loops comes from relatively limited qualitative studies of fixed complexes by electron microscopy4. Our results provide independent corroboration and future opportunities for more quantitative studies investigating structure and mechanics.

  9. Accelerated Tumor Growth Mediated by Sub-lytic Levels of Antibody-Induced Complement Activation is Associated with Activation of the PI3K/AKT Survival Pathway

    PubMed Central

    Wu, Xiaohong; Ragupathi, Govind; Panageas, Katherine; Hong, Feng; Livingston, Philip O.

    2013-01-01

    Purpose We addressed the possibility that low levels of tumor cell bound antibodies targeting gangliosides might accelerate tumor growth. Experimental Design To test this hypothesis, we treated mice with a range of mAb doses against GM2, GD2, GD3 and CD20 after challenge with tumors expressing these antigens and tested the activity of the same mAbs in-vitro. We also explored the mechanisms behind the complement-mediated tumor growth acceleration that we observed and an approach to overcome it. Results Serologically detectable levels of IgM-mAb against GM2 are able to delay or prevent tumor growth of high GM2-expressing cell lines both in-vitro and in a SCID mouse model, while very low levels of this mAb resulted in slight but consistent acceleration of tumor growth in both settings. Surprisingly, this is not restricted to IgM antibodies targeting GM2 but consistent against IgG-mAb targeting GD3 as well. These findings were mirrored by in-vitro studies with antibodies against these antigens as well as GD2 and CD20 (with Rituxan), and shown to be complement-dependent in all cases. Complement-mediated accelerated growth of cultured tumor cell lines initiated by low mAb levels was associated with activation of the PI3K/AKT survival pathway and significantly elevated levels of both p-AKT and p-PRAS40. This complement-mediated PI3K-activation and accelerated tumor growth in-vitro and in-vivo are eliminated by PI3K-inhibitors NVP-BEZ235 and Wortmannin. These PI3K-inhibitors also significantly increased efficacy of high doses of these 4 mAbs. Conclusion Our findings suggest that manipulation of the PI3K/AKT pathway and its signaling network can significantly increase the potency of passively administered mAbs and vaccine-induced-antibodies targeting a variety of tumor-cell-surface-antigens. PMID:23833306

  10. Tumor

    MedlinePlus

    ... plants (aflatoxins) Excessive sunlight exposure Genetic problems Obesity Radiation exposure Viruses Types of tumors known to be caused by viruses are: Cervical cancer (human papillomavirus) Hepatocellular carcinoma (hepatitis B and hepatitis C ...

  11. 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.

  12. 17AAG Treatment Accelerates Doxorubicin Induced Cellular Senescence: Hsp90 Interferes with Enforced Senescence of Tumor Cells

    PubMed Central

    Sarangi, Upasana; Paithankar, Khande Rao; Kumar, Jonnala Ujwal; Subramaniam, Vaidyanathan; Sreedhar, Amere Subbarao

    2012-01-01

    Hsp90 chaperone has been identified as an attractive pharmacological target to combat cancer. However, some metastatic tumors either fail to respond to Hsp90 inhibition or show recovery necessitating irreversible therapeutic strategies. In response to this enforced senescence has been proposed as an alternate strategy. Here, we demonstrate that inhibiting Hsp90 with 17AAG sensitizes human neuroblastoma to DNA damage response mediated cellular senescence. Among individual and combination drug treatments, 17AAG pre-treatment followed by doxorubicin treatment exhibited senescence-like characteristics such as increased nucleus to cytoplasm ratio, cell cycle arrest, SA-β-gal staining and the perpetual increase in SAHF. Doxorubicin induced senescence signaling was mediated by p53-p21CIP/WAF-1 and was accelerated in the absence of functional Hsp90. Sustained p16INK4a and H3K4me3 expressions correlating with unaffected telomerase activation annulled replicative senescence and appraised stress induced senescence. Despite increases in [(ROS)i] and [(Ca2+)i], a concomitant increase in cellular antioxidant defense system suggested oxidation independent senescence activation. Sustained activation of survival (Akt) and proliferative (ERK1/2) kinases fosters robustness of cells. Invigorating senescent cells with growth factor or snooping with mTOR or PI3 kinase inhibitors compromised cell survival but not senescence. Intriguingly, senescence-associated secretory factors from the senescence cells manifested established senescence in neuroblastoma, which offers clinical advantage to our approach. Our study discusses tumor selective functions of Hsp90 and discusses irrefutable strategies of Hsp90 inhibition in anticancer treatments. PMID:22915839

  13. Failure-to-Thrive Syndrome Associated with Tumor Formation by Madin–Darby Canine Kidney Cells in Newborn Nude Mice

    PubMed Central

    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

  14. The Formation of Kappa-Distribution Accelerated Electron Populations in Solar Flares

    NASA Astrophysics Data System (ADS)

    Bian, N. H.; Kontar, E.; Emslie, G.

    2015-12-01

    Driven by recent RHESSI observations of confined loop-top hard X-ray sources in solar flares, we consider stochastic acceleration of electrons in the presence of Coulomb collisions. If electron escape from the acceleration region can be neglected, the electron distribution function is determined by a balance between diffusive acceleration and collisions. Such a scenario admits a stationary solution for the electron distribution function that takes the form of a kappa distribution. We show that the evolution toward this kappa distribution involves a "wave front" propagating forwards in velocity space, so that electrons of higher energy are accelerated later; the acceleration time scales as the power three-half of the energy. At sufficiently high energies escape from the finite-length acceleration region will eventually dominate. For such energies, the electron velocity distribution function is obtained by solving a time-dependent Fokker-Planck equation in the "leaky-box" approximation. Solutions are obtained in the limit of a small escape rate from an acceleration region that can effectively be considered a thick target.

  15. The formation of kappa-distribution accelerated electron populations in solar flares

    SciTech Connect

    Bian, Nicolas H.; Stackhouse, Duncan J.; Kontar, Eduard P.; Emslie, A. Gordon E-mail: d.stackhouse.1@research.gla.ac.uk E-mail: emslieg@wku.edu

    2014-12-01

    Driven by recent RHESSI observations of confined loop-top hard X-ray sources in solar flares, we consider stochastic acceleration of electrons in the presence of Coulomb collisions. If electron escape from the acceleration region can be neglected, the electron distribution function is determined by a balance between diffusive acceleration and collisions. Such a scenario admits a stationary solution for the electron distribution function that takes the form of a kappa distribution. We show that the evolution toward this kappa distribution involves a 'wave front' propagating forward in velocity space, so that electrons of higher energy are accelerated later; the acceleration timescales with energy according to τ{sub acc} ∼ E {sup 3/2}. At sufficiently high energies escape from the finite-length acceleration region will eventually dominate. For such energies, the electron velocity distribution function is obtained by solving a time-dependent Fokker-Planck equation in the 'leaky-box' approximation. Solutions are obtained in the limit of a small escape rate from an acceleration region that can effectively be considered a thick target.

  16. Tumor-Associated Glycans and Their Role in Gynecological Cancers: Accelerating Translational Research by Novel High-Throughput Approaches

    PubMed Central

    Pochechueva, Tatiana; Jacob, Francis; Fedier, Andre; Heinzelmann-Schwarz, Viola

    2012-01-01

    Glycans are important partners in many biological processes, including carcinogenesis. The rapidly developing field of functional glycomics becomes one of the frontiers of biology and biomedicine. Aberrant glycosylation of proteins and lipids occurs commonly during malignant transformation and leads to the expression of specific tumor-associated glycans. The appearance of aberrant glycans on carcinoma cells is typically associated with grade, invasion, metastasis and overall poor prognosis. Cancer-associated carbohydrates are mostly located on the surface of cancer cells and are therefore potential diagnostic biomarkers. Currently, there is increasing interest in cancer-associated aberrant glycosylation, with growing numbers of characteristic cancer targets being detected every day. Breast and ovarian cancer are the most common and lethal malignancies in women, respectively, and potential glycan biomarkers hold promise for early detection and targeted therapies. However, the acceleration of research and comprehensive multi-target investigation of cancer-specific glycans could only be successfully achieved with the help of a combination of novel high-throughput glycomic approaches. PMID:24957768

  17. 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.

  18. Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

    PubMed

    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

  19. A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth

    PubMed Central

    Xiao, Nan; Cao, Hongbin; Chen, Che-Hong; Kong, Christina S.; Ali, Rehan; Chan, Cato; Sirjani, Davud; Graves, Edward; Koong, Albert; Giaccia, Amato; Mochly-Rosen, Daria; Le, Quynh-Thu

    2013-01-01

    Purpose To determine the effect of Alda-89 (an ALDH3 activitor) on (1) the function of irradiated (RT) submandibular gland (SMG) in mice, (2) its toxicity profile and (3) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo. Experimental Design Adult mice were infused with Alda-89 or vehicle before, during and after RT. Saliva secretion was monitored weekly. Hematology, metabolic profile and post-mortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and SCID mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 HNC patients and correlated to freedom from relapse (FFR) and overall survival (OS). Results Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after RT compared to vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared to vehicle control, Alda-89 treatment did not accelerate HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without RT. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either HPV-positive or HPV-negative group. Conclusion Alda-89 preserves salivary function after RT without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate RT-related xerostomia. PMID:23812668

  20. Formation of SCR Energy Spectra during Stochastic Acceleration with Allowance for Coulomb Losses

    NASA Astrophysics Data System (ADS)

    Ostryakov, V. M.; Kartavykh, Yu. Yu.; Koval'Tsov, G. A.

    2000-02-01

    The stochastic acceleration of heavy ions by Alfven turbulence is considered with allowance for Coulomb losses. The pattern of energy dependence of these losses gives rise to characteristic features in the energy spectra of the accelerated particles at energies of the order of several MeV per nucleon. The manifestation of these features in the spectra is sensitive to the temperature and density of the medium, which can serve as a basis for plasma diagnostics in the flare region. Some impulsive solar energetic particle events during which features in the spectra of He-3 and He-4 were observed are considered as an example.

  1. Accelerated thermokarst formation in the McMurdo Dry Valleys, Antarctica

    NASA Astrophysics Data System (ADS)

    Levy, J. S.; Fountain, A. G.; Dickson, J. L.; Head, J. W.; Okal, M. H.; Marchant, D. R.

    2013-12-01

    Thermokarst is a land surface lowered and disrupted by melting ground ice. Thermokarst is a major consequence of climate change in the Arctic, but has been considered to be a minor process in Antarctica. Garwood Valley (78°S, 164°E) is a coastal valley in the McMurdo Dry Valleys (MDV) of Southern Victoria Land, Antarctica and is a natural laboratory in which competing models of Antarctic thermokarst erosion can be tested. Garwood Valley is partially filled with a remnant of the Ross Sea Ice Sheet, a debris-covered ice mass that lodged in the valley during the Pleistocene. Rapid ablation of this buried ice mass via melting and block calving has recently been detected at a large retrogressive thaw feature referred to as the Garwood Valley ice cliff. Curiously, regional air temperatures in the MDV have been declining or stable on decadal timescales. Despite no increase in thawing degree days in Garwood Valley, biannual LiDAR scans show large-scale thermokarst backwasting occurring along the entire face of the ice cliff. Since ground-based data collection began in November 2010 to January, 2012, the ~400 m long ice cliff has backwasted ~1-3 m. Since airborne LiDAR data were first collected in 2001-2002 to January, 2012, backwasting along the ice cliff has ranged from 10-55 m, totaling 44,900 × 900 m3, or on average, 5,000 × 100 m3/year. From November 2010 to January 2011, 6,700 × 130 m3 of ice and capping sediment was removed from the Garwood Valley ice cliff; from January 2011 to January 2012, 11,300 × 230 m3 of material was removed. These melt and calving rates are comparable to the low end of retrogressive thaw slump erosion in Arctic and alpine environments, and suggest that some coastal MDV ground ice may no longer be stable under current climate conditions. Here, we combine this ground-based and airborne LiDAR data with with timelapse imaging and meteorological data to show that 1) thermokarst formation has accelerated in Garwood Valley; 2) the rate of

  2. Estrogen deprivation and excess energy supply accelerate 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in C3H/HeN mice

    PubMed Central

    Kim, Jin; Lee, Yoon Hee; Park, Jung Han Yoon

    2015-01-01

    BACKGROUND/OBJECTIVES Obesity is a risk factor of breast cancer in postmenopausal women. Estrogen deprivation has been suggested to cause alteration of lipid metabolism thereby creating a cellular microenvironment favoring tumor growth. The aim of this study is to investigate the effects of estrogen depletion in combination with excess energy supply on breast tumor development. MATERIALS/METHODS Ovariectomized (OVX) or sham-operated C3H/HeN mice at 4 wks were provided with either a normal diet or a high-fat diet (HD) for 16 weeks. Breast tumors were induced by administration of 7,12-dimethylbenz(a)anthracene once a week for six consecutive weeks. RESULTS Study results showed higher serum concentrations of free fatty acids and insulin in the OVX+HD group compared to other groups. The average tumor volume was significantly larger in OVX+HD animals than in other groups. Expressions of mammary tumor insulin receptor and mammalian target of rapamycin proteins as well as the ratio of pAKT/AKT were significantly increased, while pAMPK/AMPK was decreased in OVX+HD animals compared to the sham-operated groups. Higher relative expression of liver fatty acid synthase mRNA was observed in OVX+HD mice compared with other groups. CONCLUSIONS These results suggest that excess energy supply affects the accelerated mammary tumor growth in estrogen deprived mice. PMID:26634052

  3. Cancer cell–derived microparticles bearing P-selectin glycoprotein ligand 1 accelerate thrombus formation in vivo

    PubMed Central

    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

  4. Structural changes of tumor necrosis factor alpha associated with membrane insertion and channel formation.

    PubMed Central

    Baldwin, R L; Stolowitz, M L; Hood, L; Wisnieski, B J

    1996-01-01

    Low pH enhances tumor necrosis factor alpha (TNF)-induced cytolysis of cancer cells and TNF-membrane interactions that include binding, insertion, and ion-channel formation. We have also found that TNF increases Na+ influx in cells. Here, we examined the structural features of the TNF-membrane interaction pathway that lead to channel formation. Fluorometric studies link TNF's acid-enhanced membrane interactions to rapid but reversible acquisition of hydrophobic surface properties. Intramembranous photolabeling shows that (i) protonation of TNF promotes membrane insertion, (ii) the physical state of the target bilayer affects the kinetics and efficiency of TNF insertion, and (iii) binding and insertion of TNF are two distinct events. Acidification relaxes the trimeric structure of soluble TNF so that the cryptic carboxyl termini, centrally located at the base of the trimer cone, become susceptible to carboxypeptidase Y. After membrane insertion, TNF exhibits a trimeric configuration in which the carboxyl termini are no longer exposed; however, the proximal salt-bridged Lys-11 residues as well as regional surface amino acids (Glu-23, Arg-32, and Arg-44) are notably more accessible to proteases. The sequenced cleavage products bear the membrane-restricted photoreactive probe, proof that surface-cleaved TNF has an intramembranous disposition. In summary, the trimer's structural plasticity is a major determinant of its channel-forming ability. Channel formation occurs when cracked or partially splayed trimers bind and penetrate the bilayer. Reannealing leads to a slightly relaxed trimeric structure. The directionality of bilayer penetration conforms with x-ray data showing that receptor binding to the monomer interfaces of TNF poises the tip of the trimeric cone directly above the target cell membrane. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8577707

  5. Tumor abscess formation caused by Morganella morganii complicated with bacteremia in a patient with gastrointestinal stromal tumor.

    PubMed

    Chen, Hsuan-Wei; Lin, Te-Yu

    2012-04-01

    We report the case of a 22-year-old man who presented with a 3-day history of watery diarrhea, abdominal pain, and fever. An image of the abdomen showed a heterogeneously echogenic mass lesion in the pelvis. The results of the blood cultures performed on admission showed the presence of Morganella morganii. Computed tomography-guided tube drainage was performed, and a culture of the drained abscess fluid yielded M. morganii growth. Exploratory laparotomy with segmental resection of the jejunum and excision of the tumor was performed. Pathological examination showed a gastrointestinal stromal tumor (GIST). A GIST abscess caused by M. morganii was diagnosed on the basis of radiological, microbiological, and histopathological findings. The possibility of an infected GIST should be considered during the differential diagnosis of patients with suspected abdominal neoplasm and bacteremia.

  6. 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.

  7. 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.

  8. Graphics processing unit-accelerated non-rigid registration of MR images to CT images during CT-guided percutaneous liver tumor ablations

    PubMed Central

    Tokuda, Junichi; Plishker, William; Torabi, Meysam; Olubiyi, Olutayo I; Zaki, George; Tatli, Servet; Silverman, Stuart G.; Shekhar, Raj; Hata, Nobuhiko

    2015-01-01

    Rationale and Objectives Accuracy and speed are essential for the intraprocedural nonrigid MR-to-CT image registration in the assessment of tumor margins during CT-guided liver tumor ablations. While 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 based on volume subdivision with hardware acceleration using a graphical 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. Materials and Methods 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’s t-test. Results Accuracy of the GPU-accelerated registrations and B-spline registrations, respectively were 88.3 ± 3.7% vs 89.3 ± 4.9% (p = 0.41) for DSC and 13.1 ± 5.2 mm vs 11.4 ± 6.3 mm (p = 0.15) for HD. Total processing time of the GPU-accelerated registration and B-spline registration techniques was 88 ± 14 s vs 557 ± 116 s (p < 0.000000002), respectively; there was no significant difference in computation time despite the difference in the complexity of the algorithms (p = 0.71). Conclusion The GPU-accelerated volume subdivision technique was as accurate as the B-spline technique and required significantly less processing time. The GPU-accelerated

  9. High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice.

    PubMed

    Kwong, Alan M; Tippin, Brigette L; Materi, Alicia M; Buslon, Virgilio S; French, Samuel W; Lin, Henry J

    2011-01-01

    High doses of niacin (nicotinic acid) used to treat dyslipidemias cause flushing, due to high levels of prostaglandin D(2) (PGD(2)). GPR109A, a G-protein coupled receptor, triggers the flushing in the skin. In addition to boosting PGD(2), niacin binding to GPR109A activates the entire prostanoid cascade. We found that GPR109A occurs throughout the gastrointestinal tract. Mice that alternated between a 1% niacin diet and a control diet had higher urinary prostaglandin E(2) (PGE(2)) metabolite levels when on niacin (2.8-fold increase; 95% confidence interval, 1.8-3.9). PGE(2) promotes tumors in the intestines, whereas PGD(2) may have an opposite effect, on the basis of our report showing that transgenic hematopoietic prostaglandin D synthase suppresses intestinal adenomas in Apc(Min/+) mice. To determine if either tumor growth or tumor suppression prevails, we fed Apc(Min/+) mice a 1% niacin diet and assessed tumor development. A 1% niacin diet did not affect the number of tumors scored histologically in Apc(Min/+) mice at 14 wk (33 mice on niacin, 33 controls). Although niacin stimulates production of various prostaglandins, our results support an interpretation that very high intakes of niacin are safe in relation to intestinal tumors in this model.

  10. The tumor suppressor PTEN and the PDK1 kinase regulate formation of the columnar neural epithelium

    PubMed Central

    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

  11. Accelerated Plaque Formation by Fowlpox Virus in the Presence of Chymotrypsin

    PubMed Central

    Asch, Bonnie B.; Gifford, George E.

    1969-01-01

    Chymotrypsin enhanced fowlpox virus plaque formation in chick embryo cell cultures. A simplified plaque assay for fowlpox virus is described. Plaques were produced in 3 days when chymotrypsin was included in a serum-free fluid overlay. Plaques were also produced in 5 to 6 days under an agar overlay when a medium containing fetal calf serum was employed. Kinetics of plaque formation were also studied, and it was shown that fowlpox virus plaque diameters grow at a linear rate. Images PMID:4905607

  12. Features of accelerated electron beam formation in LHCD experiments on FT-2 tokamak

    NASA Astrophysics Data System (ADS)

    Lashkul, S. I.; Rozhdestvensky, V. V.; Altukhov, A. B.; Dyachenko, V. V.; Esipov, L. A.; Kantor, M. Yu.; Krikunov, S. V.; Kuprienko, D. V.; Stepanov, A. Yu.

    2012-12-01

    In experiments with lower hybrid current drive (LHCD) on the FT-2 tokamak, lower hybrid (LH) waves have been successfully used for the first time to ensure effective additional heating of plasma electrons from 450 to 600 eV ( I Pl = 32 kA, Δ t RF = 14 ms, P RF = 100 kW, F = 920 MHz). Several factors influencing the efficiency of plasma heating have been discovered. In particular, significant growth of radiation losses in the LHCD regime has been found, which is probably related to an increase in the intensity of synchrotron radiation from accelerated electrons. The increase in this intensity in the 53-156 GHz frequency range was accompanied by short spikes of microwave radiation, which were observed only in a narrower frequency range (53-78 GHz) and apparently resulted from interaction of a runaway electron beam with significant local mirrors of toroidal magnetic field. A model of the additional heating of plasma electrons due to absorption of the microwave radiation generated by a beam of accelerated electrons is proposed.

  13. The transcriptional regulator c2h2 accelerates mushroom formation in Agaricus bisporus.

    PubMed

    Pelkmans, Jordi F; Vos, Aurin M; Scholtmeijer, Karin; Hendrix, Ed; Baars, Johan J P; Gehrmann, Thies; Reinders, Marcel J T; Lugones, Luis G; Wösten, Han A B

    2016-08-01

    The Cys2His2 zinc finger protein gene c2h2 of Schizophyllum commune is involved in mushroom formation. Its inactivation results in a strain that is arrested at the stage of aggregate formation. In this study, the c2h2 orthologue of Agaricus bisporus was over-expressed in this white button mushroom forming basidiomycete using Agrobacterium-mediated transformation. Morphology, cap expansion rate, and total number and biomass of mushrooms were not affected by over-expression of c2h2. However, yield per day of the c2h2 over-expression strains peaked 1 day earlier. These data and expression analysis indicate that C2H2 impacts timing of mushroom formation at an early stage of development, making its encoding gene a target for breeding of commercial mushroom strains. PMID:27207144

  14. Loss of E2F1 Extends Survival and Accelerates Oral Tumor Growth in HPV-Positive Mice.

    PubMed

    Zhong, Rong; Bechill, John; Spiotto, Michael T

    2015-01-01

    The Human Papillomavirus (HPV) is associated with several human cancers, including head and neck squamous cell carcinomas (HNSCCs). HPV expresses the viral oncogene E7 that binds to the retinoblastoma protein (RB1) in order to activate the E2F pathway. RB1 can mediate contradictory pathways-cell growth and cell death via E2F family members. Here, we assessed the extent to which E2F1 mediates lethality of HPV oncogenes. Ubiquitous expression of the HPV oncogenes E6 and E7 caused lethality in mice that was associated with focal necrosis in hepatocytes and pancreatic tissues. Furthermore, all organs expressing HPV oncogenes displayed up-regulation of several E2F1 target genes. The E2F1 pathway mediated lethality in HPV-positive mice because deletion of E2F1 increased survival of mice ubiquitously expressing HPV oncogenes. E2F1 similarly functioned as a tumor suppressor in HPV-positive oral tumors as tumors grew faster with homozygous loss of E2F1 compared to tumors with heterozygous loss of E2F1. Re-expression of E2F1 caused decreased clonogenicity in HPV-positive cancer cells. Our results indicate that HPV oncogenes activated the E2F1 pathway to cause lethality in normal mice and to suppress oral tumor growth. These results suggest that selective modulation of the E2F1 pathway, which is activated in HPV tumors, may facilitate tumor regression.

  15. Mesenchymal Stem Cells Develop Tumor Tropism but Do Not Accelerate Breast Cancer Tumorigenesis in a Somatic Mouse Breast Cancer Model

    PubMed Central

    Usha, Lydia; Rao, Geetha; Christopherson II, Kent; Xu, Xiulong

    2013-01-01

    The role of mesenchymal stem cells (MSCs) on breast cancer progression, growth and tumorigenesis remains controversial or unknown. In the present study, we investigated the role of MSCs on breast tumor induction and growth in a clinically relevant somatic breast cancer model. We first conducted in vitro studies and found that conditioned media (CM) of RCAS-Neu and RCAS-PyMT breast cancer cell lines and tumor cells themselves dramatically increased the proliferation and motility of MSCs and induced morphological changes of MSCs and differentiation into fibroblast-like cells. In contrast, the CM of MSCs inhibited the proliferation of two breast cancer cell lines by arresting the cell cycle at the G0/G1 phase. In vivo studies revealed that fluorescence dye-labeled MSCs migrated into tumor tissues. Unexpectedly, single or multiple intravenous injections of MSCs did not affect the latency of breast cancer in TVA- transgenic mice induced by intraductal injection of the RCAS vector encoding polyoma middle-T antigen (PyMT) or Neu oncogenes. Moreover, MSCs had no effect on RCAS-Neu tumor growth in a syngeneic ectopic breast cancer model. While our studies consistently demonstrated the ability of breast cancer cells to profoundly induce MSCs migration, differentiation, and proliferation, the anti-proliferative effect of MSCs on breast tumor cells observed in vitro could not be translated into an antitumor activity in vivo, probably reflecting the antagonizing or complex effects of MSCs on tumor environment and tumor cells themselves. PMID:24069135

  16. Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis.

    PubMed

    Pickup, Michael W; Hover, Laura D; Guo, Yan; Gorska, Agnieszka E; Chytil, Anna; Novitskiy, Sergey V; Moses, Harold L; Owens, Philip

    2015-09-01

    Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) family. BMP ligands have been shown to be overexpressed in human breast cancers. Normal and cancerous breast tissue display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyMT oncogene with mice having conditional knockout (cKO) of BMP receptor type 1a (BMPR1a) using whey acidic protein (WAP)-Cre and found this deletion resulted in delayed tumor onset and significantly extended survival. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicates that epithelial-to-mesenchymal (EMT)-like transitions occurred in cKO tumors. We performed microarray analysis on these tumors and found changes that support EMT-like changes. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and in vivo upon implantation. cKO tumor cells had reduced migration in vitro. We analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions, and found that high BMPR1a gene expression correlates with decreased survival regardless of molecular breast cancer subtype. In conclusion, the data indicate that BMP signaling through BMPR1a functions as a tumor promoter.

  17. Deletion of the BMP receptor BMPR1a impairs mammary tumor formation and metastasis.

    PubMed

    Pickup, Michael W; Hover, Laura D; Guo, Yan; Gorska, Agnieszka E; Chytil, Anna; Novitskiy, Sergey V; Moses, Harold L; Owens, Philip

    2015-09-01

    Bone Morphogenetic Proteins (BMPs) are secreted cytokines/growth factors belonging to the Transforming Growth Factor β (TGFβ) family. BMP ligands have been shown to be overexpressed in human breast cancers. Normal and cancerous breast tissue display active BMP signaling as indicated by phosphorylated Smads 1, 5 and 9. We combined mice expressing the MMTV.PyMT oncogene with mice having conditional knockout (cKO) of BMP receptor type 1a (BMPR1a) using whey acidic protein (WAP)-Cre and found this deletion resulted in delayed tumor onset and significantly extended survival. Immunofluorescence staining revealed that cKO tumors co-expressed Keratin 5 and mesenchymal cell markers such as Vimentin. This indicates that epithelial-to-mesenchymal (EMT)-like transitions occurred in cKO tumors. We performed microarray analysis on these tumors and found changes that support EMT-like changes. We established primary tumor cell lines and found that BMPR1a cKO had slower growth in vitro and in vivo upon implantation. cKO tumor cells had reduced migration in vitro. We analyzed human databases from TCGA and survival data from microarrays to confirm BMPR1a tumor promoting functions, and found that high BMPR1a gene expression correlates with decreased survival regardless of molecular breast cancer subtype. In conclusion, the data indicate that BMP signaling through BMPR1a functions as a tumor promoter. PMID:26274893

  18. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo.

    PubMed

    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 Ras(G12V)-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.

  19. Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo

    PubMed Central

    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

  20. Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells12

    PubMed Central

    Kopp, Florian; Hermawan, Adam; Oak, Prajakta Shirish; Ulaganathan, Vijay Kumar; Herrmann, Annika; Elnikhely, Nefertiti; Thakur, Chitra; Xiao, Zhiguang; Knyazev, Pjotr; Ataseven, Beyhan; Savai, Rajkumar; Wagner, Ernst; Roidl, Andreas

    2014-01-01

    Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)–specific drug salinomycin raised hope for improved treatment options by targeting therapy-refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition. PMID:25500079

  1. Identification of immune system and response genes, and novel mutations causing melanotic tumor formation in Drosophila melanogaster

    SciTech Connect

    Rodriguez, A.; Zhou, Zhijian; Tang, My Lien

    1996-06-01

    We are using Drosophila as a model system for analysis of immunity and tumor formation and have conducted two types of screens using enhancer detector strains to find genes related to these processes: genes expressed in the immune system (type A; hemocytes, lymph glands and fat body) and genes increased in expression by bacterial infection (type B). For type A, tissue-specific reporter gene activity was determined. For type B, a variation of enhancer detection was devised in which {beta}-galactosidase is assayed spectrophotometrically with and without bacterial infection. Because of immune system involvement in melanotic tumor formation, a third type was hypothesized to be found among types A and B: genes that, when mutated, have a melanotic tumor phenotype. Enhancer detector strains (2800) were screened for type A, 900 for B, and 11 retained for further analysis. Complementation tests, cytological mapping, P-element mobilization, and determination of lethal phase and mutant phenotype have identified six novel genes, Dorothy, wizard, toto, viking, Thor and dappled, and one previously identified gene, Collagen IV. All are associated with reporter gene expression in at least one immune system tissue. Thor has increased expression upon infection. Mutations of wizard and dappled have a melanotic tumor phenotype. 72 refs., 6 figs., 3 tabs.

  2. Characteristic Formation of Hyaluronan-Cartilage Link Protein-Proteoglycan Complex in Salivary Gland Tumors.

    PubMed

    Kuwabara, Hiroko; Nishikado, Akira; Hayasaki, Hana; Isogai, Zenzo; Yoneda, Masahiko; Kawata, Ryo; Hirose, Yoshinobu

    2016-01-01

    Hyaluronan (HA) and its binding molecules, cartilage link protein (LP) and proteoglycan (PG), are structural components of the hydrated extracellular matrix. Because these molecules play important roles in the tumor microenvironment, we examined the distribution of HA, LP, versican, and aggrecan in salivary gland tumors using histochemical and immunohistochemical methods, including double staining. LP was present in pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) tissues, and aggrecan was absent in the malignant tumors that we investigated. LP colocalized with both HA and aggrecan in the chondromyxoid matrix of PA, suggesting the presence of a HA-LP-aggrecan complex. Furthermore, the HA-LP-versican complex could be observed in the pseudocystic space of the cribriform structures in ACC. The characteristic HA-LP-PG complex in PA and ACC might play a role in the behavior of tumors, and immunohistochemical analysis of these molecules could represent a diagnostic adjunct for salivary gland tumors.

  3. Expression of B-RAF V600E in Type II Pneumocytes Causes Abnormalities in Alveolar Formation, Airspace Enlargement and Tumor Formation in Mice

    PubMed Central

    Zanucco, Emanuele; Götz, Rudolf; Potapenko, Tamara; Carraretto, Irene; Ceteci, Semra; Ceteci, Fatih; Seeger, Werner; Savai, Rajkumar; Rapp, Ulf R.

    2011-01-01

    Growth factor induced signaling cascades are key regulatory elements in tissue development, maintenance and regeneration. Perturbations of these cascades have severe consequences, leading to developmental disorders and neoplastic diseases. As a major function in signal transduction, activating mutations in RAF family kinases are the cause of human tumorigenesis, where B-RAF V600E has been identified as the prevalent mutant. In order to address the oncogenic function of B-RAF V600E, we have generated transgenic mice expressing the activated oncogene specifically in lung alveolar epithelial type II cells. Constitutive expression of B-RAF V600E caused abnormalities in alveolar epithelium formation that led to airspace enlargements. These lung lesions showed signs of tissue remodeling and were often associated with chronic inflammation and low incidence of lung tumors. The inflammatory cell infiltration did not precede the formation of the lung lesions but was rather accompanied with late tumor development. These data support a model where the continuous regenerative process initiated by oncogenic B-RAF-driven alveolar disruption provides a tumor-promoting environment associated with chronic inflammation. PMID:22194995

  4. Soil-litter Mixing Accelerates Decomposition and May Promote Soil Aggregate Formation in the Chihuahuan Desert

    NASA Astrophysics Data System (ADS)

    Hewins, D. B.; Throop, H. L.; Archer, S. R.; Okin, G. S.

    2010-12-01

    Vegetation cover in drylands can strongly affect soil movement by wind and water. Many dryland systems are currently experiencing declines in grass cover due to livestock grazing and woody plant encroachment and increased soil movement is one consequence of these disturbances. Here, we test the hypothesis that declines in dryland grass cover could indirectly promote litter decomposition, an important ecosystem process that regulates carbon (C) and nutrient cycling, by enhancing soil-litter mixing. To test this hypothesis we quantified litter decomposition in the northern Chihuahuan Desert in plots where reductions in grass cover (0, 50, 75, and 100%) have been quantified and related to increases in aeolian soil movement. After 12 months of litterbag exposure we found a positive, linear relationship (R2= 0.32) between soil-litter mixing and litter mass loss. However, patterns of soil accumulation in litterbags and litter mass loss did not show a clear relationship with respect to vegetation removal treatments (R2 = 0.03 and 0.006 respectively). This lack of pattern may be due to high spatial variability that is associated with soil movement in dryland systems. Additionally, in all vegetation removal treatments we observed soil aggregate formation within litterbags. Soil aggregates were not initially evident within litterbags (1 and 3 month exposure), but were apparent after 6 and 12 months of field exposure. Although the abiotic and/or biotic mechanism of aggregation remains to be elucidated, observed aggregate formation may rely on exposure to seasonal dust storms and monsoon rains characteristic of the Chihuahuan Desert. These climatic events may increase soil-litter mixing and promote moisture conditions favorable to microbial activity. We hypothesize that the formation of aggregates, which may locally stabilize soil surfaces and affect soil C sequestration, may be promoted by the release of microbially derived extracellular compounds and inorganic C during leaf

  5. Aureolysin of Staphylococcus warneri M accelerates its proteolytic cascade, and participates in biofilm formation.

    PubMed

    Yokoi, Ken-Ji; Kuzuwa, Shinya; Iwasaki, Shu-Ichi; Yamakawa, Ayanori; Taketo, Akira; Kodaira, Ken-Ichi

    2016-06-01

    The aureolysin (Aur) gene of S. warneri M (aurWM) was cloned and sequenced. Analyses of the aurWM-inactivated mutant (S. warneri Mau) suggested that AurWM was probably associated with efficient processing of the PROM protease (homolog of V8/SspA serine protease), whereas considerable amount of mature-PROC protease (homolog of SspB cysteine protease) accumulated without AurWM. Additionally, AurWM appeared to affect biofilm formation in an uncertain suppressive way.

  6. Malignant tumor formation at the site of previously irradiated acanthomatous epulides in four dogs

    SciTech Connect

    Thrall, D.E.; Goldschmidt, M.H.; Biery, D.N.

    1981-01-15

    The radiation response of acanthomatous epulis in 32 dogs was good, with an estimated median survival time of 21 months. Of the 32 patients, 14 have died. In 4 of those 14, malignant tumors developed at the site of the acanthomatous epulis. The tumors were of epithelial origin in 3 patients and of mesenchymal origin in 1 patient. Possibilities explaining the appearance of the malignancies included spontaneous malignant transformation, radiation induction of neoplasms, and radiation induction of malignant transformation. This uncommon complication was not considered contradictory to radiotherapy of acanthomatous epulides, because of their excellent response to irradiation and the long latent period between irradiation and appearance of the malignant tumor.

  7. A Collision Probability Model of Portal Vein Tumor Thrombus Formation in Hepatocellular Carcinoma

    PubMed Central

    Xiong, Fei

    2015-01-01

    Hepatocellular carcinoma is one of the most common malignancies worldwide, with a high risk of portal vein tumor thrombus (PVTT). Some promising results have been achieved for venous metastases of hepatocellular carcinoma; however, the etiology of PVTT is largely unknown, and it is unclear why the incidence of PVTT is not proportional to its distance from the carcinoma. We attempted to address this issue using physical concepts and mathematical tools. Finally, we discuss the relationship between the probability of a collision event and the microenvironment of the PVTT. Our formulae suggest that the collision probability can alter the tumor microenvironment by increasing the number of tumor cells. PMID:26131562

  8. Acceleration of raindrop formation due to the tangling-clustering instability in a turbulent stratified atmosphere.

    PubMed

    Elperin, T; Kleeorin, N; Krasovitov, B; Kulmala, M; Liberman, M; Rogachevskii, I; Zilitinkevich, S

    2015-07-01

    Condensation of water vapor on active cloud condensation nuclei produces micron-size water droplets. To form rain, they must grow rapidly into at least 50- to 100-μm droplets. Observations show that this process takes only 15-20 min. The unexplained physical mechanism of such fast growth is crucial for understanding and modeling of rain and known as "condensation-coalescence bottleneck in rain formation." We show that the recently discovered phenomenon of the tangling clustering instability of small droplets in temperature-stratified turbulence [Phys. Fluids 25, 085104 (2013)] results in the formation of droplet clusters with drastically increased droplet number densities. The mechanism of the tangling clustering instability is much more effective than the previously considered by us the inertial clustering instability caused by the centrifugal effect of turbulent vortices. This is the reason of strong enhancement of the collision-coalescence rate inside the clusters. The mean-field theory of the droplet growth developed in this study can be useful for explanation of the observed fast growth of cloud droplets in warm clouds from the initial 1-μm-size droplets to 40- to 50-μm-size droplets within 15-20 min. PMID:26274274

  9. Acceleration of raindrop formation due to the tangling-clustering instability in a turbulent stratified atmosphere.

    PubMed

    Elperin, T; Kleeorin, N; Krasovitov, B; Kulmala, M; Liberman, M; Rogachevskii, I; Zilitinkevich, S

    2015-07-01

    Condensation of water vapor on active cloud condensation nuclei produces micron-size water droplets. To form rain, they must grow rapidly into at least 50- to 100-μm droplets. Observations show that this process takes only 15-20 min. The unexplained physical mechanism of such fast growth is crucial for understanding and modeling of rain and known as "condensation-coalescence bottleneck in rain formation." We show that the recently discovered phenomenon of the tangling clustering instability of small droplets in temperature-stratified turbulence [Phys. Fluids 25, 085104 (2013)] results in the formation of droplet clusters with drastically increased droplet number densities. The mechanism of the tangling clustering instability is much more effective than the previously considered by us the inertial clustering instability caused by the centrifugal effect of turbulent vortices. This is the reason of strong enhancement of the collision-coalescence rate inside the clusters. The mean-field theory of the droplet growth developed in this study can be useful for explanation of the observed fast growth of cloud droplets in warm clouds from the initial 1-μm-size droplets to 40- to 50-μm-size droplets within 15-20 min.

  10. The Impact of Immune System in Regulating Bone Metastasis Formation by Osteotropic Tumors.

    PubMed

    D'Amico, Lucia; Roato, Ilaria

    2015-01-01

    Bone metastases are frequent and debilitating consequence for many tumors, such as breast, lung, prostate, and kidney cancer. Many studies report the importance of the immune system in the pathogenesis of bone metastasis. Indeed, bone and immune system are strictly linked to each other because bone regulates the hematopoietic stem cells from which all cells of the immune system derive, and many immunoregulatory cytokines influence the fate of bone cells. Furthermore, both cytokines and factors produced by immune and bone cells promote the growth of tumor cells in bone, contributing to supporting the vicious cycle of bone metastasis. This review summarizes the current knowledge on the interactions among bone, immune, and tumor cells aiming to provide an overview of the osteoimmunology field in bone metastasis from solid tumors.

  11. Apigenin prevents development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats

    PubMed Central

    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

  12. A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation

    PubMed Central

    2013-01-01

    Background Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1. Results Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts. Conclusion AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC. PMID:24156782

  13. HER3 Is Required for HER2-Induced Preneoplastic Changes to the Breast Epithelium and Tumor Formation

    PubMed Central

    Vaught, David B.; Stanford, Jamie C.; Young, Christian; Hicks, Donna J.; Wheeler, Frank; Rinehart, Cammie; Sánchez, Violeta; Koland, John; Muller, William J.; Arteaga, Carlos L.; Cook, Rebecca S.

    2012-01-01

    Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu mammary glands lacking ErbB3, thus inhibiting premalignant HER2-induced hyperplasia. Using a transgenic model in which HER2 and Cre are expressed from a single polycistronic transcript, we showed that palpable tumor penetrance decreased from 93.3% to 6.7% upon ErbB3 ablation. Penetrance of ductal carcinomas in situ was also decreased. In addition, loss of ErbB3 impaired Akt and p44/42 phosphorylation in preneoplastic HER2-overexpressing mammary glands and in tumors, decreased growth of preexisting HER2-overexpressing tumors, and improved tumor response to the HER2 tyrosine kinase inhibitor lapatinib. These events were rescued by reexpression of ErbB3, but were only partially rescued by ErbB36F, an ErbB3 mutant harboring six tyrosine-to-phenylalanine mutations that block its interaction with phosphatidyl inositol 3-kinase. Taken together, our findings suggest that ErbB3 promotes HER2-induced changes in the breast epithelium before, during, and after tumor formation. These results may have important translational implications for the treatment and prevention of HER2-amplified breast tumors through ErbB3 inhibition. PMID:22461506

  14. Accelerated fluctuation analysis by graphic cards and complex pattern formation in financial markets

    NASA Astrophysics Data System (ADS)

    Preis, Tobias; Virnau, Peter; Paul, Wolfgang; Schneider, Johannes J.

    2009-09-01

    The compute unified device architecture is an almost conventional programming approach for managing computations on a graphics processing unit (GPU) as a data-parallel computing device. With a maximum number of 240 cores in combination with a high memory bandwidth, a recent GPU offers resources for computational physics. We apply this technology to methods of fluctuation analysis, which includes determination of the scaling behavior of a stochastic process and the equilibrium autocorrelation function. Additionally, the recently introduced pattern formation conformity (Preis T et al 2008 Europhys. Lett. 82 68005), which quantifies pattern-based complex short-time correlations of a time series, is calculated on a GPU and analyzed in detail. Results are obtained up to 84 times faster than on a current central processing unit core. When we apply this method to high-frequency time series of the German BUND future, we find significant pattern-based correlations on short time scales. Furthermore, an anti-persistent behavior can be found on short time scales. Additionally, we compare the recent GPU generation, which provides a theoretical peak performance of up to roughly 1012 floating point operations per second with the previous one. .

  15. Changes in Protein Expression in Two Cholangiocarcinoma Cell Lines Undergoing Formation of Multicellular Tumor Spheroids In Vitro

    PubMed Central

    Mischiati, Carlo; Ura, Blendi; Roncoroni, Leda; Elli, Luca; Cervellati, Carlo; Squerzanti, Monica; Conte, Dario; Doneda, Luisa; Polverino de Laureto, Patrizia; de Franceschi, Giorgia; Calza, Roberta; Barrero, Carlos A.; Merali, Salim; Ferrari, Carlo; Bergamini, Carlo M.; Agostinelli, Enzo

    2015-01-01

    Epithelial-to-Mesenchymal Transition (EMT) is relevant in malignant growth and frequently correlates with worsening disease progression due to its implications in metastases and resistance to therapeutic interventions. Although EMT is known to occur in several types of solid tumors, the information concerning tumors arising from the epithelia of the bile tract is still limited. In order to approach the problem of EMT in cholangiocarcinoma, we decided to investigate the changes in protein expression occurring in two cell lines under conditions leading to growth as adherent monolayers or to formation of multicellular tumor spheroids (MCTS), which are considered culture models that better mimic the growth characteristics of in-vivo solid tumors. In our system, changes in phenotypes occur with only a decrease in transmembrane E-cadherin and vimentin expression, minor changes in the transglutaminase protein/activity but with significant differences in the proteome profiles, with declining and increasing expression in 6 and in 16 proteins identified by mass spectrometry. The arising protein patterns were analyzed based on canonical pathways and network analysis. These results suggest that significant metabolic rearrangements occur during the conversion of cholangiocarcinomas cells to the MCTS phenotype, which most likely affect the carbohydrate metabolism, protein folding, cytoskeletal activity, and tissue sensitivity to oxygen. PMID:25756965

  16. Zinc oxide nanoparticles induce migration and adhesion of monocytes to endothelial cells and accelerate foam cell formation

    SciTech Connect

    Suzuki, Yuka; Tada-Oikawa, Saeko; Ichihara, Gaku; Yabata, Masayuki; Izuoka, Kiyora; Suzuki, Masako; Sakai, Kiyoshi; Ichihara, Sahoko

    2014-07-01

    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 monocyte 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.

  17. Meningioma: The role of a foreign body and irradiation in tumor formation

    SciTech Connect

    Saleh, J.; Silberstein, H.J.; Salner, A.L.; Uphoff, D.F. )

    1991-07-01

    A case of meningioma is reported. At the age of 18 years, the patient had undergone insertion of a Torkildsen shunt through a posteroparietal burr hole for obstructive hydrocephalus secondary to a tumor of the pineal region, of which no biopsy had been made. After the hydrocephalus was relieved, he underwent irradiation of the tumor. Thirty years later, he was treated for an intracranial meningioma wrapped around the shunt. The tumor followed the shunt in all of its intracranial course. Microscopy disclosed pieces of the shunt tube within the meningioma. The role of a foreign body and irradiation in the induction of meningiomas is discussed, and a comprehensive review of the literature is presented. 47 references.

  18. Survival of residual neutrophils and accelerated myelopoiesis limit the efficacy of antibody-mediated depletion of Ly-6G+ cells in tumor-bearing mice.

    PubMed

    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.

  19. Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival.

    PubMed

    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

    2015-08-20

    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.

  20. Genetic Regulation of Fate Decisions in Therapeutic T Cells to Enhance Tumor Protection and Memory Formation.

    PubMed

    Veliça, Pedro; Zech, Mathias; Henson, Sian; Holler, Angelika; Manzo, Teresa; Pike, Rebecca; Santos E Sousa, Pedro; Zhang, Lei; Heinz, Niels; Schiedlmeier, Bernhard; Pule, Martin; Stauss, Hans; Chakraverty, Ronjon

    2015-07-01

    A key challenge in the field of T-cell immunotherapy for cancer is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory. Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting. We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR. Ectopic expression of RAS homolog enriched in brain (RHEB) increased mTORC1 signaling, promoted a switch to aerobic glycolysis, and increased expansion of effector T cells. By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants. In contrast, expression of proline-rich Akt substrate of 40 kDa (PRAS40) inhibited mTORC1, promoted quiescence, and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1(low) T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T-cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal. Unlike pharmacologic inhibitors, the genetic approach described here allows for upregulation as well as inhibition of the mTORC1 pathway and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.

  1. Rac1 promotes diethylnitrosamine (DEN)-induced formation of liver tumors.

    PubMed

    Bopp, Anita; Wartlick, Friedrich; Henninger, Christian; Schwarz, Michael; Kaina, Bernd; Fritz, Gerhard

    2015-03-01

    To elucidate the function of the Ras-homologous GTPase Rac1 in hepatocarcinogenesis induced by diethylnitrosamine (DEN), mice lacking hepatic Rac1 expression were treated with DEN and compared to the wild-type (WT). Rac1 knock-out (KO) mice were found to have a lower tumor yield as compared to Rac1 proficient mice. The small-sized tumors formed in the absence of Rac1 lack an activated Ras/Raf/mitogen-activated protein kinase pathway, as indicated by the absence of p-ERK expression. Apparently, Rac1 is required for Ras-driven oncogenic pathways. Moreover, tumors in Rac1 deficient mice were glutamine synthase (GS) negative. They displayed a high number of p-H3-positive and cyclinB1 expressing cells, pointing to a defect in mitotic progression. To elucidate the influence of Rac1 on mechanisms of tumor initiation, acute DEN-induced hepatic stress responses were monitored. Rac1 deficiency caused fairly complex, partially time-dependent, alterations in both basal and/or DEN-induced messenger RNA (mRNA) and protein levels of susceptibility-related genes. Basal protein expression of DNA repair factors Brca1 and DNA repair protein RAD51 homolog (Rad51) and the cell cycle regulatory factor p27 was enhanced in the absence of Rac1. Following DEN treatment, p21 mRNA and protein expression was stimulated independent of the Rac1 status. Lack of Rac1 increased mechanisms of the DNA damage response (DDR), as shown by elevated protein levels of p-ATR, p-p53 and γH2AX 24h after DEN treatment. The data show that Rac1 is essential for DEN-stimulated hepatocarcinogenesis. We hypothesize that it promotes tumor initiation by counteracting the elimination of initiated cells and, moreover, alleviates the outgrowth of transformed cells. Hence, pharmacological targeting of Rac1 could be suitable for chemoprevention.

  2. Kif14 overexpression accelerates murine retinoblastoma development.

    PubMed

    O'Hare, Michael; Shadmand, Mehdi; Sulaiman, Rania S; Sishtla, Kamakshi; Sakisaka, Toshiaki; Corson, Timothy W

    2016-10-15

    The mitotic kinesin KIF14 has an essential role in the recruitment of proteins required for the final stages of cytokinesis. Genomic gain and/or overexpression of KIF14 has been documented in retinoblastoma and a number of other cancers, such as breast, lung and ovarian carcinomas, strongly suggesting its role as an oncogene. Despite evidence of oncogenic properties in vitro and in xenografts, Kif14's role in tumor progression has not previously been studied in a transgenic cancer model. Using a novel Kif14 overexpressing, simian virus 40 large T-antigen retinoblastoma (TAg-RB) double transgenic mouse model, we aimed to determine Kif14's role in promoting retinal tumor formation. Tumor initiation and development in double transgenics and control TAg-RB littermates were documented in vivo over a time course by optical coherence tomography, with subsequent ex vivo quantification of tumor burden. Kif14 overexpression led to an accelerated initiation of tumor formation in the TAg-RB model and a significantly decreased tumor doubling time (1.8 vs. 2.9 weeks). Moreover, overall percentage tumor burden was also increased by Kif14 overexpression. These data provide the first evidence that Kif14 can promote tumor formation in susceptible cells in vivo. PMID:27270502

  3. Rapid Circumstellar Disk Evolution and an Accelerating Star Formation Rate in the Infrared Dark Cloud M17 SWex

    NASA Astrophysics Data System (ADS)

    Povich, Matthew S.; Townsley, Leisa K.; Robitaille, Thomas P.; Broos, Patrick S.; Orbin, Wesley T.; King, Robert R.; Naylor, Tim; Whitney, Barbara A.

    2016-07-01

    We present a catalog of 840 X-ray sources and first results from a 100 ks Chandra X-ray Observatory imaging study of the filamentary infrared (IR) dark cloud G014.225-00.506, which forms the central regions of a larger cloud complex known as the M17 southwest extension (M17 SWex). In addition to the rich population of protostars and young stellar objects with dusty circumstellar disks revealed by archival data from the Spitzer Space Telescope, we discover a population of X-ray-emitting, intermediate-mass pre-main-sequence stars that lack IR excess emission from circumstellar disks. We model the IR spectral energy distributions of this source population to measure its mass function and place new constraints on the destruction timescales for the inner dust disk for 2-8 M ⊙ stars. We also place a lower limit on the star formation rate (SFR) and find that it is quite high (\\dot{M}≥slant 0.007 M ⊙ yr-1), equivalent to several Orion Nebula Clusters in G14.225-0.506 alone, and likely accelerating. The cloud complex has not produced a population of massive, O-type stars commensurate with its SFR. This absence of very massive (≳20 M ⊙) stars suggests that either (1) M17 SWex is an example of a distributed mode of star formation that will produce a large OB association dominated by intermediate-mass stars but relatively few massive clusters, or (2) the massive cores are still in the process of accreting sufficient mass to form massive clusters hosting O stars.

  4. Effect of calcium formate as an accelerator on the physicochemical and mechanical properties of pozzolanic cement pastes

    SciTech Connect

    Heikal, Mohamed

    2004-06-01

    The aim of the present work is to study the effect of calcium formate (CF) as an accelerator on the properties of pozzolanic cement pastes. Three types of cements were used in this investigation. These cements were OPC and pozzolanic cements containing 80 mass% OPC and 20 mass% silica fume (SF) or 20 mass% ground clay bricks (GCB). The dosages of CF were 0.00, 0.25, 0.50, and 0.75 mass% of cement. The compressive strength, total porosity, and hydration kinetics such as free lime and combined water contents were investigated. The results obtained in this study showed that the addition of CF shortens the initial and final setting times and increases the compressive strength and combined water content as well as gel/space ratio at all ages of hydration. On the other hand, it decreases the total porosity. CF activates the liberation of Ca(OH){sub 2} of OPC pastes. The free lime content of pozzolanic cement in the presence of CF increases up to 7 days, then decreases at the later ages of hydration.

  5. Acceleration of re-endothelialization and inhibition of neointimal formation using hybrid biodegradable nanofibrous rosuvastatin-loaded stents.

    PubMed

    Lee, Cheng-Hung; Chang, Shang-Hung; Lin, Yu-Huang; Liu, Shih-Jung; Wang, Chao-Jan; Hsu, Ming-Yi; Hung, Kuo-Chun; Yeh, Yung-Hsin; Chen, Wei-Jan; Hsieh, I-Chang; Wen, Ming-Shien

    2014-05-01

    Incomplete endothelialization and neointimal hyperplasia of injured arteries can cause acute and late stent thromboses. This work develops hybrid stent/biodegradable nanofibers for the local and sustained delivery of rosuvastatin to denuded artery walls. Biodegradable nanofibers were firstly prepared by dissolving poly(D,L)-lactide-co-glycolide and rosuvastatin in 1,1,1,3,3,3-hexafluoro-2-propanol. The solution was then electrospun into nanofibrous tubes, which were mounted onto commercially available bare-metal stents. The in vitro release rates of the pharmaceuticals from the nanofibers were determined using an elution method and a high-performance liquid chromatography assay. The experimental results thus obtained suggest that the biodegradable nanofibers released high concentrations of rosuvastatin for four weeks. The effectiveness of the local delivery of rosuvastatin in reducing platelets was studied. The tissue inflammatory reaction caused by the hybrid stents that were used to treat diseased arteries was also documented. The proposed hybrid stent/biodegradable rosuvastatin-loaded nanofibers contributed substantially to the local and sustainable delivery of a high concentration of drugs to promote re-endothelialization, improve endothelial function, reduce inflammatory reaction, and inhibit neointimal formation of the injured artery. The results of this work provide insight into how patients with a high risk of stent restenosis should be treated for accelerating re-endothelialization and inhibiting neointimal hyperplasia.

  6. Control of mammalian cell mutagenesis and differentiation by chemicals which initiate or promote tumor formation

    SciTech Connect

    Jones, C. A.; Huberman, E.

    1980-01-01

    A cell-mediated mutagenesis assay was developed to predict the potential carcinogenic hazard of some environmental chemicals. In this assay, Chinese hamster V79 cells, which are susceptible to mutagenesis, are co-cultivated with cells capable of metabolizing chemical carcinogens. Use of this assay made it possible to demonstrate a relationship between the degree of carcinogenicity and mutagenicity of a series of polycyclic hydrocarbons and nitrosamines and to study the organ specificity exhibited by some chemical carcinogens. However, most short-term in vitro assays are designed to detect mutagenic activity and therefore do not detect tumor promoting agents which are devoid of this activity. By analyzing various markers of terminal differentiation in cultured human melanoma and myeloid leukemia cells, we have established a relationship between the activity of a series of tumor promoting phorbol diesters in the mouse skin and their ability to induce terminal differentiation. We suggest that measuring alterations in the differentiation characteristics of some cultured cells may represent an approach by which environmental tumor promoting agents can be studied and detected.

  7. Induction of mutation and differentiation in mammalian cells by chemicals which initiate or promote tumor formation

    SciTech Connect

    Huberman, E.

    1980-01-01

    A cell-mediated mutagenesis assay was developed to predict the potential carcinogenic hazard of some environmental chemicals. In this assay, cells with appropriate markers for mutagenesis, such as the Chinese hamster V79 cells, are co-cultivated with cells capable of metabolizing chemical carcinogens. Use of this assay made it possible to demonstrate a relationship between the degree of carcinogenicity and mutagenicity of a series of polycyclic hydrocarbons, nitrosamines and aflatoxins, and to establish means to study organ specificity of some chemical carcinogens. However, most short term in vitro assays are designed to detect mutagenic activity and therefore do not detect tumor promoting agents which are devoid of this activity. By analyzing various markers of terminal differentiation in cultured human melanoma and myeloid leukemia cells, we have established a relationship between the activity of a series of tumor promoting phorbol diesters in the mouse skin and their ability to induce terminal differentiation. We suggest that measuring alterations in the differentiation characteristics of some cultured cells may represent an approach by which environmental tumor promoting agents can be studied and detected.

  8. Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease*

    PubMed Central

    Sarell, Claire J.; Wilkinson, Shane R.; Viles, John H.

    2010-01-01

    A role for Cu2+ ions in Alzheimer disease is often disputed, as it is believed that Cu2+ ions only promote nontoxic amorphous aggregates of amyloid-β (Aβ). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu2+ ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu2+ ions at a physiological pH causes Aβ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu2+ ions bound to Aβ are consistently more toxic to neuronal cells than Aβ in the absence of Cu2+ ions, whereas Cu2+ ions in the absence of Aβ are not cytotoxic. The degree of Cu-Aβ cytotoxicity correlates with the levels of Cu2+ ions that accelerate fiber formation. We note the effect appears to be specific for Cu2+ ions as Zn2+ ions inhibit the formation of fibers. An active role for Cu2+ ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease. PMID:20974842

  9. Tyrosine kinase inhibitor, methyl 2,5-dihydromethylcinnimate, induces PML nuclear body formation and apoptosis in tumor cells

    SciTech Connect

    Komura, Naoyuki; Asakawa, Mayako; Umezawa, Kazuo . E-mail: umezawa@applc.keio.ac.jp; Segawa, Kaoru

    2007-08-01

    Promyelocytic leukemia (PML) nuclear bodies (PML-NBs) are the nuclear structure consisting of various proteins such as PML, SUMO-1, and p53. PML-NBs are implicated in the regulation of tumor suppression, antiviral responses, and apoptosis. In this study, we searched for bioactive metabolites that would promote the formation of PML-NBs in tumor cells. As a result, methyl 2,5-dihydromethylcinnimate (2,5-MeC), a tyrosine kinase inhibitor, enhanced expression and/or stability of PML proteins and induced PML-NB formation in p53 null H1299 cells established from non-small cell lung cancer (NSCLC) and wild-type p53-expressing U2OS cells derived from osteosarcoma. Furthermore, it enhanced apoptosis by exogenously expressed wild type p53 and the expression of p53-responsive genes, such as PUMA and p21, in H1299 cells. 2,5-MeC also activated endogenous p53 and induced apoptosis in U2OS cells. The results suggest that 2,5-MeC is likely to be a promising candidate drug for the clinical treatment of terminal cancer-expressing wild-type p53.

  10. Paternal and maternal genomes confer opposite effects on proliferation, cell-cycle length, senescence, and tumor formation.

    PubMed

    Hernandez, Lidia; Kozlov, Serguei; Piras, Graziella; Stewart, Colin L

    2003-11-11

    Loss of imprinting is the silencing of active imprinted genes or the activation of silent imprinted genes, and it is one of the most common epigenetic changes associated with the development of a wide variety of tumors. Here, we have analyzed the effects that global imprinted gene expression has on cell proliferation and transformation. Primary mouse embryonic fibroblasts (MEFs), whose entire genome is either exclusively paternal (androgenetic) or maternal (parthenogenetic), exhibit dramatically contrasting patterns of growth. In comparison with biparental MEFs, andro-genetic proliferation is characterized by a shorter cell cycle, increased saturation density, spontaneous transformation, and formation of tumors at low passage number. Parthenogenetic MEFs reach a lower saturation density, senesce, and die. The maternally expressed imprinted genes p57kip2 and M6P/Igf2r retard proliferation and reduce the long-term growth of MEFs. In contrast, the paternally expressed growth factor Igf2 is essential for the long-term proliferation of all genotypes. Increased Igf2 expression in primary MEFs not only stimulates proliferation, but also results in their rapid conversion to malignancy with tumor formation of short latency. Our results reveal that paternally expressed imprinted genes, in the absence of maternal imprinted genes, predispose fibroblasts to rapid transformation. A potent factor in their transformation is IGF2, which on increased expression results in the rapid conversion of primary cells to malignancy. These results reveal a route by which malignant choriocarcinoma may arise from molar pregnancies. They also suggest that the derivation of stem cells from parthenogenetic embryos, for the purposes of therapeutic cloning, may be ineffective. PMID:14581617

  11. Long-term stability assessment of a 4D tumor tracking system integrated into a gimbaled linear accelerator.

    PubMed

    Akimoto, Mami; Nakamura, Mitsuhiro; Miyabe, Yuki; Mukumoto, Nobutaka; Yokota, Kenji; Mizowaki, Takashi; Hiraoka, Masahiro

    2015-09-08

    We assessed long-term stability of tracking accuracy using the Vero4DRT system. This metric was observed between September 2012 and March 2015. A programmable respiratory motion phantom, designed to move phantoms synchronously with respiratory surrogates, was used. The infrared (IR) markers moved in the anterior-posterior (AP) direction as respiratory surrogates, while a cube phantom with a steel ball at the center, representing the tumor, and with radiopaque markers around it moved in the superior-inferior (SI) direction with one-dimensional (1D) sinusoidal patterns. A correlation model between the tumor and IR marker motion (4D model) was created from the training data obtained for 20 s just before beam delivery. The irradiation field was set to 3 × 3 cm2 and 300 monitor units (MUs) of desired MV X-ray beam were delivered. The gantry and ring angles were set to 0° and 45°, respectively. During beam delivery, the system recorded approximately 60 electronic portal imaging device (EPID) images. We analyzed: 1) the predictive accuracy of the 4D model (EP), defined as the difference between the detected and predicted target positions during 4D model creation, and 2) the tracking accuracy (ET), defined as the difference between the center of the steel ball and the MV X-ray field on the EPID image. The median values of mean plus two standard deviations (SDs) for EP were 0.06, 0.35, and 0.06 mm in the left-right (LR), SI, and AP directions, respectively. The mean values of maximum deviation for ET were 0.38, 0.49, and 0.53 mm and the coefficients of variance (CV) were 0.16, 0.10, and 0.05 in lateral, longitudinal, and 2D directions, respectively. Consequently, the IR Tracking accuracy was consistent over a period of two years. Our proposed method assessed the overall tracking accuracy readily using real-time EPID images, and proved to be a useful QA tool for dynamic tumor tracking with the Vero4DRT system.

  12. Spontaneous and artificial lesions of magnocellular reticular formation of brainstem deteriorate avoidance learning in senescence-accelerated mouse SAM.

    PubMed

    Yagi, H; Akiguchi, I; Ohta, A; Yagi, N; Hosokawa, M; Takeda, T

    1998-04-27

    The role of the magnocellular reticular formation (MGRF) of the brainstem on learning and memory was examined in memory-deficient mice with spontaneous spongy degeneration in the brainstem (senescence-accelerated mouse, SAMP8) and control mice (accelerated-senescence resistant mouse, SAMR 1). SAMP8 showed spontaneous age-related impairment of learning and memory, as determined by passive and active avoidance responses. The deficits of learning and memory function in passive avoidance performances began at two months of age and increased with ageing. In the brains of SAMP8 at one month of age and older, spongy degeneration was mainly observed in the brainstem, while no vacuoles were evident in SAMR1 control (normal ageing mouse) brains in the age range tested (up to 12 months). The vacuolization in SAMP8 was marked in the MGRF, especially in the dorsomedial MGRF. Quantitative analysis of the vacuolization showed that the total area and number of vacuoles in the MGRF increased with age, and they were affected by the degree of deficits in learning and memory. The latency 24 h after footshock in passive avoidance tests decreased with the increase in total area and number of vacuoles in MGRF. The number of shocks in active avoidance tests increased with the increase in total number and area of vacuoles. Thus, learning and memory ability in passive and active avoidance responses deteriorated with enlargement in the vacuolated area in MGRF, and it was assumed that MGRF (especially, the dorsomedial part) possesses functions related to learning and memory. To confirm this notion, behavior and memory tests (passive avoidance and active avoidance tests, open field tests and shock sensitivity measurements) were carried out in SAMR1 mice, whose bilateral dorsomedial MGRF was destroyed electrolytically (MGRF-lesioned mice). The MGRF-lesioned mice showed no difference from sham mice in sensory threshold or open field activity; however, there was severe deterioration in passive

  13. A null-mutation in the Znt7 gene accelerates prostate tumor formation in a transgenic adenocarcinoma mouse prostate model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Decrease of cellular zinc in the epithelium of the prostate has been implicated in the development of prostate cancer. To investigate whether ZnT7, a zinc transporter involved in intracellular zinc accumulation, plays a role in prostate cancer development, we have generated and characterized a trans...

  14. Paricalcitol, a Vitamin D Receptor Activator, Inhibits Tumor Formation in a Murine Model of Uterine Fibroids

    PubMed Central

    Halder, Sunil K.; Sharan, Chakradhari; Al-Hendy, Omar

    2014-01-01

    We examined the antitumor and therapeutic potentials of paricalcitol, an analog of 1,25-dihydroxyvitamin D3 with lower calcemic activity, against uterine fibroids using in vitro and in vivo evaluations in appropriate uterine fibroid cells and animal models. We found that paricalcitol has potential to reduce the proliferation of the immortalized human uterine fibroid cells. For the in vivo study, we generated subcutaneous tumors by injecting the Eker rat-derived uterine leiomyoma cell line (ELT-3) rat uterine fibroid-derived cell line in athymic nude mice supplemented with estrogen pellets. These mice were administered with vehicle versus paricalcitol (300 ng/kg/d) or 1,25-dihydroxyvitamin D3 (500 ng/kg/d) for 4 consecutive weeks, and the data were analyzed. We found that while both paricalcitol and 1,25-dihydroxyvitamin D3 significantly reduced fibroid tumor size, the shrinkage was slightly higher in the paricalcitol-treated group. Together, our results suggest that paricalcitol may be a potential candidate for effective, safe, and noninvasive medical treatment option for uterine fibroids. PMID:24925855

  15. Paricalcitol, a vitamin d receptor activator, inhibits tumor formation in a murine model of uterine fibroids.

    PubMed

    Halder, Sunil K; Sharan, Chakradhari; Al-Hendy, Omar; Al-Hendy, Ayman

    2014-09-01

    We examined the antitumor and therapeutic potentials of paricalcitol, an analog of 1,25-dihydroxyvitamin D3 with lower calcemic activity, against uterine fibroids using in vitro and in vivo evaluations in appropriate uterine fibroid cells and animal models. We found that paricalcitol has potential to reduce the proliferation of the immortalized human uterine fibroid cells. For the in vivo study, we generated subcutaneous tumors by injecting the Eker rat-derived uterine leiomyoma cell line (ELT-3) rat uterine fibroid-derived cell line in athymic nude mice supplemented with estrogen pellets. These mice were administered with vehicle versus paricalcitol (300 ng/kg/d) or 1,25-dihydroxyvitamin D3 (500 ng/kg/d) for 4 consecutive weeks, and the data were analyzed. We found that while both paricalcitol and 1,25-dihydroxyvitamin D3 significantly reduced fibroid tumor size, the shrinkage was slightly higher in the paricalcitol-treated group. Together, our results suggest that paricalcitol may be a potential candidate for effective, safe, and noninvasive medical treatment option for uterine fibroids.

  16. SU-E-J-156: Preclinical Inverstigation of Dynamic Tumor Tracking Using Vero SBRT Linear Accelerator: Motion Phantom Dosimetry Study

    SciTech Connect

    Mamalui-Hunter, M; Wu, J; Li, Z; Su, Z

    2014-06-01

    Purpose: Following the ‘end-to-end testing’ paradigm of Dynamic Target Tracking option in our Image-Guided dedicated SBRT VeroTM linac, we verify the capability of the system to deliver planned dose to moving targets in the heterogeneous thorax phantom (CIRSTM). The system includes gimbaled C-band linac head, robotic 6 degree of freedom couch and a tumor tracking method based on predictive modeling of target position using fluoroscopically tracked implanted markers and optically tracked infrared reflecting external markers. Methods: 4DCT scan of the motion phantom with the VisicoilTM implanted marker in the close vicinity of the target was acquired, the ‘exhale’=most prevalent phase was used for planning (iPlan by BrainLabTM). Typical 3D conformal SBRT treatment plans aimed to deliver 6-8Gy/fx to two types of targets: a)solid water-equivalent target 3cm in diameter; b)single VisicoilTM marker inserted within lung equivalent material. The planning GTV/CTV-to-PTV margins were 2mm, the block margins were 3 mm. The dose calculated by MonteCarlo algorithm with 1% variance using option Dose-to-water was compared to the ion chamber (CC01 by IBA Dosimetry) measurements in case (a) and GafchromicTM EBT3 film measurements in case (b). During delivery, the target 6 motion patterns available as a standard on CIRSTM motion phantom were investigated: in case (a), the target was moving along the designated sine or cosine4 3D trajectory; in case (b), the inserted marker was moving sinusoidally in 1D. Results: The ion chamber measurements have shown the agreement with the planned dose within 1% under all the studied motion conditions. The film measurements show 98.1% agreement with the planar calculated dose (gamma criteria: 3%/3mm). Conclusion: We successfully verified the capability of the SBRT VeroTM linac to perform real-time tumor tracking and accurate dose delivery to the target, based on predictive modeling of the correlation between implanted marker motion and

  17. Formation of nitrogen- and sulfur-containing light-absorbing compounds accelerated by evaporation of water from secondary organic aerosols

    NASA Astrophysics Data System (ADS)

    Nguyen, Tran B.; Lee, Paula B.; Updyke, Katelyn M.; Bones, David L.; Laskin, Julia; Laskin, Alexander; Nizkorodov, Sergey A.

    2012-01-01

    Aqueous extracts of secondary organic aerosols (SOA) generated from the ozonolysis of d-limonene were subjected to dissolution, evaporation, and re-dissolution in the presence and absence of ammonium sulfate (AS). Evaporation with AS at pH 4-9 produced chromophores that were stable with respect to hydrolysis and had a distinctive absorption band at 500 nm. Evaporation accelerated the rate of chromophore formation by at least three orders of magnitude compared to the reaction in aqueous solution, which produced similar compounds. Absorption spectroscopy and high-resolution nanospray desorption electrospray ionization (nano-DESI) mass spectrometry experiments suggested that the molar fraction of the chromophores was small (<2%), and that they contained nitrogen atoms. Although the colored products represented only a small fraction of SOA, their large extinction coefficients (>105 L mol-1 cm-1 at 500 nm) increased the effective mass absorption coefficient of the residual organics in excess of 103 cm2 g-1 - a dramatic effect on the optical properties from minor constituents. Evaporation of SOA extracts in the absence of AS resulted in the production of colored compounds only when the SOA extract was acidified to pH ˜ 2 with sulfuric acid. These chromophores were produced by acid-catalyzed aldol condensation, followed by a conversion into organosulfates. The presence of organosulfates was confirmed by high resolution mass spectrometry experiments. Results of this study suggest that evaporation of cloud or fog droplets containing dissolved organics leads to significant modification of the molecular composition and serves as a potentially important source of light-absorbing compounds.

  18. Formation of Nitrogen- and Sulfur-Containing Light-Absorbing Compounds Accelerated by Evaporation of Water from Secondary Organic Aerosols

    SciTech Connect

    Nguyen, Tran B.; Lee, Paula B.; Updyke, Katelyn M.; Bones, David L.; Laskin, Julia; Laskin, Alexander; Nizkorodov, Sergey

    2012-01-14

    Aqueous extracts of secondary organic aerosols (SOA) generated from the ozonolysis of dlimonene were subjected to dissolution, evaporation, and re-dissolution in the presence and absence of ammonium sulfate (AS). Evaporation with AS at pH 4-9 produced chromophores that were stable with respect to hydrolysis and had a distinctive absorption band at 500 nm. Evaporation accelerated the rate of chromophore formation by at least three orders of magnitude compared to the reaction in aqueous solution, which produced similar compounds. Absorption spectroscopy and high-resolution nanospray desorption electrospray ionization (nano-DESI) mass spectrometry experiments suggested that the molar fraction of the chromophores was small (< 2%), and that they contained nitrogen atoms. Although the colored products represented only a small fraction of SOA, their large extinction coefficients (>10{sup 5} L mol{sup -1} cm{sup -1} at 500 nm) increased the effective mass absorption coefficient of the residual organics in excess of 10{sup 3} cm{sup 2} g{sup -1} - a dramatic effect on the optical properties from minor constituents. Evaporation of SOA extracts in the absence of AS resulted in the production of colored compounds only when the SOA extract was acidified to pH {approx} 2 with sulfuric acid. These chromophores were produced by acid-catalyzed aldol condensation, followed by a conversion into organosulfates. The presence of organosulfates was confirmed by high resolution mass spectrometry experiments. Results of this study suggest that evaporation of cloud or fog droplets containing dissolved organics leads to significant modification of the molecular composition and serves as a potentially important source of light-absorbing compounds.

  19. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis

    PubMed Central

    Shah, Mrinal Y.; Vasanthakumar, Aparna; Barnes, Natalie Y.; Figueroa, Maria E.; Kamp, Anna; Hendrick, Christopher; Ostler, Kelly R.; Davis, Elizabeth M.; Lin, Shang; Anastasi, John; Le Beau, Michelle M.; Moskowitz, Ivan; Melnick, Ari; Pytel, Peter; Godley, Lucy A.

    2010-01-01

    Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins, some of which lack the C-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed two lines of transgenic mice expressing DNMT3B7, a truncated DNMT3B isoform commonly found in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, when DNMT3B7 transgenic are bred with Eμ-Myc transgenic mice, which model aggressive B cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ-Myc animals. Eμ-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-Myc lymphomas. These data represent the first in vivo modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the re-distribution of DNA methylation characterizing virtually every human tumor. PMID:20587527

  20. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis.

    PubMed

    Shah, Mrinal Y; Vasanthakumar, Aparna; Barnes, Natalie Y; Figueroa, Maria E; Kamp, Anna; Hendrick, Christopher; Ostler, Kelly R; Davis, Elizabeth M; Lin, Shang; Anastasi, John; Le Beau, Michelle M; Moskowitz, Ivan P; Melnick, Ari; Pytel, Peter; Godley, Lucy A

    2010-07-15

    Epigenetic changes are among the most common alterations observed in cancer cells, yet the mechanism by which cancer cells acquire and maintain abnormal DNA methylation patterns is not understood. Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins, some of which lack the COOH-terminal catalytic domain. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed two lines of transgenic mice expressing DNMT3B7, a truncated DNMT3B isoform commonly found in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, when DNMT3B7 transgenic mice are bred with Emicro-Myc transgenic mice, which model aggressive B-cell lymphoma, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Emicro-Myc animals. Emicro-Myc/DNMT3B7 mediastinal lymphomas have more chromosomal rearrangements, increased global DNA methylation levels, and more locus-specific perturbations in DNA methylation patterns compared with Emicro-Myc lymphomas. These data represent the first in vivo modeling of cancer-associated DNA methylation changes and suggest that truncated DNMT3B isoforms contribute to the redistribution of DNA methylation characterizing virtually every human tumor.

  1. Matrix metalloproteinase-1 (MMP-1) Promoter polymorphisms are well linked with lower stomach tumor formation in eastern Indian population.

    PubMed

    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 associated with the risk of lower stomach

  2. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and genetic pathways driving tumorigenesis

    PubMed Central

    Rahrmann, Eric P; Watson, Adrienne L; Keng, Vincent W; Choi, Kwangmin; Moriarity, Branden S; Beckmann, Dominic A; Wolf, Natalie; Sarver, Aaron; Collins, Margaret H; Moertel, Christopher L; Wallace, Margaret R; Gel, Bernat; Serra, Eduard; Ratner, Nancy; Largaespada, David A

    2013-01-01

    Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell-lineage origin that occur sporadically or in association with the inherited syndrome, Neurofibromatosis Type 1. To identify genetic drivers of MPNST development, we utilized the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of tumor protein p53 (Trp53) function and/or overexpression of epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets revealed novel and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched for in Wnt/CTNNB1, PI3K/Akt/mTor, and growth factor receptor signaling pathways. Lastly, we identified several novel proto-oncogenes including forkhead box R2 (Foxr2), which we functionally validated as a proto-oncogene involved in MPNST maintenance. PMID:23685747

  3. Prevalence of heterotypic tumor/immune cell-in-cell structure in vitro and in vivo leading to formation of aneuploidy.

    PubMed

    Chen, Yu-hui; Wang, Shan; He, Mei-fang; Wang, Yanyi; Zhao, Hua; Zhu, Han-yu; Yu, Xiao-min; Ma, Jian; Che, Xiao-juan; Wang, Ju-fang; Wang, Ying; Wang, Xiao-ning

    2013-01-01

    Cell-in-cell structures refer to a unique phenomenon that one living cell enters into another living cell intactly, occurring between homotypic tumor cells or tumor (or other tissue cells) and immune cells (named as heterotypic cell-in-cell structure). In the present study, through a large scale of survey we observed that heterotypic cell-in-cell structure formation occurred commonly in vitro with host cells derived from different human carcinomas as well as xenotypic mouse tumor cell lines. Most of the lineages of human immune cells, including T, B, NK cells, monocytes as well as in vitro activated LAK cells, were able to invade tumor cell lines. Poorly differentiated stem cells were capable of internalizing immune cells as well. More significantly, heterotypic tumor/immune cell-in-cell structures were observed in a higher frequency in tumor-derived tissues than those in adjacent tissues. In mouse hepatitis models, heterotypic immune cell/hepatocyte cell-in-cell structures were also formed in a higher frequency than in normal controls. After in vitro culture, different forms of internalized immune cells in heterotypic cell-in-cell structures were observed, with one or multiple immune cells inside host cells undergoing resting, degradation or mitosis. More strikingly, some internalized immune cells penetrated directly into the nucleus of target cells. Multinuclear cells with aneuploid nucleus were formed in target tumor cells after internalizing immune cells as well as in situ tumor regions. Therefore, with the prevalence of heterotypic cell-in-cell structures observed, we suggest that shielding of immune cells inside tumor or inflammatory tissue cells implies the formation of aneuploidy with the increased multinucleation as well as fine-tuning of microenvironment under pathological status, which may define distinct mechanisms to influence the etiology and progress of tumors.

  4. Effects of the butylated hydroxyanisole and butylated hydroxytoluene on the DNA adduct formation and arylamines N-acetyltransferase activity in human colon tumor cells.

    PubMed

    Chang, S H; Chen, G W; Yeh, C C; Hung, C F; Lin, S S; Chung, J G

    2001-01-01

    The effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on N-acetyltransferase (NAT) activity were examined using a human colon tumor cell line (colo 205). BHA or BHT were added to the cytosols or to the medium of human colon tumor cells: The NAT activity was measured by high performance liquid chromatography, assaying the amounts of acetylated 2-aminoflluorene (AAF), p aminobenzoic acid (N-Ac-PABA), nonacetylated 2 aminofluorene (AF) and p-aminobenzoic acid (PABA). The NAT activity in the human colon tumor cells and cytosols was suppressed by BHA or BHT in a dose-dependent manner. The apparent values of Km and Vmax of NAT of human colon tumor cells were also decreased by BHA or BHT in cytosols and in intact cells. BHA or BHT may act as a noncompetitive inhibitor. After the incubation of human colon tumor cells with AF in the presence of BHA or BHT, the cells were recovered and DNA was prepared and hydrolysed to nucleotides. Adducted nucleotides were extracted into butanol and AF-DNA adducts were analysed by HPLC. The results also demonstrated that when BHA or BHT was added to the media, a decrease in AF-DNA adduct formation was seen in the human colon tumor cells. The finding of AF-DNA adduct formation in cultured human colon tumor cells suggest the possibility of using cultured cells for assessing arylamine-induced DNA damage.

  5. Liver tumor formation in female rat induced by fluopyram is mediated by CAR/PXR nuclear receptor activation.

    PubMed

    Tinwell, H; Rouquié, D; Schorsch, F; Geter, D; Wason, S; Bars, R

    2014-12-01

    Fluopyram is a broad spectrum fungicide targeting plant pathogenic fungi (eg. white dot, black mold, botrytis). During the general toxicity evaluation of fluopyram in rodents, the liver was identified as a target organ (hepatomegaly and liver hypertrophy were observed in all studies). At the end of the guideline carcinogenicity study, an increased incidence of hepatocellular adenomas and carcinomas was observed in female Wistar rats following exposure to the highest fluopyram dose evaluated (1500ppm). Short-term mechanistic studies (3, 7 or 28days of exposure) were conducted in the female rat to identify the initial key events responsible for the tumor formation and to establish thresholds for each of the early hepatic changes. Increased expression of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) inducible genes was recorded after each exposure period. Further confirmation of CAR/PXR activation was provided by increased activity of specific Phase I enzymes (PROD/BROD respectively). Increased hepatocellular proliferation (measured by Ki67) was observed after each exposure period with the greatest proliferative response occurring after 3days of treatment. In these studies, dose responses and clear thresholds were established for gene expression, enzyme activity and cell proliferation. Furthermore, these early hepatic changes were shown to be reversible following compound withdrawal. Other modes of action for liver tumor formation such as DNA damage, cytotoxicity and peroxisome proliferation were excluded during the investigations. In conclusion, fluopyram is a threshold carcinogen and the resultant hepatocellular carcinomas in the female rat are due to hepatocellular proliferation mediated by CAR/PXR activation.

  6. Targeting Epithelial-Mesenchymal Transition for Identification of Inhibitors for Pancreatic Cancer Cell Invasion and Tumor Spheres Formation

    PubMed Central

    Polireddy, Kishore; Dong, Ruochen; McDonald, Peter R.; Wang, Tao; Luke, Brendan; Chen, Ping; Broward, Melinda; Roy, Anuradha; Chen, Qi

    2016-01-01

    Background Pancreatic cancer has an enrichment of stem-like cancer cells (CSCs) that contribute to chemoresistant tumors prone to metastasis and recurrence. Drug screening assays based on cytotoxicity cannot identify specific CSC inhibitors, because CSCs comprise only a small portion of cancer cell population, and it is difficult to propagate stable CSC populations in vitro for high-throughput screening (HTS) assays. Based on the important role of cancer cell epithelial-to-mesenchymal transition (EMT) in promoting CSCs, we hypothesized that inhibition of EMT can be a useful strategy for inhibiting CSCs, and therefore a feasible approach for HTS can be built for identification of CSC inhibitors, based on assays detecting EMT inhibition. Methods An immunofluorescent assay was established and optimized for HTS to identify compounds that enhance E-cadherin expression, as a hallmark of inhibition of EMT. Four chemical libraries containing 41,472 compounds were screened in PANC-1 pancreatic cancer cell line. Positive hits were validated for EMT and CSC inhibition in vitro using sphere formation assay, western blotting, immune fluorescence, and scratch assay. Results Initial hits were refined to 73 compounds with a secondary screening, among which 17 exhibited concentration dependent induction of E-cadherin expression. Six compounds were selected for further study which belonged to 2 different chemical structural clusters. A novel compound 1-(benzylsulfonyl) indoline (BSI, Compound #38) significantly inhibited pancreatic cancer cell migration and invasion. BSI inhibited histone deacetylase, increased histone 4 acetylation preferably, resulting in E-cadherin up-regulation. BSI effectively inhibited tumor spheres formation. Six more analogues of BSI were tested for anti-migration and anti-CSC activities. Conclusion This study demonstrated a feasible approach for discovery of agents targeting EMT and CSCs using HTS, and identified a class of novel chemicals that could be

  7. Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene.

    PubMed

    Atwal, Gurinder Singh; Kirchhoff, Tomas; Bond, Elisabeth E; Montagna, Marco; Monagna, Marco; Menin, Chiara; Bertorelle, Roberta; Scaini, Maria Chiara; Bartel, Frank; Böhnke, Anja; Pempe, Christina; Gradhand, Elise; Hauptmann, Steffen; Offit, Kenneth; Levine, Arnold J; Bond, Gareth L

    2009-06-23

    A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1-4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.

  8. Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

    SciTech Connect

    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

    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, 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 {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.

  9. P15, MDM2, NF-κB, and Bcl-2 expression in primary bone tumor and correlation with tumor formation and metastasis

    PubMed Central

    Qian, Guibin; Hao, Songnan; Yang, Dawei; Meng, Qinggang

    2015-01-01

    Primary bone tumor is one of the most common malignant tumors in skeletal system. It seriously affected bone movement and development with unclear pathogenesis. In this paper, rabbit VX-2 malignant bone tumor model was applied to explore apoptotic genes P15, MDM2, NF-κB and Bcl-2 correlation with primary bone tumor occurrence and metastasis. 0.3 ml rabbit VX-2 tumor cell suspension (1×106/ml) was injected to the marrow cavity of the right tibia condyle to establish the rabbit malignant bone tumor model, while equal amount of the saline was injected to the left tibia as control. Real-time PCR was applied to determine P15, MDM2, NF-κB and Bcl-2 expression level. Immunohistochemistry was performed to detect the abovementioned genes expression in lung, stomach, kidney and bladder. Compared with control, P15 expression level in the inoculation site surrounding tissues decreased obviously following the inoculate time elongation (P<0.05), while Bcl-2, MDM2 and NF-κB expression significantly increased (P<0.05). Bcl-2 showed significant correlation with MDM2 and NF-κB (P<0.05). At the 2, 4, 6 weeks, Bcl-2, MDM2 and NF-κB in lung, Bcl-2 in kidney, and Bcl-2 and MDM2 in bladder positively expressed (P<0.05), whereas P15 gene exhibited no significant positive expression in these tissues (P>0.05). P15, MDM2, NF-κB, and Bcl-2 genes expression levels can effectively reflect malignant bone tumor growth of rabbit tibia. MDM2, NF-κB and Bcl-2 genes involved in primary bone tumors metastasis directly. It has important clinical significance for early diagnosis and treatment of primary bone tumor. PMID:26823818

  10. Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase.

    PubMed

    Zhang, Junjie; He, Shanping; Wang, Yi; Brulois, Kevin; Lan, Ke; Jung, Jae U; Feng, Pinghui

    2015-03-01

    G protein-coupled receptors (GPCRs) constitute the largest family of proteins that transmit signal to regulate an array of fundamental biological processes. Viruses deploy diverse tactics to hijack and harness intracellular signaling events induced by GPCR. Herpesviruses encode multiple GPCR homologues that are implicated in viral pathogenesis. Cellular GPCRs are primarily regulated by their cognate ligands, while herpesviral GPCRs constitutively activate downstream signaling cascades, including the nuclear factor of activated T cells (NFAT) pathway. However, the roles of NFAT activation and mechanism thereof in viral GPCR tumorigenesis remain unknown. Here we report that GPCRs of human Kaposi's sarcoma-associated herpesvirus (kGPCR) and cytomegalovirus (US28) shortcut NFAT activation by inhibiting the sarcoplasmic reticulum calcium ATPase (SERCA), which is necessary for viral GPCR tumorigenesis. Biochemical approaches, entailing pharmacological inhibitors and protein purification, demonstrate that viral GPCRs target SERCA2 to increase cytosolic calcium concentration. As such, NFAT activation induced by vGPCRs was exceedingly sensitive to cyclosporine A that targets calcineurin, but resistant to inhibition upstream of ER calcium release. Gene expression profiling identified a signature of NFAT activation in endothelial cells expressing viral GPCRs. The expression of NFAT-dependent genes was up-regulated in tumors derived from tva-kGPCR mouse and human KS. Employing recombinant kGPCR-deficient KSHV, we showed that kGPCR was critical for NFAT-dependent gene expression in KSHV lytic replication. Finally, cyclosporine A treatment diminished NFAT-dependent gene expression and tumor formation induced by viral GPCRs. These findings reveal essential roles of NFAT activation in viral GPCR tumorigenesis and a mechanism of "constitutive" NFAT activation by viral GPCRs.

  11. Accelerated formation of strontium silicate by solid-state reaction in NaCl-H2O(v) system at lower temperature

    NASA Astrophysics Data System (ADS)

    Zhang, Junhao; Qiu, Yushi; Huang, Man; Zheng, Hongjuan; Yanagisawa, Kazumichi

    2015-08-01

    An environmentally friendly NaCl-H2O system was developed to prepare SrSiO3 nanostructures from commercially available raw materials, SrCO3 and amorphous SiO2 (α-SiO2), by a one-step solid state reaction at 600 °C for 2 h. The formation of SrSiO3 was accelerated by NaCl-H2O(v) system. The results demonstrate that both NaCl and H2O played vital roles to accelerate the formation of SrSiO3 nanostructures at lower temperature. NaCl was considered to enhance the diffusivity of starting materials and the rate of solid state reactions, and promote the crystallization of products at lower temperature. Additionally, two different phases of SrSiO3 (JPDS 00-032-1257) and SrSiO3 (JPDS 00-006-0415) were abtained without or with the addition of NaCl. Water vapor accelerated the decomposition of SrCO3, and absorbed water on the surface of solid materials dissolved NaCl to form an aqueous ionic liquid composed of Na and Cl ions, which was similar to a hydrothermal process, and further increased the diffusivity of components and reduced the reaction temperature.

  12. I. Embryonal vasculature formation recapitulated in transgenic mammary tumor spheroids implanted pseudo-orthotopicly into mouse dorsal skin fold: the organoblasts concept

    PubMed Central

    Witkiewicz, Halina

    2013-01-01

    Inadequate understanding of cancer biology is a problem. This work focused on cellular mechanisms of tumor vascularization. According to earlier studies, the tumor vasculature derives from host endothelial cells (angiogenesis) or their precursors of bone marrow origin circulating in the blood (neo-vasculogenesis) unlike in embryos. In this study, we observed the neo-vasculature form in multiple ways from local precursor cells. Recapitulation of primitive as well as advanced embryonal stages of vasculature formation followed co-implantation of avascular ( in vitro cultured) N202 breast tumor spheroids and homologous tissue grafts into mouse dorsal skin chambers. Ultrastructural and immunocytochemical analysis of tissue sections exposed the interactions between the tumor and the graft tissue stem cells. It revealed details of vasculature morphogenesis not seen before in either tumors or embryos. A gradual increase in complexity of the vascular morphogenesis at the tumor site reflected a range of steps in ontogenic evolution of the differentiating cells. Malignant- and surgical injury repair-related tissue growth prompted local cells to initiate extramedullar erythropoiesis and vascular patterning. The new findings included: interdependence between the extramedullar hematopoiesis and assembly of new vessels (both from the locally differentiating precursors); nucleo-cytoplasmic conversion (karyolysis) as the mechanism of erythroblast enucleation; the role of megakaryocytes and platelets in vascular pattern formation before emergence of endothelial cells; lineage relationships between hematopoietic and endothelial cells; the role of extracellular calmyrin in tissue morphogenesis; and calmyrite, a new ultrastructural entity associated with anaerobic energy metabolism. The central role of the extramedullar erythropoiesis in the formation of new vasculature (blood and vessels) emerged here as part of the tissue building process including the lymphatic system and nerves

  13. Autophagy is involved in TGF-β1-induced protective mechanisms and formation of cancer-associated fibroblasts phenotype in tumor microenvironment

    PubMed Central

    Liu, Fang-Lan; Mo, En-Pan; Yang, Liu; Du, Jun; Wang, Hong-Sheng; Zhang, Huan; Kurihara, Hiroshi; Xu, Jun; Cai, Shao-Hui

    2016-01-01

    Transforming growth factor-β1 (TGF-β1) present in tumor microenvironment acts in a coordinated fashion to either suppress or promote tumor development. However, the molecular mechanisms underlying the effects of TGF-β1 on tumor microenvironment are not well understood. Our clinical data showed a positive association between TGF-β1 expression and cancer-associated fibroblasts (CAFs) in tumor microenvironment of breast cancer patients. Thus we employed starved NIH3T3 fibroblasts in vitro and 4T1 cells mixed with NIH3T3 fibroblasts xenograft model in vivo to simulate nutritional deprivation of tumor microenvironment to explore the effects of TGF-β1. We demonstrated that TGF-β1 protected NIH3T3 fibroblasts from Star-induced growth inhibition, mitochondrial damage and cell apoptosis. Interestingly, TGF-β1 induced the formation of CAFs phenotype in starvation (Star)-treated NIH3T3 fibroblasts and xenografted Balb/c mice, which promoted breast cancer tumor growth. In both models, autophagy agonist rapamycin increased TGF-β1-induced protective effects and formation of CAFs phenotypes, while autophagy inhibitor 3-methyladenine, Atg5 knockdown or TGF-β type I receptor kinase inhibitor LY-2157299 blocked TGF-β1 induced these effects. Taken together, our results indicated that TGF-β/Smad autophagy was involved in TGF-β1-induced protective effects and formation of CAFs phenotype in tumor microenvironment, which may be used as therapy targets in breast cancer. PMID:26716641

  14. Early enriched environment exposure protects spatial memory and accelerates amyloid plaque formation in APP(Swe)/PS1(L166P) mice.

    PubMed

    Montarolo, Francesca; Parolisi, Roberta; Hoxha, Eriola; Boda, Enrica; Tempia, Filippo

    2013-01-01

    Enriched environment exposure improves several aspects of cognitive performance in Alzheimer's disease patients and in animal models and, although the role of amyloid plaques is questionable, several studies also assessed their response to enriched environment, with contrasting results. Here we report that rearing APP(Swe)/PS1(L166P) mice in an enriched environment since birth rescued the spatial memory impairment otherwise present at 6 months of age. At the same time, the exposure to the enriched environment caused a transient acceleration of plaque formation, while there was no effect on intracellular staining with the 6E10 antibody, which recognizes β-amyloid, full length amyloid precursor protein and its C-terminal fragments. The anticipation of plaque formation required exposure during early development, suggesting an action within critical periods for circuits formation. On the other hand, chronic neuronal activity suppression by tetrodotoxin decreased the number of plaques without affecting intracellular amyloid. These results indicate that enriched environment exposure since early life has a protective effect on cognitive deterioration although transiently accelerates amyloid deposition. In addition, the effects of the enriched environment might be due to increased neuronal activity, because plaques were reduced by suppression of electrical signaling by tetrodotoxin.

  15. Formation and repair of pyridyloxobutyl DNA adducts and their relationship to tumor yield in A/J mice

    PubMed Central

    Urban, Anna M.; Upadhyaya, Pramod; Cao, Qing; Peterson, Lisa A.

    2012-01-01

    The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a known human carcinogen. It generates methyl and pyridyloxobutyl DNA adducts. The role of the methyl DNA adducts has been well-established in the tumorigenic properties of NNK. However, the role of the pyridyloxobutyl DNA adducts is unclear. Four pyridyloxobutyl DNA adducts have been characterized: 7-[4-3-(pyridyl)-4-oxobut-1-yl]guanine (7-pobG), O2-[4-3-(pyridyl)-4-oxobut-1-yl]-cytodine (O2-pobC), O2-[4-3-(pyridyl)-4-oxobut-1yl]thymidine (O2-pobdT), and O6-[4-3-(pyridyl)-4-oxobut-1-yl]-2'-deoxyguanosine (O6-pobdG). Mutagenic O6-pobdG is thought to contribute to the tumorigenic properties of the pyridyloxobutylation pathway. It is repaired by O6-alkylguanine-DNA alkyltransferase (AGT). To explore the role of O6-pobdG formation and repair in the tumorigenic properties of NNK, A/J mice were given single or multiple doses of the model pyridyloxobutylating agent 4-(acetoxymethyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc) in the presence or absence of the AGT depletor, O6-benzylguanine. Levels of the four pyridyloxobutyl DNA adducts were measured in the lung at 8, 48 or 96 h following treatment and compared to the lung tumorigenic activity of these treatments. AGT depletion had only a modest effect on the levels of O6-pobdG and did not increase tumor formation. Three pyridyloxobutyl DNA adducts, 7-pobG, O2-pobdT, and O6-pobdG, persisted in lung DNA at significant levels for up to 96 h post-treatment, suggesting that all three adducts may contribute to the tumorigenic properties of NNK. PMID:22928598

  16. Role of the von Hippel-Lindau tumor suppressor gene in the formation of beta1-integrin fibrillar adhesions.

    PubMed

    Esteban-Barragán, Miguel A; Avila, Pilar; Alvarez-Tejado, Miguel; Gutiérrez, M Dolores; García-Pardo, Angeles; Sánchez-Madrid, Francisco; Landázuri, Manuel O

    2002-05-15

    The von Hippel-Lindau tumor suppressor gene (VHL) is absent or inactivated in the VHLcancer syndrome and in most sporadic renal cancers. VHL is requiredfor the assembly of a proper extracellular fibronectin matrix, although the exact mechanism remains unknown. In this report, we demonstrate that 786-O renal cancer cells are unable to organize an adequate matrix even in the presence of an excess of exogenous fibronectin. Because the formation of integrin fibrillar adhesions plays a pivotal role in the organization of extracellular fibronectin, we next examined the expression and subcellular distribution of integrins in VHL- cells and their wild-type VHL stably transfected counterparts. The levels of beta1 and alphav integrins were increased in VHL- cells when compared with VHL+ transfectants. Early after plating, both VHL+ and VHL- cells were capable of assembling classic "patch-like" alphav focal contacts. As the culture advanced and cells became confluent, alphav integrins partly relocated to the intercellular junctions in VHL+ transfectants, which then developed large beta1 fibrillar-type adhesions and anchored firmly to the substrate. In contrast, confluent VHL- cells were unable to assemble beta1 fibrillar adhesions, and alphav focal contacts remained unchanged at all stages of the culture. Exogenous activation of beta1 integrins with either divalent cations or activating antibodies partly restored the capability of VHL- cells to assemble beta1 fibrillar adhesions and fibronectin fibers. Finally, pulse-chase studies of metabolically labeled 786-O cells revealed that the maturation of the common beta1-integrin chain was delayed in VHL- cells when compared with VHL+ cells. Our results show that VHL is an important regulator of integrins and is essential for the formation of beta1 fibrillar adhesions. These findings help to explain the abnormal extracellular matrix organization and increased motility of VHL- renal cancer cells. PMID:12019174

  17. A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

    PubMed Central

    Smith, Eric J.; Olson, Kara; Haber, Lauric J.; Varghese, Bindu; Duramad, Paurene; Tustian, Andrew D.; Oyejide, Adelekan; Kirshner, Jessica R.; Canova, Lauren; Menon, Jayanthi; Principio, Jennifer; MacDonald, Douglas; Kantrowitz, Joel; Papadopoulos, Nicholas; Stahl, Neil; Yancopoulos, George D.; Thurston, Gavin; Davis, Samuel

    2015-01-01

    Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies. PMID:26659273

  18. Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells

    PubMed Central

    Wu, Yi-Hui; Chiu, Wen-Tai; Young, Ming-Jer; Chang, Tzu-Hao; Huang, Yu-Fang; Chou, Cheng-Yang

    2015-01-01

    Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment. PMID:26366215

  19. Brg1 promotes both tumor-suppressive and oncogenic activities at distinct stages of pancreatic cancer formation

    PubMed Central

    Roy, Nilotpal; Malik, Shivani; Villanueva, Karina E.; Urano, Atsushi; Lu, Xinyuan; Von Figura, Guido; Seeley, E. Scott; Dawson, David W.; Collisson, Eric A.

    2015-01-01

    Pancreatic ductal adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a “ductal-like” state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells during which functional cells undergo “ductal retrogression” to form IPMN-PDA. We further identify critical antagonistic roles for Brahma-related gene 1 (Brg1), a catalytic subunit of the SWI/SNF complexes, during IPMN-PDA development. In mature duct cells, Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We further show that JQ1, a drug that is currently being tested in clinical trials for hematological malignancies, impairs PDA tumorigenesis by both mimicking some and inhibiting other Brg1-mediated functions. In summary, our study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA. PMID:25792600

  20. Depletion of the chromatin remodeler CHD4 sensitizes AML blasts to genotoxic agents and reduces tumor formation

    PubMed Central

    Sperlazza, Justin; Rahmani, Mohamed; Beckta, Jason; Aust, Mandy; Hawkins, Elisa; Wang, Shou Zhen; Zu Zhu, Sheng; Podder, Shreya; Dumur, Catherine; Archer, Kellie; Grant, Steven

    2015-01-01

    Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATPase that alters the phasing of nucleosomes on DNA and has recently been implicated in DNA double-stranded break (DSB) repair. Here, we show that depletion of CHD4 in acute myeloid leukemia (AML) blasts induces a global relaxation of chromatin that renders cells more susceptible to DSB formation, while concurrently impeding their repair. Furthermore, CHD4 depletion renders AML blasts more sensitive both in vitro and in vivo to genotoxic agents used in clinical therapy: daunorubicin (DNR) and cytarabine (ara-C). Sensitization to DNR and ara-C is mediated in part by activation of the ataxia-telangiectasia mutated pathway, which is preliminarily activated by a Tip60-dependent mechanism in response to chromatin relaxation and further activated by genotoxic agent–induced DSBs. This sensitization preferentially affects AML cells, as CHD4 depletion in normal CD34+ hematopoietic progenitors does not increase their susceptibility to DNR or ara-C. Unexpectedly, we found that CHD4 is necessary for maintaining the tumor-forming behavior of AML cells, as CHD4 depletion severely restricted the ability of AML cells to form xenografts in mice and colonies in soft agar. Taken together, these results provide evidence for CHD4 as a novel therapeutic target whose inhibition has the potential to enhance the effectiveness of genotoxic agents used in AML therapy. PMID:26265695

  1. Establishment and Characterization of Human Germline Stem Cell Line with Unlimited Proliferation Potentials and no Tumor Formation.

    PubMed

    Hou, Jingmei; Niu, Minghui; Liu, Linhong; Zhu, Zijue; Wang, Xiaobo; Sun, Min; Yuan, Qingqing; Yang, Shi; Zeng, Wenxian; Liu, Yang; Li, Zheng; He, Zuping

    2015-11-20

    Spermatogonial stem cells (SSCs) have significant applications in both reproductive and regenerative medicine. However, primary human SSCs are very rare, and a human SSC line has not yet been available. In this study, we have for the first time reported a stable human SSC line by stably expressing human SV40 large T antigen. RT-PCR, immunocytochemistry, and Western blots revealed that this cell line was positive for a number of human spermatogonial and SSC hallmarks, including VASA, DAZL, MAGEA4, GFRA1, RET, UCHL1, GPR125, PLZF and THY1, suggesting that these cells are human SSCs phenotypically. Proliferation analysis showed that the cell line could be expanded with significant increases of cells for 1.5 years, and high levels of PCNA, UCHL1 and SV40 were maintained for long-term culture. Transplantation assay indicated that human SSC line was able to colonize and proliferate in vivo in the recipient mice. Neither Y chromosome microdeletions of numerous genes nor tumor formation was observed in human SSC line although there was abnormal karyotype in this cell line. Collectively, we have established a human SSC line with unlimited proliferation potentials and no tumorgenesis, which could provide an abundant source of human SSCs for their mechanistic studies and translational medicine.

  2. Mifepristone-inducible caspase-1 expression in mouse embryonic stem cells eliminates tumor formation but spares differentiated cells in vitro and in vivo.

    PubMed

    Wang, Yi; Yang, Dehua; Song, Lin; Li, Ting; Yang, Juan; Zhang, Xiaojie; Le, Weidong

    2012-02-01

    Embryonic stem cell (ESC)-based therapy is a promising treatment for neurodegenerative diseases. But there is always a risk of tumor formation that is due to contamination of undifferentiated ESCs. To reduce the risk and improve ESC-based therapy, we have established a novel strategy by which we can selectively eliminate tumor cells derived from undifferentiated ESCs but spare differentiated cells. In this study, we generated a caspase-1-ESC line transfected with a mifepristone-regulated caspase-1 expression system. Mifepristone induced caspase-1 overexpression both in differentiated and undifferentiated caspase-1-ESCs. All the undifferentiated caspase-1-ESCs were induced to death after mifepristone treatment. Tumors derived from undifferentiated caspase-1-ESCs were eliminated following 3 weeks of mifepristone treatment in vivo. However, differentiated caspase-1-ESCs survived well under the condition of mifepristone-induced caspase-1 overexpression. To examine in vivo the impact of mifepristone-induced caspase-1 activation on grafted cells, we transplanted wild-type ESCs or caspase-1-ESCs into nude mice brains. After 8 weeks of mifepristone treatment, we could not detect any tumor cells in the caspase-1-ESC grafts in the brains of mice. However, we found that donor dopamine neurons survived in the recipient brains. These data demonstrate that mifepristone-induced caspase-1 overexpression in ESCs can eliminate the potential tumor formation meanwhile spares the differentiated cells in the host brains. These results suggest that this novel ESC-based therapy can be used in Parkinson's disease and other related disorders without the risk of tumor formation.

  3. Fail-Safe Therapy by Gamma-Ray Irradiation Against Tumor Formation by Human-Induced Pluripotent Stem Cell-Derived Neural Progenitors.

    PubMed

    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. PMID:27059007

  4. Fail-Safe Therapy by Gamma-Ray Irradiation Against Tumor Formation by Human-Induced Pluripotent Stem Cell-Derived Neural Progenitors.

    PubMed

    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.

  5. Consensus diagnoses and mode of action for the formation of gastric tumors in rats treated with the chloroacetanilide herbicides alachlor and butachlor.

    PubMed

    Furukawa, Satoshi; Harada, Takanori; Thake, Daryl; Iatropoulos, Michael J; Sherman, James H

    2014-01-01

    A panel of pathologists (Panel) was formed to evaluate the pathogenesis and human relevance of tumors that developed in the fundic region of rat stomachs in carcinogenicity and mechanistic studies with alachlor and butachlor. The Panel evaluated stomach sections stained with hematoxylin and eosin, neuron-specific enolase, and chromogranin A to determine the presence and relative proportion of enterochromaffin-like (ECL) cells in the tumors and concluded all tumors were derived from ECL cells. Biochemical and pathological data demonstrated the tumor formation involved a nongenotoxic threshold mode of action (MOA) initially characterized by profound atrophy of the glandular fundic mucosa that affected gastric glands, but not surface epithelium. This resulted in a substantial loss of parietal cells and a compensatory mucosal cell proliferation. The loss of parietal cells caused a marked increase in gastric pH (hypochlorhydria), leading to sustained and profound hypergastrinemia. The mucosal atrophy, together with the increased gastrin, stimulated cell growth in one or more ECL cell populations, resulting in neoplasia. ECL cell autocrine and paracrine effects led to dedifferentiation of ECL cell tumors. The Panel concluded the tumors develop via a threshold-dependent nongenotoxic MOA, under conditions not relevant to humans.

  6. Bacoside-A, an anti-amyloid natural substance, inhibits membrane disruption by the amyloidogenic determinant of prion protein through accelerating fibril formation.

    PubMed

    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.

  7. Bacoside-A, an anti-amyloid natural substance, inhibits membrane disruption by the amyloidogenic determinant of prion protein through accelerating fibril formation.

    PubMed

    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. PMID:27365272

  8. MAPK15 mediates BCR-ABL1-induced autophagy and regulates oncogene-dependent cell proliferation and tumor formation

    PubMed Central

    Colecchia, David; Rossi, Matteo; Sasdelli, Federica; Sanzone, Sveva; Strambi, Angela; Chiariello, Mario

    2015-01-01

    A reciprocal translocation of the ABL1 gene to the BCR gene results in the expression of the oncogenic BCR-ABL1 fusion protein, which characterizes human chronic myeloid leukemia (CML), a myeloproliferative disorder considered invariably fatal until the introduction of the imatinib family of tyrosine kinase inhibitors (TKI). Nonetheless, insensitivity of CML stem cells to TKI treatment and intrinsic or acquired resistance are still frequent causes for disease persistence and blastic phase progression experienced in patients after initial successful therapies. Here, we investigated a possible role for the MAPK15/ERK8 kinase in BCR-ABL1-dependent autophagy, a key process for oncogene-induced leukemogenesis. In this context, we showed the ability of MAPK15 to physically recruit the oncogene to autophagic vesicles, confirming our hypothesis of a biologically relevant role for this MAP kinase in signal transduction by this oncogene. Indeed, by modeling BCR-ABL1 signaling in HeLa cells and taking advantage of a physiologically relevant model for human CML, i.e. K562 cells, we demonstrated that BCR-ABL1-induced autophagy is mediated by MAPK15 through its ability to interact with LC3-family proteins, in a LIR-dependent manner. Interestingly, we were also able to interfere with BCR-ABL1-induced autophagy by a pharmacological approach aimed at inhibiting MAPK15, opening the possibility of acting on this kinase to affect autophagy and diseases depending on this cellular function. Indeed, to support the feasibility of this approach, we demonstrated that depletion of endogenous MAPK15 expression inhibited BCR-ABL1-dependent cell proliferation, in vitro, and tumor formation, in vivo, therefore providing a novel “druggable” link between BCR-ABL1 and human CML. PMID:26291129

  9. Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.

    PubMed

    Baxter, Patricia A; Lin, Qi; Mao, Hua; Kogiso, Mari; Zhao, Xiumei; Liu, Zhigang; Huang, Yulun; Voicu, Horatiu; Gurusiddappa, Sivashankarappa; Su, Jack M; Adesina, Adekunle M; Perlaky, Laszlo; Dauser, Robert C; Leung, Hon-chiu Eastwood; Muraszko, Karin M; Heth, Jason A; Fan, Xing; Lau, Ching C; Man, Tsz-Kwong; Chintagumpala, Murali; Li, Xiao-Nan

    2014-01-01

    Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.

  10. Liposomal Doxorubicin Increases Radiofrequency Ablation–induced Tumor Destruction by Increasing Cellular Oxidative and Nitrative Stress and Accelerating Apoptotic Pathways1

    PubMed Central

    Solazzo, Stephanie A.; Ahmed, Muneeb; Schor-Bardach, Rachel; Yang, Wei; Girnun, Geoffrey D.; Rahmanuddin, Syed; Levchenko, Tatyana; Signoretti, Sabina; Spitz, Douglas R.; Torchilin, Vladimir

    2010-01-01

    Purpose: To determine if oxidative and nitrative stress and/or apoptosis contribute to increased coagulation when combining radiofrequency (RF) ablation with liposomal doxorubicin. Materials and Methods: Animal care committee approval was obtained. R3230 mammary adenocarcinomas in Fischer rats were treated with either RF ablation (n = 43), 1 mg of intravenously injected liposomal doxorubicin (n = 26), or combined therapy (n = 30) and were compared with control subjects (n = 11). A subset of animals receiving combination therapy (n = 24) were treated in the presence or absence of N-acetylcysteine (NAC) administered 24 hours and 1 hour before RF ablation. Tumors were analyzed 2 minutes to 72 hours after treatment to determine the temporal range of response by using immunohistochemical staining of the apoptosis marker cleaved caspase-3, phosphorylated γH2AX, and HSP70 and of markers of oxidative and nitrative stress (8-hydroxydeoxyguanosine [8-OHdG], 4-hydroxynonenal [4-HNE]–modified proteins, and nitrotyrosine [NT]). Statistical analyses, including t tests and analysis of variance for comparisons where appropriate, were performed. Results: By 4 hours after RF ablation alone, a 0.48-mm ± 0.13 (standard deviation) peripheral band with 57.0% ± 7.3 cleaved caspase-3 positive cells was noted at the ablation margin, whereas a 0.73-mm ± 0.18 band with 77.7% ± 6.3 positivity was seen for combination therapy (P < .03 for both comparisons). Combination therapy caused increased and earlier staining for 4-HNE–modified proteins, 8-OHdG, NT, and γH2AX with colocalization to cleaved caspase-3 staining. A rim of increased HSP70 was identified peripheral to the area of cleaved caspase-3. Parameters of oxidative and nitrative stress were significantly inhibited by NAC 1 hour following RF ablation, resulting in decreased cleaved caspase-3 positivity (0.28-mm ± 0.09 band of 25.9% ± 7.4 positivity vs 0.59-mm ± 0.11 band of 62.9% ± 6.0 positivity, P < .001 for both

  11. Inhibitory Effect of a γ-Tocopherol-Rich Mixture of Tocopherols on the Formation and Growth of LNCaP Prostate Tumors in Immunodeficient Mice

    PubMed Central

    Zheng, Xi; Cui, Xiao-Xing; Khor, Tin Oo; Huang, Ying; DiPaola, Robert S; Goodin, Susan; Lee, Mao-Jung; Yang, Chung S; Kong, Ah-Ng; Allan H., Conney

    2011-01-01

    In the present study, we determined the effects of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) on the growth and apoptosis of cultured human prostate cancer LNCaP cells. We also determined the effects of dietary γ-TmT on the formation and growth of LNCaP tumors in immunodeficient mice. In the in vitro study, we found that the activity of γ-TmT was stronger than α-tocopherol for inhibiting the growth and stimulating apoptosis in LNCaP cells. In the animal study, treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT inhibited the formation and growth of LNCaP xenograft tumors in a dose-dependent manner. Mechanistic studies showed that γ-TmT administration inhibited proliferation as reflected by decreased mitosis and stimulated apoptosis as reflected by increased caspase-3 (active form) expression in LNCaP tumors. In addition, dietary administration of γ-TmT increased the levels of α-, γ- and δ- tocopherol in plasma, and increased levels of γ- and δ- tocopherol were also observed in the prostate and in tumors. The present study demonstrated that γ-TmT had strong anticancer activity both in vitro and in vivo. Additional studies are needed to determine the potential preventive effect of γ-TmT for prostate cancer in humans. PMID:24213110

  12. Formation and utilization of acetoin, an unusual product of pyruvate metabolism by Ehrlich and AS30-D tumor mitochondria.

    PubMed

    Baggetto, L G; Lehninger, A L

    1987-07-15

    [14C]Pyruvate was rapidly non-oxidatively decarboxylated by Ehrlich tumor mitochondria at a rate of 40 nmol/min/mg of protein in the presence or absence of ADP. A search for decarboxylation products led to significant amounts of acetoin formed when Ehrlich tumor mitochondria were incubated with 1 mM [14C] pyruvate in the presence of ATP. Added acetoin to aerobic tumor mitochondria was rapidly utilized in the presence of ATP at a rate of 65 nmol/min/mg of protein. Citrate has been found as a product of acetoin utilization and was exported from the tumor mitochondria. Acetoin has been found in the ascitic liquid of Ehrlich and AS30-D tumor-bearing animals. These unusual reactions were not observed in control rat liver mitochondria.

  13. Biological responses of human solid tumor cells to X-ray irradiation within a 1.5-Tesla magnetic field generated by a magnetic resonance imaging-linear accelerator.

    PubMed

    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. PMID:27434783

  14. Strain-dependent lung tumor formation in mice transplacentally exposed to 3-methylcholanthrene and post-natally exposed to butylated hydroxytoluene.

    PubMed

    Gressani, K M; Leone-Kabler, S; O'Sullivan, M G; Case, L D; Malkinson, A M; Miller, M S

    1999-11-01

    on either tumor incidence, tumor multiplicity or the mutational spectrum produced in the Ki-ras gene by in utero MC treatment. However, though not significant, there was an observable trend in increased tumor multiplicity in mice co-treated with BHT. These data demonstrate the transplacental carcinogenic effect of MC in BALB/c mice and show that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both the tumor-sensitive and tumor-resistant strains. Unlike what occurs when adult BALB/c mice are treated with MC, BHT does not appear to significantly promote the formation of lung tumors following transplacental exposure to MC, possibly due to the rapid growth and cell proliferation in the developing organism. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.

  15. Analysis of Dose at the Site of Second Tumor Formation After Radiotherapy to the Central Nervous System

    SciTech Connect

    Galloway, Thomas J.; Indelicato, Daniel J.; Amdur, Robert J.; Morris, Christopher G.; Swanson, Erika L.; Marcus, Robert B.

    2012-01-01

    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 to 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.

  16. Linear Accelerators

    SciTech Connect

    Sidorin, Anatoly

    2010-01-05

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  17. Polyanionic Candidate Microbicides Accelerate the Formation of Semen-Derived Amyloid Fibrils to Enhance HIV-1 Infection

    PubMed Central

    Tan, Suiyi; Lu, Lu; Li, Lin; Liu, Jixiang; Oksov, Yelena; Lu, Hong; Jiang, Shibo; Liu, Shuwen

    2013-01-01

    Polyanionic candidate microbicides, including cellulose sulfate, carrageenan, PRO 2000, were proven ineffective in preventing HIV-1 transmission and even cellulose sulfate showed increased risk of HIV acquisition in the Phase III efficacy trials. Semen plays critical roles in HIV-1 sexual transmission. Specifically, amyloid fibrils formed by fragments of prostatic acidic phosphatase (PAP) in semen termed semen-derived enhancer of virus infection (SEVI) could drastically enhance HIV-1 infection. Here we investigated the interaction between polyanions and PAP248-286, a prototype peptide of SEVI, to understand the possible cause of polyanionic candidate microbicides to fail in clinical trials. We found anionic polymers could efficiently promote SEVI fibril formation, most likely mediated by the natural electrostatic interaction between polyanions and PAP248-286, as revealed by acid native PAGE and Western blot. The overall anti-HIV-1 activity of polyanions in the presence or absence of PAP248-286 or semen was evaluated. In the viral infection assay, the supernatants of polyanions/PAP248-286 or polyanions/semen mixtures containing the free, unbound polyanionic molecules showed a general reduction in antiviral efficacy, while the pellets containing amyloid fibrils formed by the polyanion-bound PAP248-286 showed aggravated enhancement of viral infection. Collectively, from the point of drug-host protein interaction, our study revealed that polyanions facilitate SEVI fibril formation to promote HIV-1 infection, thus highlighting a molecular mechanism underlying the failure of polyanions in clinical trials and the importance of drug-semen interaction in evaluating the anti-HIV-1 efficacy of candidate microbicides. PMID:23544097

  18. Enhancement of lung tumor formation in mice by dietary butylated hydroxytoluene: dose-time relationships and cell kinetics

    SciTech Connect

    Witschi, H.R.; Morse, C.C.

    1983-10-01

    Strain A/J mice given injections of 1000 mg urethan/kg and fed for 12 weeks a diet containing 0.75% of butylated hydroxytoluene (BHT) had significantly more tumors per lung 4 or 9 months later than animals given urethan and fed a control diet. A 2-week exposure to dietary BHT (0.75%) was sufficient to significantly enhance tumor development, and the lowest effective BHT concentration was 0.1%, fed for 8 weeks. Tumor development was also enhanced in animals treated once with 3-methylcholanthrene, benzo(a)pyrene, or N-nitrosodimethylamine and, beginning 24 hours later, fed BHT for 8 weeks. Cell kinetic studies showed that BHT given in the diet produced increased proliferation of type II alveolar cells during the first 2 weeks and that initial cell proliferation was delayed in urethan-treated animals.

  19. A facile route to core-shell nanoparticulate formation of arsenic trioxide for effective solid tumor treatment

    NASA Astrophysics Data System (ADS)

    Zhang, Zongjun; Liu, Hanyu; Zhou, Hualu; Zhu, Xianglong; Zhao, Zhenghuan; Chi, Xiaoqin; Shan, Hong; Gao, Jinhao

    2016-02-01

    Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a ``one-pot'' method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity (57.9 wt%) and a prolonged pH-responsive releasing profile, which is crucial to increase the drug concentration at tumor sites and improve the drug efficacy. Based on these unique features, the nanodrugs significantly inhibit the growth of solid tumors without adverse side effects. Therefore, we anticipate that the arsenic-based nanodrugs generated by this facile synthetic route may be a powerful and alternative strategy for solid tumor therapy.Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a ``one-pot'' method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity

  20. A facile route to core-shell nanoparticulate formation of arsenic trioxide for effective solid tumor treatment.

    PubMed

    Zhang, Zongjun; Liu, Hanyu; Zhou, Hualu; Zhu, Xianglong; Zhao, Zhenghuan; Chi, Xiaoqin; Shan, Hong; Gao, Jinhao

    2016-02-21

    Arsenic trioxide has achieved great clinical success in the treatment of acute promyelocytic leukemia (APL). However, it is difficult to replicate the success in other cancers, such as solid tumors, in part because of the rapid renal clearance and dose-limiting toxicity. Nanotechnology is expected to overcome these disadvantages through altering its pharmacokinetics and concentrating the drug at the desired sites. Herein, we report a "one-pot" method to develop arsenic-based nanodrugs by in situ coating the as-prepared arsenic nanocomplexes with porous silica shells. This process can be easily reproduced and scaled up because no complicated synthesis and purification steps are involved. This core-shell embedding method endows nanodrugs with high loading capacity (57.9 wt%) and a prolonged pH-responsive releasing profile, which is crucial to increase the drug concentration at tumor sites and improve the drug efficacy. Based on these unique features, the nanodrugs significantly inhibit the growth of solid tumors without adverse side effects. Therefore, we anticipate that the arsenic-based nanodrugs generated by this facile synthetic route may be a powerful and alternative strategy for solid tumor therapy.

  1. 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.

  2. Can Accelerators Accelerate Learning?

    SciTech Connect

    Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.

    2009-03-10

    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.

  3. Panostotic expansile bone disease with massive jaw tumor formation and a novel mutation in the signal peptide of RANK.

    PubMed

    Schafer, Anne L; Mumm, Steven; El-Sayed, Ivan; McAlister, William H; Horvai, Andrew E; Tom, Andrea M; Hsiao, Edward C; Schaefer, Frederick V; Collins, Michael T; Anderson, Mark S; Whyte, Michael P; Shoback, Dolores M

    2014-04-01

    Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow-legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF-κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12-base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the

  4. Panostotic Expansile Bone Disease With Massive Jaw Tumor Formation and a Novel Mutation in the Signal Peptide of RANK

    PubMed Central

    Schafer, Anne L; Mumm, Steven; El-Sayed, Ivan; McAlister, William H; Horvai, Andrew E; Tom, Andrea M; Hsiao, Edward C; Schaefer, Frederick V; Collins, Michael T; Anderson, Mark S; Whyte, Michael P; Shoback, Dolores M

    2015-01-01

    Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became bow-legged during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical and radiographic findings, elevated serum markers, and disorganized bone morphology suggested amplified receptor activator of NF-κB (RANK) signaling, even though his disorder differed from conditions with known constitutive activation of RANK signaling (eg, familial expansile osteolysis). We found a unique 12-base pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the phenotypes

  5. Mammary gland specific expression of Brk/PTK6 promotes delayed involution and tumor formation associated with activation of p38 MAPK

    PubMed Central

    2011-01-01

    ; ductal and lobular carcinomas expressing Brk were significantly more likely to express elevated phospho-p38 MAPK. Conclusions These studies illustrate that forced expression of Brk/PTK6 in non-transformed mammary epithelial cells mediates p38 MAPK phosphorylation and promotes increased cellular survival, delayed involution, and latent tumor formation. Brk expression in human breast tumors may contribute to progression by inducing p38-driven pro-survival signaling pathways. PMID:21923922

  6. Effects of butylated hydroxyanisole and butylated hydroxytoluene on DNA adduct formation and arylamines N-acetyltransferase activity in PC-3 cells (human prostate tumor) in vitro.

    PubMed

    Yeh, C C; Chung, J G; Wu, H C; Li, Y C; Lee, Y M; Hung, C F

    2000-11-01

    The effects of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the N-acetyltransferase (NAT) activity and DNA adduct formation in PC-3 cells (human prostate tumor) was studied. PC-3 cells were placed into tissue culture flasks and grown in an incubator as cytosols and intact cells. The BHA or BHT were added to the cytosols and intact cells. The NAT activity in cytosol and intact PC-3 cells were measured by HPLC assaying exhibited for the amounts of N-acetyl-2-aminofluorene and N-acetyl-p-aminobenzoic acid, 2-aminofluorene and p-aminobenzoic acid. The NAT activity in PC-3 cells and cytosols were inhibited by BHA or BHT in a dose-dependent manner; that is, the higher the concentrations of BHA or BHT the higher inhibition of NAT activity. The NAT values of K(m) and V(max) from PC-3 cells were also decreased by BHA or BHT in both cytosols and intact cells. The data also demonstrated concomitant exposure to BHA or BHT decreased AF-DNA adduct formation which was seen in the PC-3 cells. In addition, the formation of DNA adduct was decreased after BHA or BHT exposure. These findings suggested the usefulness of using human cultured PC-3 cells for assessing arylamine-induced DNA adduct formation. Furthermore, the findings illustrate how effectively BHA or BHT reduce the adduct formation.

  7. 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.

  8. Lack of correlation between N-myc and MAX expression in neuroblastoma tumors and in cell lines: implication for N-myc-MAX complex formation.

    PubMed

    Raschella, G; Romeo, A; Negroni, A; Pucci, S; Dominici, C; Castello, M A; Bevilacqua, P; Felsani, A; Calabretta, B

    1994-04-15

    Detectable levels of MAX messenger RNA were found in a set of human neuroblastoma tumors and established cell lines. MAX mRNA levels were independent of tumor stage and N-myc genomic amplification. By contrast, N-myc mRNA transcripts were detectable only in tumors with amplification of N-myc gene and in cell lines. Analysis by reverse transcriptase polymerase chain reaction and hybridization to specific oligodeoxynucleotide probes revealed approximately equal amounts of two MAX transcripts in all cases analyzed. Immunoprecipitations with a specific antibody to MAX detected two proteins of M(r) 21,000 and 22,000 in approximately equal amounts in all neuroblastoma lines regardless of N-myc amplification and/or expression. On the other hand, protein binding to the myc DNA consensus sequence correlated with N-myc expression in neuroblastoma cells. Thus, N-myc expression might be a limiting factor in the formation of the N-myc-MAX heterodimer in neuroblastomas.

  9. The neuronal differentiation factor NeuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma.

    PubMed

    Huang, Peng; Kishida, Satoshi; Cao, Dongliang; Murakami-Tonami, Yuko; Mu, Ping; Nakaguro, Masato; Koide, Naoshi; Takeuchi, Ichiro; Onishi, Akira; Kadomatsu, Kenji

    2011-04-15

    The basic helix-loop-helix transcription factor NeuroD1 has been implicated in the neurogenesis and early differentiation of pancreatic endocrine cells. However, its function in relation to cancer has been poorly examined. In this study, we found that NeuroD1 is involved in the tumorigenesis of neuroblastoma. NeuroD1 was strongly expressed in a hyperplastic region comprising neuroblasts in the celiac sympathetic ganglion of 2-week-old MYCN transgenic (Tg) mice and was consistently expressed in the subsequently generated neuroblastoma tissue. NeuroD1 knockdown by short hairpin RNA (shRNA) resulted in motility inhibition of the human neuroblastoma cell lines, and this effect was reversed by shRNA-resistant NeuroD1. The motility inhibition by NeuroD1 knockdown was associated with induction of Slit2 expression, and knockdown of Slit2 could restore cell motility. Consistent with this finding, shRNA-resistant NeuroD1 suppressed Slit2 expression. NeuroD1 directly bound to the first and second E-box of the Slit2 promoter region. Moreover, we found that the growth of tumor spheres, established from neuroblastoma cell lines in MYCN Tg mice, was suppressed by NeuroD1 suppression. The functions identified for NeuroD1 in cell motility and tumor sphere growth may suggest a link between NeuroD1 and the tumorigenesis of neuroblastoma. Indeed, tumor formation of tumor sphere-derived cells was significantly suppressed by NeuroD1 knockdown. These data are relevant to the clinical features of human neuroblastoma: high NeuroD1 expression was closely associated with poor prognosis. Our findings establish the critical role of the neuronal differentiation factor NeuroD1 in neuroblastoma as well as its functional relationship with the neuronal repellent factor Slit2.

  10. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice.

    PubMed

    Suhail, Nida; Bilal, Nayeem; Hasan, Shirin; Ahmad, Ausaf; Ashraf, Ghulam Md; Banu, Naheed

    2015-11-01

    Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage.

  11. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice.

    PubMed

    Suhail, Nida; Bilal, Nayeem; Hasan, Shirin; Ahmad, Ausaf; Ashraf, Ghulam Md; Banu, Naheed

    2015-11-01

    Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage. PMID:26272695

  12. Spectroscopic Investigation of the Formation of Radiolysis By-Products By 13/9 MeV Linear Accelerator of Electrons (LAE) in Salt Solutions

    SciTech Connect

    Paviet-Hartmann, P.; Dziewinski, J.; Hartmann, T.; Marczak, S.; Lu, N.; Walthall, M.; Rafalski, A.; Zagorski, Z. P.

    2002-02-26

    In the near-field chemistry of a salt repository, the radiolytically-induced redox reactions in concentrated saline solution are of particular importance because the radiolysis of saline solutions results in oxidizing chlorine-containing species, which may oxidize actinide species to higher oxidation states. If the brines are irradiated, the solutions containing radiolytic species such as hypochlorite, hypochlorous acid or hydrogen peroxide, their pH and Eh may be altered. The oxidation and complexation states of actinides, which might be present in the salt brine, will change thus influencing their speciation and consequently their mobility. Furthermore, radiolytically formed oxidizing species such as ClO- or H2O2 may enhance the corrosion of the canister material. Therefore, radiation effects on salt brines must be integrated into the database, which described the chemical processes near a disposal site. Investigations in that context usually focus on the radiation chemistry of solid NaCl however our focus is on the radiolytic products, which are formed when salt brines are irradiated by a 10 MeV linear accelerator of electrons (LAE). We attempt to quantify the irradiation-induced formation of typical radiolysis by-products such as the hypochlorite ion (OCl-) by using a 13/9 MeV LAE with doses between 120 KGy to 216 KGy while monitoring the pH of the brine solutions.

  13. Accelerating NLTE radiative transfer by means of the Forth-and-Back Implicit Lambda Iteration: A two-level atom line formation in 2D Cartesian coordinates

    NASA Astrophysics Data System (ADS)

    Milić, Ivan; Atanacković, Olga

    2014-10-01

    State-of-the-art methods in multidimensional NLTE radiative transfer are based on the use of local approximate lambda operator within either Jacobi or Gauss-Seidel iterative schemes. Here we propose another approach to the solution of 2D NLTE RT problems, Forth-and-Back Implicit Lambda Iteration (FBILI), developed earlier for 1D geometry. In order to present the method and examine its convergence properties we use the well-known instance of the two-level atom line formation with complete frequency redistribution. In the formal solution of the RT equation we employ short characteristics with two-point algorithm. Using an implicit representation of the source function in the computation of the specific intensities, we compute and store the coefficients of the linear relations J=a+bS between the mean intensity J and the corresponding source function S. The use of iteration factors in the ‘local’ coefficients of these implicit relations in two ‘inward’ sweeps of 2D grid, along with the update of the source function in other two ‘outward’ sweeps leads to four times faster solution than the Jacobi’s one. Moreover, the update made in all four consecutive sweeps of the grid leads to an acceleration by a factor of 6-7 compared to the Jacobi iterative scheme.

  14. Carcinogenesis induced by UVA (365-nm) radiation: the dose-time dependence of tumor formation in hairless mice.

    PubMed

    de Laat, A; van der Leun, J C; de Gruijl, F R

    1997-05-01

    Although ultraviolet B (UVB wavelengths 280-315 nm) dominates the carcinogenic effect of sunlight, ultraviolet A (UVA 315-400 nm) is estimated to contribute 10-20% to the carcinogenic dose; a substantial background that is not affected by a depletion of the ozone layer. Furthermore, certain high-power modern tanning lamps emit mainly long wave UVA (UVA1; 340-400 nm). For a proper risk estimate of UVA exposure its carcinogenicity relative to that of UVB exposure needs to be determined more accurately. To this end we determined the dose-time relationship for skin tumor induction in hairless mice that were irradiated daily with custom-made Philips 365-nm sources. Irradiation of the group exposed to the highest of the four daily doses (430, 240, 140 and 75 kJ/m2) had to be discontinued because severe scratching set in after 3 months (no tumors). In the lower dose-groups the prevalence curves for skin carcinomas (percentage of tumor-bearing mice versus logarithm of time) ran virtually parallel, and were similar to those found with daily UVB exposure. However, the relationship between the daily dose (D) and the median tumor induction time (t50) appeared to differ: with UVB we found that t50 D(r) = constant, with r = 0.6, whereas with UVA1 we found r approximately 0.4. This would imply that 365-nm carcinogenesis shows less of a dose-dependency than UVB carcinogenesis, and that 365-nm radiation becomes more carcinogenic, relative to UVB, as the daily doses are lowered. This relative shift at low doses complicates extrapolation of UVB to UVA risks in humans. Based on the t50 from the lowest dose-group we found that the carcinogenicity at 365 nm (per J/m2) is 0.9 x 10(-4) times that at 293 nm, the wavelength of maximum carcinogenicity in hairless mice. This result for 365-nm carcinogenicity falls well within the margins of error of the wavelength dependency that was estimated earlier from experiments with broadband UV sources.

  15. Eldecalcitol improves mechanical strength of cortical bones by stimulating the periosteal bone formation in the senescence-accelerated SAM/P6 mice - a comparison with alfacalcidol.

    PubMed

    Shiraishi, Ayako; Sakai, Sadaoki; Saito, Hitoshi; Takahashi, Fumiaki

    2014-10-01

    Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25(OH)2D3, is a potent inhibitor of bone resorption that has demonstrated a greater effect at reducing the risk of fracture in osteoporotic patients than alfacalcidol (ALF). In the present study, we used the senescence-accelerated mouse strain P6 (SAM/P6), which has low bone mass caused by osteoblast dysfunction, to evaluate the effect of ELD on cortical bone in comparison with ALF. Four-month-old SAM/P6 mice were given either ELD (0.025 or 0.05μg/kg) or ALF (0.2 or 0.4μg/kg) by oral gavage 5 times/week for 6 weeks. Both ELD and ALF increased serum calcium (Ca) in a dose-dependent manner. Serum Ca levels in the ELD 0.05μg/kg group were comparable to those of the ALF 0.2μg/kg group. ELD 0.05μg/kg significantly improved the bone biomechanical properties of the femur compared with the vehicle control group (p<0.001) and the ALF 0.2μg/kg group (p<0.05) evaluated by 3-point bending test. The cortical area of the mid-femur in the ELD 0.05μg/kg group but not the ALF 0.2μg/kg group was significantly higher than those of the vehicle control group (p<0.001). Bone histomorphometry revealed that in the femoral endocortical surface, the suppression of bone resorption parameters (N.Oc/BS) and bone formation parameters (MS/BS) by ELD (0.05μg/kg) was greater than that by ALF (0.2μg/kg). In contrast, in the femoral periosteal surface, ELD 0.05μg/kg significantly increased bone formation parameters (BFR/BS, MS/BS) compared with the vehicle control group (p<0.05, p<0.01, respectively), whereas ALF 0.2μg/kg did not alter these parameters. These results indicate that ELD improved the biomechanical properties of femoral cortical bone not only by inhibiting endocortical bone resorption but also by stimulating the periosteal bone formation in SAM/P6 mice. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.

  16. Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation

    PubMed Central

    Park, Inai; Lee, Hae-ock; Choi, Eunhee; Lee, Yoo-Kyung; Kwon, Mi-Sun; Min, Jaewon; Park, Pil-Gu; Lee, Seonju; Kong, Young-Yun; Gong, Gyungyub

    2013-01-01

    BubR1 acetylation is essential in mitosis. Mice heterozygous for the acetylation-deficient BubR1 allele (K243R/+) spontaneously developed tumors with massive chromosome missegregations. K243R/+ mouse embryonic fibroblasts (MEFs) exhibited a weakened spindle assembly checkpoint (SAC) with shortened mitotic timing. The generation of the SAC signal was intact, as Mad2 localization to the unattached kinetochore (KT) was unaltered; however, because of the premature degradation of K243R-BubR1, the mitotic checkpoint complex disassociated prematurely in the nocodazole-treated condition, suggesting that maintenance of the SAC is compromised. BubR1 acetylation was also required to counteract excessive Aurora B activity at the KT for stable chromosome–spindle attachments. The association of acetylation-deficient BubR1 with PP2A-B56α phosphatase was reduced, and the phosphorylated Ndc80 at the KT was elevated in K243R/+ MEFs. In relation, there was a marked increase of micronuclei and p53 mutation was frequently detected in primary tumors of K243R/+ mice. Collectively, the combined effects of failure in chromosome–spindle attachment and weakened SAC cause genetic instability and cancer in K243R/+ mice. PMID:23878276

  17. Curcuma oil attenuates accelerated atherosclerosis and macrophage foam-cell formation by modulating genes involved in plaque stability, lipid homeostasis and inflammation.

    PubMed

    Singh, Vishal; Rana, Minakshi; Jain, Manish; Singh, Niharika; Naqvi, Arshi; Malasoni, Richa; Dwivedi, Anil Kumar; Dikshit, Madhu; Barthwal, Manoj Kumar

    2015-01-14

    In the present study, the anti-atherosclerotic effect and the underlying mechanism of curcuma oil (C. oil), a lipophilic fraction from turmeric (Curcuma longa L.), was evaluated in a hamster model of accelerated atherosclerosis and in THP-1 macrophages. Male golden Syrian hamsters were subjected to partial carotid ligation (PCL) or FeCl3-induced arterial oxidative injury (Ox-injury) after 1 week of treatment with a high-cholesterol (HC) diet or HC diet plus C. oil (100 and 300 mg/kg, orally). Hamsters fed with the HC diet were analysed at 1, 3 and 5 weeks following carotid injury. The HC diet plus C. oil-fed group was analysed at 5 weeks. In hyperlipidaemic hamsters with PCL or Ox-injury, C. oil (300 mg/kg) reduced elevated plasma and aortic lipid levels, arterial macrophage accumulation, and stenosis when compared with those subjected to arterial injury alone. Similarly, elevated mRNA transcripts of matrix metalloproteinase-2 (MMP-2), MMP-9, cluster of differentiation 45 (CD45), TNF-α, interferon-γ (IFN-γ), IL-1β and IL-6 were reduced in atherosclerotic arteries, while those of transforming growth factor-β (TGF-β) and IL-10 were increased after the C. oil treatment (300 mg/kg). The treatment with C. oil prevented HC diet- and oxidised LDL (OxLDL)-induced lipid accumulation, decreased the mRNA expression of CD68 and CD36, and increased the mRNA expression of PPARα, LXRα, ABCA1 and ABCG1 in both hyperlipidaemic hamster-derived peritoneal and THP-1 macrophages. The administration of C. oil suppressed the mRNA expression of TNF-α, IL-1β, IL-6 and IFN-γ and increased the expression of TGF-β in peritoneal macrophages. In THP-1 macrophages, C. oil supplementation prevented OxLDL-induced production of TNF-α and IL-1β and increased the levels of TGF-β. The present study shows that C. oil attenuates arterial injury-induced accelerated atherosclerosis, inflammation and macrophage foam-cell formation.

  18. Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice.

    PubMed Central

    Kitazawa, R; Kimble, R B; Vannice, J L; Kung, V T; Pacifici, R

    1994-01-01

    To investigate the contribution of IL-1, IL-6, and TNF to the increased osteoclastogenesis induced by estrogen deficiency, ovariectomized (ovx) mice were treated with either IL-1 receptor antagonist (IL-1ra), a competitive inhibitor of IL-1, TNF binding protein (TNFbp), an inhibitor of TNF, or the anti-IL-6 antibody (Ab) 20F3 for the first 2 wk after surgery. ovx increased the bone marrow cells secretion of IL-1 and TNF, but not IL-6, and the formation of TRAP-positive osteoclast-like multinucleated cells (MNCs) in bone marrow cultures treated with 1,25(OH)2D3. The increase in MNC formation induced by ovx was prevented by in vivo treatment with either 17 beta estradiol, IL-1ra, TNFbp, or anti-IL-6 Ab. However, the percent change in MNC formation induced by the anti-IL-6 Ab was similar in ovx and sham-operated animals, whereas IL-1ra and TNFbp were effective only in ovx mice. MNC formation was also decreased by in vitro treatment of bone marrow cultures with IL-1ra and TNFbp, but not with anti-IL-6 Ab. Ovx also increased bone resorption in vivo and in vitro, as assessed by the urinary excretion of pyridinoline cross links and the formation of resorption pits, respectively. IL-1ra, TNFbp and estrogen decreased bone resorption in vivo and in vitro whereas the anti-IL-6 Ab inhibited bone resorption in vitro but not in vivo. In conclusion, these data indicate that IL-1 and TNF play a direct role in mediating the effects of ovx on osteoclastogenesis and bone resorption. The data also suggest that IL-6 is not essential for increasing bone resorption in the early postovariectomy period. Images PMID:7989596

  19. Data on in vivo selection of SK-OV-3 Luc ovarian cancer cells and intraperitoneal tumor formation with low inoculation numbers

    PubMed Central

    De Vlieghere, Elly; Carlier, Charlotte; Ceelen, Wim; Bracke, Marc; De Wever, Olivier

    2016-01-01

    This data paper contains information about the in vivo model for peritoneal implants used in the paper “Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells” (De Vlieghere et al., 2015) [1]. A double in vivo selection of SK-OV-3 Luc human ovarian cancer cell line was used to create SK-OV-3 Luc IP1 and SK-OV-3 Luc IP2 cell lines. This data paper shows functional activities of the three cell lines in vitro and in vivo. Phase-contrast images show the morphology of these cells, metabolic and luciferase activity has been determined. Survival data of mice peritoneally injected with SK-OV-3 Luc or SK-OV-3 Luc IP2 is available with H&E histology of the peritoneal implants. Tumor growth curves and bioluminescent images of mice inoculated with a different number of SK-OV-3 Luc IP2 cells are also included. PMID:26904717

  20. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen

    PubMed Central

    Buffa, Francesca M.; Yu, Sheng; Ebner, Daniel V.; Howarth, Alison; Folkes, Lisa K.; Budwal, Balam; Chu, Kwun-Ye; Durrant, Lisa; Muschel, Ruth J.; McKenna, W. Gillies; Higgins, Geoff S.

    2015-01-01

    Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization. PMID:25788274

  1. Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen.

    PubMed

    Tiwana, Gaganpreet S; Prevo, Remko; Buffa, Francesca M; Yu, Sheng; Ebner, Daniel V; Howarth, Alison; Folkes, Lisa K; Budwal, Balam; Chu, Kwun-Ye; Durrant, Lisa; Muschel, Ruth J; McKenna, W Gillies; Higgins, Geoff S

    2015-03-20

    Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization.

  2. Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation

    PubMed Central

    Chung, S.; Shin, B.-S.; Hedlund, E.; Pruszak, J.; Ferree, A.; Kang, Un Jung; Isacson, Ole; Kim, Kwang-Soo

    2008-01-01

    Because of their ability to proliferate and to differentiate into diverse cell types, embryonic stem (ES) cells are a potential source of cells for transplantation therapy of various diseases, including Parkinson’s disease. A critical issue for this potential therapy is the elimination of undifferentiated cells that, even in low numbers, could result in teratoma formation in the host brain. We hypothesize that an efficient solution would consist of purifying the desired cell types, such as neural precursors, prior to transplantation. To test this hypothesis, we differentiated sox1-green fluorescent protein (GFP) knock-in ES cells in vitro, purified neural precursor cells by fluorescence-activated cell sorting (FACS), and characterized the purified cells in vitro as well as in vivo. Immunocytofluorescence and RT-PCR analyses showed that this genetic purification procedure efficiently removed undifferentiated pluripotent stem cells. Furthermore, when differentiated into mature neurons in vitro, the purified GFP+ cell population generated enriched neuronal populations, whereas the GFP− population generated much fewer neurons. When treated with dopaminergic inducing signals such as sonic hedgehog (SHH) and fibroblast growth factor-8 (FGF8), FACS-purified neural precursor cells responded to these molecules and generated dopaminergic neurons as well as other neural subtypes. When transplanted, the GFP+ cell population generated well contained grafts containing dopaminergic neurons, whereas the GFP− population generated significantly larger grafts (about 20-fold) and frequent tumor-related deaths in the transplanted animals. Taken together, our results demonstrate that genetic purification of neural precursor cells using FACS isolation can effectively remove unwanted proliferating cell types and avoid tumor formation after transplantation. PMID:16696855

  3. Tumor associated osteoclast-like giant cells promote tumor growth and lymphangiogenesis by secreting vascular endothelial growth factor-C

    SciTech Connect

    Hatano, Yu; Nakahama, Ken-ichi; Isobe, Mitsuaki; Morita, Ikuo

    2014-03-28

    Highlights: • M-CSF and RANKL expressing HeLa cells induced osteoclastogenesis in vitro. • We established OGC-containing tumor model in vivo. • OGC-containing tumor became larger independent of M-CSF or RANKL effect. • VEGF-C secreted from OGCs was a one of candidates for OGC-containing tumor growth. - Abstract: Tumors with osteoclast-like giant cells (OGCs) have been reported in a variety of organs and exert an invasive and prometastatic phenotype, but the functional role of OGCs in the tumor environment has not been fully clarified. We established tumors containing OGCs to clarify the role of OGCs in tumor phenotype. A mixture of HeLa cells expressing macrophage colony-stimulating factor (M-CSF, HeLa-M) and receptor activator of nuclear factor-κB ligand (RANKL, HeLa-R) effectively supported the differentiation of osteoclast-like cells from bone marrow macrophages in vitro. Moreover, a xenograft study showed OGC formation in a tumor composed of HeLa-M and HeLa-R. Surprisingly, the tumors containing OGCs were significantly larger than the tumors without OGCs, although the growth rates were not different in vitro. Histological analysis showed that lymphangiogenesis and macrophage infiltration in the tumor containing OGCs, but not in other tumors were accelerated. According to quantitative PCR analysis, vascular endothelial growth factor (VEGF)-C mRNA expression increased with differentiation of osteoclast-like cells. To investigate whether VEGF-C expression is responsible for tumor growth and macrophage infiltration, HeLa cells overexpressing VEGF-C (HeLa-VC) were established and transplanted into mice. Tumors composed of HeLa-VC mimicked the phenotype of the tumors containing OGCs. Furthermore, the vascular permeability of tumor microvessels also increased in tumors containing OGCs and to some extent in VEGF-C-expressing tumors. These results suggest that macrophage infiltration and vascular permeability are possible mediators in these tumors. These

  4. Cachectin/tumor necrosis factor-alpha formation in human decidua. Potential role of cytokines in infection-induced preterm labor.

    PubMed Central

    Casey, M L; Cox, S M; Beutler, B; Milewich, L; MacDonald, P C

    1989-01-01

    This study was conducted as part of an investigation to evaluate the hypothesis that bacterial toxins (LPS or lipoteichoic acid), acting on macrophage-like uterine decidua to cause increased formation of cytokines, may be involved in the pathogenesis of infection-associated preterm labor. We found that cachectin/tumor necrosis factor-alpha (TNF-alpha) was synthesized and secreted into the culture medium by human decidual cells and explants in response to treatment with LPS. LPS treatment also caused an increase in PGF2 alpha production by decidual cells and explants. In amnion cells in monolayer culture, TNF-alpha stimulated PGE2 formation, and TNF-alpha was cytostatic (inhibited [3H]thymidine incorporation into DNA) but not cytolytic in amnion cells. TNF-alpha was not detectable (less than 0.34 ng/ml) in the amniotic fluid of normal pregnancies at midtrimester or at term before or after the onset of labor (n = 44); but TNF-alpha was present at concentrations between 2.8 and 22.3 ng/ml in amniotic fluids of 4 of 20 pregnancies with intact membranes complicated by preterm labor (less than 34 wk gestational age). LPS was present in 10 of the 20 amniotic fluids of preterm labor pregnancies, including all four in which TNF-alpha was present. Bacteria were identified in only one of the four LPS-positive, TNF-alpha-positive fluids. Cytokine formation in macrophage-like decidua may serve a fundamental role in the pathogenesis of preterm labor, including increased prostaglandin formation and premature rupture of the membranes. Images PMID:2913048

  5. Sandwich-format electrochemiluminescence assays for tumor marker based on PAMAM dendrimer-L-cysteine-hollow gold nanosphere nanocomposites.

    PubMed

    Zhuo, Ying; Gui, Guofeng; Chai, Yaqin; Liao, Ni; Xiao, Kai; Yuan, Ruo

    2014-03-15

    In this work, a novel polyamidoamine (PAMAM) dendrimer-L-cysteine-hollow gold nanospheres nanocomposite was fabricated and used as the promoter for the peroxydisulfate/O2 ECL system to detect the concentration of the tumor marker carcinoembryonic antigen (CEA). Herein, the carboxyl-terminated PAMAM dendrimers were decorated with L-cysteine (L-Cys) by EDC/NHS coupling chemistry. Then, the hollow gold nanospheres (HGNPs) were employed as effective nano-carriers for the assembly of PAMAM-L-Cys via thiols-Au bonding, which was used for further loading of detection antibody (Ab2) to form the PAMAM-L-Cys-HGNPs-Ab2 bioconjugates. In the presence of target CEA, the sandwiched immuno-structure can be formed between the capture anti-CEA antibodies (Ab1), which self-assembled on deposited gold modified electrode, and the Ab2 on the PAMAM-L-Cys-HGNPs, thereby resulting in a proportional increase in ECL response, due to the significant enhancement of PAMAM-L-Cys-HGNPs toward peroxydisulfate/O2 ECL system. As a result, a sandwich ECL assay for CEA detection was developed with excellent sensitivity of a large concentration variation from 20 fg/mL to 1.0 ng/mL and a detection limit of 6.7 fg mL(-1).

  6. Downregulation of HDAC9 inhibits cell proliferation and tumor formation by inducing cell cycle arrest in retinoblastoma.

    PubMed

    Zhang, Yiting; Wu, Dan; Xia, Fengjie; Xian, Hongyu; Zhu, Xinyue; Cui, Hongjuan; Huang, Zhenping

    2016-04-29

    Histone deacetylase 9 (HDAC9) is a member of class II HDACs, which regulates a wide variety of normal and abnormal physiological functions. Recently, HDAC9 has been found to be overexpressed in some types of human cancers. However, the role of HDAC9 in retinoblastoma remains unclear. In this study, we found that HDAC9 was commonly expressed in retinoblastoma tissues and HDAC9 was overexpressed in prognostically poor retinoblastoma patients. Through knocking down HDAC9 in Y79 and WERI-Rb-1 cells, the expression level of HDAC9 was found to be positively related to cell proliferation in vitro. Further investigation indicated that knockdown HDAC9 could significantly induce cell cycle arrest at G1 phase in retinoblastoma cells. Western blot assay showed downregulation of HDAC9 could significantly decrease cyclin E2 and CDK2 expression. Lastly, xenograft study in nude mice showed that downregulation of HDAC9 inhibited tumor growth and development in vivo. Therefore, our results suggest that HDAC9 could serve as a novel potential therapeutic target in the treatment of retinoblastoma. PMID:27033599

  7. Plant stanols induce intestinal tumor formation by up-regulating Wnt and EGFR signaling in Apc Min mice.

    PubMed

    Marttinen, Maija; Päivärinta, Essi; Storvik, Markus; Huikko, Laura; Luoma-Halkola, Heli; Piironen, Vieno; Pajari, Anne-Maria; Mutanen, Marja

    2013-01-01

    The rate of APC mutations in the intestine increases in middle-age. At the same period of life, plant sterol and stanol enriched functional foods are introduced to diet to lower blood cholesterol. This study examined the effect of plant stanol enriched diet on intestinal adenoma formation in the Apc(Min) mouse. Apc(Min) mice were fed 0.8% plant stanol diet or control diet for nine weeks. Cholesterol, plant sterols and plant stanols were analyzed from the caecum content and the intestinal mucosa. Levels of β-catenin, cyclin D1, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1/2 (ERK1/2) were measured from the intestinal mucosa by Western blotting. Gene expression was determined from the intestinal mucosa using Affymetrix and the data were analyzed for enriched categories and pathways. Plant stanols induced adenoma formation in the small intestine, however, the adenoma size was not affected. We saw increased levels of nuclear β-catenin, phosphorylated β-catenin (Ser675 and Ser552), nuclear cyclin D1, total and phosphorylated EGFR and phosphorylated ERK1/2 in the intestinal mucosa after plant stanol feeding. The Affymetrix data demonstrate that several enzymes of cholesterol synthesis pathway were up-regulated, although the cholesterol level in the intestinal mucosa was not altered. We show that plant stanols induce adenoma formation by activating Wnt and EGFR signaling. EGFR signaling seems to have promoted β-catenin phosphorylation and its translocation into the nucleus, where the expression of cyclin D1 was increased. Up-regulated cholesterol synthesis may partly explain the increased EGFR signaling in the plant stanol-fed mice.

  8. Future accelerators (?)

    SciTech Connect

    John Womersley

    2003-08-21

    I describe the future accelerator facilities that are currently foreseen for electroweak scale physics, neutrino physics, and nuclear structure. I will explore the physics justification for these machines, and suggest how the case for future accelerators can be made.

  9. Hinokitiol, a tropolone derivative, inhibits mouse melanoma (B16-F10) cell migration and in vivo tumor formation.

    PubMed

    Huang, Chien-Hsun; Lu, Shing-Hwa; Chang, Chao-Chien; Thomas, Philip Aloysius; Jayakumar, Thanasekaran; Sheu, Joen-Rong

    2015-01-01

    Invasion and metastasis are the major causes of treatment failure in patients with cancer. Hinokitiol, a natural bioactive compound found in Chamacyparis taiwanensis, has been used in hair tonics, cosmetics, and food as an antimicrobial agent. In this study, we investigated the effects and possible mechanisms of action of hinokitiol on migration by the metastatic melanoma cell line, B16-F10, in which matrix metalloproteinase-1 (MMP-1) is found to be highly- expressed. Treatment with hinokitiol revealed a concentration-dependent inhibition of migration of B16-F10 melanoma cells. Hinokitiol appeared to achieve this effect by reducing the expression of MMP-1 and by suppressing the phosphorylation of mitogen- activated protein kinase (MAPK) signaling molecules such as extracellular signal-regulated kinase (ERK) 1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). On the other hand, hinokitiol treatment reversed IκB-α degradation and inhibited the phosphorylation of p65 nuclear factor kappa B (NF-κB) and cJun in B16-F10 cells. In addition, hinokitiol suppressed the translocation of p65 NF-κB from the cytosol to the nucleus, suggesting reduced NF-κB activation. Consistent with these in vitro findings, our in vivo study demonstrated that hinokitiol treatment significantly reduced the total number of mouse lung metastatic nodules and improved histological alterations in B16-F10 injected C57BL/6 mice. These findings suggest that treatment of B16-F10 cells with hinokitiol significantly inhibits metastasis, possibly by blocking MMP-1 activation, MAPK signaling pathways and inhibition of the transcription factors, NF-κB and c-Jun, involved in cancer cell migration. These results may accelerate the development of novel therapeutic agents for the treatment of malignant cancers. PMID:25449038

  10. DNA adduct formation in relation to lymphocyte mutations and lung tumor induction in F344 rats treated with the environmental pollutant 1,6-dinitropyrene.

    PubMed Central

    Smith, B A; Fullerton, N F; Aidoo, A; Heflich, R H; Beland, F A

    1993-01-01

    Epidemiological studies suggest an association between exposure to diesel emissions and an increased incidence of lung and bladder cancer in humans. Of the compounds associated with diesel emissions, 1,6-dinitropyrene is a particularly potent mutagen and carcinogen. In these experiments we administered [4,5,9,10-3H]1,6-dinitropyrene (30 or 100 micrograms) directly to the lungs of F344 rats according to a protocol known to induce lung tumors and characterized the DNA adducts present in the target tissue. In addition, we examined the adducts present in spleen lymphocytes and assayed for the induction of mutations at the hypoxanthine-guanine phosphoribosyltransferase locus in these cells, as measured by the frequency of 6-thioguanine-resistant (TGr) T-lymphocytes. Adduct formation was detected in both lung and spleen lymphocyte DNA, with the extent of binding being dose-dependent in the lymphocytes but not the lung. 32P-Postlabeling analyses indicated the formation of a major DNA adduct, N-(deoxyguanosin-8-yl)-1-amino-6- nitropyrene, in both tissues. 1,6-Dinitropyrene treatment resulted in a dose-dependent increase in TGr T-lymphocytes, with the increase being detected for at least 21 weeks after treatment. These data indicate that 1,6-dinitropyrene is metabolically activated by nitroreduction to form DNA adducts in both the target tissue and spleen lymphocytes and that a tumorigenic dose results in a significant induction of TGr T-lymphocytes. Images FIGURE 2. PMID:8319643

  11. Inhibition of PRL-2·CNNM3 Protein Complex Formation Decreases Breast Cancer Proliferation and Tumor Growth*

    PubMed Central

    Kostantin, Elie; Hardy, Serge; Valinsky, William C.; Kompatscher, Andreas; de Baaij, Jeroen H. F.; Zolotarov, Yevgen; Landry, Melissa; Uetani, Noriko; Martínez-Cruz, Luis Alfonso; Hoenderop, Joost G. J.; Shrier, Alvin; Tremblay, Michel L.

    2016-01-01

    The oncogenic phosphatase of regenerating liver 2 (PRL-2) has been shown to regulate intracellular magnesium levels by forming a complex through an extended amino acid loop present in the Bateman module of the CNNM3 magnesium transporter. Here we identified highly conserved residues located on this amino acid loop critical for the binding with PRL-2. A single point mutation (D426A) of one of those critical amino acids was found to completely disrupt PRL-2·human Cyclin M 3 (CNNM3) complex formation. Whole-cell voltage clamping revealed that expression of CNNM3 influenced the surface current, whereas overexpression of the binding mutant had no effect, indicating that the binding of PRL-2 to CNNM3 is important for the activity of the complex. Interestingly, overexpression of the CNNM3 D426A-binding mutant in cancer cells decreased their ability to proliferate under magnesium-deprived situations and under anchorage-independent growth conditions, demonstrating a PRL-2·CNNM3 complex-dependent oncogenic advantage in a more stringent environment. We further confirmed the importance of this complex in vivo using an orthotopic xenograft breast cancer model. Finally, because molecular modeling showed that the Asp-426 side chain in CNNM3 buries into the catalytic cavity of PRL-2, we showed that a PRL inhibitor could abrogate complex formation, resulting in a decrease in proliferation of human breast cancer cells. In summary, we provide evidence that this fundamental regulatory aspect of PRL-2 in cancer cells could potentially lead to broadly applicable and innovative therapeutic avenues. PMID:26969161

  12. Dimerization of VirD2 Binding Protein Is Essential for Agrobacterium Induced Tumor Formation in Plants

    PubMed Central

    Padavannil, Abhilash; Jobichen, Chacko; Qinghua, Yang; Seetharaman, Jayaraman; Velazquez-Campoy, Adrian; Yang, Liu; Pan, Shen Q.; Sivaraman, J.

    2014-01-01

    The Type IV Secretion System (T4SS) is the only bacterial secretion system known to translocate both DNA and protein substrates. The VirB/D4 system from Agrobacterium tumefaciens is a typical T4SS. It facilitates the bacteria to translocate the VirD2-T-DNA complex to the host cell cytoplasm. In addition to protein-DNA complexes, the VirB/D4 system is also involved in the translocation of several effector proteins, including VirE2, VirE3 and VirF into the host cell cytoplasm. These effector proteins aid in the proper integration of the translocated DNA into the host genome. The VirD2-binding protein (VBP) is a key cytoplasmic protein that recruits the VirD2–T-DNA complex to the VirD4-coupling protein (VirD4 CP) of the VirB/D4 T4SS apparatus. Here, we report the crystal structure and associated functional studies of the C-terminal domain of VBP. This domain mainly consists of α-helices, and the two monomers of the asymmetric unit form a tight dimer. The structural analysis of this domain confirms the presence of a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) fold. Biophysical studies show that VBP is a dimer in solution and that the HEPN domain is the dimerization domain. Based on structural and mutagenesis analyses, we show that substitution of key residues at the interface disrupts the dimerization of both the HEPN domain and full-length VBP. In addition, pull-down analyses show that only dimeric VBP can interact with VirD2 and VirD4 CP. Finally, we show that only Agrobacterium harboring dimeric full-length VBP can induce tumors in plants. This study sheds light on the structural basis of the substrate recruiting function of VBP in the T4SS pathway of A. tumefaciens and in other pathogenic bacteria employing similar systems. PMID:24626239

  13. Dimerization of VirD2 binding protein is essential for Agrobacterium induced tumor formation in plants.

    PubMed

    Padavannil, Abhilash; Jobichen, Chacko; Qinghua, Yang; Seetharaman, Jayaraman; Velazquez-Campoy, Adrian; Yang, Liu; Pan, Shen Q; Sivaraman, J

    2014-03-01

    The Type IV Secretion System (T4SS) is the only bacterial secretion system known to translocate both DNA and protein substrates. The VirB/D4 system from Agrobacterium tumefaciens is a typical T4SS. It facilitates the bacteria to translocate the VirD2-T-DNA complex to the host cell cytoplasm. In addition to protein-DNA complexes, the VirB/D4 system is also involved in the translocation of several effector proteins, including VirE2, VirE3 and VirF into the host cell cytoplasm. These effector proteins aid in the proper integration of the translocated DNA into the host genome. The VirD2-binding protein (VBP) is a key cytoplasmic protein that recruits the VirD2-T-DNA complex to the VirD4-coupling protein (VirD4 CP) of the VirB/D4 T4SS apparatus. Here, we report the crystal structure and associated functional studies of the C-terminal domain of VBP. This domain mainly consists of α-helices, and the two monomers of the asymmetric unit form a tight dimer. The structural analysis of this domain confirms the presence of a HEPN (higher eukaryotes and prokaryotes nucleotide-binding) fold. Biophysical studies show that VBP is a dimer in solution and that the HEPN domain is the dimerization domain. Based on structural and mutagenesis analyses, we show that substitution of key residues at the interface disrupts the dimerization of both the HEPN domain and full-length VBP. In addition, pull-down analyses show that only dimeric VBP can interact with VirD2 and VirD4 CP. Finally, we show that only Agrobacterium harboring dimeric full-length VBP can induce tumors in plants. This study sheds light on the structural basis of the substrate recruiting function of VBP in the T4SS pathway of A. tumefaciens and in other pathogenic bacteria employing similar systems. PMID:24626239

  14. Interleukin-1 and tumor necrosis factor antagonists attenuate ethanol-induced inhibition of bone formation in a rat model of distraction osteogenesis.

    PubMed

    Perrien, Daniel S; Brown, Elizabeth C; Fletcher, Terry W; Irby, David J; Aronson, James; Gao, Guan G; Skinner, Robert A; Hogue, William R; Feige, Ulrich; Suva, Larry J; Ronis, Martin J J; Badger, Thomas M; Lumpkin, Charles K

    2002-12-01

    Chronic ethanol exposure inhibits rapid bone formation during distraction osteogenesis (DO; fracture and limb lengthening) and decreases volumetric bone mineral density (BMD) in a model of intragastric dietary infusion [total enteral nutrition (TEN)] in the rat. The hypothesis tested herein was that overexpression of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mediates these deleterious effects of ethanol on the rat skeleton. Two studies (study 1, female rats; study 2, male rats) were performed to test the potential protective effects of the IL-1 and TNF antagonists: IL-1 receptor antagonist (IL-1ra) and 30-kDa polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1). All rats were infused with a liquid diet +/- ethanol (EtOH) and underwent tibial fractures and DO. During distraction, the animals received a combination of IL-1ra (1.8-2.0 mg/kg/day) and sTNFR1 (2.0 mg/kg/2 days) or vehicle. A comparison of distracted tibial histological sections demonstrated 1) significant antagonist-related increases in bone column formation over the EtOH controls (studies 1 and 2), and 2) restoration of new bone equivalent to that of the TEN controls (study 2). In contrast, examination of intact proximal tibial metaphyses by peripheral quantitative computerized tomography revealed decreases in volumetric BMD of both EtOH control and EtOH antagonist groups (study 2). These results demonstrate that short-term systemic administration of IL-1 and TNF antagonists together protect rapid bone formation during DO from the deleterious effects of chronic ethanol but are ineffective in regard to intact bone homeostasis.

  15. A Novel Carboline Derivative Inhibits Nitric Oxide Formation in Macrophages Independent of Effects on Tumor Necrosis Factor α and Interleukin-1β Expression

    PubMed Central

    Poola, Bhaskar; Pasupuleti, Nagarekha; Nantz, Michael H.; Lein, Pamela J.; Gorin, Fredric

    2015-01-01

    Neuropathic pain is a maladaptive immune response to peripheral nerve injury that causes a chronic painful condition refractory to most analgesics. Nitric oxide (NO), which is produced by nitric oxide synthases (NOSs), has been implicated as a key factor in the pathogenesis of neuropathic pain. β-Carbolines are a large group of natural and synthetic indole alkaloids, some of which block activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), a predominant transcriptional regulator of NOS expression. Here, we characterize the inhibitory effects of a novel 6-chloro-8-(glycinyl)-amino-β-carboline (8-Gly carb) on NO formation and NF-κB activation in macrophages. 8-Gly carb was significantly more potent than the NOS inhibitor NG-nitro-l-arginine methyl ester in inhibiting constitutive and inducible NO formation in primary rat macrophages. 8-Gly carb interfered with NF-κB–mediated gene expression in differentiated THP1-XBlue cells, a human NF-κB reporter macrophage cell line, but only at concentrations severalfold higher than needed to significantly inhibit NO production. 8-Gly carb also had no effect on tumor necrosis factor α (TNFα)–induced phosphorylation of the p38 mitogen-activated protein kinase in differentiated THP1 cells, and did not inhibit lipopolysaccharide- or TNFα-stimulated expression of TNFα and interleukin-1β. These data demonstrate that relative to other carbolines and pharmacologic inhibitors of NOS, 8-Gly carb exhibits a unique pharmacological profile by inhibiting constitutive and inducible NO formation independent of NF-κB activation and cytokine expression. Thus, this novel carboline derivative holds promise as a parent compound, leading to therapeutic agents that prevent the development of neuropathic pain mediated by macrophage-derived NO without interfering with cytokine expression required for neural recovery following peripheral nerve injury. PMID:25538105

  16. IARC Database of p53 gene mutations in human tumors and cell lines: updated compilation, revised formats and new visualisation tools.

    PubMed Central

    Hainaut, P; Hernandez, T; Robinson, A; Rodriguez-Tome, P; Flores, T; Hollstein, M; Harris, C C; Montesano, R

    1998-01-01

    Since 1989, about 570 different p53 mutations have been identified in more than 8000 human cancers. A database of these mutations was initiated by M. Hollstein and C. C. Harris in 1990. This database originally consisted of a list of somatic point mutations in the p 53 gene of human tumors and cell lines, compiled from the published literature and made available in a standard electronic form. The database is maintained at the International Agency for Research on Cancer (IARC) and updated versions are released twice a year (January and July). The current version (July 1997) contains records on 6800 published mutations and will surpass the 8000 mark in the January 1998 release. The database now contains information on somatic and germline mutations in a new format to facilitate data retrieval. In addition, new tools are constructed to improve data analysis, such as a Mutation Viewer Java applet developed at the European Bioinformatics Institute (EBI) to visualise the location and impact of mutations on p53 protein structure. The database is available in different electronic formats at IARC (http://www.iarc. fr/p53/homepage.htm ) or from the EBI server (http://www.ebi.ac.uk ). The IARC p53 website also provides reports on database analysis and links with other p53 sites as well as with related databases. In this report, we describe the criteria for inclusion of data, the revised format and the new visualisation tools. We also briefly discuss the relevance of p 53 mutations to clinical and biological questions. PMID:9399837

  17. Transforming growth factor-alpha abrogates glucocorticoid-stimulated tight junction formation and growth suppression in rat mammary epithelial tumor cells.

    PubMed

    Buse, P; Woo, P L; Alexander, D B; Cha, H H; Reza, A; Sirota, N D; Firestone, G L

    1995-03-24

    The glucocorticoid and transforming growth factor-alpha (TGF-alpha) regulation of growth and cell-cell contact was investigated in the Con8 mammary epithelial tumor cell line derived from a 7,12-dimethylbenz(alpha)anthracene-induced rat mammary adenocarcinoma. In Con8 cell monolayers cultured on permeable filter supports, the synthetic glucocorticoid, dexamethasone, coordinately suppressed [3H]thymidine incorporation, stimulated monolayer transepithelial electrical resistance (TER), and decreased the paracellular leakage of [3H]inulin or [14C]mannitol across the monolayer. These processes dose dependently correlated with glucocorticoid receptor occupancy and function. Constitutive production of TGF-alpha in transfected cells or exogenous treatment with TGF-alpha prevented the glucocorticoid growth suppression response and disrupted tight junction formation without affecting glucocorticoid responsiveness. Treatment with hydroxyurea or araC demonstrated that de novo DNA synthesis is not a requirement for the growth factor disruption of tight junctions. Immunofluorescence analysis revealed that the ZO-1 tight junction protein is localized exclusively at the cell periphery in dexamethasone-treated cells and that TGF-alpha caused-ZO-1 to relocalize from the cell periphery back to a cytoplasmic compartment. Taken together, our results demonstrate that glucocorticoids can coordinately regulate growth inhibition and cell-cell contact of mammary tumor cells and that TGF-alpha, can override both effects of glucocorticoids. These results have uncovered a novel functional "cross-talk" between glucocorticoids and TGF-alpha which potentially regulates the proliferation and differentiation of mammary epithelial cells.

  18. Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.

    PubMed

    Xu, Leqin; Luo, Jian; Jin, Rongrong; Yue, Zhiying; Sun, Peng; Yang, Zhengfeng; Yang, Xinghai; Wan, Wei; Zhang, Jishen; Li, Shichang; Liu, Mingyao; Xiao, Jianru

    2016-05-01

    Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-κB signaling-related cytokines, including TNFα, MCP-1, IL1α, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-κB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cell-induced bone destruction in vivo As a result, bortezomib suppressed NF-κB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-κB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB. Mol Cancer Ther; 15(5); 854-65. ©2016 AACR.

  19. Neurologic complications of cardiac tumors.

    PubMed

    Roeltgen, David; Kidwell, Chelsea S

    2014-01-01

    Cardiac tumors are an uncommon cause for neurologic disease, but if undiagnosed can be associated with devastating neurologic consequences. Primary cardiac tumors, both benign and neoplastic, and metastatic tumors occur. Primary cardiac tumors are more likely to be associated with neurologic embolic complications. Metastatic cardiac tumors are more likely to be associated with valvular distraction, arrhythmia, diminished cardiac output and indirect neurological dysfunction. Primary and metastatic cardiac tumors may result in cerebral metastatic disease. Atrial myxoma, a benign primary cardiac tumor, is the most common cardiac tumor associated with neurologic disease, and most commonly causes cerebral embolization and stroke. The use of thrombolytic therapy for these strokes is controversial. Additionally, delayed manifestations, including aneurysm formation and intracranial hemorrhage, are possible. Aneurysm formation has been described as occurring after removal of the primary tumor. The availability of noninvasive cardiac imaging has significantly helped decrease the neurologic morbidity of cardiac tumors and has led to frequent successful intervention. PMID:24365298

  20. The Accelerator Markup Language and the Universal Accelerator Parser

    SciTech Connect

    Sagan, D.; Forster, M.; Bates, D.A.; Wolski, A.; Schmidt, F.; Walker, N.J.; Larrieu, T.; Roblin, Y.; Pelaia, T.; Tenenbaum, P.; Woodley, M.; Reiche, S.; /UCLA

    2006-10-06

    A major obstacle to collaboration on accelerator projects has been the sharing of lattice description files between modeling codes. To address this problem, a lattice description format called Accelerator Markup Language (AML) has been created. AML is based upon the standard eXtensible Markup Language (XML) format; this provides the flexibility for AML to be easily extended to satisfy changing requirements. In conjunction with AML, a software library, called the Universal Accelerator Parser (UAP), is being developed to speed the integration of AML into any program. The UAP is structured to make it relatively straightforward (by giving appropriate specifications) to read and write lattice files in any format. This will allow programs that use the UAP code to read a variety of different file formats. Additionally, this will greatly simplify conversion of files from one format to another. Currently, besides AML, the UAP supports the MAD lattice format.

  1. Primary intraosseous hybrid nerve sheath tumor of femur: a hitherto undescribed occurrence in bone with secondary aneurysmal bone cyst formation resulting in pathological fracture.

    PubMed

    Chow, Louis Tsun Cheung

    2015-05-01

    Soft tissue perineurioma besides its pure form may coexist with schwannoma as hybrid nerve sheath tumor (HNST) which occurs in the limbs, head and neck, trunk and occasionally colon but origination in other organ sites has not been reported. We report the first case of primary intraosseous HNST. An 18-year-old man suffered from pathological fracture of his right femur after an impact which was preceded by a similar episode two weeks previously. Plain radiograph revealed a displaced fracture in the superior diaphysis of the right femur where an expansile osteolytic lesion with relatively well defined borders was seen. Histologic examination of the curetted lesion showed a well circumscribed spindle cell neoplasm displaying predominantly storiform but focally whorled patterns. In areas, the cells possessed thin wavy spindle nuclei and delicate elongated bipolar cytoplasmic processes supported in a fibromyxoid stroma. They stained positively for EMA, claudin, CD34, collagen 4 and focally for S100 but negatively for MUC4 and BCL-2, indicative of perineurial differentiation. Situated in the periphery of some of these perineurial whorls are spindle cells bearing plump tapering wavy nuclei and palely eosinophilic cytoplasm with indistinct cell borders. They stained intensely for S100 but negatively for EMA, claudin, CD34, collagen 4, MUC4 and BCL-2, consistent with schwannian differentiation. Focally, these two varieties of cells intimately intermingled with each other. Features of aneurysmal bone cyst (ABC) formation were present but no mitotic figures, establishing the final diagnosis of primary intraosseous HNST with secondary ABC formation. The patient remained well 7 months after curettage and internal fixation of his fracture.

  2. Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol.

    PubMed

    Lee, Jeong Hyun; Oh, Goo Taeg; Park, So Youn; Choi, Jae-Hoon; Park, Jong-Gil; Kim, Chi Dae; Lee, Won Suk; Rhim, Byung Yong; Shin, Yung Woo; Hong, Ki Whan

    2005-05-01

    This study shows that 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) suppresses the atherosclerotic lesion formation in the low-density lipoprotein receptor (Ldlr)-null mice. Ldlr-null mice fed a high cholesterol diet showed multiple plaque lesions in the proximal ascending aorta including aortic sinus, accompanied by increased macrophage accumulation with increased expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). Supplementation of cilostazol (0.2% w/w) in diet significantly decreased the plaque lesions with reduced macrophage accumulation and suppression of VCAM-1 and MCP-1 in situ. Increased superoxide and tumor necrosis factor-alpha (TNF-alpha) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF-alpha-induced increased inhibitory kappaBalpha degradation in the cytoplasm and nuclear factor-kappaB (NF-kappaB) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 approximately 100 microM) as well as by (E)-3[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 microM), suggesting that cilostazol strongly inhibits NF-kappaB activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-kappaB/DNA complex and nuclear DNA-binding activity of the NF-kappaB in the nuclear extracts of the RAW 264.7 cells. Taken together, it is suggested that the anti-atherogenic effect of cilostazol in cholesterol-fed Ldlr-null mice is ascribed to its property to suppress superoxide and TNF-alpha formation, and thereby reducing NF-kappaB activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments.

  3. Determination of the relative biological effectiveness and oxygen enhancement ratio for micronuclei formation using high-LET radiation in solid tumor cells: An in vitro and in vivo study.

    PubMed

    Hirayama, Ryoichi; Uzawa, Akiko; Obara, Maki; Takase, Nobuhiro; Koda, Kana; Ozaki, Masakuni; Noguchi, Miho; Matsumoto, Yoshitaka; Li, Huizi; Yamashita, Kei; Koike, Sachiko; Ando, Koichi; Shirai, Toshiyuki; Matsufuji, Naruhiro; Furusawa, Yoshiya

    2015-11-01

    We determined the relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) of micronuclei (MN) formation in clamped (hypoxic) and non-clamped (normoxic) solid tumors in mice legs following exposure to X-rays and heavy ions. Single-cell suspensions (aerobic) of non-irradiated tumors were prepared in parallel and used directly to determine the radiation response for aerobic cells. Squamous cell carcinoma (SCCVII) cells were transplanted into the right hind legs of syngeneic C3H/He male mice. Irradiation doses with either X-rays or heavy ions at a dose-averaged LET (linear energy transfer) of 14-192keV/μm were delivered to 5-mm diameter tumors and aerobic single-cells in sample-tubes. After irradiation, the tumors were excised and trypsinized to observe MN in single-cells. The single-cell suspensions were used for MN formation assays. The RBE values increased with increasing LET. The maximum RBE values for the three different oxygen conditions; hypoxic tumor, normoxic tumor, and aerobic cells, were 8.18, 5.30, and 3.76 at an LET of 192keV/μm, respectively. After X-irradiation, the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.73 and 2.58, respectively. We found that the OER for the in vivo studies were smaller in comparison to that for the in vitro studies. Both of the OER values at 192keV/μm were small in comparison to those of the X-ray irradiated samples. The OERh/n and OERh/a values at 192keV/μm were 1.12 and 1.19, respectively. Our results suggest that high LET radiation has a large biological effect even if a solid tumor includes substantial numbers of hypoxic cells. To conclude, we found that the RBE values under each oxygen state for non-MN fraction increased with increasing LET and that the OER values for both tumors in vivo and cells in vitro decreased with increasing LET.

  4. Sinus Tumors

    MedlinePlus

    ... Tumors Nasal Deformities Choanal Atresia Epiphora (Excessive Tearing) Disclosure Statement Printer Friendly Sinus Tumors Abtin Tabaee, MD Introduction Tumors of the nose and paranasal sinuses are rare, accounting for fewer than 1% of all tumors. These ...

  5. Overexpression of the dynein light chain km23-1 in human ovarian carcinoma cells inhibits tumor formation in vivo and causes mitotic delay at prometaphase/metaphase.

    PubMed

    Pulipati, Nageswara R; Jin, Qunyan; Liu, Xin; Sun, Baodong; Pandey, Manoj K; Huber, Jonathan P; Ding, Wei; Mulder, Kathleen M

    2011-08-01

    km23-1 is a dynein light chain that was identified as a TGFβ receptor-interacting protein. To investigate whether km23-1 controls human ovarian carcinoma cell (HOCC) growth, we established a tet-off inducible expression system in SKOV-3 cells in which the expression of km23-1 is induced upon doxycycline removal. We found that forced expression of km23-1 inhibited both anchorage-dependent and anchorage-independent growth of SKOV-3 cells. More importantly, induction of km23-1 expression substantially reduced the tumorigenicity of SKOV-3 cells in a xenograft model in vivo. Fluorescence-activated cell sorting analysis of SKOV-3 and IGROV-1 HOCCs demonstrated that the cells were accumulating at G2/M. Phospho-MEK, phospho-ERK and cyclin B1 were elevated, as was the mitotic index, suggesting that km23-1 suppresses HOCCs growth by inducing a mitotic delay. Immunofluorescence analyses demonstrated that the cells were accumulating at prometaphase/metaphase with increases in multipolar and multinucleated cells. Further, although the mitotic spindle assembly checkpoint protein BubR1 was present at the prometaphase kinetochore in Dox+/- cells, it was inappropriately retained at the metaphase kinetochore in Dox- cells. Thus, the mechanism by which high levels of km23-1 suppress ovarian carcinoma growth in vitro and inhibit ovary tumor formation in vivo appears to involve a BubR1-related mitotic delay.

  6. The role of ion-neutral interaction in the formation of the spatial distribution of accelerated ions in the induced magnetosphere of comet 67P

    NASA Astrophysics Data System (ADS)

    Nemeth, Zoltan; Szego, Karoly; Burch, Jim; Goldstein, Ray; Mandt, , Kathleen; Mokashi, Pat

    2016-04-01

    In the spring and early summer of 2015 Rosetta observed peculiar ion events in the induced magnetosphere of comet 67P/Churyumov-Gerasimenko. These events apeared again during the dayside excursion of Rosetta, and also in the last months of 2015. In these events accelerated cometary ions dominate the ion spectra measured by the Ion Electron Sensor (IES) of the Rosetta Plasma Consortium. In the 200 eV - 2 keV energy range these ions arrive from the SW direction. During the events the main energy of the population first increases, then saturates and later decreases. We present a mechanism, which can be responsible for these events. The ions are accelerated in the outer magnetosphere then decelerated when they enter the dense inner regions of the cometary neutral atmosphere. Investigating this deceleration mechanism allows us to determine a kind of penetration depth beyond which the accelerated population cannot reach. This mechanism leads to a well-defined spatial distribution of accelerated ions of different energies, which in turn, together with CME induced contractions of the magnetosphere, explain the observed ion events.

  7. Cartilage-forming tumors.

    PubMed

    Qasem, Shadi A; DeYoung, Barry R

    2014-01-01

    Cartilage-forming tumors as a group are the most common primary bone tumors; this is largely due to the common occurrence of asymptomatic benign lesions such as osteochondroma and enchondroma. The common feature of these tumors is the presence of chondrocytic cells and the formation of cartilaginous tumor matrix. Some of these tumors are true neoplasms while others are hamartomas or developmental abnormalities. The morphologic heterogeneity of these tumors may be explained by a common multipotent mesenchymal cell differentiating along the lines of fetal-adult cartilage maturation. Recently mutations in IDH1 and IDH2 have been detected in a variety of benign and malignant cartilaginous tumors.(1-4.) PMID:24680178

  8. Adsorption behavior of beryllium(II) on copper-oxide nanoparticles dispersed in water: A model for (7)Be colloid formation in the cooling water for electromagnets at high-energy accelerator facilities.

    PubMed

    Bessho, Kotaro; Kanaya, Naoki; Shimada, Saki; Katsuta, Shoichi; Monjushiro, Hideaki

    2014-01-01

    The adsorption behavior of Be(II) on CuO nanoparticles dispersed in water was studied as a model for colloid formation of radioactive (7)Be nuclides in the cooling water used for electromagnets at high-energy proton accelerator facilities. An aqueous Be(II) solution and commercially available CuO nanoparticles were mixed, and the adsorption of Be(II) on CuO was quantitatively examined. From a detailed analysis of the adsorption data measured as a function of the pH, it was confirmed that Be(II) is adsorbed on the CuO nanoparticles by complex formation with the hydroxyl groups on the CuO surface (>S-OH) according to the following equation: n > S-OH + Be(2+) ⇔ (>S-O)n Be((2-n)+) + nH(+) (n = 2, 3) S : solid surface. The surface-complexation constants corresponding to the above equilibrium, β(s,2) and β(s,3), were determined for four types of CuO nanoparticles. The β(s,2) value was almost independent of the type of nanoparticle, whereas the β(s,3) values varied with the particle size. These complexation constants successfully explain (7)Be colloid formation in the cooling water used for electromagnets at the 12-GeV proton accelerator facility.

  9. On the role of local CIR-associated particle acceleration in formation of time-intensity profiles of suprathermal particle fluxes

    NASA Astrophysics Data System (ADS)

    Khabarova, Olga; Malandraki, Olga E.

    2015-04-01

    A possibility of local acceleration of particles up to several MeV at the edge of corotating interaction regions (CIRs) in the solar wind is discussed. Recently, evidence for significant local particle energization due to magnetic reconnection that occurs at the heliospheric current sheet (HCS) and followed by consequent trapping and re-acceleration of suprathermal particles in magnetic islands surrounding the rippled HCS was provided (Khabarova et al. 2014). We investigate this phenomenon in application to particle energization at current sheets of various scales (from the HCS to local small-scale current sheets), including current sheets frequently observed at the edge of CIRs, and explore the role of magnetic islands in the picture of suprathermal particle flux enhancements associated with CIRs. It is commonly believed that CIRs serve as one of the sources of suprathermal particles at the Earth's orbit in addition to flares and pre-CME shocks because of particle acceleration by reverse shocks formed beyond 2-3AU. However, this paradigm demands a free way of particles back from the shocks to 1 AU, which produces specific timing and ion/electron flux features that are not observed every time. We suggest that local particle acceleration may take place directly at the CIR edge in the case of the HCS-CIR interaction, as well as be determined by the occurrence of electric field in merging/contracting magnetic islands and local reconnecting current sheets (Zank et al. 2014) in the turbulent plasma of CIRs. Multi-spacecraft data analysis (STEREO, Wind, ACE and Ulysses) is performed. Khabarova O., Zank G.P., Li G., le Roux J.A., Webb G.M., Dosch A., Zharkova V.V. and Malandraki O.E., Small-scale magnetic islands in the solar wind and their role in particle acceleration. Part 1: Dynamics of magnetic islands near the heliospheric current sheet. Submitted to ApJ, 2014 Zank G.P., le Roux J.A., Webb G.M., Dosch A., and O. Khabarova. Particle acceleration via reconnection

  10. Wakefield accelerators

    SciTech Connect

    Simpson, J.D.

    1990-01-01

    The search for new methods to accelerate particle beams to high energy using high gradients has resulted in a number of candidate schemes. One of these, wakefield acceleration, has been the subject of considerable R D in recent years. This effort has resulted in successful proof of principle experiments and in increased understanding of many of the practical aspects of the technique. Some wakefield basics plus the status of existing and proposed experimental work is discussed, along with speculations on the future of wake field acceleration. 10 refs., 6 figs.

  11. LINEAR ACCELERATOR

    DOEpatents

    Colgate, S.A.

    1958-05-27

    An improvement is presented in linear accelerators for charged particles with respect to the stable focusing of the particle beam. The improvement consists of providing a radial electric field transverse to the accelerating electric fields and angularly introducing the beam of particles in the field. The results of the foregoing is to achieve a beam which spirals about the axis of the acceleration path. The combination of the electric fields and angular motion of the particles cooperate to provide a stable and focused particle beam.

  12. Phase 2 Trial of Accelerated, Hypofractionated Whole-Breast Irradiation of 39 Gy in 13 Fractions Followed by a Tumor Bed Boost Sequentially Delivering 9 Gy in 3 Fractions in Early-Stage Breast Cancer

    SciTech Connect

    Kim, Ja Young; Jung, So-Youn; Lee, Seeyoun; Kang, Han-Sung; Lee, Eun Sook; Park, In Hae; Lee, Keun Seok; Ro, Jungsil; Lee, Nam Kwon; Shin, Kyung Hwan

    2013-12-01

    Purpose: To report a phase 2 trial of accelerated, hypofractionated whole-breast irradiation (AH-WBI) delivered as a daily dose of 3 Gy to the whole breast followed by a tumor bed boost. Methods and Materials: Two hundred seventy-six patients diagnosed with breast cancer (pT1-2 and pN0-1a) who had undergone breast-conserving surgery in which the operative margins were negative were treated with AH-WBI delivered as 39 Gy in 13 fractions of 3 Gy to the whole breast once daily over 5 consecutive working days, and 9 Gy in 3 sequential fractions of 3 Gy to a lumpectomy cavity, all within 3.2 weeks. Results: After a median follow-up period of 57 months (range: 27-75 months), the rate of 5-year locoregional recurrence was 1.4% (n=4), whereas that of disease-free survival was 97.4%. No grade 3 skin toxicity was reported during the follow-up period. Qualitative physician cosmetic assessments of good or excellent were noted in 82% of the patients at 2 months after the completion of AH-WBI. The global cosmetic outcome did not worsen over time, and a good or excellent cosmetic outcome was reported in 82% of the patients at 3 years. The mean pretreatment percentage breast retraction assessment was 12.00 (95% confidence interval [CI]: 11.14-12.86). The mean value of percentage breast retraction assessment increased to 13.99 (95% CI: 12.17-15.96) after 1 year and decreased to 13.54 (95% CI: 11.84-15.46) after 3 years but was not significant (P>.05). Conclusions: AH-WBI consisting of 39 Gy in 13 fractions followed by a tumor bed boost sequentially delivering 9 Gy in 3 fractions can be delivered with excellent disease control and tolerable skin toxicity in patients with early-stage breast cancer after breast-conserving surgery.

  13. ION ACCELERATOR

    DOEpatents

    Bell, J.S.

    1959-09-15

    An arrangement for the drift tubes in a linear accelerator is described whereby each drift tube acts to shield the particles from the influence of the accelerating field and focuses the particles passing through the tube. In one embodiment the drift tube is splii longitudinally into quadrants supported along the axis of the accelerator by webs from a yoke, the quadrants. webs, and yoke being of magnetic material. A magnetic focusing action is produced by energizing a winding on each web to set up a magnetic field between adjacent quadrants. In the other embodiment the quadrants are electrically insulated from each other and have opposite polarity voltages on adjacent quadrants to provide an electric focusing fleld for the particles, with the quadrants spaced sufficienily close enough to shield the particles within the tube from the accelerating electric field.

  14. Acceleration switch

    DOEpatents

    Abbin, J.P. Jr.; Devaney, H.F.; Hake, L.W.

    1979-08-29

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  15. Acceleration switch

    DOEpatents

    Abbin, Jr., Joseph P.; Devaney, Howard F.; Hake, Lewis W.

    1982-08-17

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  16. LINEAR ACCELERATOR

    DOEpatents

    Christofilos, N.C.; Polk, I.J.

    1959-02-17

    Improvements in linear particle accelerators are described. A drift tube system for a linear ion accelerator reduces gap capacity between adjacent drift tube ends. This is accomplished by reducing the ratio of the diameter of the drift tube to the diameter of the resonant cavity. Concentration of magnetic field intensity at the longitudinal midpoint of the external sunface of each drift tube is reduced by increasing the external drift tube diameter at the longitudinal center region.

  17. Feasibility of single-isocenter, multi-arc non-coplanar volumetric modulated arc therapy for multiple brain tumors using a linear accelerator with a 160-leaf multileaf collimator: a phantom study

    PubMed Central

    Iwai, Yoshio; Ozawa, Shuichi; Ageishi, Tatsuya; Pellegrini, Roberto; Yoda, Kiyoshi

    2014-01-01

    The feasibility of single isocenter, multi-arc non-coplanar volumetric modulated arc therapy (VMAT) for multiple brain tumors was studied using an Elekta Synergy linear accelerator with an Agility multileaf collimator and a Monaco treatment planning system. Two VMAT radiosurgery plans consisting of a full arc and three half arcs were created with a prescribed dose of 20 Gy in a single fraction. After dose delivery to a phantom, ionization chambers and radiochromic films were used for dose measurement. The first VMAT radiosurgery plan had nine targets inside the phantom, and the doses were measured by the chambers at two different points and by the films on three sagittal and three coronal planes. The differences between the calculated dose and the dose measured by a Farmer ionization chamber and a pinpoint ionization chamber were <1.00% and <2.30%, respectively, and the average pass rates of gamma indices among the six planes under each of 3%/3 mm and 2%/2 mm criteria were 98.6% and 92.6%, respectively. The second VMAT radiosurgery plan was based on a clinical 14 brain metastases. Differences between calculated and film-measured doses were evaluated on two sagittal planes. The average pass rates of the gamma indices on the planes under each of 3%/3 mm and 2%/2 mm criteria were 97.8% and 88.8%, respectively. It was confirmed that single-isocenter, non-coplanar multi-arc VMAT radiosurgery for multiple brain metastases was feasible using Elekta Synergy with Agility and Monaco treatment planning systems. It was further shown that film dosimetry was accurately performed for a dose of up to nearly 25 Gy. PMID:24944266

  18. Characterization of moderator assembly dimension for accelerator boron neutron capture therapy of brain tumors using 7Li(p, n) neutrons at proton energy of 2.5 MeV.

    PubMed

    Tanaka, Kenichi; Kobayashi, Tooru; Bengua, Gerard; Nakagawa, Yoshinobu; Endo, Satoru; Hoshi, Masaharu

    2006-06-01

    The characteristics of moderator assembly dimension are investigated for the usage of 7Li(p,n) neutrons by 2.5 MeV protons in boron newtron capture therapy (BNCT) of brain tumors in the present study. The indexes checked are treatable protocol depth (TPD), which is the greatest depth of the region satisfying the dose requirements in BNCT protocol, proton current necessary to complete BNCT by 1 h irradiation, and the heat flux deposited in the Li target which should be removed. Assumed materials are D2O for moderator, and mixture of polyethylene and LiF with 50 wt % for collimator. Dose distributions have been computed with MCNP 4B and 4C codes. Consequently, realized TPD does not show a monotonical tendency for the Li target diameter. However, the necessary proton current and heat flux in the Li target decreases as the Li target diameter increases, while this trend reverses at around 10 cm of the Li target diameter for the necessary proton current in the condition of this study. As to the moderator diameter, TPD does not exhibit an apparent dependence. On the other hand, necessary proton current and heat flux decrease as the moderator diameter increases, and this tendency saturates at around 60 cm of the moderator diameter in this study. As to the collimator, increase in inner diameter is suitable from the viewpoint of increasing TPD and decreasing necessary proton current and heat flux, while these indexes do not show apparent difference for collimator inner diameters over 14 cm for the parameters treated here. The practical viewpoint in selecting the parameters of moderator assembly dimension is to increase TPD, within the technically possible condition of accelerated proton current and heat removal from the Li target. In this process, the values for which the resultant characteristics mentioned above saturate or reverse would be important factors. PMID:16872076

  19. Feasibility of single-isocenter, multi-arc non-coplanar volumetric modulated arc therapy for multiple brain tumors using a linear accelerator with a 160-leaf multileaf collimator: a phantom study.

    PubMed

    Iwai, Yoshio; Ozawa, Shuichi; Ageishi, Tatsuya; Pellegrini, Roberto; Yoda, Kiyoshi

    2014-09-01

    The feasibility of single isocenter, multi-arc non-coplanar volumetric modulated arc therapy (VMAT) for multiple brain tumors was studied using an Elekta Synergy linear accelerator with an Agility multileaf collimator and a Monaco treatment planning system. Two VMAT radiosurgery plans consisting of a full arc and three half arcs were created with a prescribed dose of 20 Gy in a single fraction. After dose delivery to a phantom, ionization chambers and radiochromic films were used for dose measurement. The first VMAT radiosurgery plan had nine targets inside the phantom, and the doses were measured by the chambers at two different points and by the films on three sagittal and three coronal planes. The differences between the calculated dose and the dose measured by a Farmer ionization chamber and a pinpoint ionization chamber were <1.00% and <2.30%, respectively, and the average pass rates of gamma indices among the six planes under each of 3%/3 mm and 2%/2 mm criteria were 98.6% and 92.6%, respectively. The second VMAT radiosurgery plan was based on a clinical 14 brain metastases. Differences between calculated and film-measured doses were evaluated on two sagittal planes. The average pass rates of the gamma indices on the planes under each of 3%/3 mm and 2%/2 mm criteria were 97.8% and 88.8%, respectively. It was confirmed that single-isocenter, non-coplanar multi-arc VMAT radiosurgery for multiple brain metastases was feasible using Elekta Synergy with Agility and Monaco treatment planning systems. It was further shown that film dosimetry was accurately performed for a dose of up to nearly 25 Gy.

  20. Characterization of moderator assembly dimension for accelerator boron neutron capture therapy of brain tumors using {sup 7}Li(p,n) neutrons at proton energy of 2.5 MeV

    SciTech Connect

    Tanaka, Kenichi; Kobayashi, Tooru; Bengua, Gerard; Nakagawa, Yoshinobu; Endo, Satoru; Hoshi, Masaharu

    2006-06-15

    The characteristics of moderator assembly dimension are investigated for the usage of {sup 7}Li(p,n) neutrons by 2.5 MeV protons in boron newtron capture therapy (BNCT) of brain tumors in the present study. The indexes checked are treatable protocol depth (TPD), which is the greatest depth of the region satisfying the dose requirements in BNCT protocol, proton current necessary to complete BNCT by 1 h irradiation, and the heat flux deposited in the Li target which should be removed. Assumed materials are D{sub 2}O for moderator, and mixture of polyethylene and LiF with 50 wt % for collimator. Dose distributions have been computed with MCNP 4B and 4C codes. Consequently, realized TPD does not show a monotonical tendency for the Li target diameter. However, the necessary proton current and heat flux in the Li target decreases as the Li target diameter increases, while this trend reverses at around 10 cm of the Li target diameter for the necessary proton current in the condition of this study. As to the moderator diameter, TPD does not exhibit an apparent dependence. On the other hand, necessary proton current and heat flux decrease as the moderator diameter increases, and this tendency saturates at around 60 cm of the moderator diameter in this study. As to the collimator, increase in inner diameter is suitable from the viewpoint of increasing TPD and decreasing necessary proton current and heat flux, while these indexes do not show apparent difference for collimator inner diameters over 14 cm for the parameters treated here. The practical viewpoint in selecting the parameters of moderator assembly dimension is to increase TPD, within the technically possible condition of accelerated proton current and heat removal from the Li target. In this process, the values for which the resultant characteristics mentioned above saturate or reverse would be important factors.

  1. 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.

  2. Low-temperature (180 °C) formation of large-grained Ge (111) thin film on insulator using accelerated metal-induced crystallization

    SciTech Connect

    Toko, K. Numata, R.; Oya, N.; Suemasu, T.; Fukata, N.; Usami, N.

    2014-01-13

    The Al-induced crystallization (AIC) yields a large-grained (111)-oriented Ge thin film on an insulator at temperatures as low as 180 °C. We accelerated the AIC of an amorphous Ge layer (50-nm thickness) by initially doping Ge in Al and by facilitating Ge diffusion into Al. The electron backscatter diffraction measurement demonstrated the simultaneous achievement of large grains over 10 μm and a high (111) orientation fraction of 90% in the polycrystalline Ge layer formed at 180 °C. This result opens up the possibility for developing Ge-based electronic and optical devices fabricated on inexpensive flexible substrates.

  3. Glycosaminoglycan-mediated coacervation of tropoelastin abolishes the critical concentration, accelerates coacervate formation, and facilitates spherule fusion: implications for tropoelastin microassembly.

    PubMed

    Tu, Yidong; Weiss, Anthony S

    2008-07-01

    Elastogenesis and elastin repair depend on the secretion of tropoelastin from the cell, yet cellular production is low in the many biological systems that have been studied. To address the apparent paradox of a paucity of tropoelastin for cell surface microassembly, we examined the effects of the glycosaminoglycans heparin, heparan sulfate, and chondroitin sulfate B, on tropoelastin aggregate formation through coacervation. We found a significant effect, particularly of heparin, on the minimum or critical concentration of tropoelastin, which was required for microassembly, lowering critical concentration to a point that it was no longer detectable. The assemblies resulted in protein droplet formation that was visually indistinguishable from the spherules that typify coacervation. The spherules readily coalesced in the presence of heparin and higher concentrations of tropoelastin, resulting in an almost continuous layer of coacervated tropoelastin. Four stages of droplet behavior were observed: early droplet formation, approximately 6 mum droplet formation, and fusion of droplets followed by the formation of a coalesced layer. We conclude that glycosaminoglycans in the extracellular matrix have the capacity to promote coacervation at low concentrations of tropoelastin.

  4. Spinal tumor

    MedlinePlus

    Tumor - spinal cord ... spinal tumors occur in the nerves of the spinal cord itself. Most often these are ependymomas and other ... gene mutations. Spinal tumors can occur: Inside the spinal cord (intramedullary) In the membranes (meninges) covering the spinal ...

  5. Particle acceleration

    NASA Technical Reports Server (NTRS)

    Vlahos, L.; Machado, M. E.; Ramaty, R.; Murphy, R. J.; Alissandrakis, C.; Bai, T.; Batchelor, D.; Benz, A. O.; Chupp, E.; Ellison, D.

    1986-01-01

    Data is compiled from Solar Maximum Mission and Hinothori satellites, particle detectors in several satellites, ground based instruments, and balloon flights in order to answer fundamental questions relating to: (1) the requirements for the coronal magnetic field structure in the vicinity of the energization source; (2) the height (above the photosphere) of the energization source; (3) the time of energization; (4) transistion between coronal heating and flares; (5) evidence for purely thermal, purely nonthermal and hybrid type flares; (6) the time characteristics of the energization source; (7) whether every flare accelerates protons; (8) the location of the interaction site of the ions and relativistic electrons; (9) the energy spectra for ions and relativistic electrons; (10) the relationship between particles at the Sun and interplanetary space; (11) evidence for more than one acceleration mechanism; (12) whether there is single mechanism that will accelerate particles to all energies and also heat the plasma; and (13) how fast the existing mechanisms accelerate electrons up to several MeV and ions to 1 GeV.

  6. Accelerated Achievement

    ERIC Educational Resources Information Center

    Ford, William J.

    2010-01-01

    This article focuses on the accelerated associate degree program at Ivy Tech Community College (Indiana) in which low-income students will receive an associate degree in one year. The three-year pilot program is funded by a $2.3 million grant from the Lumina Foundation for Education in Indianapolis and a $270,000 grant from the Indiana Commission…

  7. ACCELERATION INTEGRATOR

    DOEpatents

    Pope, K.E.

    1958-01-01

    This patent relates to an improved acceleration integrator and more particularly to apparatus of this nature which is gyrostabilized. The device may be used to sense the attainment by an airborne vehicle of a predetermined velocitv or distance along a given vector path. In its broad aspects, the acceleration integrator utilizes a magnetized element rotatable driven by a synchronous motor and having a cylin drical flux gap and a restrained eddy- current drag cap deposed to move into the gap. The angular velocity imparted to the rotatable cap shaft is transmitted in a positive manner to the magnetized element through a servo feedback loop. The resultant angular velocity of tae cap is proportional to the acceleration of the housing in this manner and means may be used to measure the velocity and operate switches at a pre-set magnitude. To make the above-described dcvice sensitive to acceleration in only one direction the magnetized element forms the spinning inertia element of a free gyroscope, and the outer housing functions as a gimbal of a gyroscope.

  8. Plasma accelerator

    DOEpatents

    Wang, Zhehui; Barnes, Cris W.

    2002-01-01

    There has been invented an apparatus for acceleration of a plasma having coaxially positioned, constant diameter, cylindrical electrodes which are modified to converge (for a positive polarity inner electrode and a negatively charged outer electrode) at the plasma output end of the annulus between the electrodes to achieve improved particle flux per unit of power.

  9. Evaluation of a combined respiratory-gating system comprising the TrueBeam linear accelerator and a new real-time tumor-tracking radiotherapy system: a preliminary study.

    PubMed

    Shiinoki, Takehiro; Kawamura, Shinji; Uehara, Takuya; Yuasa, Yuki; Fujimoto, Koya; Koike, Masahiro; Sera, Tatsuhiro; Emoto, Yuki; Hanazawa, Hideki; Shibuya, Keiko

    2016-07-08

    A combined system comprising the TrueBeam linear accelerator and a new real-time, tumor-tracking radiotherapy system, SyncTraX, was installed in our institution. The goals of this study were to assess the capability of SyncTraX in measuring the position of a fiducial marker using color fluoroscopic images, and to evaluate the dosimetric and geometric accuracy of respiratory-gated radiotherapy using this combined system for the simple geometry. For the fundamental evaluation of respiratory-gated radiotherapy using SyncTraX, the following were performed:1) determination of dosimetric and positional characteristics of sinusoidal patterns using a motor-driven base for several gating windows; 2) measurement of time delay using an oscilloscope; 3) positional verification of sinusoidal patterns and the pattern in the case of a lung cancer patient; 4) measurement of the half-value layer (HVL in mm AL), effective kVp, and air kerma, using a solid-state detector for each fluoroscopic condition, to determine the patient dose. The dose profile in a moving phantom with gated radiotherapy having a gating window ≤ 4 mm was in good agreement with that under static conditions for each photon beam. The total time delay between TrueBeam and SyncTraX was < 227 ms for each photon beam. The mean of the positional tracking error was < 0.4 mm for sinusoidal patterns and for the pattern in the case of a lung cancer patient. The air-kerma rates from one fluoroscopy direction were 1.93 ± 0.01, 2.86 ± 0.01, 3.92 ± 0.04, 5.28 ± 0.03, and 6.60 ± 0.05 mGy/min for 70, 80, 90, 100, and 110 kV X-ray beams at 80 mA, respectively. The combined system comprising TrueBeam and SyncTraX could track the motion of the fiducial marker and control radiation delivery with reasonable accuracy; therefore, this system provides significant dosimetric improvement. However, patient exposure dose from fluoroscopy was not clinically negligible.

  10. Evaluation of a combined respiratory-gating system comprising the TrueBeam linear accelerator and a new real-time tumor-tracking radiotherapy system: a preliminary study.

    PubMed

    Shiinoki, Takehiro; Kawamura, Shinji; Uehara, Takuya; Yuasa, Yuki; Fujimoto, Koya; Koike, Masahiro; Sera, Tatsuhiro; Emoto, Yuki; Hanazawa, Hideki; Shibuya, Keiko

    2016-01-01

    A combined system comprising the TrueBeam linear accelerator and a new real-time, tumor-tracking radiotherapy system, SyncTraX, was installed in our institution. The goals of this study were to assess the capability of SyncTraX in measuring the position of a fiducial marker using color fluoroscopic images, and to evaluate the dosimetric and geometric accuracy of respiratory-gated radiotherapy using this combined system for the simple geometry. For the fundamental evaluation of respiratory-gated radiotherapy using SyncTraX, the following were performed:1) determination of dosimetric and positional characteristics of sinusoidal patterns using a motor-driven base for several gating windows; 2) measurement of time delay using an oscilloscope; 3) positional verification of sinusoidal patterns and the pattern in the case of a lung cancer patient; 4) measurement of the half-value layer (HVL in mm AL), effective kVp, and air kerma, using a solid-state detector for each fluoroscopic condition, to determine the patient dose. The dose profile in a moving phantom with gated radiotherapy having a gating window ≤ 4 mm was in good agreement with that under static conditions for each photon beam. The total time delay between TrueBeam and SyncTraX was < 227 ms for each photon beam. The mean of the positional tracking error was < 0.4 mm for sinusoidal patterns and for the pattern in the case of a lung cancer patient. The air-kerma rates from one fluoroscopy direction were 1.93 ± 0.01, 2.86 ± 0.01, 3.92 ± 0.04, 5.28 ± 0.03, and 6.60 ± 0.05 mGy/min for 70, 80, 90, 100, and 110 kV X-ray beams at 80 mA, respectively. The combined system comprising TrueBeam and SyncTraX could track the motion of the fiducial marker and control radiation delivery with reasonable accuracy; therefore, this system provides significant dosimetric improvement. However, patient exposure dose from fluoroscopy was not clinically negligible. PMID:27455483

  11. Study of beam optics and beam halo by integrated modeling of negative ion beams from plasma meniscus formation to beam acceleration

    SciTech Connect

    Miyamoto, K.; Okuda, S.; Hatayama, A.; Hanada, M.; Kojima, A.

    2013-01-14

    To understand the physical mechanism of the beam halo formation in negative ion beams, a two-dimensional particle-in-cell code for simulating the trajectories of negative ions created via surface production has been developed. The simulation code reproduces a beam halo observed in an actual negative ion beam. The negative ions extracted from the periphery of the plasma meniscus (an electro-static lens in a source plasma) are over-focused in the extractor due to large curvature of the meniscus.

  12. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease

    PubMed Central

    Wagner, Martin; Greten, Florian R.; Weber, Christoph K.; Koschnick, Stefan; Mattfeldt, Torsten; Deppert, Wolfgang; Kern, Horst; Adler, Guido; Schmid, Roland M.

    2001-01-01

    This study describes a tumor progression model for ductal pancreatic cancer in mice overexpressing TGF-α. Activation of Ras and Erk causes induction of cyclin D1-Cdk4 without increase of cyclin E or PCNA in ductal lesions. Thus, TGF-α is able to promote progression throughout G1, but not S phase. Crossbreeding with p53 null mice accelerates tumor development in TGF-α transgenic mice dramatically. In tumors developing in these mice, biallelic deletion of Ink4a/Arf or LOH of the Smad4 locus is found suggesting that loci in addition to p53 are involved in antitumor activities. We conclude that these genetic events are critical for pancreatic tumor formation in mice. This model recapitulates pathomorphological features and genetic alterations of the human disease. PMID:11159909

  13. Compact accelerator

    DOEpatents

    Caporaso, George J.; Sampayan, Stephen E.; Kirbie, Hugh C.

    2007-02-06

    A compact linear accelerator having at least one strip-shaped Blumlein module which guides a propagating wavefront between first and second ends and controls the output pulse at the second end. Each Blumlein module has first, second, and third planar conductor strips, with a first dielectric strip between the first and second conductor strips, and a second dielectric strip between the second and third conductor strips. Additionally, the compact linear accelerator includes a high voltage power supply connected to charge the second conductor strip to a high potential, and a switch for switching the high potential in the second conductor strip to at least one of the first and third conductor strips so as to initiate a propagating reverse polarity wavefront(s) in the corresponding dielectric strip(s).

  14. Reductive off-odors in wines: Formation and release of H₂S and methanethiol during the accelerated anoxic storage of wines.

    PubMed

    Franco-Luesma, Ernesto; Ferreira, Vicente

    2016-05-15

    In order to better understand the processes involved in the development of H2S and methanethiol (MeSH) along anoxic storage of wines, 24 wines were stored in strict anoxia at 50°C for 3weeks. Free and total forms of H2S and MeSH were measured at different times. Results showed that: (1) all wines contain relevant proportions of bonded forms of H2S and MeSH (93% and 47% on average); (2) such % decreases with age; (3) levels of total forms are related to wine metal composition; (4) anoxic storage brings about an increase of free forms, a strong decrease in the percentage of bonded forms, and except for H2S in red wines, an increase in total forms. Both de novo formation and release contribute to reductive off-odors. Release is predominant for reds and H2S, while at 50°C, de novo formation dominates for whites and rosés and MeSH.

  15. A complex of YlbF, YmcA and YaaT regulates sporulation, competence and biofilm formation by accelerating the phosphorylation of Spo0A

    PubMed Central

    Carabetta, Valerie J.; Tanner, Andrew W.; Greco, Todd M.; Defrancesco, Melissa; Cristea, Ileana M.; Dubnau, David

    2013-01-01

    Summary Bacillus subtilis has adopted a bet-hedging strategy to ensure survival in changing environments. From a clonal population, numerous sub-populations can emerge, expressing different sets of genes that govern the developmental processes of sporulation, competence and biofilm formation. The master transcriptional regulator Spo0A controls the entry into all three fates and the production of the phosphorylated active form of Spo0A is precisely regulated via a phosphorelay, involving at least four proteins. Two proteins, YmcA and YlbF were previously shown to play an unidentified role in the regulation of biofilm formation, and in addition, YlbF was shown to regulate competence and sporulation. Using an unbiased proteomics screen, we demonstrate that YmcA and YlbF interact with a third protein, YaaT to form a tripartite complex. We show that all three proteins are required for proper establishment of the three above-mentioned developmental states. We show that the complex regulates the activity of Spo0A in vivo and, using in vitro reconstitution experiments, determine that they stimulate the phosphorelay, probably by interacting with Spo0F and Spo0B. We propose that the YmcA-YlbF-YaaT ternary complex is required to increase Spo0A~P levels above the thresholds needed to induce development. PMID:23490197

  16. BICEP's acceleration

    SciTech Connect

    Contaldi, Carlo R.

    2014-10-01

    The recent Bicep2 [1] detection of, what is claimed to be primordial B-modes, opens up the possibility of constraining not only the energy scale of inflation but also the detailed acceleration history that occurred during inflation. In turn this can be used to determine the shape of the inflaton potential V(φ) for the first time — if a single, scalar inflaton is assumed to be driving the acceleration. We carry out a Monte Carlo exploration of inflationary trajectories given the current data. Using this method we obtain a posterior distribution of possible acceleration profiles ε(N) as a function of e-fold N and derived posterior distributions of the primordial power spectrum P(k) and potential V(φ). We find that the Bicep2 result, in combination with Planck measurements of total intensity Cosmic Microwave Background (CMB) anisotropies, induces a significant feature in the scalar primordial spectrum at scales k∼ 10{sup -3} Mpc {sup -1}. This is in agreement with a previous detection of a suppression in the scalar power [2].

  17. The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence

    PubMed Central

    Thompson, Keyata N.; Whipple, Rebecca A.; Yoon, Jennifer R.; Lipsky, Michael; Charpentier, Monica S.; Boggs, Amanda E.; Chakrabarti, Kristi R.; Bhandary, Lekhana; Hessler, Lindsay K.; Martin, Stuart S.; Vitolo, Michele I.

    2015-01-01

    A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN−/−KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common. PMID:26497685

  18. The combinatorial activation of the PI3K and Ras/MAPK pathways is sufficient for aggressive tumor formation, while individual pathway activation supports cell persistence.

    PubMed

    Thompson, Keyata N; Whipple, Rebecca A; Yoon, Jennifer R; Lipsky, Michael; Charpentier, Monica S; Boggs, Amanda E; Chakrabarti, Kristi R; Bhandary, Lekhana; Hessler, Lindsay K; Martin, Stuart S; Vitolo, Michele I

    2015-11-01

    A high proportion of human tumors maintain activation of both the PI3K and Ras/MAPK pathways. In basal-like breast cancer (BBC), PTEN expression is decreased/lost in over 50% of cases, leading to aberrant activation of the PI3K pathway. Additionally, BBC cell lines and tumor models have been shown to exhibit an oncogenic Ras-like gene transcriptional signature, indicating activation of the Ras/MAPK pathway. To directly test how the PI3K and Ras/MAPK pathways contribute to tumorigenesis, we deleted PTEN and activated KRas within non-tumorigenic MCF-10A breast cells. Neither individual mutation was sufficient to promote tumorigenesis, but the combination promoted robust tumor growth in mice. However, in vivo bioluminescence reveals that each mutation has the ability to promote a persistent phenotype. Inherent in the concept of tumor cell dormancy, a stage in which residual disease is present but remains asymptomatic, viable cells with each individual mutation can persist in vivo during a period of latency. The persistent cells were excised from the mice and showed increased levels of the cell cycle arrest proteins p21 and p27 compared to the aggressively growing PTEN-/-KRAS(G12V) cells. Additionally, when these persistent cells were placed into growth-promoting conditions, they were able to re-enter the cell cycle and proliferate. These results highlight the potential for either PTEN loss or KRAS activation to promote cell survival in vivo, and the unique ability of the combined mutations to yield rapid tumor growth. This could have important implications in determining recurrence risk and disease progression in tumor subtypes where these mutations are common. PMID:26497685

  19. Cell Line IDG-SW3 Replicates Osteoblast-to-Late-Osteocyte Differentiation in vitro and Accelerates Bone Formation in vivo

    PubMed Central

    Woo, Stacey M.; Rosser, Jennifer; Dusevich, Vladimir; Kalajzic, Ivo; Bonewald, Lynda F.

    2011-01-01

    Osteocytes are the most abundant cells in bone yet are the most challenging to study as they are embedded in a mineralized matrix. We generated a clonal cell line called IDG-SW3 (for Immortomouse/Dmp1-GFP-SW3) from long bone chips from mice carrying a Dmp1 promoter driving GFP crossed with the Immortomouse, which expresses a thermolabile SV40 large T-antigen regulated by IFN-γ. Cells from these mice can be expanded at 33°C in the presence of IFN-γ and then allowed to resume their original phenotype at 37°C in the absence of IFN-γ. IDG-SW3 cells are Dmp1-GFP-negative and T-antigen-positive under immortalizing conditions but Dmp1-GFP-positive and T-antigen-negative under osteogenic conditions. Like osteoblasts, they express alkaline phosphatase and produce and mineralize a type I collagen matrix containing calcospherulites. Like early osteocytes, they express E11/gp38, Dmp1, MEPE, and Phex. Like late osteocytes, they develop a dendritic morphology and express SOST/sclerostin and FGF23, regulated by PTH and 1,25-dihydroxyvitamin-D3. When cultured on 3D matrices, they express Dmp1-GFP and sclerostin. When the 3D cultures are implanted in calvarial defects in vivo, they accelerate bone healing. This cell line should prove useful for studying osteoblast-to-osteocyte transition, mechanisms for biomineralization, osteocyte function, and regulation of SOST/sclerostin and FGF23. PMID:21735478

  20. An Agomir of miR-144-3p Accelerates Plaque Formation through Impairing Reverse Cholesterol Transport and Promoting Pro-Inflammatory Cytokine Production

    PubMed Central

    Zhao, Jia-Yi; Li, Shu-Fen; Ma, Xin; Wu, Shao-Guo; Lu, Jing-Bo; Qiu, Yu-Rong; Sha, Yan-Hua; Wang, Yan-Chao; Gao, Ji-Juan; Zheng, Lei; Wang, Qian

    2014-01-01

    Aims ATP-binding cassette transporter A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to lipid-poor apolipoproteins, which then form nascent HDL, a key step in the mechanism of reverse cholesterol transport (RCT). While a series of microRNAs (miRNAs) have been identified as potent post-transcriptional regulators of lipid metabolism, their effects on ABCA1 function and associated mechanisms remain unclear. Methods and Results ABCA1 was identified as a potential target of miR-144-3p, based on the results of bioinformatic analysis and the luciferase reporter assay, and downregulated after transfection of cells with miR-144-3p mimics, as observed with real-time PCR and western blot. Moreover, miR-144-3p mimics (agomir) enhanced the expression of inflammatory factors, including IL-1β, IL-6 and TNF-α, in vivo and in vitro, inhibited cholesterol efflux in THP-1 macrophage-derived foam cells, decreased HDL-C circulation and impaired RCT in vivo, resulting in accelerated pathological progression of atherosclerosis in apoE−/− mice. Clinical studies additionally revealed a positive correlation of circulating miR-144-3p with serum CK, CK-MB, LDH and AST in subjects with AMI. Conclusions Our findings clearly indicate that miR-144-3p is essential for the regulation of cholesterol homeostasis and inflammatory reactions, supporting its utility as a potential therapeutic target of atherosclerosis and a promising diagnostic biomarker of AMI. PMID:24733347

  1. Brain tumors.

    PubMed Central

    Black, K. L.; Mazziotta, J. C.; Becker, D. P.

    1991-01-01

    Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors, which are sparse in normal brain, is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors, the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors. Images PMID:1848735

  2. Surface modification of nano-silica on the ligament advanced reinforcement system for accelerated bone formation: primary human osteoblasts testing in vitro and animal testing in vivo.

    PubMed

    Li, Mengmeng; Wang, Shiwen; Jiang, Jia; Sun, Jiashu; Li, Yuzhuo; Huang, Deyong; Long, Yun-Ze; Zheng, Wenfu; Chen, Shiyi; Jiang, Xingyu

    2015-05-01

    The Ligament Advanced Reinforcement System (LARS) has been considered as a promising graft for ligament reconstruction. To improve its biocompatibility and effectiveness on new bone formation, we modified the surface of a polyethylene terephthalate (PET) ligament with nanoscale silica using atom transfer radical polymerization (ATRP) and silica polymerization. The modified ligament is tested by both in vitro and in vivo experiments. Human osteoblast testing in vitro exhibits an ∼21% higher value in cell viability for silica-modified grafts compared with original grafts. Animal testing in vivo shows that there is new formed bone in the case of a nanoscale silica-coated ligament. These results demonstrate that our approach for nanoscale silica surface modification on LARS could be potentially applied for ligament reconstruction.

  3. Surface modification of nano-silica on the ligament advanced reinforcement system for accelerated bone formation: primary human osteoblasts testing in vitro and animal testing in vivo

    NASA Astrophysics Data System (ADS)

    Li, Mengmeng; Wang, Shiwen; Jiang, Jia; Sun, Jiashu; Li, Yuzhuo; Huang, Deyong; Long, Yun-Ze; Zheng, Wenfu; Chen, Shiyi; Jiang, Xingyu

    2015-04-01

    The Ligament Advanced Reinforcement System (LARS) has been considered as a promising graft for ligament reconstruction. To improve its biocompatibility and effectiveness on new bone formation, we modified the surface of a polyethylene terephthalate (PET) ligament with nanoscale silica using atom transfer radical polymerization (ATRP) and silica polymerization. The modified ligament is tested by both in vitro and in vivo experiments. Human osteoblast testing in vitro exhibits an ~21% higher value in cell viability for silica-modified grafts compared with original grafts. Animal testing in vivo shows that there is new formed bone in the case of a nanoscale silica-coated ligament. These results demonstrate that our approach for nanoscale silica surface modification on LARS could be potentially applied for ligament reconstruction.The Ligament Advanced Reinforcement System (LARS) has been considered as a promising graft for ligament reconstruction. To improve its biocompatibility and effectiveness on new bone formation, we modified the surface of a polyethylene terephthalate (PET) ligament with nanoscale silica using atom transfer radical polymerization (ATRP) and silica polymerization. The modified ligament is tested by both in vitro and in vivo experiments. Human osteoblast testing in vitro exhibits an ~21% higher value in cell viability for silica-modified grafts compared with original grafts. Animal testing in vivo shows that there is new formed bone in the case of a nanoscale silica-coated ligament. These results demonstrate that our approach for nanoscale silica surface modification on LARS could be potentially applied for ligament reconstruction. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr01439e

  4. Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation

    PubMed Central

    Bohrer, Laura R.; Chuntova, Pavlina; Bade, Lindsey K.; Beadnell, Thomas C.; Leon, Ronald P.; Brady, Nicholas J.; Ryu, Yungil; Goldberg, Jodi E.; Schmechel, Stephen C.; Koopmeiners, Joseph S.; McCarthy, James B.; Schwertfeger, Kathryn L.

    2014-01-01

    Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to breast cancer growth, progression and therapeutic resistance. Due to the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan (HA) within the extracellular matrix (ECM) and that blocking HA synthesis decreases proliferation, migration and therapeutic resistance. Furthermore, FGFR-mediated HA accumulation requires activation of the signal transducer and activator of transcription 3 (STAT3) pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent HA synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and HA levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and HA synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a pro-tumorigenic microenvironment. PMID:24197137

  5. Advanced concepts for acceleration

    SciTech Connect

    Keefe, D.

    1986-07-01

    Selected examples of advanced accelerator concepts are reviewed. Such plasma accelerators as plasma beat wave accelerator, plasma wake field accelerator, and plasma grating accelerator are discussed particularly as examples of concepts for accelerating relativistic electrons or positrons. Also covered are the pulsed electron-beam, pulsed laser accelerator, inverse Cherenkov accelerator, inverse free-electron laser, switched radial-line accelerators, and two-beam accelerator. Advanced concepts for ion acceleration discussed include the electron ring accelerator, excitation of waves on intense electron beams, and two-wave combinations. (LEW)

  6. Accelerators and the Accelerator Community

    SciTech Connect

    Malamud, Ernest; Sessler, Andrew

    2008-06-01

    In this paper, standing back--looking from afar--and adopting a historical perspective, the field of accelerator science is examined. How it grew, what are the forces that made it what it is, where it is now, and what it is likely to be in the future are the subjects explored. Clearly, a great deal of personal opinion is invoked in this process.

  7. Tumor Types

    MedlinePlus

    ... acoustic neuroma is also known as a schwannoma, vestibular schwannoma, or neurilemmoma. Characteristics Arises from cells that ... multiple CNS tumors, including neurofibromas, multiple meningiomas, bilateral vestibular schwannomas, optic nerve gliomas, and spinal cord tumors. ...

  8. Vasculogenic mimicry and tumor metastasis.

    PubMed

    Zhang, Jingxin; Qiao, Lili; Liang, Ning; Xie, Jian; Luo, Hui; Deng, Guodong; Zhang, Jiandong

    2016-01-01

    Vasculogenic mimicry (VM), a microvascular channel made up of nonendothelial cells, has been accepted as a new model of neovascularization in aggressive tumors, owning to the specific capacity of malignant cells to form vessel-like networks which provide sufficient blood supply for tumor growth. Multiple molecular mechanisms, especially vascular endothelial (VE)-cadherin, erythropoietin-producing hepatocellular receptor A2 (EphA2), phosphatidyl inositol 3-kinase (PI3K), matrix metalloproteinases (MMPs), vascular endothelial growth factor receptor (VEGFR1), and hypoxia inducible factor (HIF)-1a, have been reported to participate in VM formation which is associated with tumor migration and invasion. In addition, hypoxia, cancer stem cells (CSCs) and epithelial-mesenehymal transition (EMT) are regarded as significant factors in VM formation and tumor metastasis. Due to the important effects of VM on tumor progression, a review was carried out in the present study, to synthetically analyze the relationship between VM and tumor metastasis. PMID:27569069

  9. Brain Tumors

    MedlinePlus

    A brain tumor is a growth of abnormal cells in the tissues of the brain. Brain tumors can be benign, with no cancer cells, ... cancer cells that grow quickly. Some are primary brain tumors, which start in the brain. Others are ...

  10. Urogenital tumors

    SciTech Connect

    Weller, R.E.

    1994-03-01

    An overview is provided for veterinary care of urogenital tumors in companion animals, especially the dog. Neoplasms discussed include tumors of the kidney, urinary bladder, prostate, testis, ovary, vagina, vulva and the canine transmissible venereal tumor. Topics addressed include description, diagnosis and treatment.

  11. Wild-Type N-Ras, Overexpressed in Basal-like Breast Cancer, Promotes Tumor Formation by Inducing IL-8 Secretion via JAK2 Activation.

    PubMed

    Zheng, Ze-Yi; Tian, Lin; Bu, Wen; Fan, Cheng; Gao, Xia; Wang, Hai; Liao, Yi-Hua; Li, Yi; Lewis, Michael T; Edwards, Dean; Zwaka, Thomas P; Hilsenbeck, Susan G; Medina, Daniel; Perou, Charles M; Creighton, Chad J; Zhang, Xiang H-F; Chang, Eric C

    2015-07-21

    Basal-like breast cancers (BLBCs) are aggressive, and their drivers are unclear. We have found that wild-type N-RAS is overexpressed in BLBCs but not in other breast cancer subtypes. Repressing N-RAS inhibits transformation and tumor growth, whereas overexpression enhances these processes even in preinvasive BLBC cells. We identified N-Ras-responsive genes, most of which encode chemokines; e.g., IL8. Expression levels of these chemokines and N-RAS in tumors correlate with outcome. N-Ras, but not K-Ras, induces IL-8 by binding and activating the cytoplasmic pool of JAK2; IL-8 then acts on both the cancer cells and stromal fibroblasts. Thus, BLBC progression is promoted by increasing activities of wild-type N-Ras, which mediates autocrine/paracrine signaling that can influence both cancer and stroma cells.

  12. Expression of Tax-interacting protein 1 (TIP-1) facilitates angiogenesis and tumor formation of human glioblastoma cells in nude mice

    PubMed Central

    Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang; Han, Zhaozhong

    2012-01-01

    Glioblastoma is the most common and fatal type of primary brain tumors featured with hyperplastic blood vessels. Here, we performed meta-analyses of published data and established a correlation between high TIP-1 expression levels and the poor prognosis of glioblastoma patients. Next, we explored the biological relevance of TIP-1 expression in the pathogenesis of glioblastoma. By using orthotopic and heterotopic mouse models of human glioblastomas, this study has characterized TIP-1 as one contributing factor to the tumor-driven angiogenesis. In vitro and in vivo functional assays, along with biochemical analyses with microarrays and antibody arrays, have demonstrated that TIP-1 utilizes multiple pathways including modulating fibronectin gene expression and uPA protein secretion, to establish or maintain a pro-angiogenic microenvironment within human glioblastoma. In conclusion, this work supports the hypothesis that TIP-1 represents a novel prognostic biomarker and a therapeutic target of human glioblastoma. PMID:23010083

  13. miR-141 is involved in BRD7-mediated cell proliferation and tumor formation through suppression of the PTEN/AKT pathway in nasopharyngeal carcinoma.

    PubMed

    Liu, Y; Zhao, R; Wang, H; Luo, Y; Wang, X; Niu, W; Zhou, Y; Wen, Q; Fan, S; Li, X; Xiong, W; Ma, J; Li, X; Tan, M; Li, G; Zhou, M

    2016-01-01

    Bromodomain containing 7 (BRD7) was identified as a nuclear transcriptional regulatory factor. BRD7 functions as a tumor suppressor in multiple cancers, including nasopharyngeal carcinoma (NPC). In this study, we reported a novel mechanism of BRD7 in NPC progression. We demonstrated that the expression of miR-141 was remarkably increased in NPC tissues and was negatively correlated with the expression of BRD7 and the survival rate of NPC patients. Decreased expression levels of miR-141, including the primary, the precursor and the mature forms of miR-141, were found in BRD7-overexpressing HEK293, 5-8F and HNE1 cells compared the control cells, while there was no obvious effect on the expression levels of the two critical enzymes Drosha and Dicer. BRD7 can negatively regulate the promoter activity of miR-141, while no obvious binding site of BRD7 was found in the potential promoter region of miR-141. Moreover, ectopic expression of miR-141 can significantly promote cell proliferation and inhibit apoptosis in NPC, and rescuing the expression of miR-141 in BRD7-overexpressing NPC cells could partially reverse the tumor suppressive effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Furthermore, the activation of the PTEN/AKT pathway mediated by the overexpression of BRD7 could be inhibited by rescuing the expression of miR-141, which accordingly results in the partial restoration of cell proliferation and tumor growth. Our findings demonstrate that the BRD7/miR-141/PTEN/AKT axis has critical roles in the progression of NPC and provide some promising targets for the diagnosis and treatment of NPC. PMID:27010857

  14. Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy

    PubMed Central

    2012-01-01

    Background Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects. PMID:22236378

  15. 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.

  16. [Tumors of the parotid gland].

    PubMed

    Tresserra, L; Tresserra, F

    1997-09-01

    Tumors of the parotid are the most frequently encountered salivary gland tumors. Knowledge of the histology and anatomy of the salivary gland is important when considering the histiogenesis of salivary gland tumors, requiring close cooperation between the pathologist and the surgeon. Most tumors are benign epithelial formations. Pleomorphous adenomas predominate. Superficial lobectomy is adequate treatment. When the tumor involves a deep lobe, total parotidectomy is indicated. Treatment of malignant tumors depends on the histology, its TNM stage and other factors. Total parotidectomy with lymphadectomy and radiotherapy are needed in case of high grade malignancy. In children, vascular neoplasias are the most frequent, followed by malignant tumors. Their histological features and treatment are the same as for adults.

  17. An AzTEC 1.1mm Survey of a Highly-biased Extragalactic Field Tracing Accelerated Galaxy Formation at z 3.8 towards 4C41.17

    NASA Astrophysics Data System (ADS)

    Hughes, David; Ade, P. A.; Aretxaga, I.; Austermann, J.; Bock, J. J.; Dunlop, J.; Gaztanagal, E.; Ivison, R.; Kang, Y.; Kim, S.; Lowenthal, J.; Mauskopf, P.; Montana, A.; Plionis, M.; Scott, K.; Smail, I.; Stevens, J.; Wagg, J.; Wilson, G.; Yun, M.

    2006-12-01

    Aztec has recently conducted a sensitive, wide-area (300 sq. arcmin'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 10^12 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.

  18. Id1 Deficiency Protects against Tumor Formation in Apc(Min/+) Mice but Not in a Mouse Model of Colitis-Associated Colon Cancer.

    PubMed

    Zhang, Ning; Subbaramaiah, Kotha; Yantiss, Rhonda K; Zhou, Xi Kathy; Chin, Yvette; Benezra, Robert; Dannenberg, Andrew J

    2015-04-01

    Different mechanisms contribute to the development of sporadic, hereditary and colitis-associated colorectal cancer. Inhibitor of DNA binding/differentiation (Id) proteins act as dominant-negative antagonists of basic helix-loop-helix transcription factors. Id1 is a promising target for cancer therapy, but little is known about its role in the development of colon cancer. We used immunohistochemistry to demonstrate that Id1 is overexpressed in human colorectal adenomas and carcinomas, whether sporadic or syndromic. Furthermore, elevated Id1 levels were found in dysplasia and colon cancer arising in patients with inflammatory bowel disease. Because levels of PGE2 are also elevated in both colitis and colorectal neoplasia, we determined whether PGE2 could induce Id1. PGE2 via EP4 stimulated protein kinase A activity resulting in enhanced pCREB-mediated Id1 transcription in human colonocytes. To determine the role of Id1 in carcinogenesis, two mouse models were used. Consistent with the findings in humans, Id1 was overexpressed in tumors arising in both Apc(Min) (/+) mice, a model of familial adenomatous polyposis, and in experimental colitis-associated colorectal neoplasia. Id1 deficiency led to significant decrease in the number of intestinal tumors in Apc(Min) (/+) mice and prolonged survival. In contrast, Id1 deficiency did not affect the number or size of tumors in the model of colitis-associated colorectal neoplasia, likely due to exacerbation of colitis associated with Id1 loss. Collectively, these results suggest that Id1 plays a role in gastrointestinal carcinogenesis. Our findings also highlight the need for different strategies to reduce the risk of colitis-associated colorectal cancer compared with sporadic or hereditary colorectal cancer.

  19. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. PMID:24477002

  20. Antioxidants accelerate lung cancer progression in mice.

    PubMed

    Sayin, Volkan I; Ibrahim, Mohamed X; Larsson, Erik; Nilsson, Jonas A; Lindahl, Per; Bergo, Martin O

    2014-01-29

    Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production.

  1. Spontaneous squamous cell carcinoma induced by the somatic inactivation of retinoblastoma and Trp53 tumor suppressors.

    PubMed

    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. PMID:18245467

  2. Hyperdiploid tumor cells increase phenotypic heterogeneity within Glioblastoma tumors.

    PubMed

    Donovan, Prudence; Cato, Kathleen; Legaie, Roxane; Jayalath, Rumal; Olsson, Gemma; Hall, Bruce; Olson, Sarah; Boros, Samuel; Reynolds, Brent A; Harding, Angus

    2014-04-01

    Here we report the identification of a proliferative, viable, and hyperdiploid tumor cell subpopulation present within Glioblastoma (GB) patient tumors. Using xenograft tumor models, we demonstrate that hyperdiploid cell populations are maintained in xenograft tumors and that clonally expanded hyperdiploid cells support tumor formation and progression in vivo. In some patient tumorsphere lines, hyperdiploidy is maintained during long-term culture and in vivo within xenograft tumor models, suggesting that hyperdiploidy can be a stable cell state. In other patient lines hyperdiploid cells display genetic drift in vitro and in vivo, suggesting that in these patients hyperdiploidy is a transient cell state that generates novel phenotypes, potentially facilitating rapid tumor evolution. We show that the hyperdiploid cells are resistant to conventional therapy, in part due to infrequent cell division due to a delay in the G₀/G₁ phase of the cell cycle. Hyperdiploid tumor cells are significantly larger and more metabolically active than euploid cancer cells, and this correlates to an increased sensitivity to the effects of glycolysis inhibition. Together these data identify GB hyperdiploid tumor cells as a potentially important subpopulation of cells that are well positioned to contribute to tumor evolution and disease recurrence in adult brain cancer patients, and suggest tumor metabolism as a promising point of therapeutic intervention against this subpopulation. PMID:24448662

  3. Tumor endothelial marker 1-specific DNA vaccination targets tumor vasculature.

    PubMed

    Facciponte, John G; Ugel, Stefano; De Sanctis, Francesco; Li, Chunsheng; Wang, Liping; Nair, Gautham; Sehgal, Sandy; Raj, Arjun; Matthaiou, Efthymia; Coukos, George; Facciabene, Andrea

    2014-04-01

    Tumor endothelial marker 1 (TEM1; also known as endosialin or CD248) is a protein found on tumor vasculature and in tumor stroma. Here, we tested whether TEM1 has potential as a therapeutic target for cancer immunotherapy by immunizing immunocompetent mice with Tem1 cDNA fused to the minimal domain of the C fragment of tetanus toxoid (referred to herein as Tem1-TT vaccine). Tem1-TT vaccination elicited CD8+ and/or CD4+ T cell responses against immunodominant TEM1 protein sequences. Prophylactic immunization of animals with Tem1-TT prevented or delayed tumor formation in several murine tumor models. Therapeutic vaccination of tumor-bearing mice reduced tumor vascularity, increased infiltration of CD3+ T cells into the tumor, and controlled progression of established tumors. Tem1-TT vaccination also elicited CD8+ cytotoxic T cell responses against murine tumor-specific antigens. Effective Tem1-TT vaccination did not affect angiogenesis-dependent physiological processes, including wound healing and reproduction. Based on these data and the widespread expression of TEM1 on the vasculature of different tumor types, we conclude that targeting TEM1 has therapeutic potential in cancer immunotherapy.

  4. ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer

    PubMed Central

    Gumireddy, Kiranmai; Li, Anping; Yao, Weimin; Gao, Lu; Chen, Shuliang; Hao, Jun; Wang, Ji; Huang, Qihong; Xu, Hua; Ye, Zhangqun

    2015-01-01

    Inactivation or mutation of the VHL gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). In the present study, we identified ZBRK1 as a novel VHL interacting protein by yeast two-hybrid screening, and found a single ZBRK1-binding site located in the VHL promoter region. Ectopic expression of ZBRK1 increases transcriptional activity of the VHL, whereas the depletion of endogenous ZBRK1 by shRNA leads to reduction of VHL expression. We also demonstrate that the inhibition of VEGF transcription by ZBRK1 overexpression is dependent on VHL/HIF pathway. Moreover, VHL is confirmed to serve as a bridge component for the association of ZBRK1 and p300, which leads to an increase in ZBRK1 transcriptional activity in the VHL promoter. We further provide striking evidences that ZBRK1 acts as a tumor suppressor in renal carcinoma by a variety of in vitro and in vivo assays, and ZBRK1 may represent a molecular marker to distinguish patients with ccRCC at high risk from those with a better survival prognosis. Taken together, these findings suggest that ZBRK1 suppresses renal cancer progression perhaps by regulating VHL expression. PMID:25749518

  5. Slug inhibits the proliferation and tumor formation of human cervical cancer cells by up-regulating the p21/p27 proteins and down-regulating the activity of the Wnt/β-catenin signaling pathway via the trans-suppression Akt1/p-Akt1 expression

    PubMed Central

    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

  6. Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma tumor formation in NOD/SCID mice is inhibited by neomycin and neamine blocking angiogenin's nuclear translocation.

    PubMed

    Bottero, Virginie; Sadagopan, Sathish; Johnson, Karen E; Dutta, Sujoy; Veettil, Mohanan Valiya; Chandran, Bala

    2013-11-01

    Angiogenin (ANG) is a 14-kDa multifunctional proangiogenic secreted protein whose expression level correlates with the aggressiveness of several tumors. We observed increased ANG expression and secretion in endothelial cells during de novo infection with Kaposi's sarcoma-associated herpesvirus (KSHV), in cells expressing only latency-associated nuclear antigen 1 (LANA-1) protein, and in KSHV latently infected primary effusion lymphoma (PEL) BCBL-1 and BC-3 cells. Inhibition of phospholipase Cγ (PLCγ) mediated ANG's nuclear translocation by neomycin, an aminoglycoside antibiotic (not G418-neomicin), resulted in reduced KSHV latent gene expression, increased lytic gene expression, and increased cell death of KSHV(+) PEL and endothelial cells. ANG detection in significant levels in KS and PEL lesions highlights its importance in KSHV pathogenesis. To assess the in vivo antitumor activity of neomycin and neamine (a nontoxic derivative of neomycin), BCBL-1 cells were injected intraperitoneally into NOD/SCID mice. We observed significant extended survival of mice treated with neomycin or neamine. Markers of lymphoma establishment, such as increases in animal body weight, spleen size, tumor cell spleen infiltration, and ascites volume, were observed in nontreated animals and were significantly diminished by neomycin or neamine treatments. A significant decrease in LANA-1 expression, an increase in lytic gene expression, and an increase in cleaved caspase-3 were also observed in neomycin- or neamine-treated animal ascitic cells. These studies demonstrated that ANG played an essential role in KSHV latency maintenance and BCBL-1 cell survival in vivo, and targeting ANG function by neomycin/neamine to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV-associated malignancies.

  7. Pindborg tumor

    PubMed Central

    Caliaperoumal, Santhosh Kumar; Gowri, S.; Dinakar, J.

    2016-01-01

    Calcifying epithelial odontogenic tumor (CEOT), also known as Pindborg tumor, is a rare odontogenic epithelial neoplasm. So far, nearly 200 cases have been reported in the literature. We are reporting a case of CEOT in a 42-year-old male patient with painless bony swelling in the mandible. The clinical, radiographic, and histopathologic features are discussed with relevant references. PMID:27041911

  8. Hypothalamic tumor

    MedlinePlus

    ... occur at any age. They are often more aggressive in adults than in children. In adults, tumors ... The treatment depends on how aggressive the tumor is, and whether it is a glioma or another type of cancer. Treatment may involve combinations of surgery, radiation , ...

  9. Pituitary Tumors

    MedlinePlus

    ... pituitary is the "master control gland" - it makes hormones that affect growth and the functions of other glands in the body. Pituitary tumors are common, but often they don't cause health ... tumor produces hormones and disrupts the balance of hormones in your ...

  10. DDX3 enhances oncogenic KRAS-induced tumor invasion in colorectal cancer via the β-catenin/ZEB1 axis

    PubMed Central

    Wu, De-Wei; Lin, Po-Lin; Cheng, Ya-Wen; Huang, Chi-Chou; Wang, Lee; Lee, Huei

    2016-01-01

    DDX3 plays a dual role in colorectal cancer; however, the role and underlying mechanism of DDX3 in colorectal tumorigenesis remains unclear. Here, we provide evidence that DDX3 enhances oncogenic KRAS transcription via an increase in SP1 binding to its promoter. Accelerating oncogenic KRAS expression by DDX3 promotes the invasion capability via the ERK/PTEN/AKT/β-catenin cascade. Moreover, the β-catenin/ZEB1 axis is responsible for DDX3-induced cell invasiveness and xenograft lung tumor nodule formation. The xenograft lung tumor nodules induced by DDX3-overexpressing T84 stable clone were nearly suppressed by the inhibitor of AKT (perifosine) or β-catenin (XAV939). Among patients, high KRAS, positive nuclear β-catenin expression and high ZEB1 were more commonly occurred in high-DDX3 tumors than in low-DDX3 tumors. High-DDX3, high-KRAS, positive nuclear β-catenin tumors, and high-ZEB1 exhibited worse overall survival (OS) and relapse free survival (RFS) than their counterparts. In conclusion, DDX3 may play an oncogenic role to promote tumor growth and invasion in colon cancer cells via the β-catenin/ZEB1 axis due to increasing KRAS transcription. We therefore suggest that AKT or β-catenin may potentially act as a therapeutic target to improve tumor regression and outcomes in colorectal cancer patients who harbored high-DDX3 tumors. PMID:27007150

  11. Lung tumorigenesis induced by human vascular endothelial growth factor (hVEGF)-A165 overexpression in transgenic mice and amelioration of tumor formation by miR-16

    PubMed Central

    Chou, Yu-Ching; Lai, Cheng-Wei; Wang, Hsiu-Po; Ho, Heng-Chien; Yen, Chih-Ching; Tu, Chih-Yen; Tsai, Tung-Chou; Yeh, Dah-Cherng; Wang, Jiun-Long; Chong, Kowit-Yu; Chen, Chuan-Mu

    2015-01-01

    Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A165 (hVEGF-A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes (hvegf-A165, cyclin b1, cdc2, egfr, mmp9, nrp-1, and kdr) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A165 in Clara cells increases CD105, fibrogenic genes (collagen α1, α-SMA, TGF-β1, and TIMP1), and inflammatory cytokines (IL-1, IL-6, and TNF-α) in the lungs of hVEGF-A165-overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma. PMID:25912305

  12. New Trends in Induction Accelerator Technology

    SciTech Connect

    Caporaso, G J

    2002-12-05

    Recent advances in solid-state modulators now permit the design of a new class of high current accelerators. These new accelerators will be able to operate in burst mode at frequencies of several MHz with unprecedented flexibility and precision in pulse format. These new modulators can drive accelerators to high average powers that far exceed those of any other technology and can be used to enable precision beam manipulations. New insulator technology combined with novel pulse forming lines and switching may enable the construction of a new type of high gradient, high current accelerator. Recent developments in these areas will be reviewed.

  13. Gender-related effects of 17-{beta}-estradiol and B-hexachlorocyclohexane on liver tumor formation in medaka (Oryzias latipes)

    SciTech Connect

    Cooke, J.B.; Hinton, D.E.

    1994-12-31

    When medaka were acutely exposed to diethylnitrosamine (DEN), greater incidence of hepatocarcinoma was seen in female versus male fish. This is possibly related to elevated female endogenous estrogens, which increase liver weight and production of vitellogenin. To examine roles of estrogens in tumor modulation, 21-day old medaka were exposed to DEN (200 ppm for 24 hr.), then fed purified diets containing the estrogenic compound {beta}-hexachlorocyclohexane ({beta}-HCH) or 17-{beta}estradiol (E2) for 6 months. Incidences of basophilic preneoplastic foci of cellular alteration in females receiving DEN and 0.01, 0.1, or 1.0 ppm E2 were three times the incidences in similarly-treated males. Also, incidences of basophilic foci in DEN + 0.1 ppm E2 males were significantly increased over DEN-only males and were equal to incidences in DEN-only females. Liver weights and hepatosomatic indices of males given 0.1 ppm E2 were not significantly different than females fed control diet. Females fed 0.01-10.0 ppm {beta}-HCH after DEN had 4--5 times greater incidences of basophilic foci as males. Gender-related effects on kinetics of growth rates and volumes of foci are being examined.

  14. Edward Maxwell (Max) Nicholls (1927-2011), a Key Player in the Development of the Two-Hit Model of Tumor Formation.

    PubMed

    Stark, Alan E; Otto, Paulo A

    2016-08-01

    E. M. Nicholls (1927-2011) was a humanist, medical practitioner, human biologist, geneticist and, above all, a teacher, as well as a husband and father. He believed that he had made a fundamental contribution to the two-hit model of cancer formation. This hypothesis is associated with retinoblastoma, in particular. Nicholls presented it through his observations on neurofibromatosis. He received little credit for what he believed was his most original contribution to medical science. This note attempts to redress the balance in his favor. PMID:27302649

  15. Edward Maxwell (Max) Nicholls (1927-2011), a Key Player in the Development of the Two-Hit Model of Tumor Formation.

    PubMed

    Stark, Alan E; Otto, Paulo A

    2016-08-01

    E. M. Nicholls (1927-2011) was a humanist, medical practitioner, human biologist, geneticist and, above all, a teacher, as well as a husband and father. He believed that he had made a fundamental contribution to the two-hit model of cancer formation. This hypothesis is associated with retinoblastoma, in particular. Nicholls presented it through his observations on neurofibromatosis. He received little credit for what he believed was his most original contribution to medical science. This note attempts to redress the balance in his favor.

  16. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity

    PubMed Central

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-01-01

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1–S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1–S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics. PMID:26329134

  17. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity.

    PubMed

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-09-02

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

  18. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Zhang, Wen; Chen, Min; Ling Wu, Yan; Tanaka, Yoshimasa; Juan Ji, Yan; Lin Zhang, Su; He Wei, Chuan; Xu, Yan

    2015-09-01

    G-quadruplexes formed in telomeric DNA sequences at human chromosome ends can be a novel target for the development of therapeutics for the treatment of cancer patients. Herein, we examined the ability of six novel benzothioxanthene derivatives S1-S6 to induce the formation of and stabilize an antiparallel G-quadruplex by EMSA, UV-melting and CD techniques and the influence of S1-S6 on A549 and SGC7901 cells through real-time cell analysis, wound healing, trap assay methods. Results show that six compounds could differentially induce 26 nt G-rich oligonucleotides to form the G-quadruplex with high selectivity vs C-rich DNA, mutated DNA and double-stranded DNA, stabilize it with high affinity, promote apoptosis and inhibit mobility and telomerase activity of A549 cells and SGC7901 cells. Especially, S1, S3, S4 displayed stronger abilities, of which S3 was the most optimal with the maximum ΔTm value being up to 29.8 °C for G-quadruplex, the minimum IC50 value being 0.53 μM and the maximum cell inhibitory rate being up to 97.2%. This study suggests that this type of compounds that induce the formation of and stabilize the telomeric antiparallel G-quadruplex, and consequently inhibit telomerase activity, leading to cell apoptosis, can be screened for the discovery of novel antitumor therapeutics.

  19. [Adipocytic tumors].

    PubMed

    Stock, Nathalie

    2015-01-01

    Adipocytic tumors are the most common mesenchymal neoplasms, liposarcoma accounting for approximately 20% of soft tissue sarcomas. The differential diagnosis between benign and malignant tumors is often problematic and represents a significant proportion of consultation cases. The goal of this article is to review liposarcoma subtypes, the main benign adipocytic neoplasms: lipoblastoma, hibernoma, spindle/pleomorphic cell lipoma, chondroid lipoma, as well as non adipocytic neoplasms with a lipomatous component such as lipomatous solitary fibrous tumor, emphasizing on practical differential diagnosis issues, and immunohistochemical and molecular tools allowing their resolution.

  20. Runt-related Transcription Factor 1 (RUNX1) Stimulates Tumor Suppressor p53 Protein in Response to DNA Damage through Complex Formation and Acetylation*

    PubMed Central

    Wu, Dan; Ozaki, Toshinori; Yoshihara, Yukari; Kubo, Natsumi; Nakagawara, Akira

    2013-01-01

    Representative tumor suppressor p53 plays a critical role in the regulation of proper DNA damage response. In this study, we have found for the first time that Runt-related transcription factor 1 (RUNX1) contributes to p53-dependent DNA damage response. Upon adriamycin (ADR) exposure, p53 as well as RUNX1 were strongly induced in p53-proficient HCT116 and U2OS cells, which were closely associated with significant transactivation of p53 target genes, such as p21WAF1, BAX, NOXA, and PUMA. RUNX1 was exclusively expressed in the cell nucleus and formed a complex with p53 in response to ADR. Chromatin immunoprecipitation assay demonstrated that p53 together with RUNX1 are efficiently recruited onto p53 target gene promoters following ADR exposure, indicating that RUNX1 is involved in p53-mediated transcriptional regulation. Indeed, forced expression of RUNX1 stimulated the transcriptional activity of p53 in response to ADR. Consistent with these observations, knockdown of RUNX1 attenuated ADR-mediated induction of p53 target genes and suppressed ADR-dependent apoptosis. Furthermore, RUNX1 was associated with p300 histone acetyltransferase, and ADR-dependent acetylation of p53 at Lys-373/382 was markedly inhibited in RUNX1 knockdown cells. In addition, knockdown of RUNX1 resulted in a significant decrease in the amount of p53-p300 complex following ADR exposure. Taken together, our present results strongly suggest that RUNX1 is required for the stimulation of p53 in response to DNA damage and also provide novel insight into understanding the molecular mechanisms behind p53-dependent DNA damage response. PMID:23148227

  1. Wilms Tumor

    MedlinePlus

    ... diagnosis, and the condition, or histology , of the cancer cells when observed under a microscope. "Favorable" histology is associated with a good chance of a cure; tumors with "unfavorable" histology are more aggressive and ...

  2. Tumor Markers

    MedlinePlus

    ... types: Germ cell tumors, lymphoma, leukemia, melanoma, and neuroblastoma Tissue analyzed: Blood How used: To assess stage, ... NSE) Cancer types: Small cell lung cancer and neuroblastoma Tissue analyzed: Blood How used: To help in ...

  3. Comparative genetics of host response to N-methyl-N'-nitro-N-nitrosoguanidine. II. Inverse relationship between tumor susceptibility and salt-hydrocortisone conditioned acceleration of water turnover in rodents.

    PubMed

    Kodama, M; Inoue, F; Kodama, T; Kodama, M

    1992-01-01

    The purpose of this study was to investigate the nature of the action of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the modulator of gene expression. Practically, both the acceleration of daily liquid consumption following salt-hydrocortisone conditioning (sea water adaptation phenomenon) and the suppressive effect of MNNG on that gene expression were comparatively investigated among Wistar rats of both sexes, Buffalo rats of both sexes and Swiss/ICR mice of both sexes. Results obtained are as follows: 1) the responsiveness to the salt-hydrocortisone conditioning, as assessed in terms of weight-adjusted liquid consumption, decreased in the order of female Swiss mice greater than male Swiss mice greater than Buffalo rats of both sexes greater than female Wistar rats greater than male Wistar rats, a finding which indicates that an inverse relationship exists between the expression of the sea water adaptation gene and that of putative stomach proto-oncogene. 2) Additional MNNG conditioning (provision of MNNG drink) eradicated the accelerating effect of the salt-hydrocortisone conditioning on the water turnover of a rodent. 3) Evidence was presented to indicate that MNNG acted as an antiandrogen in expressing the above effect. In conclusion, our findings are taken as evidence to support the proposition that the sea water adaptation gene and the stomach proto-oncogene compete with each other in the possession of one common MNNG-sensitive (and/or steroid-sensitive) enhancer gene in their gene expressions.

  4. Retrorectal tumors.

    PubMed

    Bullard Dunn, Kelli

    2010-02-01

    Retrorectal or presacral tumors are rare and can be challenging to diagnose and treat. Because the retrorectal space contains multiple embryologic remnants derived from various tissues, the tumors that develop in this space are heterogeneous. Most lesions are benign, but malignant neoplasms are not uncommon. Lesions are classified as congenital, neurogenic, osseous, inflammatory, or miscellaneous. Although treatment depends on diagnosis and anatomic location, most retrorectal lesions will require surgical resection.

  5. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2006-04-18

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  6. Regulatory roles of tumor necrosis factor-alpha and interleukin-1 beta in monocyte chemoattractant protein-1-mediated pulmonary granuloma formation in the rat.

    PubMed Central

    Flory, C. M.; Jones, M. L.; Miller, B. F.; Warren, J. S.

    1995-01-01

    Intravenous infusion of particulate yeast cell wall glucan into rats results in the synchronous development of angiocentric pulmonary granulomas that are composed almost entirely of monocytes and macrophages. Previous studies indicate that locally produced monocyte chemoattractant protein-1 (MCP-1) is required for full granuloma development. Because tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) can induce MCP-1 production in a variety of cell types, we sought to determine their potential regulatory roles in this model. A single infusion of anti-TNF-alpha antibody at the time of glucan infusion (time 0) markedly reduced MCP-1 mRNA levels at 1 and 6 hours but not at later time points; there was no effect on granuloma size or number measured at 48 hours. When multiple infusions of anti-TNF-alpha antibody were administered over a 23-hour period (0 to 23 hours), MCP-1 mRNA was reduced through 24 hours, there was a significant reduction in peak bronchoalveolar lavage fluid MCP-1 activity at 48 hours, and there were marked reductions in granuloma size and number at 48 hours. Similar results were observed in animals that received infusions of anti-IL-1 beta. Infusion of anti-IL-1 beta at time 0 resulted in moderate reductions in MCP-1 mRNA at 1 and 6 hours and had no effect on granuloma size or number measured at 48 hours. When multiple infusions of anti-IL-1 beta were administered over a 23-hour period (0 to 23 hours), MCP-1 mRNA was reduced through 24 hours, there was a moderate reduction in peak bronchoalveolar lavage fluid MCP-1 activity at 48 hours, and there were marked reductions in granuloma size and number at 48 hours. A single infusion of anti-TNF-alpha and anti-IL-1 beta together at time 0 resulted in marked reductions in whole lung MCP-1 and mRNA at 1 and 6 hours, but not at 24 hours. Multiple combined infusions of anti-TNF-alpha and anti-IL-1 beta over a 23-hour period resulted in additive reductions in MCP-1 mRNA through 24 hours

  7. Accelerating Dynamic Magnetic Resonance Imaging (MRI) for Lung Tumor Tracking Based on Low-Rank Decomposition in the Spatial–Temporal Domain: A Feasibility Study Based on Simulation and Preliminary Prospective Undersampled MRI

    SciTech Connect

    Sarma, Manoj; Hu, Peng; Rapacchi, Stanislas; Ennis, Daniel; Thomas, Albert; Lee, Percy; Kupelian, Patrick; Sheng, Ke

    2014-03-01

    Purpose: To evaluate a low-rank decomposition method to reconstruct down-sampled k-space data for the purpose of tumor tracking. Methods and Materials: Seven retrospective lung cancer patients were included in the simulation study. The fully-sampled k-space data were first generated from existing 2-dimensional dynamic MR images and then down-sampled by 5 × -20 × before reconstruction using a Cartesian undersampling mask. Two methods, a low-rank decomposition method using combined dynamic MR images (k-t SLR based on sparsity and low-rank penalties) and a total variation (TV) method using individual dynamic MR frames, were used to reconstruct images. The tumor trajectories were derived on the basis of autosegmentation of the resultant images. To further test its feasibility, k-t SLR was used to reconstruct prospective data of a healthy subject. An undersampled balanced steady-state free precession sequence with the same undersampling mask was used to acquire the imaging data. Results: In the simulation study, higher imaging fidelity and low noise levels were achieved with the k-t SLR compared with TV. At 10 × undersampling, the k-t SLR method resulted in an average normalized mean square error <0.05, as opposed to 0.23 by using the TV reconstruction on individual frames. Less than 6% showed tracking errors >1 mm with 10 × down-sampling using k-t SLR, as opposed to 17% using TV. In the prospective study, k-t SLR substantially reduced reconstruction artifacts and retained anatomic details. Conclusions: Magnetic resonance reconstruction using k-t SLR on highly undersampled dynamic MR imaging data results in high image quality useful for tumor tracking. The k-t SLR was superior to TV by better exploiting the intrinsic anatomic coherence of the same patient. The feasibility of k-t SLR was demonstrated by prospective imaging acquisition and reconstruction.

  8. Role of mast cells in tumor growth.

    PubMed

    Conti, Pio; Castellani, Maria L; Kempuraj, Durasamy; Salini, Vincenzo; Vecchiet, Jacopo; Tetè, Stefano; Mastrangelo, Filiberto; Perrella, Alessandro; De Lutiis, Maria Anna; Tagen, Michael; Theoharides, Theoharis C

    2007-01-01

    The growth of malignant tumors is determined in large part by the proliferative capacity of the tumor cells. Clinical observations and animal experiments have established that tumor cells elicit immune responses. Histopathologic studies show that many tumors are surrounded by mononuclear cell and mast cell infiltrates. Mast cells are ubiquitous in the body and are critical for allergic reactions. Increasing evidence indicates that mast cells secrete proinflammatory cytokines and are involved in neuro-inflammatory processes and cancer. Mast cells accumulate in the stroma surrounding certain tumors, especially mammary adenocarcinoma, and the molecules they secrete can benefit the tumor. However, mast cells can also increase at the site of tumor growth and participate in tumor rejection. Mast cells may be recruited by tumor-derived chemoattractants and selectively secrete molecules such as growth factors, histamine, heparin, VEGF, and IL-8, as well as proteases that permit the formation of new blood vessels and metastases. Tumor mast cell intersections play regulatory and modulatory roles affecting various aspects of tumor growth. Discovery of these new roles of mast cells further complicates the understanding of tumor growth. This review focuses on the strategic importance of mast cells to the progression of tumors, and proposes a revised immune effector mechanism of mast cell involvement in tumor growth. PMID:18000287

  9. Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

    PubMed Central

    Choi, Suk Hyun; Lee, Jue Yeon; Suh, Jin Sook; Park, Yoon Shin; Chung, Chong Pyoung; Park, Yoon Jeong

    2016-01-01

    Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor’s phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment.

  10. Dual-function synthetic peptide derived from BMP4 for highly efficient tumor targeting and antiangiogenesis

    PubMed Central

    Choi, Suk Hyun; Lee, Jue Yeon; Suh, Jin Sook; Park, Yoon Shin; Chung, Chong Pyoung; Park, Yoon Jeong

    2016-01-01

    Angiogenesis plays a critical role in the growth and metastasis of cancer, and growth factors released from cancer promote blood-vessel formation in the tumor microenvironment. The angiogenesis is accelerated via interactions of growth factors with the high-affinity receptors on cancer cells. In particular, heparan sulfate proteoglycans (HSPGs) on the surface of cancer cells have been shown to be important in many aspects of determining a tumor’s phenotype and development. Specifically, the regulation of the interactions between HSPGs and growth factors results in changes in tumor progression. A peptide with heparin-binding (HBP) activity has been developed and synthesized to inhibit tumor growth via the prevention of angiogenesis. We hypothesized that HBP could inhibit the interaction of growth factors and HSPGs on the surface of cancer cells, decrease paracrine signaling in endothelial cells (ECs), and finally decrease angiogenesis in the tumor microenvironment. In this study, we found that HBP had antiangiogenic effects in vitro and in vivo. The conditioned media obtained from a breast cancer cell line treated with HBP were used to culture human umbilical vein ECs (HUVECs) to evaluate the antiangiogenic effect of HBP on ECs. HBP effectively inhibited the migration, invasion, and tube formation of HUVECs in vitro. In addition, the expressions of angiogenesis-mediating factors, including ERK, FAK, and Akt, were considerably decreased. HBP also decreased the levels of invasive factors, including MMP2 and MMP9, secreted by the HUVECs. We demonstrated significant suppression of tumor growth in a breast cancer xenograft model and enhanced distribution of HBP at the site of tumors. Taken together, our results show that HBP has antiangiogenic effects on ECs, and suggest that it may serve as a potential antitumor agent through control of the tumor microenvironment. PMID:27695323

  11. TURBULENT SHEAR ACCELERATION

    SciTech Connect

    Ohira, Yutaka

    2013-04-10

    We consider particle acceleration by large-scale incompressible turbulence with a length scale larger than the particle mean free path. We derive an ensemble-averaged transport equation of energetic charged particles from an extended transport equation that contains the shear acceleration. The ensemble-averaged transport equation describes particle acceleration by incompressible turbulence (turbulent shear acceleration). We find that for Kolmogorov turbulence, the turbulent shear acceleration becomes important on small scales. Moreover, using Monte Carlo simulations, we confirm that the ensemble-averaged transport equation describes the turbulent shear acceleration.

  12. The direction of acceleration

    NASA Astrophysics Data System (ADS)

    Wilhelm, Thomas; Burde, Jan-Philipp; Lück, Stephan

    2015-11-01

    Acceleration is a physical quantity that is difficult to understand and hence its complexity is often erroneously simplified. Many students think of acceleration as equivalent to velocity, a ˜ v. For others, acceleration is a scalar quantity, which describes the change in speed Δ|v| or Δ|v|/Δt (as opposed to the change in velocity). The main difficulty with the concept of acceleration therefore lies in developing a correct understanding of its direction. The free iOS app AccelVisu supports students in acquiring a correct conception of acceleration by showing acceleration arrows directly at moving objects.

  13. Deregulated proliferation and differentiation in brain tumors

    PubMed Central

    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

  14. Interaction of tumor cells with the microenvironment

    PubMed Central

    2011-01-01

    Recent advances in tumor biology have revealed that a detailed analysis of the complex interactions of tumor cells with their adjacent microenvironment (tumor stroma) is mandatory in order to understand the various mechanisms involved in tumor growth and the development of metastasis. The mutual interactions between tumor cells and cellular and non-cellular components (extracellular matrix = ECM) of the tumor microenvironment will eventually lead to a loss of tissue homeostasis and promote tumor development and progression. Thus, interactions of genetically altered tumor cells and the ECM on the one hand and reactive non-neoplastic cells on the other hand essentially control most aspects of tumorigenesis such as epithelial-mesenchymal-transition (EMT), migration, invasion (i.e. migration through connective tissue), metastasis formation, neovascularisation, apoptosis and chemotherapeutic drug resistance. In this mini-review we will focus on these issues that were recently raised by two review articles in CCS. PMID:21914164

  15. Superior sulcus tumors (Pancoast tumors).

    PubMed

    Marulli, Giuseppe; Battistella, Lucia; Mammana, Marco; Calabrese, Francesca; Rea, Federico

    2016-06-01

    Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horner's syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach.

  16. Superior sulcus tumors (Pancoast tumors).

    PubMed

    Marulli, Giuseppe; Battistella, Lucia; Mammana, Marco; Calabrese, Francesca; Rea, Federico

    2016-06-01

    Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horner's syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach. PMID:27429965

  17. Superior sulcus tumors (Pancoast tumors)

    PubMed Central

    Battistella, Lucia; Mammana, Marco; Calabrese, Francesca; Rea, Federico

    2016-01-01

    Superior Sulcus Tumors, frequently termed as Pancoast tumors, are a wide range of tumors invading the apical chest wall. Due to its localization in the apex of the lung, with the potential invasion of the lower part of the brachial plexus, first ribs, vertebrae, subclavian vessels or stellate ganglion, the superior sulcus tumors cause characteristic symptoms, like arm or shoulder pain or Horner’s syndrome. The management of superior sulcus tumors has dramatically evolved over the past 50 years. Originally deemed universally fatal, in 1956, Shaw and Paulson introduced a new treatment paradigm with combined radiotherapy and surgery ensuring 5-year survival of approximately 30%. During the 1990s, following the need to improve systemic as well as local control, a trimodality approach including induction concurrent chemoradiotherapy followed by surgical resection was introduced, reaching 5-year survival rates up to 44% and becoming the standard of care. Many efforts have been persecuted, also, to obtain higher complete resection rates using appropriate surgical approaches and involving multidisciplinary team including spine surgeon or vascular surgeon. Other potential treatment options are under consideration like prophylactic cranial irradiation or the addition of other chemotherapy agents or biologic agents to the trimodality approach. PMID:27429965

  18. Genetically Engineered Mouse Models of Pituitary Tumors

    PubMed Central

    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

  19. [Proton therapy and particle accelerators].

    PubMed

    Fukumoto, Sadayoshi

    2012-01-01

    Since the high energy accelerator plan was changed from a 40 GeV direct machine to a 12GeV cascade one, a 500 MeV rapid cycling booster synchrotron was installed between the injector linac and the 12 GeV main ring at KEK, National Lab. for High Energy Physics. The booster beams were used not only for injection to the main ring but also for medical use. Their energy was reduced to 250 MeV by a graphite block for clinical trial of cancer therapy. In 1970's, pi(-) or heavy ions were supposed to be promising. Although advantage of protons with Bragg Peak was pointed out earlier, they seemed effective only for eye melanoma at that time. In early 1980's, it was shown that they were effective for deep-seated tumor by Tsukuba University with KEK beams. The first dedicated facility was built at Loma Linda University Medical Center. Its synchrotron was made by Fermi National Accelerator Lab. Since a non-resonant accelerating rf cavity was installed, operation of the synchrotron became much easier. Later, innovation of the cyclotron was achieved. Its weight was reduced from 1,000 ton to 200 ton. Some of the cyclotrons are equipped with superconducting coils.

  20. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis Accelerates the Progression of Renal Fibrosis in Lupus Nephritis by Activating SMAD and p38 MAPK in TGF-β1 Signaling Pathway

    PubMed Central

    Liu, Zhiqin; Xue, Leixi; Liu, Zhichun; Huang, Jun; Wen, Jian; Hu, Ji; Bo, Lin; Yang, Ru

    2016-01-01

    This study aim was to explore the effects of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis and its potential underlying mechanisms. MRL/lpr mice were used for in vivo experiments and human proximal tubular cells (HK2 cells) were used for in vitro experiments. Results showed that MRL/lpr mice treated with vehicle solution or LV-Control shRNA displayed significant proteinuria and severe renal histopathological changes. LV-TWEAK-shRNA treatment reversed these changes and decreased renal expressions of TWEAK, TGF-β1, p-p38 MAPK, p-Smad2, COL-1, and α-SMA proteins. In vitro, hTWEAK treatment upregulated the expressions of TGF-β1, p-p38 MAPK, p-SMAD2, α-SMA, and COL-1 proteins in HK2 cells and downregulated the expressions of E-cadherin protein, which were reversed by cotreatment with anti-TWEAK mAb or SB431542 treatment. These findings suggest that TWEAK may contribute to chronic renal changes and renal fibrosis by activating TGF-β1 signaling pathway, and phosphorylation of Smad2 and p38 MAPK proteins was also involved in this signaling pathway. PMID:27365897

  1. Tumor Necrosis Factor-stimulated Gene-6 (TSG-6) Is Constitutively Expressed in Adult Central Nervous System (CNS) and Associated with Astrocyte-mediated Glial Scar Formation following Spinal Cord Injury*

    PubMed Central

    Coulson-Thomas, Vivien J.; Lauer, Mark E.; Soleman, Sara; Zhao, Chao; Hascall, Vincent C.; Day, Anthony J.; Fawcett, James W.

    2016-01-01

    Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6) binds to hyaluronan and can reorganize/stabilize its structure, also enhancing the binding of this glycosaminoglycan to its cell surface receptor, CD44. TSG-6 is rapidly up-regulated in response to inflammatory cytokines protecting tissues from the damaging effects of inflammation. Despite TSG-6 treatment having been shown to improve outcomes in an experimental model of traumatic brain injury, TSG-6 expression has not been extensively studied in the central nervous system (CNS). We hereby analyzed the expression profile of TSG-6 in the developing CNS and following injury. We show that TSG-6 is expressed in the rat CNS by GFAP+ and CD44+ astrocytes, solely in the mature brain and spinal cord, and is not present during the development of the CNS. TSG-6−/− mice present a reduced number of GFAP+ astrocytes when compared with the littermate TSG-6+/− mice. TSG-6 expression is drastically up-regulated after injury, and the TSG-6 protein is present within the glial scar, potentially coordinating and stabilizing the formation of this hyaluronan-rich matrix. This study shows that TSG-6 is expressed in the CNS, suggesting a role for TSG-6 in astrocyte activation and tissue repair. We hypothesize that within this context TSG-6 could participate in the formation of the glial scar and confer anti-inflammatory properties. Further studies are required to elucidate the therapeutic potential of targeting TSG-6 after CNS injury to promote its protective effects while reducing the inhibitory properties of the glial scar in axon regeneration. PMID:27435674

  2. Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome.

    PubMed

    Menendez, Javier A; Folguera-Blasco, Núria; Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Joven, Jorge; Alarcón, Tomás

    2016-03-15

    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

  3. Accelerated geroncogenesis in hereditary breast-ovarian cancer syndrome

    PubMed Central

    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

  4. Promotion of lung tumors in mice

    SciTech Connect

    Witschi, H.P.

    1981-01-01

    Several elements of two-stage carcinogenesis apply to the development of lung tumors in mice. At least three agents, identified as promoters, will also enhance tumor formation in lung: phorbol, saccharin, and butylated hydroxytoluene (BHT). The antioxidant BHT is effective only if animals are treated after exposure to an initiating agent. Administration can be delayed up to 5 months after urethan treatment and still enhance tumor formation. BHT enhances lung tumor formation regardless of its route of administration. The lowest dose required to produce an effect has not yet been determined. In at least one mouse strain, BHT also enhances tumor formation in animals initiated with 3-methylcholanthren or diethylnitrosaine. No evidence is available yet to show that BHT would enhance tumor development in animals treated with subcarcinogenic doses of an initiating compound. Nor has it been possible to produce more tumors with BHT in mouse strains which have a low spontaneous tumor incidence and respond poorly to urethan. Neveretheless, the data collected on the effects of BHT on mouse lung tumor development have broadened the concept of two-stage carcinogenesis and complement the evidence for initiation-promotion available for other epithelial tissues. (ERB)

  5. Accelerating Particles with Plasma

    SciTech Connect

    Litos, Michael; Hogan, Mark

    2014-11-05

    Researchers at SLAC explain how they use plasma wakefields to accelerate bunches of electrons to very high energies over only a short distance. Their experiments offer a possible path for the future of particle accelerators.

  6. Accelerator Technology Division

    NASA Astrophysics Data System (ADS)

    1992-04-01

    In fiscal year (FY) 1991, the Accelerator Technology (AT) division continued fulfilling its mission to pursue accelerator science and technology and to develop new accelerator concepts for application to research, defense, energy, industry, and other areas of national interest. This report discusses the following programs: The Ground Test Accelerator Program; APLE Free-Electron Laser Program; Accelerator Transmutation of Waste; JAERI, OMEGA Project, and Intense Neutron Source for Materials Testing; Advanced Free-Electron Laser Initiative; Superconducting Super Collider; The High-Power Microwave Program; (Phi) Factory Collaboration; Neutral Particle Beam Power System Highlights; Accelerator Physics and Special Projects; Magnetic Optics and Beam Diagnostics; Accelerator Design and Engineering; Radio-Frequency Technology; Free-Electron Laser Technology; Accelerator Controls and Automation; Very High-Power Microwave Sources and Effects; and GTA Installation, Commissioning, and Operations.

  7. Linear accelerator: A concept

    NASA Technical Reports Server (NTRS)

    Mutzberg, J.

    1972-01-01

    Design is proposed for inexpensive accelerometer which would work by applying pressure to fluid during acceleration. Pressure is used to move shuttle, and shuttle movement is sensed and calibrated to give acceleration readings.

  8. Improved plasma accelerator

    NASA Technical Reports Server (NTRS)

    Cheng, D. Y.

    1971-01-01

    Converging, coaxial accelerator electrode configuration operates in vacuum as plasma gun. Plasma forms by periodic injections of high pressure gas that is ionized by electrical discharges. Deflagration mode of discharge provides acceleration, and converging contours of plasma gun provide focusing.

  9. MEQALAC rf accelerating structure

    SciTech Connect

    Keane, J.; Brodowski, J.

    1981-01-01

    A prototype MEQALAC capable of replacing the Cockcroft Walton pre-injector at BNL is being fabricated. Ten milliamperes of H/sup -/ beam supplied from a source sitting at a potential of -40 kilovolt is to be accelerated to 750 keV. This energy gain is provided by a 200 Megahertz accelerating system rather than the normal dc acceleration. Substantial size and cost reduction would be realized by such a system over conventional pre-accelerator systems.

  10. Acceleration gradient of a plasma wakefield accelerator

    SciTech Connect

    Uhm, Han S.

    2008-02-25

    The phase velocity of the wakefield waves is identical to the electron beam velocity. A theoretical analysis indicates that the acceleration gradient of the wakefield accelerator normalized by the wave breaking amplitude is K{sub 0}({xi})/K{sub 1}({xi}), where K{sub 0}({xi}) and K{sub 1}({xi}) are the modified Bessel functions of the second kind of order zero and one, respectively and {xi} is the beam parameter representing the beam intensity. It is also shown that the beam density must be considerably higher than the diffuse plasma density for the large radial velocity of plasma electrons that are required for a high acceleration gradient.

  11. Accelerated glass reaction under PCT conditions

    SciTech Connect

    Ebert, W.L.; Bates, J.K.; Buck, E.C.; Bradley, C.R.

    1992-01-01

    Static leach tests similar to PCT (Product Consistency Test) were performed for up to 2 years to assess long-term reaction behavior of high-level nuclear waste glasses similar to those at Defense Waste Processing Facility. These tests show the reaction rate to decrease with the reaction time from an initially high rate to a low rate, but then to accelerate to a higher rate after reaction times of about 1 year, depending on glass surface area/leachant volume ratio used. Solution concentrations of soluble glass components increase as the reaction is accelerated, while release of other glass components into solution is controlled by secondary phases. Net result is that transformation of glass to stable phases is accelerated while the solution becomes enriched in soluble components not effectively contained in secondary phases. Rate becomes linear in time after the acceleration and may be similar to the initial forward rate. A current model of glass reaction predicts that the glass reaction will be accelerated upon the formation of secondary phases which lower the silicic acid solution concentration. These tests show total Si concentration to increase upon reaction acceleration, however, which may be due to the slightly higher pH attained with the acceleration. The sudden change in the reaction rate is likely due to secondary phase formation. 17 refs, 2 tabs, 3 figs.

  12. Accelerated glass reaction under PCT conditions

    SciTech Connect

    Ebert, W.L.; Bates, J.K.; Buck, E.C.; Bradley, C.R.

    1992-12-31

    Static leach tests similar to PCT (Product Consistency Test) were performed for up to 2 years to assess long-term reaction behavior of high-level nuclear waste glasses similar to those at Defense Waste Processing Facility. These tests show the reaction rate to decrease with the reaction time from an initially high rate to a low rate, but then to accelerate to a higher rate after reaction times of about 1 year, depending on glass surface area/leachant volume ratio used. Solution concentrations of soluble glass components increase as the reaction is accelerated, while release of other glass components into solution is controlled by secondary phases. Net result is that transformation of glass to stable phases is accelerated while the solution becomes enriched in soluble components not effectively contained in secondary phases. Rate becomes linear in time after the acceleration and may be similar to the initial forward rate. A current model of glass reaction predicts that the glass reaction will be accelerated upon the formation of secondary phases which lower the silicic acid solution concentration. These tests show total Si concentration to increase upon reaction acceleration, however, which may be due to the slightly higher pH attained with the acceleration. The sudden change in the reaction rate is likely due to secondary phase formation. 17 refs, 2 tabs, 3 figs.

  13. Tumor-associated macrophages and anti-tumor therapies: complex links.

    PubMed

    Belgiovine, Cristina; D'Incalci, Maurizio; Allavena, Paola; Frapolli, Roberta

    2016-07-01

    Myeloid cells infiltrating the tumor microenvironment, especially tumor-associated macrophages (TAMs), are essential providers of cancer-related inflammation, a condition known to accelerate tumor progression and limit the response to anti-tumor therapies. As a matter of fact, TAMs may have a dual role while interfering with cancer treatments, as they can either promote or impair their functionality. Here we review the connection between macrophages and anticancer therapies; moreover, we provide an overview of the different strategies to target or re-program TAMs for therapeutic purposes. PMID:26956893

  14. Acceleration: It's Elementary

    ERIC Educational Resources Information Center

    Willis, Mariam

    2012-01-01

    Acceleration is one tool for providing high-ability students the opportunity to learn something new every day. Some people talk about acceleration as taking a student out of step. In actuality, what one is doing is putting a student in step with the right curriculum. Whole-grade acceleration, also called grade-skipping, usually happens between…

  15. Far field acceleration

    SciTech Connect

    Fernow, R.C.

    1995-07-01

    Far fields are propagating electromagnetic waves far from their source, boundary surfaces, and free charges. The general principles governing the acceleration of charged particles by far fields are reviewed. A survey of proposed field configurations is given. The two most important schemes, Inverse Cerenkov acceleration and Inverse free electron laser acceleration, are discussed in detail.

  16. Angular Acceleration without Torque?

    ERIC Educational Resources Information Center

    Kaufman, Richard D.

    2012-01-01

    Hardly. Just as Robert Johns qualitatively describes angular acceleration by an internal force in his article "Acceleration Without Force?" here we will extend the discussion to consider angular acceleration by an internal torque. As we will see, this internal torque is due to an internal force acting at a distance from an instantaneous center.

  17. Linear Accelerator (LINAC)

    MedlinePlus

    ... is the device most commonly used for external beam radiation treatments for patients with cancer. The linear ... shape of the patient's tumor and the customized beam is directed to the patient's tumor. The beam ...

  18. Tumor Bioengineering Using a Transglutaminase Crosslinked Hydrogel

    PubMed Central

    Fang, Josephine Y.; Tan, Shih-Jye; Yang, Zhi; Tayag, Charisse; Han, Bo

    2014-01-01

    Development of a physiologically relevant 3D model system for cancer research and drug development is a current challenge. We have adopted a 3D culture system based on a transglutaminase-crosslinked gelatin gel (Col-Tgel) to mimic the tumor 3D microenvironment. The system has several unique advantages over other alternatives including presenting cell-matrix interaction sites from collagen-derived peptides, geometry-initiated multicellular tumor spheroids, and metabolic gradients in the tumor microenvironment. Also it provides a controllable wide spectrum of gel stiffness for mechanical signals, and technical compatibility with imaging based screening due to its transparent properties. In addition, the Col-Tgel provides a cure-in-situ delivery vehicle for tumor xenograft formation in animals enhancing tumor cell uptake rate. Overall, this distinctive 3D system could offer a platform to more accurately mimic in vivo situations to study tumor formation and progression both in vitro and in vivo. PMID:25133673

  19. [Research advance on clinical blood transfusion and tumor therapy].

    PubMed

    Jiang, Xue-Bing; Zhang, Li-Ping; Wang, Yan-Ju; Ma, Cong

    2010-08-01

    Clinical blood transfusion is one of the most important supportive therapy for patients with tumor. The blood transfusion has dual effects for patients with tumor. First, blood transfusion can rectify anemia and improve oxygen saturation, accelerate oxidation and necrosis for tumor cells; the second, blood transfusion can induce immunosuppression, tumor recurrence and postoperative infection for tumor patients. Filtering white blood cells (WBC) before blood transfusion can decrease the incidence of the adverse reactions. The rational perioperative autotransfusion for patients with tumors is focus to which the world medical sciences pay close attention. In this article, the support effect of blood transfusion for treatment of tumor patients, blood transfusion and immunosuppression, blood transfusion and postoperative infection and relapse of tumor patients, depleted leukocyte blood transfusion and autologous transfusion of tumor patients are reviewed.

  20. Compact Plasma Accelerator

    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.

  1. Naked singularities as particle accelerators

    SciTech Connect

    Patil, Mandar; Joshi, Pankaj S.

    2010-11-15

    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 energy of collision in the center of mass frame will be arbitrarily high, thus offering a window to Planck scale physics.

  2. High brightness electron accelerator

    DOEpatents

    Sheffield, Richard L.; Carlsten, Bruce E.; Young, Lloyd M.

    1994-01-01

    A compact high brightness linear accelerator is provided for use, e.g., in a free electron laser. The accelerator has a first plurality of acclerating cavities having end walls with four coupling slots for accelerating electrons to high velocities in the absence of quadrupole fields. A second plurality of cavities receives the high velocity electrons for further acceleration, where each of the second cavities has end walls with two coupling slots for acceleration in the absence of dipole fields. The accelerator also includes a first cavity with an extended length to provide for phase matching the electron beam along the accelerating cavities. A solenoid is provided about the photocathode that emits the electons, where the solenoid is configured to provide a substantially uniform magnetic field over the photocathode surface to minimize emittance of the electons as the electrons enter the first cavity.

  3. Fiber Accelerating Structures

    SciTech Connect

    Hammond, Andrew P.; /Reed Coll. /SLAC

    2010-08-25

    One of the options for future particle accelerators are photonic band gap (PBG) fiber accelerators. PBG fibers are specially designed optical fibers that use lasers to excite an electric field that is used to accelerate electrons. To improve PBG accelerators, the basic parameters of the fiber were tested to maximize defect size and acceleration. Using the program CUDOS, several accelerating modes were found that maximized these parameters for several wavelengths. The design of multiple defects, similar to having closely bound fibers, was studied to find possible coupling or the change of modes. The amount of coupling was found to be dependent on distance separated. For certain distances accelerating coupled modes were found and examined. In addition, several non-periodic fiber structures were examined using CUDOS. The non-periodic fibers produced several interesting results and promised more modes given time to study them in more detail.

  4. Acceleration in astrophysics

    SciTech Connect

    Colgate, S.A.

    1993-12-31

    The origin of cosmic rays and applicable laboratory experiments are discussed. Some of the problems of shock acceleration for the production of cosmic rays are discussed in the context of astrophysical conditions. These are: The presumed unique explanation of the power law spectrum is shown instead to be a universal property of all lossy accelerators; the extraordinary isotropy of cosmic rays and the limited diffusion distances implied by supernova induced shock acceleration requires a more frequent and space-filling source than supernovae; the near perfect adiabaticity of strong hydromagnetic turbulence necessary for reflecting the accelerated particles each doubling in energy roughly 10{sup 5} to {sup 6} scatterings with negligible energy loss seems most unlikely; the evidence for acceleration due to quasi-parallel heliosphere shocks is weak. There is small evidence for the expected strong hydromagnetic turbulence, and instead, only a small number of particles accelerate after only a few shock traversals; the acceleration of electrons in the same collisionless shock that accelerates ions is difficult to reconcile with the theoretical picture of strong hydromagnetic turbulence that reflects the ions. The hydromagnetic turbulence will appear adiabatic to the electrons at their much higher Larmor frequency and so the electrons should not be scattered incoherently as they must be for acceleration. Therefore the electrons must be accelerated by a different mechanism. This is unsatisfactory, because wherever electrons are accelerated these sites, observed in radio emission, may accelerate ions more favorably. The acceleration is coherent provided the reconnection is coherent, in which case the total flux, as for example of collimated radio sources, predicts single charge accelerated energies much greater than observed.

  5. Brain tumor (image)

    MedlinePlus

    Brain tumors are classified depending on the exact site of the tumor, the type of tissue involved, benign ... tendencies of the tumor, and other factors. Primary brain tumors can arise from the brain cells, the meninges ( ...

  6. Understanding Brain Tumors

    MedlinePlus

    ... to Know About Brain Tumors . What is a Brain Tumor? A brain tumor is an abnormal growth
 ... Tumors” from Frankly Speaking Frankly Speaking About Cancer: Brain Tumors Download the full book Questions to ask ...

  7. Brain Tumor Diagnosis

    MedlinePlus

    ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ... Types of Brain Scans X-rays Laboratory Tests DNA Profiling Biopsy Procedure Malignant and Benign Brain Tumors Tumor ...

  8. The miR-24-Bim pathway promotes tumor growth and angiogenesis in pancreatic carcinoma.

    PubMed

    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.

  9. 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.

  10. ELECTROMAGNETIC SIMULATIONS OF LINEAR PROTON ACCELERATOR STRUCTURES USING DIELECTRIC WALL ACCELERATORS

    SciTech Connect

    Nelson, S; Poole, B; Caporaso, G

    2007-06-15

    Proton accelerator structures for medical applications using Dielectric Wall Accelerator (DWA) technology allow for the utilization of high electric field gradients on the order of 100 MV/m to accelerate the proton bunch. Medical applications involving cancer therapy treatment usually desire short bunch lengths on the order of hundreds of picoseconds in order to limit the extent of the energy deposited in the tumor site (in 3D space, time, and deposited proton charge). Electromagnetic simulations of the DWA structure, in combination with injections of proton bunches have been performed using 3D finite difference codes in combination with particle pushing codes. Electromagnetic simulations of DWA structures includes these effects and also include the details of the switch configuration and how that switch time affects the electric field pulse which accelerates the particle beam.

  11. KLF10, transforming growth factor-{beta}-inducible early gene 1, acts as a tumor suppressor

    SciTech Connect

    Song, Ki-Duk; Kim, Duk-Jung; Lee, Jong Eun; Yun, Cheol-Heui; Lee, Woon Kyu

    2012-03-09

    Highlights: Black-Right-Pointing-Pointer KLF10{sup -/-} mice exhibited accelerated papilloma development after DMBA/TPA treatment. Black-Right-Pointing-Pointer KLF10{sup -/-} keratinocytes showed increased proliferation and apoptosis. Black-Right-Pointing-Pointer KLF10{sup -/-} MEFs yielded more colonies than wild-type one with H-Ras transfection. Black-Right-Pointing-Pointer KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription. Black-Right-Pointing-Pointer KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription. -- Abstract: Krueppel-like factor 10 (KLF10) has been suggested to be a putative tumor suppressor. In the present study, we generated KLF10 deficient mice to explore this hypothesis in vivo. KLF10 deficient mice exhibited increased predisposition to skin tumorigenesis and markedly accelerated papilloma development after DMBA/TPA treatment. On the other hand, KLF10 deficient keratinocytes showed increased proliferation and apoptosis. In colony formation assays after oncogenic H-Ras transfection, KLF10 deficient mouse embryonic fibroblasts (MEFs) yielded more colonies than wild-type MEFs. Furthermore, KLF10 dose-dependently activated p21{sup WAF1/CIP1} transcription, which was independent of p53 and Sp1 binding sites in p21{sup WAF1/CIP1} promoter. This study demonstrates that KLF10 is a tumor suppressor and that it targets p21{sup WAF1/CIP1} transcription.

  12. Brain Tumor Symptoms

    MedlinePlus

    ... Types of Tumors Risk Factors Brain Tumor Statistics Brain Tumor Dictionary Webinars Anytime Learning About Us Our Founders Board of Directors Staff ... Types of Tumors Risk Factors Brain Tumor Statistics Brain Tumor Dictionary Webinars Anytime Learning Donate to the ABTA Help advance the understanding ...

  13. [Tumor surgery].

    PubMed

    Hausamen, J E

    2000-05-01

    Surgery is still the primary therapeutic approach in treatment of tumors in the head and neck area, dating back to the early nineteenth century. More than 150 years ago, hemimaxillectomies and mandibular resections as well as hemiglossectomies were already performed by leading surgeons. The block principle we are now following dates back to Crile, who also established the principle of cervical lymph node dissection. Ablative oncologic surgery has always been closely linked with plastic and reconstructive surgery, rendering radical surgical interventions possible without disfiguring patients. The development of facial reconstructive surgery proceeded in stages, in the first instance as secondary reconstruction using tube pedicled flaps. The change to the concept of primary reconstruction occurred via arterialized skin flaps and myocutaneous flaps to the widely accepted and performed free tissue transfer. Free bone grafting, inaugurated earlier and still representing the majority of bone grafting, has been supplemented for certain reconstructive purposes by free vascularized bone transfer from various donor sites. Although the five-year-survival rate of carcinoma of the oral cavity has remained unchanged in the past 30 years, distinctive improvements in tumor surgery can be recorded. This is primarily based on improved diagnostics such as modern imaging techniques and the refinement of surgical techniques. The DOSAK has worked out distinctive guidelines for effective ablative oncologic surgery. Surgical approaches offering wide exposure and carrying low morbidity play a decisive role in radical resections. For this reason, midfacial degloving offers an essential improvement for the resection of midface tumors, especially from an aesthetic point of view. Tumors situated deep behind the viscerocranium at the skull base can be clearly exposed either through a lateral approach following a temporary osteotomy of the mandibular ramus or a transmandibular, transmaxillar, or

  14. The Dielectric Wall Accelerator

    SciTech Connect

    Caporaso, George J.; Chen, Yu-Jiuan; Sampayan, Stephen E.

    2009-01-01

    The Dielectric Wall Accelerator (DWA), a class of induction accelerators, employs a novel insulating beam tube to impress a longitudinal electric field on a bunch of charged particles. The surface flashover characteristics of this tube may permit the attainment of accelerating gradients on the order of 100 MV/m for accelerating pulses on the order of a nanosecond in duration. A virtual traveling wave of excitation along the tube is produced at any desired speed by controlling the timing of pulse generating modules that supply a tangential electric field to the tube wall. Because of the ability to control the speed of this virtual wave, the accelerator is capable of handling any charge to mass ratio particle; hence it can be used for electrons, protons and any ion. The accelerator architectures, key technologies and development challenges will be described.

  15. Switched matrix accelerator

    SciTech Connect

    Whittum, David H.; Tantawi, Sami G.

    2001-01-01

    We describe a new concept for a microwave circuit functioning as a charged-particle accelerator at mm wavelengths, permitting an accelerating gradient higher than conventional passive circuits can withstand consistent with cyclic fatigue. The device provides acceleration for multiple bunches in parallel channels, and permits a short exposure time for the conducting surface of the accelerating cavities. Our analysis includes scalings based on a smooth transmission line model and a complementary treatment with a coupled-cavity simulation. We also provide an electromagnetic design for the accelerating structure, arriving at rough dimensions for a seven-cell accelerator matched to standard waveguide and suitable for bench tests at low power in air at 91.392 GHz. A critical element in the concept is a fast mm-wave switch suitable for operation at high power, and we present the considerations for implementation in an H-plane tee. We discuss the use of diamond as the photoconductor switch medium.

  16. Switched Matrix Accelerator

    SciTech Connect

    Whittum, David H

    2000-10-04

    We describe a new concept for a microwave circuit functioning as a charged-particle accelerator at mm-wavelengths, permitting an accelerating gradient higher than conventional passive circuits can withstand consistent with cyclic fatigue. The device provides acceleration for multiple bunches in parallel channels, and permits a short exposure time for the conducting surface of the accelerating cavities. Our analysis includes scalings based on a smooth transmission line model and a complementary treatment with a coupled-cavity simulation. We provide also an electromagnetic design for the accelerating structure, arriving at rough dimensions for a seven-cell accelerator matched to standard waveguide and suitable for bench tests at low power in air at 91.392. GHz. A critical element in the concept is a fast mm-wave switch suitable for operation at high-power, and we present the considerations for implementation in an H-plane tee. We discuss the use of diamond as the photoconductor switch medium.

  17. Familial pituitary tumors.

    PubMed

    Alband, Neda; Korbonits, Márta

    2014-01-01

    Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern due to hormone overproduction and/or tumor mass effects. The majority of pituitary adenomas occur sporadically; however, familial cases are increasingly being recognized, such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and familial isolated pituitary adenoma (FIPA). Familial pituitary tumors appear to differ from their sporadic counterparts both in their genetic basis and in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, tumors are more aggressive and affect patients at a younger age, therefore justifying the importance of early diagnosis, while in Carney complex pituitary hyperplasia is common. The genetic alterations responsible for the formation of familial pituitary syndromes include the MEN1 gene, responsible for about 80% of MEN1 cases, the regulatory subunit of the protein kinase A, PRKAR1A, responsible for about 70% of Carney complex cases, and AIP, the gene coding the aryl hydrocarbon receptor interacting protein, responsible for about 20% of FIPA cases. Rarely other genes have also been found responsible for familial pituitary adenoma cases. McCune-Albright syndrome (MAS) also has a genetic origin due to mosaic mutations in the G protein-coupled α subunit coded by the GNAS1 gene. In this chapter, we summarize the genetic and clinical characteristics of these familial pituitary syndromes and MAS. PMID:25248598

  18. Wake field accelerators

    SciTech Connect

    Wilson, P.B.

    1986-02-01

    In a wake field accelerator a high current driving bunch injected into a structure or plasma produces intense induced fields, which are in turn used to accelerate a trailing charge or bunch. The basic concepts of wake field acceleration are described. Wake potentials for closed cavities and periodic structures are derived, as are wake potentials on a collinear path with a charge distribution. Cylindrically symmetric structures excited by a beam in the form of a ring are considered. (LEW)

  19. ACCELERATION RESPONSIVE SWITCH

    DOEpatents

    Chabrek, A.F.; Maxwell, R.L.

    1963-07-01

    An acceleration-responsive device with dual channel capabilities whereby a first circuit is actuated upon attainment of a predetermined maximum acceleration level and when the acceleration drops to a predetermined minimum acceleriltion level another circuit is actuated is described. A fluid-damped sensing mass slidably mounted in a relatively frictionless manner on a shaft through the intermediation of a ball bushing and biased by an adjustable compression spring provides inertially operated means for actuating the circuits. (AEC)

  20. Optically pulsed electron accelerator

    DOEpatents

    Fraser, John S.; Sheffield, Richard L.

    1987-01-01

    An optically pulsed electron accelerator can be used as an injector for a free electron laser and comprises a pulsed light source, such as a laser, for providing discrete incident light pulses. A photoemissive electron source emits electron bursts having the same duration as the incident light pulses when impinged upon by same. The photoemissive electron source is located on an inside wall of a radio frequency powered accelerator cell which accelerates the electron burst emitted by the photoemissive electron source.

  1. Optically pulsed electron accelerator

    DOEpatents

    Fraser, J.S.; Sheffield, R.L.

    1985-05-20

    An optically pulsed electron accelerator can be used as an injector for a free electron laser and comprises a pulsed light source, such as a laser, for providing discrete incident light pulses. A photoemissive electron source emits electron bursts having the same duration as the incident light pulses when impinged upon by same. The photoemissive electron source is located on an inside wall of a radiofrequency-powered accelerator cell which accelerates the electron burst emitted by the photoemissive electron source.

  2. Tumor sialylation impedes T cell mediated anti-tumor responses while promoting tumor associated-regulatory T cells.

    PubMed

    Perdicchio, Maurizio; Cornelissen, Lenneke A M; Streng-Ouwehand, Ingeborg; Engels, Steef; Verstege, Marleen I; Boon, Louis; Geerts, Dirk; van Kooyk, Yvette; Unger, Wendy W J

    2016-02-23

    The increased presence of sialylated glycans on the tumor surface has been linked to poor prognosis, yet the effects on tumor-specific T cell immunity are hardly studied. We here show that hypersialylation of B16 melanoma substantially influences tumor growth by preventing the formation of effector T cells and facilitating the presence of high regulatory T cell (Treg) frequencies. Knock-down of the sialic acid transporter created "sialic acid low" tumors, that grew slower in-vivo than hypersialylated tumors, altered the Treg/Teffector balance, favoring immunological tumor control. The enhanced effector T cell response in developing "sialic acid low" tumors was preceded by and dependent on an increased influx and activity of Natural Killer (NK) cells. Thus, tumor hypersialylation orchestrates immune escape at the level of NK and Teff/Treg balance within the tumor microenvironment, herewith dampening tumor-specific T cell control. Reducing sialylation provides a therapeutic option to render tumors permissive to immune attack. PMID:26741508

  3. Acceleration of polarized protons in circular accelerators

    SciTech Connect

    Courant, E.D.; Ruth, R.D.

    1980-09-12

    The theory of depolarization in circular accelerators is presented. The spin equation is first expressed in terms of the particle orbit and then converted to the equivalent spinor equation. The spinor equation is then solved for three different situations: (1) a beam on a flat top near a resonance, (2) uniform acceleration through an isolated resonance, and (3) a model of a fast resonance jump. Finally, the depolarization coefficient, epsilon, is calculated in terms of properties of the particle orbit and the results are applied to a calculation of depolarization in the AGS.

  4. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-01-01

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  5. Particle acceleration in flares

    NASA Technical Reports Server (NTRS)

    Benz, Arnold O.; Kosugi, Takeo; Aschwanden, Markus J.; Benka, Steve G.; Chupp, Edward L.; Enome, Shinzo; Garcia, Howard; Holman, Gordon D.; Kurt, Victoria G.; Sakao, Taro

    1994-01-01

    Particle acceleration is intrinsic to the primary energy release in the impulsive phase of solar flares, and we cannot understand flares without understanding acceleration. New observations in soft and hard X-rays, gamma-rays and coherent radio emissions are presented, suggesting flare fragmentation in time and space. X-ray and radio measurements exhibit at least five different time scales in flares. In addition, some new observations of delayed acceleration signatures are also presented. The theory of acceleration by parallel electric fields is used to model the spectral shape and evolution of hard X-rays. The possibility of the appearance of double layers is further investigated.

  6. Accelerator-based BNCT.

    PubMed

    Kreiner, A J; Baldo, M; Bergueiro, J R; Cartelli, D; Castell, W; Thatar Vento, V; Gomez Asoia, J; Mercuri, D; Padulo, J; Suarez Sandin, J C; Erhardt, J; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Igarzabal, M; Minsky, D M; Herrera, M S; Capoulat, M E; Gonzalez, S J; del Grosso, M F; Gagetti, L; Suarez Anzorena, M; Gun, M; Carranza, O

    2014-06-01

    The activity in accelerator development for accelerator-based BNCT (AB-BNCT) both worldwide and in Argentina is described. Projects in Russia, UK, Italy, Japan, Israel, and Argentina to develop AB-BNCT around different types of accelerators are briefly presented. In particular, the present status and recent progress of the Argentine project will be reviewed. The topics will cover: intense ion sources, accelerator tubes, transport of intense beams, beam diagnostics, the (9)Be(d,n) reaction as a possible neutron source, Beam Shaping Assemblies (BSA), a treatment room, and treatment planning in realistic cases.

  7. Accelerator-based BNCT.

    PubMed

    Kreiner, A J; Baldo, M; Bergueiro, J R; Cartelli, D; Castell, W; Thatar Vento, V; Gomez Asoia, J; Mercuri, D; Padulo, J; Suarez Sandin, J C; Erhardt, J; Kesque, J M; Valda, A A; Debray, M E; Somacal, H R; Igarzabal, M; Minsky, D M; Herrera, M S; Capoulat, M E; Gonzalez, S J; del Grosso, M F; Gagetti, L; Suarez Anzorena, M; Gun, M; Carranza, O

    2014-06-01

    The activity in accelerator development for accelerator-based BNCT (AB-BNCT) both worldwide and in Argentina is described. Projects in Russia, UK, Italy, Japan, Israel, and Argentina to develop AB-BNCT around different types of accelerators are briefly presented. In particular, the present status and recent progress of the Argentine project will be reviewed. The topics will cover: intense ion sources, accelerator tubes, transport of intense beams, beam diagnostics, the (9)Be(d,n) reaction as a possible neutron source, Beam Shaping Assemblies (BSA), a treatment room, and treatment planning in realistic cases. PMID:24365468

  8. Charged particle accelerator grating

    DOEpatents

    Palmer, Robert B.

    1986-09-02

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams into the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  9. Immunosuppressive activity of human neuroblastoma tumor gangliosides.

    PubMed

    Floutsis, G; Ulsh, L; Ladisch, S

    1989-01-15

    Gangliosides are shed in substantial amounts by some tumors, including human neuroblastoma, and these molecules modulate experimental tumor formation in vivo. We now demonstrate that neuroblastoma tumor gangliosides have potent immunoregulatory activity. Gangliosides of every one of 17 tumors studied were highly inhibitory for the normal in vitro human lymphoproliferative responses to the soluble antigen, tetanus toxoid; 30 nmol ganglioside/ml caused 43% to greater than 99% inhibition and the mean concentration causing 50% inhibition was only 17.3 nmol/ml. Furthermore, gangliosides isolated from clinically more aggressive tumors (Stage III or IV) were up to twice as immunosuppressive as those of the generally less aggressive tumors (Stage I or II) (p less than 0.05). Taken together with the lack of immunosuppressive activity of normal plasma gangliosides, the potent activity of neuroblastoma gangliosides supports the hypothesis that one mechanism by which these shed molecules may act to enhance tumor formation in vivo is through abrogation of the host cellular immune response at the site of tumor formation.

  10. AIP1 expression in tumor niche suppresses tumor progression and metastasis

    PubMed Central

    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

  11. Angular velocities, angular accelerations, and coriolis accelerations

    NASA Technical Reports Server (NTRS)

    Graybiel, A.

    1975-01-01

    Weightlessness, rotating environment, and mathematical analysis of Coriolis acceleration is described for man's biological effective force environments. Effects on the vestibular system are summarized, including the end organs, functional neurology, and input-output relations. Ground-based studies in preparation for space missions are examined, including functional tests, provocative tests, adaptive capacity tests, simulation studies, and antimotion sickness.

  12. Accelerators Beyond The Tevatron?

    SciTech Connect

    Lach, Joseph; /Fermilab

    2010-07-01

    Following the successful operation of the Fermilab superconducting accelerator three new higher energy accelerators were planned. They were the UNK in the Soviet Union, the LHC in Europe, and the SSC in the United States. All were expected to start producing physics about 1995. They did not. Why?

  13. Accelerators Beyond The Tevatron?

    SciTech Connect

    Lach, Joseph

    2010-07-29

    Following the successful operation of the Fermilab superconducting accelerator three new higher energy accelerators were planned. They were the UNK in the Soviet Union, the LHC in Europe, and the SSC in the United States. All were expected to start producing physics about 1995. They did not. Why?.

  14. Accelerators (4/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  15. Induction linear accelerators

    NASA Astrophysics Data System (ADS)

    Birx, Daniel

    1992-03-01

    Among the family of particle accelerators, the Induction Linear Accelerator is the best suited for the acceleration of high current electron beams. Because the electromagnetic radiation used to accelerate the electron beam is not stored in the cavities but is supplied by transmission lines during the beam pulse it is possible to utilize very low Q (typically<10) structures and very large beam pipes. This combination increases the beam breakup limited maximum currents to of order kiloamperes. The micropulse lengths of these machines are measured in 10's of nanoseconds and duty factors as high as 10-4 have been achieved. Until recently the major problem with these machines has been associated with the pulse power drive. Beam currents of kiloamperes and accelerating potentials of megavolts require peak power drives of gigawatts since no energy is stored in the structure. The marriage of liner accelerator technology and nonlinear magnetic compressors has produced some unique capabilities. It now appears possible to produce electron beams with average currents measured in amperes, peak currents in kiloamperes and gradients exceeding 1 MeV/meter, with power efficiencies approaching 50%. The nonlinear magnetic compression technology has replaced the spark gap drivers used on earlier accelerators with state-of-the-art all-solid-state SCR commutated compression chains. The reliability of these machines is now approaching 1010 shot MTBF. In the following paper we will briefly review the historical development of induction linear accelerators and then discuss the design considerations.

  16. Accelerators (3/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  17. Accelerators (5/5)

    ScienceCinema

    None

    2016-07-12

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  18. Accelerators (5/5)

    SciTech Connect

    2009-07-09

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  19. Accelerators (4/5)

    SciTech Connect

    2009-07-08

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  20. Accelerators (3/5)

    SciTech Connect

    2009-07-07

    1a) Introduction and motivation 1b) History and accelerator types 2) Transverse beam dynamics 3a) Longitudinal beam dynamics 3b) Figure of merit of a synchrotron/collider 3c) Beam control 4) Main limiting factors 5) Technical challenges Prerequisite knowledge: Previous knowledge of accelerators is not required.

  1. Ion Induction Accelerators

    NASA Astrophysics Data System (ADS)

    Barnard, John J.; Horioka, Kazuhiko

    The description of beams in RF and induction accelerators share many common features. Likewise, there is considerable commonality between electron induction accelerators (see Chap. 7) and ion induction accelerators. However, in contrast to electron induction accelerators, there are fewer ion induction accelerators that have been operated as application-driven user facilities. Ion induction accelerators are envisioned for applications (see Chap. 10) such as Heavy Ion Fusion (HIF), High Energy Density Physics (HEDP), and spallation neutron sources. Most ion induction accelerators constructed to date have been limited scale facilities built for feasibility studies for HIF and HEDP where a large numbers of ions are required on target in short pulses. Because ions are typically non-relativistic or weakly relativistic in much of the machine, space-charge effects can be of crucial importance. This contrasts the situation with electron machines, which are usually strongly relativistic leading to weaker transverse space-charge effects and simplified longitudinal dynamics. Similarly, the bunch structure of ion induction accelerators relative to RF machines results in significant differences in the longitudinal physics.

  2. Particle Acceleration in Jets

    NASA Technical Reports Server (NTRS)

    Nishikawa, Ken-Ichi

    2005-01-01

    Nonthermal radiation observed from astrophysical systems containing relativistic jets and shocks, e.g., active galactic nuclei (AGNs), gamma ray burst (GRBs), and Galactic microquasar systems usually have power-law emission spectra. Fermi acceleration is the mechanism usually assumed for the acceleration of particles in astrophysical environments.

  3. Microscale acceleration history discriminators

    DOEpatents

    Polosky, Marc A.; Plummer, David W.

    2002-01-01

    A new class of micromechanical acceleration history discriminators is claimed. These discriminators allow the precise differentiation of a wide range of acceleration-time histories, thereby allowing adaptive events to be triggered in response to the severity (or lack thereof) of an external environment. Such devices have applications in airbag activation, and other safety and surety applications.

  4. Diagnostics for induction accelerators

    SciTech Connect

    Fessenden, T.J.

    1996-04-01

    The induction accelerator was conceived by N. C. Christofilos and first realized as the Astron accelerator that operated at LLNL from the early 1960`s to the end of 1975. This accelerator generated electron beams at energies near 6 MeV with typical currents of 600 Amperes in 400 ns pulses. The Advanced Test Accelerator (ATA) built at Livermore`s Site 300 produced 10,000 Ampere beams with pulse widths of 70 ns at energies approaching 50 MeV. Several other electron and ion induction accelerators have been fabricated at LLNL and LBNL. This paper reviews the principal diagnostics developed through efforts by scientists at both laboratories for measuring the current, position, energy, and emittance of beams generated by these high current, short pulse accelerators. Many of these diagnostics are closely related to those developed for other accelerators. However, the very fast and intense current pulses often require special diagnostic techniques and considerations. The physics and design of the more unique diagnostics developed for electron induction accelerators are presented and discussed in detail.

  5. KEK digital accelerator

    NASA Astrophysics Data System (ADS)

    Iwashita, T.; Adachi, T.; Takayama, K.; Leo, K. W.; Arai, T.; Arakida, Y.; Hashimoto, M.; Kadokura, E.; Kawai, M.; Kawakubo, T.; Kubo, Tomio; Koyama, K.; Nakanishi, H.; Okazaki, K.; Okamura, K.; Someya, H.; Takagi, A.; Tokuchi, A.; Wake, M.

    2011-07-01

    The High Energy Accelerator Research Organization KEK digital accelerator (KEK-DA) is a renovation of the KEK 500 MeV booster proton synchrotron, which was shut down in 2006. The existing 40 MeV drift tube linac and rf cavities have been replaced by an electron cyclotron resonance (ECR) ion source embedded in a 200 kV high-voltage terminal and induction acceleration cells, respectively. A DA is, in principle, capable of accelerating any species of ion in all possible charge states. The KEK-DA is characterized by specific accelerator components such as a permanent magnet X-band ECR ion source, a low-energy transport line, an electrostatic injection kicker, an extraction septum magnet operated in air, combined-function main magnets, and an induction acceleration system. The induction acceleration method, integrating modern pulse power technology and state-of-art digital control, is crucial for the rapid-cycle KEK-DA. The key issues of beam dynamics associated with low-energy injection of heavy ions are beam loss caused by electron capture and stripping as results of the interaction with residual gas molecules and the closed orbit distortion resulting from relatively high remanent fields in the bending magnets. Attractive applications of this accelerator in materials and biological sciences are discussed.

  6. Controllable Laser Ion Acceleration

    NASA Astrophysics Data System (ADS)

    Kawata, S.; Kamiyama, D.; Ohtake, Y.; Takano, M.; Barada, D.; Kong, Q.; Wang, P. X.; Gu, Y. J.; Wang, W. M.; Limpouch, J.; Andreev, A.; Bulanov, S. V.; Sheng, Z. M.; Klimo, O.; Psikal, J.; Ma, Y. Y.; Li, X. F.; Yu, Q. S.

    2016-02-01

    In this paper a future laser ion accelerator is discussed to make the laser-based ion accelerator compact and controllable. Especially a collimation device is focused in this paper. The future laser ion accelerator should have an ion source, ion collimators, ion beam bunchers, and ion post acceleration devices [Laser Therapy 22, 103(2013)]: the ion particle energy and the ion energy spectrum are controlled to meet requirements for a future compact laser ion accelerator for ion cancer therapy or for other purposes. The energy efficiency from the laser to ions is improved by using a solid target with a fine sub-wavelength structure or a near-critical density gas plasma. The ion beam collimation is performed by holes behind the solid target or a multi-layered solid target. The control of the ion energy spectrum and the ion particle energy, and the ion beam bunching would be successfully realized by a multistage laser-target interaction.

  7. Cascaded radiation pressure acceleration

    SciTech Connect

    Pei, Zhikun; Shen, Baifei E-mail: zhxm@siom.ac.cn; Zhang, Xiaomei E-mail: zhxm@siom.ac.cn; Wang, Wenpeng; Zhang, Lingang; Yi, Longqing; Shi, Yin; Xu, Zhizhan

    2015-07-15

    A cascaded radiation-pressure acceleration scheme is proposed. When an energetic proton beam is injected into an electrostatic field moving at light speed in a foil accelerated by light pressure, protons can be re-accelerated to much higher energy. An initial 3-GeV proton beam can be re-accelerated to 7 GeV while its energy spread is narrowed significantly, indicating a 4-GeV energy gain for one acceleration stage, as shown in one-dimensional simulations and analytical results. The validity of the method is further confirmed by two-dimensional simulations. This scheme provides a way to scale proton energy at the GeV level linearly with laser energy and is promising to obtain proton bunches at tens of gigaelectron-volts.

  8. Accelerators, Beams And Physical Review Special Topics - Accelerators And Beams

    SciTech Connect

    Siemann, R.H.; /SLAC

    2011-10-24

    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.

  9. Accelerated Math[TM]. What Works Clearinghouse Intervention Report

    ERIC Educational Resources Information Center

    What Works Clearinghouse, 2010

    2010-01-01

    "Accelerated Math"[TM], published by Renaissance Learning, is a software tool used to customize assignments and monitor progress in mathematics for students in grades 1-12. "Accelerated Math"[TM] creates individualized assignments that align with state standards and national guidelines, scores student work, and generates formative feedback through…

  10. Faculty Speak on the Impact of Time in Accelerated Courses

    ERIC Educational Resources Information Center

    Johnson, Carrie

    2009-01-01

    Eighteen faculty members participated in this qualitative study to determine the impact of reduced seat time in accelerated courses. The findings challenge critics who believe the accelerated delivery format compromises academic quality. The participants noted the importance of students in the learning process, emphasizing the significant workload…

  11. Secondary optic nerve tumors.

    PubMed

    Christmas, N J; Mead, M D; Richardson, E P; Albert, D M

    1991-01-01

    Secondary tumors of the optic nerve are more common than primary optic nerve tumors. The involvement of the optic nerve may arise from direct invasion from intraocular malignancies, from hematopoietic malignancy, from meningeal carcinomatosis, or from distant primary tumors. Orbital tumors rarely invade the optic nerve, and brain tumors involve it only in their late stages.

  12. Tumor initiating cells in malignant gliomas

    PubMed Central

    Hadjipanayis, Costas G.; Van Meir, Erwin G.

    2009-01-01

    A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas. PMID:19189072

  13. Chitosan-Based Thermoreversible Hydrogel as an in Vitro Tumor Microenvironment for Testing Breast Cancer Therapies

    PubMed Central

    2015-01-01

    Breast cancer is a major health problem for women worldwide. Although in vitro culture of established breast cancer cell lines is the most widely used model for preclinical assessment, it poorly represents the behavior of breast cancers in vivo. Acceleration of the development of effective therapeutic strategies requires a cost-efficient in vitro model that can more accurately resemble the in vivo tumor microenvironment. Here, we report the use of a thermoreversible poly(ethylene glycol)-g-chitosan hydrogel (PCgel) as an in vitro breast cancer model. We hypothesized that PCgel could provide a tumor microenvironment that promotes cultured cancer cells to a more malignant phenotype with drug and immune resistance. Traditional tissue culture plates and Matrigel were applied as controls in our studies. In vitro cellular proliferation and morphology, the secretion of angiogenesis-related growth factors and cytokines, and drug and immune resistance were assessed. Our results show that PCgel cultures promoted tumor aggregate formation, increased secretion of various angiogenesis- and metastasis-related growth factors and cytokines, and increased tumor cell resistance to chemotherapeutic drugs and immunotherapeutic T cells. This PCgel platform may offer a valuable strategy to bridge the gap between standard in vitro and costly animal studies for a wide variety of experimental designs. PMID:24779767

  14. Enhancement or inhibition of tumor growth by interferon: dependence on treatment protocol.

    PubMed

    Murasko, D M; Fresa, K; Mark, R

    1983-12-15

    MSC cells are tumor cells originally induced in BALB/c mice by Moloney sarcoma virus. In these studies we demonstrated that, although these tumor cells are sensitive in vitro both to lysis by NK or NK-like cells and to the growth-inhibitory effect of murine L-cell interferon (IFN), the growth of the tumor in vivo could be either inhibited or enhanced by IFN. The outcome of in vivo IFN treatment was dependent on the timing and route of IFN administration relative to tumor challenge. IFN given systematically at the same time as tumor challenge resulted in enhancement of primary tumor formation, rate of tumor growth and subsequent progressive tumor growth. In contrast, IFN administered at the site of tumor inoculation on days 1-3 after tumor challenge inhibited tumor formation and growth. Histopathology of tissue sections obtained from the site of tumor challenge confirmed these results. Similar studies performed in mice given 450 rads of X-irradiation showed that IFN could still inhibit tumor growth when administered at the site of tumor inoculation on days 1-3 after tumor challenge. IFN administered simultaneously with tumor challenge, however, did not enhance tumor growth in irradiated mice. These results are consistent with the interpretation that 1) inhibition of MSC-induced tumor growth by IFN has a radioresistant component and 2) the enhancement of MSC-induced tumor formation by IFN is dependent on interaction with a radiosensitive population of cells, possibly lymphoid cells. PMID:6360916

  15. The FRC Acceleration Space Thruster (FAST) Experiment

    NASA Technical Reports Server (NTRS)

    Martin, Adam; Eskridge, Richard; Houts, Mike; Slough, John; Rodgers, Stephen L. (Technical Monitor)

    2002-01-01

    The objective of the FRC (Field Reversed Configuration) Acceleration Space Thruster (FAST) Experiment is to investigate the use of a repetitive FRC source as a thruster, specifically for an NEP (nuclear electric propulsion) system. The Field Reversed Configuration is a plasmoid with a closed poloidal field line structure, and has been extensively studied as a fusion reactor core. An FRC thruster works by repetitively producing FRCs and accelerating them to high velocity. An FRC thruster should be capable of I(sub sp)'s in the range of 5,000 - 25,000 seconds and efficiencies in the range of 60 - 80 %. In addition, they can have thrust densities as high as 10(exp 6) N/m2, and as they are inductively formed, they do not suffer from electrode erosion. The jet-power should be scalable from the low to the high power regime. The FAST experiment consists of a theta-pinch formation chamber, followed by an acceleration stage. Initially, we will produce and accelerate single FRCs. The initial focus of the experiment will be on the ionization, formation and acceleration of a single plasmoid, so as to determine the likely efficiency and I(sub sp). Subsequently, we will modify the device for repetitive burst-mode operation (5-10 shots). A variety of diagnostics are or will be available for this work, including a HeNe interferometer, high-speed cameras, and a Thomson-scattering system. The status of the experiment will be described.

  16. Production, Characterization, and Acceleration of Optical Microbunches

    SciTech Connect

    Sears, Christopher M.S.

    2008-06-20

    Optical microbunches with a spacing of 800 nm have been produced for laser acceleration research. The microbunches are produced using a inverse Free-Electron-Laser (IFEL) followed by a dispersive chicane. The microbunched electron beam is characterized by coherent optical transition radiation (COTR) with good agreement to the analytic theory for bunch formation. In a second experiment the bunches are accelerated in a second stage to achieve for the first time direct net acceleration of electrons traveling in a vacuum with visible light. This dissertation presents the theory of microbunch formation and characterization of the microbunches. It also presents the design of the experimental hardware from magnetostatic and particle tracking simulations, to fabrication and measurement of the undulator and chicane magnets. Finally, the dissertation discusses three experiments aimed at demonstrating the IFEL interaction, microbunch production, and the net acceleration of the microbunched beam. At the close of the dissertation, a separate but related research effort on the tight focusing of electrons for coupling into optical scale, Photonic Bandgap, structures is presented. This includes the design and fabrication of a strong focusing permanent magnet quadrupole triplet and an outline of an initial experiment using the triplet to observe wakefields generated by an electron beam passing through an optical scale accelerator.

  17. Large electrostatic accelerators

    SciTech Connect

    Jones, C.M.

    1984-01-01

    The increasing importance of energetic heavy ion beams in the study of atomic physics, nuclear physics, and materials science has partially or wholly motivated the construction of a new generation of large electrostatic accelerators designed to operate at terminal potentials of 20 MV or above. In this paper, the author briefly discusses the status of these new accelerators and also discusses several recent technological advances which may be expected to further improve their performance. The paper is divided into four parts: (1) a discussion of the motivation for the construction of large electrostatic accelerators, (2) a description and discussion of several large electrostatic accelerators which have been recently completed or are under construction, (3) a description of several recent innovations which may be expected to improve the performance of large electrostatic accelerators in the future, and (4) a description of an innovative new large electrostatic accelerator whose construction is scheduled to begin next year. Due to time and space constraints, discussion is restricted to consideration of only tandem accelerators.

  18. 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.

  19. PTEN deficiency in a luminal ErbB-2 mouse model results in dramatic acceleration of mammary tumorigenesis and metastasis.

    PubMed

    Schade, Babette; Rao, Trisha; Dourdin, Nathalie; Lesurf, Robert; Hallett, Michael; Cardiff, Robert D; Muller, William J

    2009-07-10

    Overexpression and/or amplification of the ErbB-2 oncogene as well as inactivation of the PTEN tumor suppressor are two important genetic events in human breast carcinogenesis. To address the biological impact of conditional inactivation of PTEN on ErbB-2-induced mammary tumorigenesis, we generated a novel transgenic mouse model that utilizes the murine mammary tumor virus (MMTV) promoter to directly couple expression of activated ErbB-2 and Cre recombinase to the same mammary epithelial cell (MMTV-NIC). Disruption of PTEN in the mammary epithelium of the MMTV-NIC model system dramatically accelerated the formation of multifocal and highly metastatic mammary tumors, which exhibited homogenous pathology. PTEN-deficient/NIC-induced tumorigenesis was associated with an increase in angiogenesis. Moreover, inactivation of PTEN in the MMTV-NIC mouse model resulted in hyperactivation of the phosphatidylinositol 3'-kinase/Akt signaling pathway. However, like the parental strain, tumors obtained from PTEN-deficient/NIC mice displayed histopathological and molecular features of the luminal subtype of primary human breast cancer. Taken together, our findings provide important implications in understanding the molecular determinants of mammary tumorigenesis driven by PTEN deficiency and ErbB-2 activation and could provide a valuable tool for testing the efficacy of therapeutic strategies that target these critical signaling pathways.

  20. ROLE OF CHEMOKINES IN TUMOR GROWTH

    PubMed Central

    Raman, Dayanidhi; Baugher, Paige J.; Thu, Yee Mon; Richmond, Ann

    2007-01-01

    Chemokines play a paramount role in the tumor progression. Chronic inflammation promotes tumor formation. Both tumor cells and stromal cells elaborate chemokines and cytokines. These act either by autocrine or paracrine mechanisms to sustain tumor cell growth, induce angiogenesis and facilitate evasion of immune surveillance through immunoediting. The chemokine receptor CXCR2 and its ligands promote tumor angiogenesis and leukocyte infiltration into the tumor microenvironment. In harsh acidic and hypoxic microenvironmental conditions tumor cells up-regulate their expression of CXCR4, which equips them to migrate up a gradient of CXCL12 elaborated by carcinoma associated fibroblasts (CAFs) to a normoxic microenvironment. The CXCL12-CXCR4 axis facilitates metastasis to distant organs and the CCL21-CCR7 chemokine ligand-receptor pair favors metastasis to lymph nodes. These two chemokine ligand-receptor systems are common key mediators of tumor cell metastasis for several malignancies and as such provide key targets for chemotherapy. In this paper, the role of specific chemokines/chemokine receptor interactions in tumor progression, growth and metastasis and the role of chemokine/chemokine receptor interactions in the stromal compartment as related to angiogenesis, metastasis, and immune response to the tumor are reviewed. PMID:17629396

  1. Tumors and Pregnancy

    MedlinePlus

    Tumors during pregnancy are rare, but they can happen. Tumors can be either benign or malignant. Benign tumors aren't cancer. Malignant ones are. The most common cancers in pregnancy are breast cancer, cervical cancer, lymphoma, and melanoma. ...

  2. Pancreatic islet cell tumor

    MedlinePlus

    Complications of these tumors include: Diabetes Hormone crises (if the tumor releases certain types of hormones) Severe low blood sugar (from insulinomas) Severe ulcers in the stomach and small intestine (from gastrinomas) Spread of the tumor to the liver

  3. Childhood Brain Tumors

    MedlinePlus

    Brain tumors are abnormal growths inside the skull. They are among the most common types of childhood ... still be serious. Malignant tumors are cancerous. Childhood brain and spinal cord tumors can cause headaches and ...

  4. Pathology of eyelid tumors

    PubMed Central

    Pe’er, Jacob

    2016-01-01

    The eyelids are composed of four layers: skin and subcutaneous tissue including its adnexa, striated muscle, tarsus with the meibomian glands, and the palpebral conjunctiva. Benign and malignant tumors can arise from each of the eyelid layers. Most eyelid tumors are of cutaneous origin, mostly epidermal, which can be divided into epithelial and melanocytic tumors. Benign epithelial lesions, cystic lesions, and benign melanocytic lesions are very common. The most common malignant eyelid tumors are basal cell carcinoma in Caucasians and sebaceous gland carcinoma in Asians. Adnexal and stromal tumors are less frequent. The present review describes the more important eyelid tumors according to the following groups: Benign and malignant epithelial tumors, benign and malignant melanocytic tumors, benign and malignant adnexal tumors, stromal eyelid tumors, lymphoproliferative and metastatic tumors, other rare eyelid tumors, and inflammatory and infections lesions that simulate neoplasms. PMID:27146927

  5. Pathology of eyelid tumors.

    PubMed

    Pe'er, Jacob

    2016-03-01

    The eyelids are composed of four layers: skin and subcutaneous tissue including its adnexa, striated muscle, tarsus with the meibomian glands, and the palpebral conjunctiva. Benign and malignant tumors can arise from each of the eyelid layers. Most eyelid tumors are of cutaneous origin, mostly epidermal, which can be divided into epithelial and melanocytic tumors. Benign epithelial lesions, cystic lesions, and benign melanocytic lesions are very common. The most common malignant eyelid tumors are basal cell carcinoma in Caucasians and sebaceous gland carcinoma in Asians. Adnexal and stromal tumors are less frequent. The present review describes the more important eyelid tumors according to the following groups: Benign and malignant epithelial tumors, benign and malignant melanocytic tumors, benign and malignant adnexal tumors, stromal eyelid tumors, lymphoproliferative and metastatic tumors, other rare eyelid tumors, and inflammatory and infections lesions that simulate neoplasms. PMID:27146927

  6. Overview of Heart Tumors

    MedlinePlus

    ... the heart. Most heart tumors are metastatic cancer. Did You Know... Noncancerous tumors can be as deadly ... slow the tumor's growth. Resources In This Article Did You Know 1 Did You Know... Table 2 ...

  7. Brain Tumors (For Parents)

    MedlinePlus

    ... Story" 5 Things to Know About Zika & Pregnancy Brain Tumors KidsHealth > For Parents > Brain Tumors Print A ... radiation therapy or chemotherapy, or both. Types of Brain Tumors There are many different types of brain ...

  8. Confronting Twin Paradox Acceleration

    NASA Astrophysics Data System (ADS)

    Murphy, Thomas W.

    2016-05-01

    The resolution to the classic twin paradox in special relativity rests on the asymmetry of acceleration. Yet most students are not exposed to a satisfactory analysis of what exactly happens during the acceleration phase that results in the nonaccelerated observer's more rapid aging. The simple treatment presented here offers both graphical and quantitative solutions to the problem, leading to the correct result that the acceleration-induced age gap is 2Lβ years when the one-way distance L is expressed in light-years and velocity β ≡v/c .

  9. Twisted waveguide accelerating structure.

    SciTech Connect

    Kang, Y. W.

    2000-08-15

    A hollow waveguide with a uniform cross section may be used for accelerating charged particles if the phase velocity of an accelerating mode is equal to or less than the free space speed of light. Regular straight hollow waveguides have phase velocities of propagating electromagnetic waves greater than the free-space speed of light. if the waveguide is twisted, the phase velocities of the waveguide modes become slower. The twisted waveguide structure has been modeled and computer simulated in 3-D electromagnetic solvers to show the slow-wave properties for the accelerating mode.

  10. Ion beam accelerator system

    NASA Technical Reports Server (NTRS)

    Aston, Graeme (Inventor)

    1984-01-01

    A system is described that combines geometrical and electrostatic focusing to provide high ion extraction efficiency and good focusing of an accelerated ion beam. The apparatus includes a pair of curved extraction grids (16, 18) with multiple pairs of aligned holes positioned to direct a group of beamlets (20) along converging paths. The extraction grids are closely spaced and maintained at a moderate potential to efficiently extract beamlets of ions and allow them to combine into a single beam (14). An accelerator electrode device (22) downstream from the extraction grids, is at a much lower potential than the grids to accelerate the combined beam.

  11. Ion beam accelerator system

    NASA Technical Reports Server (NTRS)

    Aston, G. (Inventor)

    1981-01-01

    A system is described that combines geometrical and electrostatic focusing to provide high ion extraction efficiency and good focusing of an accelerated ion beam. The apparatus includes a pair of curved extraction grids with multiple pairs of aligned holes positioned to direct a group of beamlets along converging paths. The extraction grids are closely spaced and maintained at a moderate potential to efficiently extract beamlets of ions and allow them to combine into a single beam. An accelerator electrode device downstream from the extraction grids is at a much lower potential than the grids to accelerate the combined beam. The application of the system to ion implantation is mentioned.

  12. Tumor Markers

    SciTech Connect

    Weller, Richard E.

    2000-04-18

    Veterinary oncology has seen tremendous growth since the first textbook devoted to the subject in the late 1970s. Cancer is usually at the top of the list when owners ask about health concerns for their pets (and it remains the leading cause of death among dogs and cats). The volume, Veterinary Oncology Secrets, joins others in the series by presenting in question and answer format the type of information so important to veterinary students, interns and residents, general practitioners, and specialists in a number of clinical fields.

  13. Rapid tumor formation of human T-cell leukemia virus type 1-infected cell lines in novel NOD-SCID/gammac(null) mice: suppression by an inhibitor against NF-kappaB.

    PubMed

    Dewan, M Zahidunnabi; Terashima, Kazuo; Taruishi, Midori; Hasegawa, Hideki; Ito, Mamoru; Tanaka, Yuetsu; Mori, Naoki; Sata, Tetsutaro; Koyanagi, Yoshio; Maeda, Michiyuki; Kubuki, Yoko; Okayama, Akihiko; Fujii, Masahiro; Yamamoto, Naoki

    2003-05-01

    We established a novel experimental model for human T-cell leukemia virus type 1 (HTLV-1)-induced tumor using NOD-SCID/gammac(null) (NOG) mice. This model is very useful for investigating the mechanism of tumorigenesis and malignant cell growth of adult T-cell leukemia (ATL)/lymphoma, which still remains unclear. Nine HTLV-1-infected cell lines were inoculated subcutaneously in the postauricular region of NOG mice. As early as 2 to 3 weeks after inoculation, seven cell lines produced a visible tumor while two transformed cell lines failed to do so. Five of seven lines produced a progressively growing large tumor with leukemic infiltration of the cells in various organs that eventually killed the animals. Leukemic cell lines formed soft tumors, whereas some transformed cell lines developed into hemorrhagic hard tumors in NOG mice. One of the leukemic cell lines, ED-40515(-), was unable to produce visible tumors in NOD-SCID mice with a common gamma-chain after 2 weeks. In vivo NF-kappaB DNA binding activity of the ED-40515(-) cell line was higher and the NF-kappaB components were changed compared to cells in vitro. Bay 11-7082, a specific and effective NF-kappaB inhibitor, prevented tumor growth at the sites of the primary region and leukemic infiltration in various organs of NOG mice. This in vivo model of ATL could provide a novel system for use in clarifying the mechanism of growth of HTLV-1-infected cells as well as for the development of new drugs against ATL.

  14. An in vivo platform for tumor biomarker assessment.

    PubMed

    Servais, Elliot L; Suzuki, Kei; Colovos, Christos; Rodriguez, Luis; Sima, Camelia; Fleisher, Martin; Rusch, Valerie W; Sadelain, Michel; Adusumilli, Prasad S

    2011-01-01

    Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers--serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response--a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research. PMID:22046338

  15. Accelerator on a Chip

    ScienceCinema

    England, Joel

    2016-07-12

    SLAC's Joel England explains how the same fabrication techniques used for silicon computer microchips allowed their team to create the new laser-driven particle accelerator chips. (SLAC Multimedia Communications)

  16. Charged particle accelerator grating

    DOEpatents

    Palmer, R.B.

    1985-09-09

    A readily disposable and replaceable accelerator grating for a relativistic particle accelerator is described. The grating is formed for a plurality of liquid droplets that are directed in precisely positioned jet streams to periodically dispose rows of droplets along the borders of a predetermined particle beam path. A plurality of lasers are used to direct laser beams onto the droplets, at predetermined angles, thereby to excite the droplets to support electromagnetic accelerating resonances on their surfaces. Those resonances operate to accelerate and focus particles moving along the beam path. As the droplets are distorted or destroyed by the incoming radiation, they are replaced at a predetermined frequency by other droplets supplied through the jet streams.

  17. Non-accelerator experiments

    SciTech Connect

    Goldhaber, M.

    1986-01-01

    This report discusses several topics which can be investigated without the use of accelerators. Topics covered are: (1) proton decay, (2) atmospheric neutrinos, (3) neutrino detection, (4) muons from Cygnus X-3, and (5) the double-beta decay.

  18. Dielectric assist accelerating structure

    NASA Astrophysics Data System (ADS)

    Satoh, D.; Yoshida, M.; Hayashizaki, N.

    2016-01-01

    A higher-order TM02 n mode accelerating structure is proposed based on a novel concept of dielectric loaded rf cavities. This accelerating structure consists of ultralow-loss dielectric cylinders and disks with irises which are periodically arranged in a metallic enclosure. Unlike conventional dielectric loaded accelerating structures, most of the rf power is stored in the vacuum space near the beam axis, leading to a significant reduction of the wall loss, much lower than that of conventional normal-conducting linac structures. This allows us to realize an extremely high quality factor and a very high shunt impedance at room temperature. A simulation of a 5 cell prototype design with an existing alumina ceramic indicates an unloaded quality factor of the accelerating mode over 120 000 and a shunt impedance exceeding 650 M Ω /m at room temperature.

  19. CLASHING BEAM PARTICLE ACCELERATOR

    DOEpatents

    Burleigh, R.J.

    1961-04-11

    A charged-particle accelerator of the proton synchrotron class having means for simultaneously accelerating two separate contra-rotating particle beams within a single annular magnet structure is reported. The magnet provides two concentric circular field regions of opposite magnetic polarity with one field region being of slightly less diameter than the other. The accelerator includes a deflector means straddling the two particle orbits and acting to collide the two particle beams after each has been accelerated to a desired energy. The deflector has the further property of returning particles which do not undergo collision to the regular orbits whereby the particles recirculate with the possibility of colliding upon subsequent passages through the deflector.

  20. Rare Isotope Accelerators

    NASA Astrophysics Data System (ADS)

    Savard, Guy

    2002-04-01

    The next frontier for low-energy nuclear physics involves experimentation with accelerated beams of short-lived radioactive isotopes. A new facility, the Rare Isotope Accelerator (RIA), is proposed to produce large amount of these rare isotopes and post-accelerate them to energies relevant for studies in nuclear physics, astrophysics and the study of fundamental interactions at low energy. The basic science motivation for this facility will be introduced. The general facility layout, from the 400 kW heavy-ion superconducting linac used for production of the required isotopes to the novel production and extraction schemes and the highly efficient post-accelerator, will be presented. Special emphasis will be put on a number of technical breakthroughs and recent R&D results that enable this new facility.

  1. Accelerator on a Chip

    SciTech Connect

    England, Joel

    2014-06-30

    SLAC's Joel England explains how the same fabrication techniques used for silicon computer microchips allowed their team to create the new laser-driven particle accelerator chips. (SLAC Multimedia Communications)

  2. HEAVY ION LINEAR ACCELERATOR

    DOEpatents

    Van Atta, C.M.; Beringer, R.; Smith, L.

    1959-01-01

    A linear accelerator of heavy ions is described. The basic contributions of the invention consist of a method and apparatus for obtaining high energy particles of an element with an increased charge-to-mass ratio. The method comprises the steps of ionizing the atoms of an element, accelerating the resultant ions to an energy substantially equal to one Mev per nucleon, stripping orbital electrons from the accelerated ions by passing the ions through a curtain of elemental vapor disposed transversely of the path of the ions to provide a second charge-to-mass ratio, and finally accelerating the resultant stripped ions to a final energy of at least ten Mev per nucleon.

  3. Wake field acceleration experiments

    SciTech Connect

    Simpson, J.D.

    1988-01-01

    Where and how will wake field acceleration devices find use for other than, possibly, accelerators for high energy physics. I don't know that this can be responsibly answered at this time. What I can do is describe some recent results from an ongoing experimental program at Argonne which support the idea that wake field techniques and devices are potentially important for future accelerators. Perhaps this will spawn expanded interest and even new ideas for the use of this new technology. The Argonne program, and in particular the Advanced Accelerator Test Facility (AATF), has been reported in several fairly recent papers and reports. But because this is a substantially new audience for the subject, I will include a brief review of the program and the facility before describing experiments. 10 refs., 7 figs.

  4. Vibration control in accelerators

    SciTech Connect

    Montag, C.

    2011-01-01

    In the vast majority of accelerator applications, ground vibration amplitudes are well below tolerable magnet jitter amplitudes. In these cases, it is necessary and sufficient to design a rigid magnet support structure that does not amplify ground vibration. Since accelerator beam lines are typically installed at an elevation of 1-2m above ground level, special care has to be taken in order to avoid designing a support structure that acts like an inverted pendulum with a low resonance frequency, resulting in untolerable lateral vibration amplitudes of the accelerator components when excited by either ambient ground motion or vibration sources within the accelerator itself, such as cooling water pumps or helium flow in superconducting magnets. In cases where ground motion amplitudes already exceed the required jiter tolerances, for instance in future linear colliders, passive vibration damping or active stabilization may be considered.

  5. Breakthrough: Fermilab Accelerator Technology

    ScienceCinema

    None

    2016-07-12

    There are more than 30,000 particle accelerators in operation around the world. At Fermilab, scientists are collaborating with other laboratories and industry to optimize the manufacturing processes for a new type of powerful accelerator that uses superconducting niobium cavities. Experimenting with unique polishing materials, a Fermilab team has now developed an efficient and environmentally friendly way of creating cavities that can propel particles with more than 30 million volts per meter.

  6. Collective field accelerator

    DOEpatents

    Luce, John S.

    1978-01-01

    A collective field accelerator which operates with a vacuum diode and utilizes a grooved cathode and a dielectric anode that operates with a relativistic electron beam with a .nu./.gamma. of .about. 1, and a plurality of dielectric lenses having an axial magnetic field thereabout to focus the collectively accelerated electrons and ions which are ejected from the anode. The anode and lenses operate as unoptimized r-f cavities which modulate and focus the beam.

  7. Rolamite acceleration sensor

    DOEpatents

    Abbin, Joseph P.; Briner, Clifton F.; Martin, Samuel B.

    1993-01-01

    A rolamite acceleration sensor which has a failsafe feature including a housing, a pair of rollers, a tension band wrapped in an S shaped fashion around the rollers, wherein the band has a force-generation cut out and a failsafe cut out or weak portion. The failsafe cut out or weak portion breaks when the sensor is subjected to an excessive acceleration so that the sensor fails in an open circuit (non-conducting) state permanently.

  8. Microgravity Acceleration Measurement System

    NASA Technical Reports Server (NTRS)

    Foster, William

    2009-01-01

    Microgravity Acceleration Measurement System (MAMS) is an ongoing study of the small forces (vibrations and accelerations) on the ISS that result from the operation of hardware, crew activities, as well as dockings and maneuvering. Results will be used to generalize the types of vibrations affecting vibration-sensitive experiments. Investigators seek to better understand the vibration environment on the space station to enable future research.

  9. Rolamite acceleration sensor

    DOEpatents

    Abbin, J.P.; Briner, C.F.; Martin, S.B.

    1993-12-21

    A rolamite acceleration sensor is described which has a failsafe feature including a housing, a pair of rollers, a tension band wrapped in an S shaped fashion around the rollers, wherein the band has a force-generation cut out and a failsafe cut out or weak portion. The failsafe cut out or weak portion breaks when the sensor is subjected to an excessive acceleration so that the sensor fails in an open circuit (non-conducting) state permanently. 6 figures.

  10. Microwave inverse Cerenkov accelerator

    NASA Astrophysics Data System (ADS)

    Zhang, T. B.; Marshall, T. C.; LaPointe, M. A.; Hirshfield, J. L.

    1997-03-01

    A Microwave Inverse Cerenkov Accelerator (MICA) is currently under construction at the Yale Beam Physics Laboratory. The accelerating structure in MICA consists of an axisymmetric dielectrically lined waveguide. For the injection of 6 MeV microbunches from a 2.856 GHz RF gun, and subsequent acceleration by the TM01 fields, particle simulation studies predict that an acceleration gradient of 6.3 MV/m can be achieved with a traveling-wave power of 15 MW applied to the structure. Synchronous injection into a narrow phase window is shown to allow trapping of all injected particles. The RF fields of the accelerating structure are shown to provide radial focusing, so that longitudinal and transverse emittance growth during acceleration is small, and that no external magnetic fields are required for focusing. For 0.16 nC, 5 psec microbunches, the normalized emittance of the accelerated beam is predicted to be less than 5πmm-mrad. Experiments on sample alumina tubes have been conducted that verify the theoretical dispersion relation for the TM01 mode over a two-to-one range in frequency. No excitation of axisymmetric or non-axisymmetric competing waveguide modes was observed. High power tests showed that tangential electric fields at the inner surface of an uncoated sample of alumina pipe could be sustained up to at least 8.4 MV/m without breakdown. These considerations suggest that a MICA test accelerator can be built to examine these predictions using an available RF power source, 6 MeV RF gun and associated beam line.

  11. Amps particle accelerator definition study

    NASA Technical Reports Server (NTRS)

    Sellen, J. M., Jr.

    1975-01-01

    The Particle Accelerator System of the AMPS (Atmospheric, Magnetospheric, and Plasmas in Space) payload is a series of charged particle accelerators to be flown with the Space Transportation System Shuttle on Spacelab missions. In the configuration presented, the total particle accelerator system consists of an energetic electron beam, an energetic ion accelerator, and both low voltage and high voltage plasma acceleration devices. The Orbiter is illustrated with such a particle accelerator system.

  12. Laser Plasma Accelerators

    NASA Astrophysics Data System (ADS)

    Malka, Victor

    The continuing development of powerful laser systems has permitted to extend the interaction of laser beams with matter far into the relativistic domain, and to demonstrate new approaches for producing energetic particle beams. The extremely large electric fields, with amplitudes exceeding the TV/m level, that are produced in plasma medium are of relevance particle acceleration. Since the value of this longitudinal electric field, 10,000 times larger than those produced in conventional radio-frequency cavities, plasma accelerators appear to be very promising for the development of compact accelerators. The incredible progresses in the understanding of laser plasma interaction physic, allows an excellent control of electron injection and acceleration. Thanks to these recent achievements, laser plasma accelerators deliver today high quality beams of energetic radiation and particles. These beams have a number of interesting properties such as shortness, brightness and spatial quality, and could lend themselves to applications in many fields, including medicine, radio-biology, chemistry, physics and material science,security (material inspection), and of course in accelerator science.

  13. Biomedical accelerator mass spectrometry

    NASA Astrophysics Data System (ADS)

    Freeman, Stewart P. H. T.; Vogel, John S.

    1995-05-01

    Ultrasensitive SIMS with accelerator based spectrometers has recently begun to be applied to biomedical problems. Certain very long-lived radioisotopes of very low natural abundances can be used to trace metabolism at environmental dose levels ( [greater-or-equal, slanted] z mol in mg samples). 14C in particular can be employed to label a myriad of compounds. Competing technologies typically require super environmental doses that can perturb the system under investigation, followed by uncertain extrapolation to the low dose regime. 41Ca and 26Al are also used as elemental tracers. Given the sensitivity of the accelerator method, care must be taken to avoid contamination of the mass spectrometer and the apparatus employed in prior sample handling including chemical separation. This infant field comprises the efforts of a dozen accelerator laboratories. The Center for Accelerator Mass Spectrometry has been particularly active. In addition to collaborating with groups further afield, we are researching the kinematics and binding of genotoxins in-house, and we support innovative uses of our capability in the disciplines of chemistry, pharmacology, nutrition and physiology within the University of California. The field can be expected to grow further given the numerous potential applications and the efforts of several groups and companies to integrate more the accelerator technology into biomedical research programs; the development of miniaturized accelerator systems and ion sources capable of interfacing to conventional HPLC and GMC, etc. apparatus for complementary chemical analysis is anticipated for biomedical laboratories.

  14. Accelerators for America's Future

    NASA Astrophysics Data System (ADS)

    Bai, Mei

    2016-03-01

    Particle accelerator, a powerful tool to energize beams of charged particles to a desired speed and energy, has been the working horse for investigating the fundamental structure of matter and fundermental laws of nature. Most known examples are the 2-mile long Stanford Linear Accelerator at SLAC, the high energy proton and anti-proton collider Tevatron at FermiLab, and Large Hadron Collider that is currently under operation at CERN. During the less than a century development of accelerator science and technology that led to a dazzling list of discoveries, particle accelerators have also found various applications beyond particle and nuclear physics research, and become an indispensible part of the economy. Today, one can find a particle accelerator at almost every corner of our lives, ranging from the x-ray machine at the airport security to radiation diagnostic and therapy in hospitals. This presentation will give a brief introduction of the applications of this powerful tool in fundermental research as well as in industry. Challenges in accelerator science and technology will also be briefly presented

  15. The altered glucose metabolism in tumor and a tumor acidic microenvironment associated with extracellular matrix metalloproteinase inducer and monocarboxylate transporters

    PubMed Central

    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

  16. Death receptor 6 (DR6) is required for mouse B16 tumor angiogenesis via the NF-κB, P38 MAPK and STAT3 pathways

    PubMed Central

    Yang, X; Shi, B; Li, L; Xu, Z; Ge, Y; Shi, J; Liu, Y; Zheng, D

    2016-01-01

    Although death receptor 6 (DR6) is aberrantly expressed in certain cancer cell lines, its function, signaling pathway and potential clinical significance in tumor progression are not well characterized. We report here that knocking down DR6 in the mouse B16 cell line has no effect on B16 cell death in vitro but suppresses xenograft B16 tumor growth by preventing tumor blood vessel formation in vivo. Deficiency of DR6 changes cytokine expression and secretion; in particular, it inhibits the proinflammatory cytokine interleukin-6 (IL-6), which is able to induce the expression of the angiogenesis-related factors: vascular endothelial growth factor-A, platelet-derived growth factor-β, vascular endothelial growth factor-D and platelet-derived growth factor receptor-α. Further experiments demonstrate that DR6-dependent angiogenesis is involved in the IL-6/P38 MAPK and IL-6/STAT3 pathways. Our novel findings demonstrate for the first time that DR6 expression in B16 cells facilitates tumor growth by accelerating tumor angiogenesis. Moreover, these results suggest that DR6 is involved in three important intracellular pathways that lead to homeostatic angiogenesis in tumor growth. PMID:26950598

  17. Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K

    PubMed Central

    Liu, Jeff C; Voisin, Veronique; Wang, Sharon; Wang, Dong-Yu; Jones, Robert A; Datti, Alessandro; Uehling, David; Al-awar, Rima; Egan, Sean E; Bader, Gary D; Tsao, Ming; Mak, Tak W; Zacksenhaus, Eldad

    2014-01-01

    The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV-Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53-deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling. PMID:25330770

  18. Diffusive Shock Acceleration and Reconnection Acceleration Processes

    NASA Astrophysics Data System (ADS)

    Zank, G. P.; Hunana, P.; Mostafavi, P.; Le Roux, J. A.; Li, Gang; Webb, G. M.; Khabarova, O.; Cummings, A.; Stone, E.; Decker, R.

    2015-12-01

    Shock waves, as shown by simulations and observations, can generate high levels of downstream vortical turbulence, including magnetic islands. We consider a combination of diffusive shock acceleration (DSA) and downstream magnetic-island-reconnection-related processes as an energization mechanism for charged particles. Observations of electron and ion distributions downstream of interplanetary shocks and the heliospheric termination shock (HTS) are frequently inconsistent with the predictions of classical DSA. We utilize a recently developed transport theory for charged particles propagating diffusively in a turbulent region filled with contracting and reconnecting plasmoids and small-scale current sheets. Particle energization associated with the anti-reconnection electric field, a consequence of magnetic island merging, and magnetic island contraction, are considered. For the former only, we find that (i) the spectrum is a hard power law in particle speed, and (ii) the downstream solution is constant. For downstream plasmoid contraction only, (i) the accelerated spectrum is a hard power law in particle speed; (ii) the particle intensity for a given energy peaks downstream of the shock, and the distance to the peak location increases with increasing particle energy, and (iii) the particle intensity amplification for a particular particle energy, f(x,c/{c}0)/f(0,c/{c}0), is not 1, as predicted by DSA, but increases with increasing particle energy. The general solution combines both the reconnection-induced electric field and plasmoid contraction. The observed energetic particle intensity profile observed by Voyager 2 downstream of the HTS appears to support a particle acceleration mechanism that combines both DSA and magnetic-island-reconnection-related processes.

  19. Rosiglitazone impedes Porphyromonas gingivalis-accelerated atherosclerosis by downregulating the TLR/NF-κB signaling pathway in atherosclerotic mice.

    PubMed

    Pan, Shengbo; Lei, Lang; Chen, Shuai; Li, Houxuan; Yan, Fuhua

    2014-12-01

    Porphyromonas gingivalis,a predominant periodontal pathogen, is known to accelerate atherosclerosis in hyperlipidemic animals via aberrant inflammatory responses. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to exert anti-inflammatory effects in vitro. The purpose of the present study was to investigate the potential protective role of the PPARγ agonist rosiglitazone in pathogen accelerated atherosclerosis in an apolipoprotein E-deficient (ApoE-/-) mouse model. ApoE-/- mice were inoculated intravenously with live P. gingivalis (strain 33277) or the buffer vehicle and treated with rosiglitazone or saline over a 10-week period. Their atherosclerotic status in aortic artery was assessed through histomorphometric analysis, inflammatory agent and lipid profiles in blood was determined by ELISA, and levels of relevant cytokines and Toll-like receptors (TLRs) in aortic tissues were evaluated using immunohistochemistry and quantitative PCR. P. gingivalis inoculation was associated with increased atherosclerotic plaque formation in the aorta and higher levels of serum pro-inflammatory cytokines (tumor necrosis factor-α, monocyte chemotactic protein-1 and interleukin-1β), but the serum lipid profile was not affected by P. gingivalis infection. Levels of tumor necrosis factor-α, monocyte chemotactic protein-1 intercellular cell adhesion molecule-1 and TLRs were higher in the aortic tissues of mice exposed to P. gingivalis, and activation of nuclear factor-κB was also observed. In both P. gingivalis-treated and -untreated ApoE-/- mice, rosiglitazone treatment was associated with less atherosclerotic plaque formation; lower serum inflammatory cytokines, total cholesterol, and low density lipoprotein cholesterol; higher levels of PPARγ, lower amounts of TLR2/4 and downregulated nuclear factor-κB activity in aortic tissues. These findings suggest that rosiglitazone mitigates or prevents P. gingivalis-accelerated atherosclerosis by

  20. Trends in accelerator technology for hadron therapy

    NASA Astrophysics Data System (ADS)

    Kostromin, S. A.; Syresin, E. M.

    2013-12-01

    Hadron therapy with protons and carbon ions is one of the most effective branches in radiation oncology. It has advantages over therapy using gamma radiation and electron beams. Fifty thousand patients a year need such treatment in Russia. A review of the main modern trends in the development of accelerators for therapy and treatment techniques concerned with respiratory gated irradiation and scanning with the intensity modulated pencil beams is given. The main stages of formation, time structure, and the main parameters of the beams used in proton therapy, as well as the requirements for medicine accelerators, are considered. The main results of testing with the beam of the C235-V3 cyclotron for the first Russian specialized hospital proton therapy center in Dimitrovgrad are presented. The use of superconducting accelerators and gantry systems for hadron therapy is considered.