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Sample records for cell chymase limits

  1. Chymase

    DEFF Research Database (Denmark)

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar

    2015-01-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical...... condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition...... resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell...

  2. Mast cell chymase potentiates histamine-induced wheal formation in the skin of ragweed-allergic dogs.

    OpenAIRE

    Rubinstein, I; Nadel, J A; Graf, P D; Caughey, G H

    1990-01-01

    Skin mast cells release the neutral protease chymase along with histamine during degranulation. To test the hypothesis that chymase modulates histamine-induced plasma extravasation, we measured wheal formation following intradermal injection of purified mast cell chymase and histamine into the skin of ragweed-allergic dogs. We found that chymase greatly augments histamine-induced wheal formation. The magnitude of the potentiating effect increases with increasing doses of chymase and becomes m...

  3. GPR30 decreases cardiac chymase/angiotensin II by inhibiting local mast cell number

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Zhuo [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Department of Cardiology, Jinan Central Hospital, Affiliated with Shandong University, 105 Jiefang Road, Jinan, 250013 (China); Wang, Hao; Lin, Marina [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Groban, Leanne, E-mail: lgroban@wakehealth.edu [Department of Anesthesiology, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27159-1009 (United States); Hypertension and Vascular Disease Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States); Office of Women in Medicine and Science, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (United States)

    2015-03-27

    Chronic activation of the novel estrogen receptor GPR30 by its agonist G1 mitigates the adverse effects of estrogen (E2) loss on cardiac structure and function. Using the ovariectomized (OVX) mRen2.Lewis rat, an E2-sensitive model of diastolic dysfunction, we found that E2 status is inversely correlated with local cardiac angiotensin II (Ang II) levels, likely via Ang I/chymase-mediated production. Since chymase is released from cardiac mast cells during stress (e.g., volume/pressure overload, inflammation), we hypothesized that GPR30-related cardioprotection after E2 loss might occur through its opposing actions on cardiac mast cell proliferation and chymase production. Using real-time quantitative PCR, immunohistochemistry, and immunoblot analysis, we found mast cell number, chymase expression, and cardiac Ang II levels were significantly increased in the hearts of OVX-compared to ovary-intact mRen2.Lewis rats and the GPR30 agonist G1 (50 mg/kg/day, s.c.) administered for 2 weeks limited the adverse effects of estrogen loss. In vitro studies revealed that GPR30 receptors are expressed in the RBL-2H3 mast cell line and G1 inhibits serum-induced cell proliferation in a dose-dependent manner, as determined by cell counting, BrdU incorporation assay, and Ki-67 staining. Using specific antagonists to estrogen receptors, blockage of GPR30, but not ERα or ERβ, attenuated the inhibitory effects of estrogen on BrdU incorporation in RBL-2H3 cells. Further study of the mechanism underlying the effect on cell proliferation showed that G1 inhibits cyclin-dependent kinase 1 (CDK1) mRNA and protein expression in RBL-2H3 cells in a dose-dependent manner. - Highlights: • GPR30 activation limits mast cell number in hearts from OVX mRen2.Lewis rats. • GPR30 activation decreases cardiac chymase/angiotensin II after estrogen loss. • GPR30 activation inhibits RBL-2H3 mast cell proliferation and CDK1 expression.

  4. Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis.

    Science.gov (United States)

    Kosanovic, Djuro; Luitel, Himal; Dahal, Bhola Kumar; Cornitescu, Teodora; Janssen, Wiebke; Danser, A H Jan; Garrelds, Ingrid M; De Mey, Jo G R; Fazzi, Gregorio; Schiffers, Paul; Iglarz, Marc; Fischli, Walter; Ghofrani, Hossein Ardeschir; Weissmann, Norbert; Grimminger, Friedrich; Seeger, Werner; Reiss, Irwin; Schermuly, Ralph Theo

    2015-10-01

    Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. Copyright ©ERS 2015.

  5. Mast Cells and MCPT4 Chymase Promote Renal Impairment after Partial Ureteral Obstruction

    Directory of Open Access Journals (Sweden)

    Maguelonne Pons

    2017-05-01

    Full Text Available Obstructive nephropathy constitutes a major cause of pediatric renal progressive disease. The mechanisms leading to disease progression are still poorly understood. Kidney fibrotic lesions are reproduced using a model of partial unilateral ureteral obstruction (pUUO in newborn mice. Based on data showing significant mast cell (MC infiltration in patients, we investigated the role of MC and murine MCPT4, a MC-released chymase, in pUUO using MC- (Wsh/sh, MCPT4-deficient (Mcpt4−/−, and wild-type (WT mice. Measurement of kidney length and volume by magnetic resonance imaging (MRI as well as postmortem kidney weight revealed hypotrophy of operated right kidneys (RKs and compensatory hypertrophy of left kidneys. Differences between kidneys were major for WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− mice. Fibrosis development was focal and increased only in WT-obstructed kidneys. No differences were noticed for local inflammatory responses, but serum CCL2 was significantly higher in WT versus Mcpt4−/− and Wsh/sh mice. Alpha-smooth muscle actin (αSMA expression, a marker of epithelial–mesenchymal transition (EMT, was high in WT, minimal for Wsh/sh, and intermediate for Mcpt4−/− RK. Supernatants of activated MC induced αSMA in co-culture experiments with proximal tubular epithelial cells. Our results support a role of MC in EMT and parenchyma lesions after pUUO involving, at least partly, MCPT4 chymase. They confirm the importance of morphologic impairment evaluation by MRI in pUUO.

  6. Mast cell lines HMC-1 and LAD2 in comparison with mature human skin mast cells--drastically reduced levels of tryptase and chymase in mast cell lines.

    Science.gov (United States)

    Guhl, Sven; Babina, Magda; Neou, Angelos; Zuberbier, Torsten; Artuc, Metin

    2010-09-01

    To circumvent the costly isolation procedure associated with tissue mast cells (MC), two human MC lines, i.e. HMC-1 and LAD2, are frequently employed, but their relation to mature MC is unknown. Here, we quantitatively assessed their expression of MC markers in direct comparison to skin MC (sMC). sMC expressed all lineage markers at highest and HMC-1 cells at lowest levels. LAD2 cells expressed comparable high-affinity IgE receptor alpha (FcepsilonRIalpha) and FcepsilonRIgamma but less FcepsilonRIbeta than sMC and displayed slightly reduced, but robust FcepsilonRI-mediated histamine release. Only minor differences were found for total histamine content and c-Kit expression. Huge, and to this level unexpected, differences were found for MC tryptase and chymase, with sMC > LAD2 > HMC-1. Taken together, HMC-1 cells represent very immature malignantly transformed MC, whereas LAD2 cells can be considered intermediately differentiated. Because of the minute levels of MC proteases, MC lines can serve as surrogates of tissue MC to a limited degree only.

  7. Airway responsiveness to mannitol in asthma is associated with chymase-positive mast cells and eosinophilic airway inflammation

    DEFF Research Database (Denmark)

    Sverrild, Asger; Bergqvist, A; Baines, K J

    2016-01-01

    BACKGROUND: Airway hyperresponsiveness (AHR) to inhaled mannitol is associated with indirect markers of mast cell activation and eosinophilic airway inflammation. It is unknown how AHR to mannitol relates to mast cell phenotype, mast cell function and measures of eosinophilic inflammation in airway...... tissue. We compared the number and phenotype of mast cells, mRNA expression of mast cell-associated genes and number of eosinophils in airway tissue of subjects with asthma and healthy controls in relation to AHR to mannitol. METHODS: Airway hyperresponsiveness to inhaled mannitol was measured in 23 non......-smoking, corticosteroid-free asthmatic individuals and 10 healthy controls. Mast cells and eosinophils were identified in mucosal biopsies from all participants. Mast cells were divided into phenotypes based on the presence of chymase. mRNA expression of mast cell-associated genes was measured by real-time PCR. RESULTS...

  8. The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

    DEFF Research Database (Denmark)

    Grujic, Mirjana; Paivandy, Aida; Gustafson, Ann-Marie

    2017-01-01

    by higher expression of melanoma-specific genes in lungs of Mcpt4/Mcpt6/CPA3-deficient vs. wildtype mice. Cytokine profiling showed that the levels of CXCL16, a chemokine with effects on T cell populations and NKT cells, were significantly lower in lungs of Mcpt4/Mcpt6/Cpa3-deficient animals vs. controls......, suggesting that multiple mast cell protease deficiency might affect T cell or NKT cell populations. In line with this, we found that the Mcpt4/Mcpt6/Cpa3-deficiency was associated with a reduction in cells expressing CD1d, a MHC class 1-like molecule that is crucial for presenting antigen to invariant NKT (iNKT......) cells. Together, these findings indicate a protective role of mast cell-specific proteases in melanoma dissemination, and suggest that this effect involves a CXCL16/CD1d/NKT cell axis....

  9. Chymase mediates injury and mitochondrial damage in cardiomyocytes during acute ischemia/reperfusion in the dog.

    Science.gov (United States)

    Zheng, Junying; Wei, Chih-Chang; Hase, Naoki; Shi, Ke; Killingsworth, Cheryl R; Litovsky, Silvio H; Powell, Pamela C; Kobayashi, Tsunefumi; Ferrario, Carlos M; Rab, Andras; Aban, Inmaculada; Collawn, James F; Dell'Italia, Louis J

    2014-01-01

    Cardiac ischemia and reperfusion (I/R) injury occurs because the acute increase in oxidative/inflammatory stress during reperfusion culminates in the death of cardiomyocytes. Currently, there is no drug utilized clinically that attenuates I/R injury in patients. Previous studies have demonstrated degranulation of mast cell contents into the interstitium after I/R. Using a dog model of I/R, we tested the role of chymase, a mast cell protease, in cardiomyocyte injury using a specific oral chymase inhibitor (CI). 15 adult mongrel dogs had left anterior descending artery occlusion for 60 min and reperfusion for 100 minutes. 9 dogs received vehicle and 6 were pretreated with a specific CI. In vivo cardiac microdialysis demonstrated a 3-fold increase in interstitial fluid chymase activity in I/R region that was significantly decreased by CI. CI pretreatment significantly attenuated loss of laminin, focal adhesion complex disruption, and release of troponin I into the circulation. Microarray analysis identified an I/R induced 17-fold increase in nuclear receptor subfamily 4A1 (NR4A1) and significantly decreased by CI. NR4A1 normally resides in the nucleus but can induce cell death on migration to the cytoplasm. I/R caused significant increase in NR4A1 protein expression and cytoplasmic translocation, and mitochondrial degradation, which were decreased by CI. Immunohistochemistry also revealed a high concentration of chymase within cardiomyocytes after I/R. In vitro, chymase added to culture HL-1 cardiomyocytes entered the cytoplasm and nucleus in a dynamin-dependent fashion, and promoted cytoplasmic translocation of NR4A1 protein. shRNA knockdown of NR4A1 on pre-treatment of HL-1 cells with CI significantly decreased chymase-induced cell death and mitochondrial damage. These results suggest that the beneficial effects of an orally active CI during I/R are mediated in the cardiac interstitium as well as within the cardiomyocyte due to a heretofore-unrecognized chymase

  10. Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients.

    Science.gov (United States)

    Tissera, Hasitha; Rathore, Abhay P S; Leong, Wei Yee; Pike, Brian L; Warkentien, Tyler E; Farouk, Farouk S; Syenina, Ayesa; Eong Ooi, Eng; Gubler, Duane J; Wilder-Smith, Annelies; St John, Ashley L

    2017-11-27

    Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels. Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS. An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF. These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

  11. Molecular modeling study for inhibition mechanism of human chymase and its application in inhibitor design.

    Directory of Open Access Journals (Sweden)

    Mahreen Arooj

    Full Text Available Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41 upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most active compound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes.

  12. Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

    OpenAIRE

    Yang Ting; Xu Dan; An Jin; He Guang-Ming; Chen Ya-Juan; Chen Lei; Ning Yun-Ye; Zhang Shang-Fu; Han Su-Xia; Wang Tao; Zhang Xiao-Hong; Wen Fu-Qiang

    2010-01-01

    Abstract Background Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-β1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH. Methods Hamsters were exposed ...

  13. Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

    Directory of Open Access Journals (Sweden)

    Yang Ting

    2010-03-01

    Full Text Available Abstract Background Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH in chronic obstructive pulmonary disease (COPD. Chymase has been shown to function in the enzymatic production of angiotensin II (AngII and the activation of transforming growth factor (TGF-β1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH. Methods Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction. Results Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-β1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE activity in hamster lungs. Conclusions These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-β1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.

  14. Interaction of human chymase with ginkgolides, terpene trilactones of Ginkgo biloba investigated by molecular docking simulations.

    Science.gov (United States)

    Dubey, Amit; Marabotti, Anna; Ramteke, Pramod W; Facchiano, Angelo

    2016-04-29

    The search for natural chymase inhibitors has a good potential to provide a novel therapeutic approach against the cardiovascular diseases and other heart ailments. We selected from literature 20 promising Ginkgo biloba compounds, and tested them for their potential ability to bind chymase enzyme using docking and a deep analysis of surface pocket features. Docking results indicated that the compounds may interact with the active site of human chymase, with favorable distinct interactions with important residues Lys40, His57, Lys192, Phe191, Val146, Ser218, Gly216, and Ser195. In particular, proanthocyanidin is the one with the best-predicted binding energy, with seven hydrogen bonds. Interestingly, all active G. biloba compounds have formed the hydrogen bond interactions with the positively charged Lys192 residue at the active site, involved in the mechanism of pH enhancement for the cleavage of angiotensin I site. Ginkgolic acid and proanthocyanidin have better predicted binding energy towards chymase than other serine proteases, i.e kallikrein, tryptase and elastase, suggesting specificity for chymase inhibition. Our study suggests these G. biloba compounds are a promising starting point for developing chymase inhibitors for the potential development of future drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Psoriasis pathogenesis - Pso p27 is generated from SCCA1 with chymase.

    Science.gov (United States)

    Lysvand, Hilde; Hagen, Lars; Klubicka, Lidija; Slupphaug, Geir; Iversen, Ole-Jan

    2014-05-01

    Psoriasis is a chronic inflammatory skin disease with unknown aetiology. Infiltration of inflammatory cells as the initial event in the development of new psoriatic plaques together with the defined inflamed areas of such lesions argues for an immunological disease with a local production of a causal antigen. The auto-antigen Pso p27 is a protein expressed in the skin lesions. We recently demonstrated that Pso p27 is homologous to the core amino acid sequences of squamous cell carcinoma antigens 1 and 2 (SCCA1/2) and it is apparently generated from SCCA molecules by digestion with highly specific endoproteases. In this communication we demonstrate the generation of Pso p27 from SCCA1 with extracts from psoriatic scale and even more remarkably, the generation of Pso p27 from SCCA1 in the presence of mast cell associated chymase. These findings open up for new therapeutic strategies in psoriasis and probably also in other autoimmune diseases as Pso p27 epitopes have been detected in diseased tissues from patients with various chronic inflammatory diseases. Copyright © 2014. Published by Elsevier B.V.

  16. Pericytes limit tumor cell metastasis

    DEFF Research Database (Denmark)

    Xian, Xiaojie; Håkansson, Joakim; Ståhlberg, Anders

    2006-01-01

    Previously we observed that neural cell adhesion molecule (NCAM) deficiency in beta tumor cells facilitates metastasis into distant organs and local lymph nodes. Here, we show that NCAM-deficient beta cell tumors grew leaky blood vessels with perturbed pericyte-endothelial cell-cell interactions...... and deficient perivascular deposition of ECM components. Conversely, tumor cell expression of NCAM in a fibrosarcoma model (T241) improved pericyte recruitment and increased perivascular deposition of ECM molecules. Together, these findings suggest that NCAM may limit tumor cell metastasis by stabilizing...... the microvessel wall. To directly address whether pericyte dysfunction increases the metastatic potential of solid tumors, we studied beta cell tumorigenesis in primary pericyte-deficient Pdgfb(ret/ret) mice. This resulted in beta tumor cell metastases in distant organs and local lymph nodes, demonstrating a role...

  17. Atick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation

    Czech Academy of Sciences Publication Activity Database

    Chmelař, Jindřich; Oliveira, C. J.; Řezáčová, Pavlína; Francischetti, I.M.B.; Kovářová, Zuzana; Pejler, G.; Kopáček, Petr; Ribeiro, J.M.C.; Mareš, Michael; Kopecký, Jan; Kotsyfakis, Michalis

    2011-01-01

    Roč. 117, č. 2 (2011), s. 736-744 ISSN 0006-4971 R&D Projects: GA AV ČR IAA600960811; GA MŠk(CZ) LC06009; GA ČR(CZ) GAP207/10/2183 Institutional research plan: CEZ:AV0Z60220518; CEZ:AV0Z40550506 Keywords : parasite serpin * IRS-2 * tick * Ixodes ricinus * platelet aggregation * inflammation * cathepsin G * chymase Subject RIV: EC - Immunology Impact factor: 9.898, year: 2011

  18. ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?

    NARCIS (Netherlands)

    B. Tom (Beril); I.M. Garrelds (Ingrid); E. Scalbert; A.P.A. Stegmann (Sander); F. Boomsma (Frans); P.R. Saxena (Pramod Ranjan); A.H.J. Danser (Jan)

    2003-01-01

    textabstractOBJECTIVE: The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II,

  19. Limitations of Commercializing Fuel Cell Technologies

    Science.gov (United States)

    Nordin, Normayati

    2010-06-01

    Fuel cell is the technology that, nowadays, is deemed having a great potential to be used in supplying energy. Basically, fuel cells can be categorized particularly by the kind of employed electrolyte. Several fuel cells types which are currently identified having huge potential to be utilized, namely, Solid Oxide Fuel Cells (SOFC), Molten Carbonate Fuel Cells (MCFC), Alkaline Fuel Cells (AFC), Phosphoric Acid Fuel Cells (PAFC), Polymer Electron Membrane Fuel Cell (PEMFC), Direct Methanol Fuel Cells (DMFC) and Regenerative Fuel Cells (RFC). In general, each of these fuel cells types has their own characteristics and specifications which assign the capability and suitability of them to be utilized for any particular applications. Stationary power generations and transport applications are the two most significant applications currently aimed for the fuel cell market. It is generally accepted that there are lots of advantages if fuel cells can be excessively commercialized primarily in context of environmental concerns and energy security. Nevertheless, this is a demanding task to be accomplished, as there is some gap in fuel cells technology itself which needs a major enhancement. It can be concluded, from the previous study, cost, durability and performance are identified as the main limitations to be firstly overcome in enabling fuel cells technology become viable for the market.

  20. Retinoic Acid Negatively Impacts Proliferation and MCTC Specific Attributes of Human Skin Derived Mast Cells, but Reinforces Allergic Stimulability

    Directory of Open Access Journals (Sweden)

    Magda Babina

    2017-02-01

    Full Text Available The Vitamin-A-metabolite retinoic acid (RA acts as a master regulator of cellular programs. Mast cells (MCs are primary effector cells of type-I-allergic reactions. We recently uncovered that human cutaneous MCs are enriched with RA network components over other skin cells. Yet, direct experimental evidence on the significance of the RA-MC axis is limited. Here, skin-derived cultured MCs were exposed to RA for seven days and investigated by flow-cytometry (BrdU incorporation, Annexin/PI, FcεRI, microscopy, RT-qPCR, histamine quantitation, protease activity, and degranulation assays. We found that while MC size and granularity remained unchanged, RA potently interfered with MC proliferation. Conversely, a modest survival-promoting effect from RA was noted. The granule constituents, histamine and tryptase, remained unaffected, while RA had a striking impact on MC chymase, whose expression dropped by gene and by peptidase activity. The newly uncovered MRGPRX2 performed similarly to chymase. Intriguingly, RA fostered allergic MC degranulation, in a way completely uncoupled from FcεRI expression, but it simultaneously restricted MRGPRX2-triggered histamine release in agreement with the reduced receptor expression. Vitamin-A-derived hormones thus re-shape skin-derived MCs numerically, phenotypically, and functionally. A general theme emerges, implying RA to skew MCs towards processes associated with (allergic inflammation, while driving them away from the skin-imprinted MCTC (“MCs containing tryptase and chymase” signature (chymase, MRGPRX2. Collectively, MCs are substantial targets of the skin retinoid network.

  1. Cell Reprogramming, IPS Limitations, and Overcoming Strategies in Dental Bioengineering

    Directory of Open Access Journals (Sweden)

    Gaskon Ibarretxe

    2012-01-01

    Full Text Available The procurement of induced pluripotent stem cells, or IPS cells, from adult differentiated animal cells has the potential to revolutionize future medicine, where reprogrammed IPS cells may be used to repair disease-affected tissues on demand. The potential of IPS cell technology is tremendous, but it will be essential to improve the methodologies for IPS cell generation and to precisely evaluate each clone and subclone of IPS cells for their safety and efficacy. Additionally, the current state of knowledge on IPS cells advises that research on their regenerative properties is carried out in appropriate tissue and organ systems that permit a safe assessment of the long-term behavior of these reprogrammed cells. In the present paper, we discuss the mechanisms of cell reprogramming, current technical limitations of IPS cells for their use in human tissue engineering, and possibilities to overcome them in the particular case of dental regeneration.

  2. The limiting efficiency of band gap graded solar cells

    Energy Technology Data Exchange (ETDEWEB)

    Rafat, Nadia H. [Faculty of Engineering, Cairo University, Giza (Egypt); Habib, S.E.D. [Faculty of electronics and communication, Cairo University, Giza (Egypt)

    1998-09-04

    Two fundamental mechanisms limit the maximum attainable efficiency of solar cells, namely the radiative recombination and Auger recombination. We show in this paper that proper band gap grading of the solar cell localizes the Auger recombination around the metallurgical junction. Two beneficial effects result from this Auger recombination localization; first the cell is less sensitive to the surface conditions, and second, the previous estimates for the limiting efficiency of solar cells by Shockley, Tiedje, and Green are revised upwardly. We calculate the optimum bandgap grading profile for several real material systems, including GaInAsP lattice matched to InP, and a-SiGe on a-Si substrate

  3. The limited application of stem cells in medicine: a review.

    Science.gov (United States)

    Poulos, Jordan

    2018-01-02

    The history of stem cell therapies is one of a limited number of clinical applications despite a vast therapeutic potential. Major breakthroughs in stem cell research have not yet enjoyed clinical success-all stem cell therapies bar hematopoietic stem cell transplantations remain experimental. With the increased risk of organ failure and neurodegenerative disease associated with our ability to push the boundaries of life expectancy comes an increased pressure to pioneer novel stem cell-based therapeutic approaches. We conclude that the failure of such therapies to achieve clinical translation stems from the polarising effect of the ethical debate around their use. The intractability of the ethical debate is double edged: legislators not only have placed tighter restrictions on certain stem cell therapies, but do so in favour of less controversial cells which will have worse outcomes for patients. It is by considering this relationship between the politics, ethics and science of stem cells that the reasons for the currently limited clinical significance of stem cell therapies be realised.

  4. The generalized Shockley-Queisser limit for nanostructured solar cells

    Science.gov (United States)

    Xu, Yunlu; Gong, Tao; Munday, Jeremy N.

    2015-09-01

    The Shockley-Queisser limit describes the maximum solar energy conversion efficiency achievable for a particular material and is the standard by which new photovoltaic technologies are compared. This limit is based on the principle of detailed balance, which equates the photon flux into a device to the particle flux (photons or electrons) out of that device. Nanostructured solar cells represent a novel class of photovoltaic devices, and questions have been raised about whether or not they can exceed the Shockley-Queisser limit. Here we show that single-junction nanostructured solar cells have a theoretical maximum efficiency of ˜42% under AM 1.5 solar illumination. While this exceeds the efficiency of a non-concentrating planar device, it does not exceed the Shockley-Queisser limit for a planar device with optical concentration. We consider the effect of diffuse illumination and find that with optical concentration from the nanostructures of only × 1,000, an efficiency of 35.5% is achievable even with 25% diffuse illumination. We conclude that nanostructured solar cells offer an important route towards higher efficiency photovoltaic devices through a built-in optical concentration.

  5. Induced Pluripotent Stem Cells in Dermatology: Potentials, Advances, and Limitations

    Science.gov (United States)

    Bilousova, Ganna; Roop, Dennis R.

    2014-01-01

    The discovery of methods for reprogramming adult somatic cells into induced pluripotent stem cells (iPSCs) has raised the possibility of producing truly personalized treatment options for numerous diseases. Similar to embryonic stem cells (ESCs), iPSCs can give rise to any cell type in the body and are amenable to genetic correction by homologous recombination. These ESC properties of iPSCs allow for the development of permanent corrective therapies for many currently incurable disorders, including inherited skin diseases, without using embryonic tissues or oocytes. Here, we review recent progress and limitations of iPSC research with a focus on clinical applications of iPSCs and using iPSCs to model human diseases for drug discovery in the field of dermatology. PMID:25368014

  6. Recurrent anal fistulae: limited surgery supported by stem cells.

    Science.gov (United States)

    Garcia-Olmo, Damian; Guadalajara, Hector; Rubio-Perez, Ines; Herreros, Maria Dolores; de-la-Quintana, Paloma; Garcia-Arranz, Mariano

    2015-03-21

    To study the results of stem-cell therapy under a Compassionate-use Program for patients with recurrent anal fistulae. Under controlled circumstances, and approved by European and Spanish laws, a Compassionate-use Program allows the use of stem-cell therapy for patients with very complex anal fistulae. Candidates had previously undergone multiple surgical interventions that had failed to resolve the fistulae, and presented symptomatic recurrence. The intervention consisted of limited surgery (with closure of the internal opening), followed by local implant of stem cells in the fistula-tract wall. Autologous expanded adipose-derived stem cells were the main cell type selected for implant. The first evaluation was performed on the 8(th) postoperative week; outcome was classified as response or partial response. Evaluation one year after the intervention confirmed if complete healing of the fistula was achieved. Ten patients (8 male) with highly recurrent and complex fistulae were treated (mean age: 49 years, range: 28-76 years). Seven cases were non-Crohn's fistulae, and three were Crohn's-associated fistulae. Previous surgical attempts ranged from 3 to 12. Two patients presented with preoperative incontinence (Wexner scores of 12 and 13 points). After the intervention, six patients showed clinical response on the 8(th) postoperative week, with a complete cessation of suppuration from the fistula. Three patients presented a partial response, with an evident decrease in suppuration. A year later, six patients (60%) remained healed, with complete reepithelization of the external opening. Postoperative Wexner Scores were 0 in six cases. The two patients with previous incontinence improved their scores from 12 to 8 points and from 13 to 5 points. No adverse reactions or complications related to stem-cell therapy were reported during the study period. Stem cells are safe and useful for treating anal fistulae. Healing can be achieved in severe cases, sparing fecal

  7. Immunoprofiling of human uterine mast cells identifies three phenotypes and expression of ERβ and glucocorticoid receptor [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Bianca De Leo

    2017-05-01

    Full Text Available Background: Human mast cells (MCs are long-lived tissue-resident immune cells characterised by granules containing the proteases chymase and/or tryptase. Their phenotype is modulated by their tissue microenvironment. The human uterus has an outer muscular layer (the myometrium surrounding the endometrium, both of which play an important role in supporting a pregnancy. The endometrium is a sex steroid target tissue consisting of epithelial cells (luminal, glandular surrounded by a multicellular stroma, with the latter containing an extensive vascular compartment as well as fluctuating populations of immune cells that play an important role in regulating tissue function. The role of MCs in the human uterus is poorly understood with little known about their regulation or the impact of steroids on their differentiation status. The current study had two aims: 1 To investigate the spatial and temporal location of uterine MCs and determine their phenotype; 2 To determine whether MCs express receptors for steroids implicated in uterine function, including oestrogen (ERα, ERβ, progesterone (PR and glucocorticoids (GR. Methods: Tissue samples from women (n=46 were used for RNA extraction or fixed for immunohistochemistry. Results: Messenger RNAs encoded by TPSAB1 (tryptase and CMA1 (chymase were detected in endometrial tissue homogenates. Immunohistochemistry revealed the relative abundance of tryptase MCs was myometrium>basal endometrium>functional endometrium. We show for the first time that uterine MCs are predominantly of the classical MC subtypes: (positive, +; negative, - tryptase+/chymase- and tryptase+/chymase+, but a third subtype was also identified (tryptase-/chymase+. Tryptase+ MCs were of an ERβ+/ERα-/PR-/GR+ phenotype mirroring other uterine immune cell populations, including natural killer cells. Conclusions: Endometrial tissue resident immune MCs have three protease-specific phenotypes. Expression of both ERβ and GR in MCs mirrors

  8. Limiter

    Science.gov (United States)

    Cohen, S.A.; Hosea, J.C.; Timberlake, J.R.

    1984-10-19

    A limiter with a specially contoured front face is provided. The front face of the limiter (the plasma-side face) is flat with a central indentation. In addition, the limiter shape is cylindrically symmetric so that the limiter can be rotated for greater heat distribution. This limiter shape accommodates the various power scrape-off distances lambda p, which depend on the parallel velocity, V/sub parallel/, of the impacting particles.

  9. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Heizmann, Beate [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Sellars, MacLean [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Macias-Garcia, Alejandra [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139 (United States); Chan, Susan, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Kastner, Philippe, E-mail: scpk@igbmc.fr [Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch (France); Faculté de Médecine, Université de Strasbourg, Strasbourg (France)

    2016-02-12

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  10. Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways

    International Nuclear Information System (INIS)

    Heizmann, Beate; Sellars, MacLean; Macias-Garcia, Alejandra; Chan, Susan; Kastner, Philippe

    2016-01-01

    The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.

  11. Simulation of limiting dilution technique in determination of immunocompetent cells frequency in irradiated cell cultures

    International Nuclear Information System (INIS)

    Martini Filho, R.J.; Barlette, V.E.; Goes, E.G.; Covas, D.T.; Orellana, M.

    2001-01-01

    Limiting dilution techniques (LDA) dose-response data have been used to detect immunocompetent T-Cells in microcultures. In this work, LDA frequencies estimates was obtained using χ2 minimization for irradiated cells in a range of 500 to 1,500 cGy. (author)

  12. Limiting dilution analysis of the stem cells for T cell lineage

    International Nuclear Information System (INIS)

    Katsura, Y.; Kina, T.; Amagai, T.; Tsubata, T.; Hirayoshi, K.; Takaoki, Y.; Sado, T.; Nishikawa, S.I.

    1986-01-01

    Stem cell activities of bone marrow, spleen, thymus, and fetal liver cells for T cell lineage were studied comparatively by transferring the cells from these organs through i.v. or intrathymus (i.t.) route into right leg- and tail-shielded (L-T-shielded) and 900 R-irradiated recipient mice, which were able to survive without supplying hemopoietic stem cells. Cells from B10.Thy-1.1 (H-2b, Thy-1.1) mice were serially diluted and were transferred into L-T-shielded and irradiated C57BL/6 (H-2b, Thy-1.2) mice, and 21 days later the thymus cells of recipient mice were assayed for Thy-1.1+ cells by flow cytofluorometry. The percentage of recipient mice possessing donor-type T cells was plotted against the number of cells transferred, and the stem cell activity in each cell source was expressed as the 50% positive value, the number of donor cells required for generating donor-type T cells in the thymuses of 50% of recipient mice. In i.v. transfer experiments, the activity of bone marrow cells was similar to that of fetal liver cells, and about 100 times and nearly 1000 times higher than those of spleen cells and thymus cells, respectively. In i.t. transfer experiments, the number of cells required for generating donor-type T cells was much lower than that in i.v. transfer experiments, although the ratio in 50% positive values between i.v. and i.t. transfers differed among cell sources. In i.t. transfers, the 50% positive value of bone marrow cells was five times, 400 times, and 500 times higher than that of fetal liver cells, spleen cells, and thymus cells, respectively. Our previous finding that stem cells are enriched in the spleens of mice which were whole body-irradiated and marrow-reconstituted 7 days earlier was confirmed also by the present limiting dilution assay carried out in i.v. as well as i.t. transfers

  13. The Limits of Linked Suppression for Regulatory T cells

    Directory of Open Access Journals (Sweden)

    Toshiro eIto

    2016-03-01

    Full Text Available Background: We have previously found that CD4+CD25+ regulatory T cells (T regs can adoptively transfer tolerance after its induction with co-stimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: 1 the T regs that transfer tolerance have the capacity for linked suppression, 2 the determinants that stimulate the T regs are expressed by the indirect pathway, and 3 the donor peptides contributing to these indirect determinants are derived from donor MHC antigens. Methods: 1st heart transplants were performed from the indicated donor strain to B10.D2 recipients along with co-stimulatory blockade treatment (250μg i.p. injection of MR1 on day 0 and 250μg i.p. injection of CTLA-4 Ig on day 2. At least 8 weeks later a 2nd heart transplant was performed to a new B10.D2 recipient that had been irradiated with 450 cGy. This recipient was given 40 x 106 naïve B10.D2 spleen cells plus 40 x 106 B10.D2 spleen cells from the first (tolerant recipient. We performed 3 different types of heart transplants with using various donor.Results: 1. T regs suppress the graft rejection in an antigen-specific manner. 2. T regs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion:The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC antigens.

  14. Association of mast cell-derived VEGF and proteases in Dengue shock syndrome.

    Directory of Open Access Journals (Sweden)

    Takahisa Furuta

    Full Text Available BACKGROUND: Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase and -related cytokines (IL-4, -9, and -17 between patients with differing severity of Dengue fever and healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: The study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF, Dengue hemorrhagic fever (DHF, and Dengue shock syndrome (DSS, as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9. CONCLUSIONS: As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.

  15. Association of Mast Cell-Derived VEGF and Proteases in Dengue Shock Syndrome

    Science.gov (United States)

    Furuta, Takahisa; Murao, Lyre Anni; Lan, Nguyen Thi Phuong; Huy, Nguyen Tien; Huong, Vu Thi Que; Thuy, Tran Thi; Tham, Vo Dinh; Nga, Cao Thi Phi; Ha, Tran Thi Ngoc; Ohmoto, Yasukazu; Kikuchi, Mihoko; Morita, Kouichi; Yasunami, Michio; Hirayama, Kenji; Watanabe, Naohiro

    2012-01-01

    Background Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase) and -related cytokines (IL-4, -9, and -17) between patients with differing severity of Dengue fever and healthy controls. Methodology/Principal Findings The study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF), Dengue hemorrhagic fever (DHF), and Dengue shock syndrome (DSS), as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9. Conclusions As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity. PMID:22363824

  16. Prosthetic graft infection: limitations of indium white blood cell scanning

    International Nuclear Information System (INIS)

    Brunner, M.C.; Mitchell, R.S.; Baldwin, J.C.; James, D.R.; Olcott, C. IV; Mehigan, J.T.; McDougall, I.R.; Miller, D.C.

    1986-01-01

    The lack of a rapid, noninvasive, and accurate method to confirm or rule out prosthetic graft infection continues to constitute a compelling and vexing clinical problem. A host of adjunctive diagnostic techniques has been used in the past, but early promising results subsequently have usually not yielded acceptable sensitivity (reflecting false negatives) and specificity (reflecting false positive) data. White blood cell (WBC) indium 111 scanning has recently been added to this list. The utility and accuracy of 111 In WBC scans were assessed by retrospective review of WBC scan results in 70 patients undergoing evaluation for possible prosthetic graft infection over a 7-year period. Operative and autopsy data (mean follow-up, 18 months for survivors with negative scans) were used to confirm the 22 positive, 45 negative, and three equivocal WBC scans. The false positive rate (+/- 70% confidence limits) was 36% +/- 6% (n = 8) among the 22 patients with positive scans (44% +/- 6% [11 of 25] if the three equivocal scans are included as false positive), yielding a specificity of 85% +/- 5% and an overall accuracy rate of 88% +/- 4% (80% +/- 5% and 84% +/- 5%, respectively, if the three equivocal cases are considered as false positive). All three patients with equivocal scans ultimately were judged not to have prosthetic graft infection. As implied by the high accuracy rate, the sensitivity of the test was absolute (100% [14 of 14]); there were no false negative results

  17. Potential and Limitation of HLA-Based Banking of Human Pluripotent Stem Cells for Cell Therapy

    Directory of Open Access Journals (Sweden)

    Casimir de Rham

    2014-01-01

    Full Text Available Great hopes have been placed on human pluripotent stem (hPS cells for therapy. Tissues or organs derived from hPS cells could be the best solution to cure many different human diseases, especially those who do not respond to standard medication or drugs, such as neurodegenerative diseases, heart failure, or diabetes. The origin of hPS is critical and the idea of creating a bank of well-characterized hPS cells has emerged, like the one that already exists for cord blood. However, the main obstacle in transplantation is the rejection of tissues or organ by the receiver, due to the three main immunological barriers: the human leukocyte antigen (HLA, the ABO blood group, and minor antigens. The problem could be circumvented by using autologous stem cells, like induced pluripotent stem (iPS cells, derived directly from the patient. But iPS cells have limitations, especially regarding the disease of the recipient and possible difficulties to handle or prepare autologous iPS cells. Finally, reaching standards of good clinical or manufacturing practices could be challenging. That is why well-characterized and universal hPS cells could be a better solution. In this review, we will discuss the interest and the feasibility to establish hPS cells bank, as well as some economics and ethical issues.

  18. Prospects and limitations of T cell receptor gene therapy

    NARCIS (Netherlands)

    Jorritsma, Annelies; Schotte, Remko; Coccoris, Miriam; de Witte, Moniek A.; Schumacher, Ton N. M.

    2011-01-01

    Adoptive transfer of antigen-specific T cells is an attractive means to provide cancer patients with immune cells of a desired specificity and the efficacy of such adoptive transfers has been demonstrated in several clinical trials. Because the T cell receptor is the single specificity-determining

  19. Two-dimensional diffusion limited system for cell growth

    International Nuclear Information System (INIS)

    Hlatky, L.

    1985-11-01

    A new cell system, the ''sandwich'' system, was developed to supplement multicellular spheroids as tumor analogues. Sandwiches allow new experimental approaches to questions of diffusion, cell cycle effects and radiation resistance in tumors. In this thesis the method for setting up sandwiches is described both theoretically and experimentally followed by its use in x-ray irradiation studies. In the sandwich system, cells are grown in a narrow gap between two glass slides. Where nutrients and waste products can move into or out of the local environment of the cells only by diffusing through the narrow gap between the slides. Due to the competition between cells, self-created gradients of nutrients and metabolic products are set up resulting in a layer of cells which resembles a living spheroid cross section. Unlike the cells of the spheroid, however, cells in all regions of the sandwich are visible. Therefore, the relative sizes of the regions and their time-dependent growth can be monitored visually without fixation or sectioning. The oxygen and nutrient gradients can be ''turned off'' at any time without disrupting the spatial arrangement of the cells by removing the top slide of the assembly and subsequently turned back on if desired. Removal of the top slide also provides access to all the cells, including those near the necrotic center, of the sandwich. The cells can then be removed for analysis outside the sandwich system. 61 refs., 17 figs

  20. Updated assessment of possibilities and limits for solar cells.

    Science.gov (United States)

    Nayak, Pabitra K; Cahen, David

    2014-03-12

    The remarkable advances over the past few years in performance of photovoltaic cells, including the advent of new absorber materials, call for an update to the previous assessment of prospects for future progress. The same simple criteria with some refinements, based on cell and module performance data, serve to evaluate and compare most types of solar cells. Apart from Si and InP, for all types the "best cells" have improved in conversion performances (and crystalline Si modules have made major strides in cost reduction). New cell types, such as "perovskite", sustainable chalcogenide, and quantum dot cells, are included. CdTe results bring those cells in line with other well-developed ones, lending some credence to the idea that the criteria provide the reader with knowledge, useful for gauging possible future technological developments. Additionally, the developments of the past few years show that, while the advent of more new cell types cannot be predicted, it can be aided and stimulated by innovative, daring, and creative new materials research. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Novel bandgap grading technique for enhancing the limiting efficiency of solar cells

    Energy Technology Data Exchange (ETDEWEB)

    Habib, S.E.-D.; Rafat, N.H. [Cairo Univ., Giza (Egypt). Faculty of Engineering

    1997-02-01

    The efficiency of solar cells is limited by radiative and/or Auger recombination losses. Radiative recombination can be reduced by limiting the escape angle of the re-emitted rays. Auger recombination can be reduced by limiting the cells` thickness. A novel technique for reducing the Auger recombination limit is proposed in this work. We show that bandgap grading can be effectively utilized to suppress the Auger recombination limit. The optimum bandgap grading profile that maximises the limiting efficiency for an idealized, one dimensional solar cell is hence calculated under AMO irradiation conditions. (author)

  2. Surgery in limited stage small cell lung cancer

    DEFF Research Database (Denmark)

    Lassen, U; Hansen, H H

    1999-01-01

    The role of surgery in small cell lung cancer (SCLC) is controversial. Surgery has several potential advantages because it may reduce the frequency of local relapses, it does not impede the intensity of chemotherapy, it does not affect the bone marrow, and surgical staging may be of prognostic...... significance. Several smaller retrospective studies which focus on surgery alone, surgery with adjuvant chemotherapy or radiotherapy, or chemotherapy followed by adjuvant surgery have been reported. Five-year survival data have ranged from 10-50% according to stage, both T-status and nodal status appearing...

  3. Legal Limitations of Researching and Using the Stem Cells

    Directory of Open Access Journals (Sweden)

    Rustin-Petru CIASC

    2013-11-01

    Full Text Available The importance of research in view of using stem cells for scientific and medical purposes must be regulated in a clear and, to the degree possible, single manner, at European and world level. Beginning with this obvious necessity, this article attempts to review the relevant provisions in the domestic legislation, while supplying the required appreciations and criticism. In the end, it reaches the idea, also upon replying on some compared law elements, that not only some legislative modifications or adaptations are imposed, in connection to the normative acts in force, but particularly the creation of a complete and complex legislative framework. It must cover the existence of all practical situations and regulate the scientific research activity in this domain, without ignoring at any time the inviolability of human dignity and acknowledging the right of integrity of the person’s body and mind.

  4. Efficiency limit of solar cells with index-near-zero photon management layers

    Energy Technology Data Exchange (ETDEWEB)

    Kirk, A.P.

    2017-05-15

    As single-junction solar cells saturate in efficiency, the topic of photon management has generated interest in the long running quest to exceed the Shockley-Queisser efficiency limit. While a mirror applied to the backside of a solar cell has proven its benefit as a photon management layer in record setting devices that fall within the Shockley-Queisser limit, it has been proposed that a new type of photon management layer – a transparent index-near-zero (INZ) material – applied to the top surface of a solar cell will allow it to finally exceed the Shockley-Queisser limit. INZ layers – and their influence on solar cell current density, open circuit voltage, and power conversion efficiency – are analyzed. By considering the principle of detailed balance, Snell's law, and the role that entropy plays, it is shown that INZ layers do not allow a solar cell to exceed the Shockley-Queisser efficiency limit. At best, a solar cell with an INZ layer would have the same Shockley-Queisser limiting efficiency as a conventional solar cell tracked under a direct solar spectrum (direct beam radiation only), yet would suffer diminished efficiency under a global solar spectrum (direct beam plus diffuse light) due to the presence of an external critical acceptance angle.

  5. Efficiency limit of solar cells with index-near-zero photon management layers

    Science.gov (United States)

    Kirk, A. P.

    2017-05-01

    As single-junction solar cells saturate in efficiency, the topic of photon management has generated interest in the long running quest to exceed the Shockley-Queisser efficiency limit. While a mirror applied to the backside of a solar cell has proven its benefit as a photon management layer in record setting devices that fall within the Shockley-Queisser limit, it has been proposed that a new type of photon management layer - a transparent index-near-zero (INZ) material - applied to the top surface of a solar cell will allow it to finally exceed the Shockley-Queisser limit. INZ layers - and their influence on solar cell current density, open circuit voltage, and power conversion efficiency - are analyzed. By considering the principle of detailed balance, Snell's law, and the role that entropy plays, it is shown that INZ layers do not allow a solar cell to exceed the Shockley-Queisser efficiency limit. At best, a solar cell with an INZ layer would have the same Shockley-Queisser limiting efficiency as a conventional solar cell tracked under a direct solar spectrum (direct beam radiation only), yet would suffer diminished efficiency under a global solar spectrum (direct beam plus diffuse light) due to the presence of an external critical acceptance angle.

  6. Detection of alloreactive T cells by flow cytometry : A new test compared with limiting dilution assay

    NARCIS (Netherlands)

    de Haan, A; van der Gun, [No Value; van der Bij, W; de Leij, LFMH; Prop, J

    2002-01-01

    Background. Frequencies of alloreactive T cells determined by limiting dilution assays (LDA) may not adequately reflect the donor-reactive immune status in transplant recipients. To reevaluate LDA frequencies, we developed a flow cytometry test for direct determination of alloreactive T-cell

  7. CD47 limits antibody dependent phagocytosis against non-malignant B cells.

    Science.gov (United States)

    Gallagher, Sandra; Turman, Sean; Lekstrom, Kristen; Wilson, Susan; Herbst, Ronald; Wang, Yue

    2017-05-01

    Recent studies have demonstrated the importance of CD47 in protecting malignant B cells from antibody dependent cellular phagocytosis (ADCP). Combined treatment of anti-CD47 and -CD20 antibodies synergistically augment elimination of tumor B cells in xenograft mouse models. This has led to the development of novel reagents that can potentially enhance killing of malignant B cells in patients. B cell depleting therapy is also a promising treatment for autoimmune patients. In the current study, we aimed to investigate whether or not CD47 protects non-malignant B cells from ADCP. We show that CD47 is expressed on all B cells in mice, with the highest level on plasma cells in bone marrow and spleen. Although its expression is dispensable for B cell development in mice, CD47 on B cells limits antibody mediated phagocytosis. B cell depletion following in vivo anti-CD19 treatment is more efficient in CD47-/- mice than in wild type mice. In vitro, both naïve and activated B cells from CD47-/- mice are more sensitive to ADCP than wild type B cells. Lastly, we show in an ADCP assay that blocking CD47 can enhance anti-CD19 antibody mediated phagocytosis of wild type B cells. These results suggest that in addition to its already demonstrated benefit in cancer, targeting CD47 may be used as an adjunct in combination with B cell depletion antibodies for treatment of autoimmune diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Numerical simulation of the limiting efficiency of the graded bandgap solar cell

    Energy Technology Data Exchange (ETDEWEB)

    Rafat, N.H. [Department of Mathematics and Engineering Physics, Faculty of Engineering, Cairo University, Giza (Egypt); Abdel Haleem, A.M. [Department of Mathematics and Engineering Physics, Faculty of Engineering, El Fayoum University, El Fayoum (Egypt); Habib, S.E.-D. [Electronics and Communication Department, Faculty of Engineering, Cairo University, Giza (Egypt)

    2007-01-15

    The limiting efficiency of the compositionally graded bandgap solar cell is calculated using a 1-D numerical simulator. Our simulator calculates the limiting efficiency by solving the coupled semiconductor equations, namely, Poisson's equation, the current continuity equations, together with the Boltzmann photon equation, rather than the detailed balance equations that are usually used in such calculations. The non-avoidable radiative and Auger bulk losses are the only losses considered in the calculations. The effect of photon recycling on the cell's parameters is included in the calculations of radiative recombination rates. We verified numerically that bandgap grading, under optimum profile, increases the limiting efficiency of the solar cell, over the previously published values. The effect of the bandgap grading on desensitizing the surface of the cell is discussed. (author)

  9. Circadian rhythms in the cell cycle and biomass composition of Neochloris oleoabundans under nitrogen limitation.

    Science.gov (United States)

    de Winter, Lenneke; Schepers, Lutz W; Cuaresma, Maria; Barbosa, Maria J; Martens, Dirk E; Wijffels, René H

    2014-10-10

    The circadian clock schedules processes in microalgae cells at suitable times in the day/night cycle. To gain knowledge about these biological time schedules, Neochloris oleoabundans was grown under constant light conditions and nitrogen limitation. Under these constant conditions, the only variable was the circadian clock. The results were compared to previous work done under nitrogen-replete conditions, in order to determine the effect of N-limitation on circadian rhythms in the cell cycle and biomass composition of N. oleoabundans. The circadian clock was not affected by nitrogen-limitation, and cell division was timed in the natural night, despite of constant light conditions. However, because of nitrogen-limitation, not the entire population was able to divide every day. Two subpopulations were observed, which divided alternately every other day. This caused oscillations in biomass yield and composition. Starch and total fatty acids (TFA) were accumulated during the day. Also, fatty acid composition changed during the cell cycle. Neutral lipids were built up during the day, especially in cells that were arrested in their cell cycle (G2 and G3). These findings give insight in the influence of circadian rhythms on the cell cycle and biomass composition. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Immunoglobulin E and mast cell proteases are potential risk factors of human pre-diabetes and diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Zhen Wang

    Full Text Available Recent studies have suggested that mast-cell activation and inflammation are important in obesity and diabetes. Plasma levels of mast cell proteases and the mast cell activator immunoglobulin E (IgE may serve as novel inflammatory markers that associate with the risk of pre-diabetes and diabetes mellitus.A total of 340 subjects 55 to 75 years of age were grouped according to the American Diabetes Association 2003 criteria of normal glucose tolerance, pre-diabetes, and diabetes mellitus. The Kruskal-Wallis test demonstrated significant differences in plasma IgE levels (P = 0.008 among groups with different glucose tolerance status. Linear regression analysis revealed significant correlations between plasma levels of chymase (P = 0.030 or IgE (P = 0.022 and diabetes mellitus. Ordinal logistic regression analysis showed that IgE was a significant risk factor of pre-diabetes and diabetes mellitus (odds ratio [OR]: 1.674, P = 0.034. After adjustment for common diabetes risk factors, including age, sex, hypertension, body-mass index, cholesterol, homeostatic model assessment (HOMA index, high-sensitivity C-reactive protein (hs-CRP, and mast cell chymase and tryptase, IgE remained a significant risk factor (OR: 1.866, P = 0.015. Two-variable ordinal logistic analysis indicated that interactions between hs-CRP and IgE, or between IgE and chymase, increased further the risks of developing pre-diabetes and diabetes mellitus before (OR: 2.204, P = 0.044; OR: 2.479, P = 0.033 and after (OR: 2.251, P = 0.040; OR: 2.594, P = 0.026 adjustment for common diabetes risk factors.Both IgE and chymase associate with diabetes status. While IgE and hs-CRP are individual risk factors of pre-diabetes and diabetes mellitus, interactions of IgE with hs-CRP or with chymase further increased the risk of pre-diabetes and diabetes mellitus.

  11. Nano-photonic light trapping near the Lambertian limit in organic solar cell architectures.

    Science.gov (United States)

    Biswas, Rana; Timmons, Erik

    2013-09-09

    A critical step to achieving higher efficiency solar cells is the broad band harvesting of solar photons. Although considerable progress has recently been achieved in improving the power conversion efficiency of organic solar cells, these cells still do not absorb upto ~50% of the solar spectrum. We have designed and developed an organic solar cell architecture that can boost the absorption of photons by 40% and the photo-current by 50% for organic P3HT-PCBM absorber layers of typical device thicknesses. Our solar cell architecture is based on all layers of the solar cell being patterned in a conformal two-dimensionally periodic photonic crystal architecture. This results in very strong diffraction of photons- that increases the photon path length in the absorber layer, and plasmonic light concentration near the patterned organic-metal cathode interface. The absorption approaches the Lambertian limit. The simulations utilize a rigorous scattering matrix approach and provide bounds of the fundamental limits of nano-photonic light absorption in periodically textured organic solar cells. This solar cell architecture has the potential to increase the power conversion efficiency to 10% for single band gap organic solar cells utilizing long-wavelength absorbers.

  12. Mast Cells: Key Contributors to Cardiac Fibrosis

    Directory of Open Access Journals (Sweden)

    Scott P. Levick

    2018-01-01

    Full Text Available Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis.

  13. The efficiency limit of CH3NH3PbI3 perovskite solar cells

    International Nuclear Information System (INIS)

    Sha, Wei E. I.; Ren, Xingang; Chen, Luzhou; Choy, Wallace C. H.

    2015-01-01

    With the consideration of photon recycling effect, the efficiency limit of methylammonium lead iodide (CH 3 NH 3 PbI 3 ) perovskite solar cells is predicted by a detailed balance model. To obtain convincing predictions, both AM 1.5 spectrum of Sun and experimentally measured complex refractive index of perovskite material are employed in the detailed balance model. The roles of light trapping and angular restriction in improving the maximal output power of thin-film perovskite solar cells are also clarified. The efficiency limit of perovskite cells (without the angular restriction) is about 31%, which approaches to Shockley-Queisser limit (33%) achievable by gallium arsenide (GaAs) cells. Moreover, the Shockley-Queisser limit could be reached with a 200 nm-thick perovskite solar cell, through integrating a wavelength-dependent angular-restriction design with a textured light-trapping structure. Additionally, the influence of the trap-assisted nonradiative recombination on the device efficiency is investigated. The work is fundamentally important to high-performance perovskite photovoltaics

  14. Influence of nitrogen limitation on performance of a microbial fuel cell.

    Science.gov (United States)

    Belleville, P; Strong, P J; Dare, P H; Gapes, D J

    2011-01-01

    We describe the operation of a microbial fuel cell (MFC) system operating on a synthetic wastewater (acetic acid), under conditions of increasing nitrogen limitation. Two MFCs were operated under feed conditions which spanned a range of TKN/COD values of 1.6-28 mg/g. Stable operation was observed in all cases, even when no ammoniacal nitrogen was added to the cell. Improved electrochemical performance (measured as power density, W/m2) was observed as nitrogen limitation was imposed on the cells. Even with no ammonium addition, continuous function of the cell was maintained, at levels consistent with operation at balanced nutrient supplementation. The work has implicated biological nitrogen fixation as a potential source of nitrogen within the MFC. Whilst this hypothesis has yet to be confirmed, the work highlights the opportunity for continuous operation of microbial fuel cells utilising wastewaters with extremely low nitrogen levels, present in pulp and paper, pharmaceutical and petrochemical industries. Further, the described increases in some of the electrochemical indices (e.g. power density) under application of nitrogen limitation may provide a new approach to increasing fuel cell performance. Finally, the lack of any need to add supplemental nitrogen to a MFC-based wastewater treatment technology holds potential for significant financial and environmental savings.

  15. Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner.

    Science.gov (United States)

    Liu, Rui; King, Ashleigh; Bouillet, Philippe; Tarlinton, David M; Strasser, Andreas; Heierhorst, Jörg

    2018-01-01

    The proapoptotic BH3-only protein BIM ( Bcl2l11 ) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid-specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre ) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre ) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim -deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro , conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc -driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non-activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions.

  16. Haematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability.

    Science.gov (United States)

    Leiva, Magdalena; Quintana, Juan A; Ligos, José M; Hidalgo, Andrés

    2016-01-08

    The life-long maintenance of haematopoietic stem and progenitor cells (HSPCs) critically relies on environmental signals produced by cells that constitute the haematopoietic niche. Here we report a cell-intrinsic mechanism whereby haematopoietic cells limit proliferation within the bone marrow, and show that this pathway is repressed by E-selectin ligand 1 (ESL-1). Mice deficient in ESL-1 display aberrant HSPC quiescence, expansion of the immature pool and reduction in niche size. Remarkably, the traits were transplantable and dominant when mutant and wild-type precursors coexisted in the same environment, but were independent of E-selectin, the vascular receptor for ESL-1. Instead, quiescence is generated by unrestrained production of the cytokine TGFβ by mutant HSPC, and in vivo or in vitro blockade of the cytokine completely restores the homeostatic properties of the haematopoietic niche. These findings reveal that haematopoietic cells, including the more primitive compartment, can actively shape their own environment.

  17. Circadian rhythms in the cell cycle and biomass composition of Neochloris oleoabundans under nitrogen limitation

    NARCIS (Netherlands)

    Winter, de L.; Schepers, L.W.; Cuaresma Franco, M.; Barbosa, M.J.; Martens, D.E.; Wijffels, R.H.

    2014-01-01

    The circadian clock schedules processes in microalgae cells at suitable times in the day/night cycle. To gain knowledge about these biological time schedules, Neochloris oleoabundans was grown under constant light conditions and nitrogen limitation. Under these constant conditions, the only variable

  18. Categorical methods for the interpretation of RNA profiles as cell type evidence and their limitations

    NARCIS (Netherlands)

    de Zoete, J.; Curran, J.; Sjerps, M.

    2015-01-01

    Existing methods for the interpretation of RNA profiles as evidence for the presence of certain cell types aim for making categorical statements. Such statements limit the possibility to report the associated uncertainty. From a statistical point of view, a probabilistic approach is a preferable

  19. The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors

    Science.gov (United States)

    Bayley, Rachel; Ahmed, Forhad; Glen, Katie; McCall, Mark; Stacey, Adrian

    2017-01-01

    Abstract Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high (2 × 1012) cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred‐tank bioreactor and determine engineering limitations of commercial red blood cells production. Cord blood derived CD34+ cells were cultured under erythroid differentiation conditions in a stirred micro‐bioreactor (Ambr™). Enucleated cells of 80% purity could be created under optimal physical conditions: pH 7.5, 50% oxygen, without gas‐sparging (which damaged cells) and with mechanical agitation (which directly increased enucleation). O2 consumption was low (~5 × 10–8 μg/cell.h) theoretically enabling erythroblast densities in excess of 5 × 108/ml in commercial bioreactors and sub‐10 l/unit production volumes. The bioreactor process achieved a 24% and 42% reduction in media volume and culture time, respectively, relative to unoptimized flask processing. However, media exchange limited productivity to 1 unit of erythroblasts per 500 l of media. Systematic replacement of media constituents, as well as screening for inhibitory levels of ammonia, lactate and key cytokines did not identify a reason for this limitation. We conclude that the properties of erythroblasts are such that the conventional constraints on cell manufacturing efficiency, such as mass transfer and metabolic demand, should not prevent high intensity production; furthermore, this could be achieved in industry standard equipment. However, identification and removal of an inhibitory mediator is required to enable these economies to be realized. Copyright © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd. PMID:27696710

  20. Limit-dilution assay and clonal expansion of all T cells capable of proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, W.F.; Wilson, A.; Scollay, R.; Shortman, K. (Walter and Eliza Hall Inst. of Medical Research, Parkville (Australia))

    1982-08-13

    A limit-dilution microculture system is presented in which almost all mature T cells, cultured at a level of about 1 cell/well, grow and expand to clones averaging 60,000 cells over an 8-9 day period. Cloning efficiency is 70-100%, so the set of expanded clones is representative of the starting T-cell population. T cells of all Lyt phenotypes form clones of progeny cells. The system involves culture in flat-bottom microtitre trays, in the presence of concanavalin A as the initiating stimulus, together with appropriately irradiated spleen filler cells and a supplementary source of soluble T cell growth factors. The resultant clones may be screened for cytolytic function, as described in the accompanying paper. The system may be used to assay the level of T cells capable of expansion or precursor function (PTL-p) by using (/sup 3/H)TdR uptake as a readout for the presence or absence of proliferating clones. Analysis of the frequency of positive cultures shows a good fit to the expected Poisson distribution, with no evidence of complicating suppressor or helper effects.

  1. Limit-dilution assay and clonal expansion of all T cells capable of proliferation

    International Nuclear Information System (INIS)

    Chen, W.-F.; Wilson, A.; Scollay, R.; Shortman, K.

    1982-01-01

    A limit-dilution microculture system is presented in which almost all mature T cells, cultured at a level of about 1 cell/well, grow and expand to clones averaging 60,000 cells over an 8-9 day period. Cloning efficiency is 70-100%, so the set of expanded clones is representative of the starting T-cell population. T cells of all Lyt phenotypes form clones of progeny cells. The system involves culture in flat-bottom microtitre trays, in the presence of concanavalin A as the initiating stimulus, together with appropriately irradiated spleen filler cells and a supplementary source of soluble T cell growth factors. The resultant clones may be screened for cytolytic function, as described in the accompanying paper. The system may be used to assay the level of T cells capable of expansion or precursor function (PTL-p) by using [ 3 H]TdR uptake as a readout for the presence or absence of proliferating clones. Analysis of the frequency of positive cultures shows a good fit to the expected Poisson distribution, with no evidence of complicating suppressor or helper effects. (Auth.)

  2. Limits to anaerobic energy and cytosolic concentration in the living cell

    Science.gov (United States)

    Paglietti, A.

    2015-11-01

    For many physical systems at any given temperature, the set of all states where the system's free energy reaches its largest value can be determined from the system's constitutive equations of internal energy and entropy, once a state of that set is known. Such an approach is fraught with complications when applied to a living cell, because the cell's cytosol contains thousands of solutes, and thus thousands of state variables, which makes determination of its state impractical. We show here that, when looking for the maximum energy that the cytosol can store and release, detailed information on cytosol composition is redundant. Compatibility with cell's life requires that a single variable that represents the overall concentration of cytosol solutes must fall between defined limits, which can be determined by dehydrating and overhydrating the cell to its maximum capacity. The same limits are shown to determine, in particular, the maximum amount of free energy that a cell can supply in fast anaerobic processes, starting from any given initial state. For a typical skeletal muscle in normal physiological conditions this energy, i.e., the maximum anaerobic capacity to do work, is calculated to be about 960 J per kg of muscular mass. Such energy decreases as the overall concentration of solutes in the cytosol is increased. Similar results apply to any kind of cell. They provide an essential tool to understand and control the macroscopic response of single cells and multicellular cellular tissues alike. The applications include sport physiology, cell aging, disease produced cell damage, drug absorption capacity, to mention the most obvious ones.

  3. Use of Monoclonal Antibodies for the Diagnosis of T-cell Malignancies: Applications and Limitations.

    Science.gov (United States)

    Hastrup, N; Pallesen, G; Ralfikiaer, E

    1990-01-01

    Biopsy samples from 136 peripheral T-cell lymphomas have been examined and compared with benign inflammatory T-cell infiltrates in an attempt to establish whether immunohistological methods may help to improve the distinction between these conditions. The results confirm and extend previous reports and indicate that the aberrant T-cell phenotypes constitute the single most reliable criterion for the distinction between benign and malignant T-cell infiltrates. These phenotypes are expressed frequently in T-cell malignancies in. lymphoid organs and are also seen in a substantial number of biopsy samples from advanced cutaneous T-cell lymphomas (CTCL). In contrast, early CTCL do not express aberrant T-cell phenotypes and are indistinguishable from benign cutaneous conditions in terms of their immunophenotypic properties. It is concluded that immunophenotypic techniques form a valuable supplement to routine histological methods for the diagnosis of T-cell lymphomas in lymphoid organs. The methods may also help to improve the diagnosis of advanced CTCL, but are of no or only limited help for the recognition of the early stages.

  4. An improved model for nucleation-limited ice formation in living cells during freezing.

    Directory of Open Access Journals (Sweden)

    Jingru Yi

    Full Text Available Ice formation in living cells is a lethal event during freezing and its characterization is important to the development of optimal protocols for not only cryopreservation but also cryotherapy applications. Although the model for probability of ice formation (PIF in cells developed by Toner et al. has been widely used to predict nucleation-limited intracellular ice formation (IIF, our data of freezing Hela cells suggest that this model could give misleading prediction of PIF when the maximum PIF in cells during freezing is less than 1 (PIF ranges from 0 to 1. We introduce a new model to overcome this problem by incorporating a critical cell volume to modify the Toner's original model. We further reveal that this critical cell volume is dependent on the mechanisms of ice nucleation in cells during freezing, i.e., surface-catalyzed nucleation (SCN and volume-catalyzed nucleation (VCN. Taken together, the improved PIF model may be valuable for better understanding of the mechanisms of ice nucleation in cells during freezing and more accurate prediction of PIF for cryopreservation and cryotherapy applications.

  5. Epitope-Specific Vaccination Limits Clonal Expansion of Heterologous Naive T Cells during Viral Challenge

    Directory of Open Access Journals (Sweden)

    Lexus R. Johnson

    2016-10-01

    Full Text Available Despite robust secondary T cell expansion primed by vaccination, the impact on primary immune responses to heterotypic antigens remains undefined. Here we show that secondary expansion of epitope-specific memory CD8+ T cells primed by prior infection with recombinant pathogens limits the primary expansion of naive CD8+ T cells with specificity to new heterologous antigens, dampening protective immunity against subsequent pathogen challenge. The degree of naive T cell repression directly paralleled the magnitude of the recall response. Suppressed primary T cell priming reflects competition for antigen accessibility, since clonal expansion was not inhibited if the primary and secondary epitopes were expressed on different dendritic cells. Interestingly, robust recall responses did not impact antigen-specific NK cells, suggesting that adaptive and innate lymphocyte responses possess different activation requirements or occur in distinct anatomical locations. These findings have important implications in pathogen vaccination strategies that depend on the targeting of multiple T cell epitopes.

  6. Recent advances on enzymatic glucose/oxygen and hydrogen/oxygen biofuel cells: Achievements and limitations

    Science.gov (United States)

    Cosnier, Serge; Gross, Andrew J.; Le Goff, Alan; Holzinger, Michael

    2016-09-01

    The possibility of producing electrical power from chemical energy with biological catalysts has induced the development of biofuel cells as viable energy sources for powering portable and implanted electronic devices. These power sources employ biocatalysts, called enzymes, which are highly specific and catalytic towards the oxidation of a biofuel and the reduction of oxygen or hydrogen peroxide. Enzymes, on one hand, are promising candidates to replace expensive noble metal-based catalysts in fuel cell research. On the other hand, they offer the exciting prospect of a new generation of fuel cells which harvest energy from body fluids. Biofuel cells which use glucose as a fuel are particularly interesting for generating electricity to power electronic devices inside a living body. Hydrogen consuming biofuel cells represent an emerging alternative to platinum catalysts due to comparable efficiencies and the capability to operate at lower temperatures. Currently, these technologies are not competitive with existing commercialised fuel cell devices due to limitations including insufficient power outputs and lifetimes. The advantages and challenges facing glucose biofuel cells for implantation and hydrogen biofuel cells will be summarised along with recent promising advances and the future prospects of these exotic energy-harvesting devices.

  7. TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion

    Directory of Open Access Journals (Sweden)

    Nicholas C. Vierra

    2018-03-01

    Full Text Available Objective: Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K+ (K2P channel TALK-1 is abundantly expressed in somatostatin-secreting δ-cells. However, a physiological role for TALK-1 in δ-cells remains unknown. We previously determined that in β-cells, K+ flux through endoplasmic reticulum (ER-localized TALK-1 channels enhances ER Ca2+ leak, modulating Ca2+ handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca2+-induced Ca2+ release (CICR from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Ca2+ handling and somatostatin secretion. Methods: To define the functions of islet δ-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO mice expressing fluorescent reporters specifically in δ- and α-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca2+ imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts δ- and α-cell function. Results: TALK-1 channels are expressed in both mouse and human δ-cells, where they modulate glucose-stimulated changes in cytosolic Ca2+ and somatostatin secretion. Measurement of cytosolic Ca2+ levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Ca2+ with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Ca2+ oscillations in TALK-1 KO islets, and found that blockade of α-cell somatostatin signaling with a somatostatin receptor 2 (SSTR2 antagonist restored glucagon secretion in TALK-1 KO islets. Conclusions: These data indicate that TALK-1 reduces δ-cell cytosolic Ca2+ elevations and somatostatin release by limiting δ-cell CICR, modulating the intraislet paracrine signaling

  8. Limited HIV-1 Reactivation in Resting CD4+T cells from Aviremic Patients under Protease Inhibitors.

    Science.gov (United States)

    Kumar, Amit; Abbas, Wasim; Bouchat, Sophie; Gatot, Jean-Stéphane; Pasquereau, Sébastien; Kabeya, Kabamba; Clumeck, Nathan; De Wit, Stéphane; Van Lint, Carine; Herbein, Georges

    2016-12-06

    A latent viral reservoir that resides in resting CD4 + T cells represents a major barrier for eradication of HIV infection. We test here the impact of HIV protease inhibitor (PI) based combination anti-retroviral therapy (cART) over nonnucleoside reverse transcriptase inhibitor (NNRTI)-based cART on HIV-1 reactivation and integration in resting CD4 + T cells. This is a prospective cohort study of patients with chronic HIV-1 infection treated with conventional cART with an undetectable viremia. We performed a seven-year study of 47 patients with chronic HIV-infection treated with cART regimens and with undetectable plasma HIV-1 RNA levels for at least 1 year. Of these 47 patients treated with cART, 24 were treated with a PI-based regimen and 23 with a NNRTI-based regimen as their most recent treatment for more than one year. We evaluated the HIV-1 reservoir using reactivation assay and integrated HIV-1 DNA, respectively, in resting CD4 + T cells. Resting CD4 + T cells isolated from PI-treated patients compared to NNRTI-treated patients showed a limited HIV-1 reactivation upon T-cell stimulation (p = 0·024) and a lower level of HIV-1 integration (p = 0·024). Our study indicates that PI-based cART could be more efficient than NNRTI-based cART for limiting HIV-1 reactivation in aviremic chronically infected patients.

  9. FCγ Chimeric Receptor-Engineered T Cells: Methodology, Advantages, Limitations, and Clinical Relevance

    Directory of Open Access Journals (Sweden)

    Giuseppe Sconocchia

    2017-04-01

    Full Text Available For many years, disappointing results have been generated by many investigations, which have utilized a variety of immunologic strategies to enhance the ability of a patient’s immune system to recognize and eliminate malignant cells. However, in recent years, immunotherapy has been used successfully for the treatment of hematologic and solid malignancies. The impressive clinical responses observed in many types of cancer have convinced even the most skeptical clinical oncologists that a patient’s immune system can recognize and reject his tumor if appropriate strategies are implemented. The success immunotherapy is due to the development of at least three therapeutic strategies. They include tumor-associated antigen (TAA-specific monoclonal antibodies (mAbs, T cell checkpoint blockade, and TAA-specific chimeric antigen receptors (CARs T cell-based immunotherapy. However, the full realization of the therapeutic potential of these approaches requires the development of strategies to counteract and overcome some limitations. They include off-target toxicity and mechanisms of cancer immune evasion, which obstacle the successful clinical application of mAbs and CAR T cell-based immunotherapies. Thus, we and others have developed the Fc gamma chimeric receptors (Fcγ-CRs-based strategy. Like CARs, Fcγ-CRs are composed of an intracellular tail resulting from the fusion of a co-stimulatory molecule with the T cell receptor ζ chain. In contrast, the extracellular CAR single-chain variable fragment (scFv, which recognizes the targeted TAA, has been replaced with the extracellular portion of the FcγRIIIA (CD16. Fcγ-CR T cells have a few intriguing features. First, given in combination with mAbs, Fcγ-CR T cells mediate anticancer activity in vitro and in vivo by an antibody-mediated cellular cytotoxicity mechanism. Second, CD16-CR T cells can target multiple cancer types provided that TAA-specific mAbs with the appropriate specificity are available

  10. Limited transplantation of antigen-expressing hematopoietic stem cells induces long-lasting cytotoxic T cell responses.

    Directory of Open Access Journals (Sweden)

    Warren L Denning

    2011-02-01

    Full Text Available Harnessing the ability of cytotoxic T lymphocytes (CTLs to recognize and eradicate tumor or pathogen-infected cells is a critical goal of modern immune-based therapies. Although multiple immunization strategies efficiently induce high levels of antigen-specific CTLs, the initial increase is typically followed by a rapid contraction phase resulting in a sharp decline in the frequency of functional CTLs. We describe a novel approach to immunotherapy based on a transplantation of low numbers of antigen-expressing hematopoietic stem cells (HSCs following nonmyeloablative or partially myeloablative conditioning. Continuous antigen presentation by a limited number of differentiated transgenic hematopoietic cells results in an induction and prolonged maintenance of fully functional effector T cell responses in a mouse model. Recipient animals display high levels of antigen-specific CTLs four months following transplantation in contrast to dendritic cell-immunized animals in which the response typically declines at 4-6 weeks post-immunization. Majority of HSC-induced antigen-specific CD8+ T cells display central memory phenotype, efficiently kill target cells in vivo, and protect recipients against tumor growth in a preventive setting. Furthermore, we confirm previously published observation that high level engraftment of antigen-expressing HSCs following myeloablative conditioning results in tolerance and an absence of specific cytotoxic activity in vivo. In conclusion, the data presented here supports potential application of immunization by limited transplantation of antigen-expressing HSCs for the prevention and treatment of cancer and therapeutic immunization of chronic infectious diseases such as HIV-1/AIDS.

  11. Poisson-Boltzmann theory of charged colloids: limits of the cell model for salty suspensions

    International Nuclear Information System (INIS)

    Denton, A R

    2010-01-01

    Thermodynamic properties of charge-stabilized colloidal suspensions and polyelectrolyte solutions are commonly modelled by implementing the mean-field Poisson-Boltzmann (PB) theory within a cell model. This approach models a bulk system by a single macroion, together with counterions and salt ions, confined to a symmetrically shaped, electroneutral cell. While easing numerical solution of the nonlinear PB equation, the cell model neglects microion-induced interactions and correlations between macroions, precluding modelling of macroion ordering phenomena. An alternative approach, which avoids the artificial constraints of cell geometry, exploits the mapping of a macroion-microion mixture onto a one-component model of pseudo-macroions governed by effective interparticle interactions. In practice, effective-interaction models are usually based on linear-screening approximations, which can accurately describe strong nonlinear screening only by incorporating an effective (renormalized) macroion charge. Combining charge renormalization and linearized PB theories, in both the cell model and an effective-interaction (cell-free) model, we compute osmotic pressures of highly charged colloids and monovalent microions, in Donnan equilibrium with a salt reservoir, over a range of concentrations. By comparing predictions with primitive model simulation data for salt-free suspensions, and with predictions from nonlinear PB theory for salty suspensions, we chart the limits of both the cell model and linear-screening approximations in modelling bulk thermodynamic properties. Up to moderately strong electrostatic couplings, the cell model proves accurate for predicting osmotic pressures of deionized (counterion-dominated) suspensions. With increasing salt concentration, however, the relative contribution of macroion interactions to the osmotic pressure grows, leading predictions from the cell and effective-interaction models to deviate. No evidence is found for a liquid

  12. Highly Efficient Perovskite-Perovskite Tandem Solar Cells Reaching 80% of the Theoretical Limit in Photovoltage.

    Science.gov (United States)

    Rajagopal, Adharsh; Yang, Zhibin; Jo, Sae Byeok; Braly, Ian L; Liang, Po-Wei; Hillhouse, Hugh W; Jen, Alex K-Y

    2017-09-01

    Organic-inorganic hybrid perovskite multijunction solar cells have immense potential to realize power conversion efficiencies (PCEs) beyond the Shockley-Queisser limit of single-junction solar cells; however, they are limited by large nonideal photovoltage loss (V oc,loss ) in small- and large-bandgap subcells. Here, an integrated approach is utilized to improve the V oc of subcells with optimized bandgaps and fabricate perovskite-perovskite tandem solar cells with small V oc,loss . A fullerene variant, Indene-C 60 bis-adduct, is used to achieve optimized interfacial contact in a small-bandgap (≈1.2 eV) subcell, which facilitates higher quasi-Fermi level splitting, reduces nonradiative recombination, alleviates hysteresis instabilities, and improves V oc to 0.84 V. Compositional engineering of large-bandgap (≈1.8 eV) perovskite is employed to realize a subcell with a transparent top electrode and photostabilized V oc of 1.22 V. The resultant monolithic perovskite-perovskite tandem solar cell shows a high V oc of 1.98 V (approaching 80% of the theoretical limit) and a stabilized PCE of 18.5%. The significantly minimized nonideal V oc,loss is better than state-of-the-art silicon-perovskite tandem solar cells, which highlights the prospects of using perovskite-perovskite tandems for solar-energy generation. It also unlocks opportunities for solar water splitting using hybrid perovskites with solar-to-hydrogen efficiencies beyond 15%. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Design and modeling of an SJ infrared solar cell approaching upper limit of theoretical efficiency

    Science.gov (United States)

    Sahoo, G. S.; Mishra, G. P.

    2018-01-01

    Recent trends of photovoltaics account for the conversion efficiency limit making them more cost effective. To achieve this we have to leave the golden era of silicon cell and make a path towards III-V compound semiconductor groups to take advantages like bandgap engineering by alloying these compounds. In this work we have used a low bandgap GaSb material and designed a single junction (SJ) cell with a conversion efficiency of 32.98%. SILVACO ATLAS TCAD simulator has been used to simulate the proposed model using both Ray Tracing and Transfer Matrix Method (under 1 sun and 1000 sun of AM1.5G spectrum). A detailed analyses of photogeneration rate, spectral response, potential developed, external quantum efficiency (EQE), internal quantum efficiency (IQE), short-circuit current density (JSC), open-circuit voltage (VOC), fill factor (FF) and conversion efficiency (η) are discussed. The obtained results are compared with previously reported SJ solar cell reports.

  14. DAZL Limits Pluripotency, Differentiation, and Apoptosis in Developing Primordial Germ Cells

    Directory of Open Access Journals (Sweden)

    Hsu-Hsin Chen

    2014-11-01

    Full Text Available The scarcity of primordial germ cells (PGCs in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell development. Using Dazl-GFP reporter ESCs, we demonstrate that DAZL plays a central role in a large mRNA/protein interactive network that blocks the translation of core pluripotency factors, including Sox2 and Sall4, as well as of Suz12, a polycomb family member required for differentiation of pluripotent cells. Thus, DAZL limits both pluripotency and somatic differentiation in nascent PGCs. In addition, we observed that DAZL associates with mRNAs of key Caspases and similarly inhibits their translation. This elegant fail-safe mechanism ensures that, whereas loss of DAZL results in prolonged expression of pluripotency factors, teratoma formation is avoided due to the concomitant activation of the apoptotic cascade.

  15. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

    Science.gov (United States)

    Pauken, Kristen E; Sammons, Morgan A; Odorizzi, Pamela M; Manne, Sasikanth; Godec, Jernej; Khan, Omar; Drake, Adam M; Chen, Zeyu; Sen, Debattama R; Kurachi, Makoto; Barnitz, R Anthony; Bartman, Caroline; Bengsch, Bertram; Huang, Alexander C; Schenkel, Jason M; Vahedi, Golnaz; Haining, W Nicholas; Berger, Shelley L; Wherry, E John

    2016-12-02

    Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (T EX ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T EX into durable memory T cells (T MEM ) is unclear. We found that reinvigoration of T EX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T EX became reexhausted if antigen concentration remained high and failed to become T MEM upon antigen clearance. T EX acquired an epigenetic profile distinct from that of effector T cells (T EFF ) and T MEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that T EX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the T EX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies. Copyright © 2016, American Association for the Advancement of Science.

  16. Modeling the Performance Limitations and Prospects of Perovskite/Si Tandem Solar Cells under Realistic Operating Conditions.

    Science.gov (United States)

    Futscher, Moritz H; Ehrler, Bruno

    2017-09-08

    Perovskite/Si tandem solar cells have the potential to considerably out-perform conventional solar cells. Under standard test conditions, perovskite/Si tandem solar cells already outperform the Si single junction. Under realistic conditions, however, as we show, tandem solar cells made from current record cells are hardly more efficient than the Si cell alone. We model the performance of realistic perovskite/Si tandem solar cells under real-world climate conditions, by incorporating parasitic cell resistances, nonradiative recombination, and optical losses into the detailed-balance limit. We show quantitatively that when optimizing these parameters in the perovskite top cell, perovskite/Si tandem solar cells could reach efficiencies above 38% under realistic conditions, even while leaving the Si cell untouched. Despite the rapid efficiency increase of perovskite solar cells, our results emphasize the need for further material development, careful device design, and light management strategies, all necessary for highly efficient perovskite/Si tandem solar cells.

  17. Klebsiella pneumoniae alleviates influenza-induced acute lung injury via limiting NK cell expansion.

    Science.gov (United States)

    Wang, Jian; Li, Fengqi; Sun, Rui; Gao, Xiang; Wei, Haiming; Tian, Zhigang

    2014-08-01

    A protective effect induced by bacterial preinfection upon a subsequent lethal influenza virus infection has been observed, but the underlying immune mechanisms have not yet been fully elucidated. In this study, we used a mouse model of Klebsiella pneumoniae preinfection to gain insight into how bacterial preinfection influences the subsequent lethal influenza virus infection. We found that K. pneumoniae preinfection significantly attenuated lung immune injury and decreased mortality during influenza virus infection, but K. pneumoniae-specific immunity was not involved in this cross-protection against influenza virus. K. pneumoniae preinfection limited NK cell expansion, which was involved in influenza-induced immune injury and death. Furthermore, K. pneumoniae preinfection could not control NK cell expansion and death during influenza virus infection in Rag1(-/-) mice, but adoptive transfer of T cells from wild-type mice was able to restore this protective effect. Our data suggest that the adaptive immune response activated by bacterial infection limits the excessive innate immune response induced by a subsequent influenza infection, ultimately protecting mice from death. Copyright © 2014 by The American Association of Immunologists, Inc.

  18. Lifetime limiting effects in pre-commercial solid oxide cell devices

    DEFF Research Database (Denmark)

    Skafte, Theis Løye

    of degradationand lifetime was conducted. It is shown that the technology is approaching the officialtargets required for commercialization, but that work remains to be done.  It is further recognized that targeting nicheapplications initially will allow for employment of economies of scale, whichwill bring down......The solidoxide electrochemical cell technology is promising for efficient energy storage,especially when the share of intermittent renewable electricity production ishigh. The technology is being commercialized in niche markets, but large-scale employmentis still hindered by limited durability...... of the devices. The lifetime limitingmechanisms are addressed in this work. A generalintroduction into mechanisms limiting the durability is presented. A databaseof more than 50 parameters from 150 publications and 1 000 000 hours ofaccumulated testing was established, and a quantitative analysis...

  19. Prospective study on stereotactic radiotherapy of limited-stage non-small-cell lung cancer

    DEFF Research Database (Denmark)

    Høyer, Morten; Roed, Henrik; Hansen, Anders Traberg

    2006-01-01

    Purpose: To test the effect of stereotactic body radiotherapy (SBRT) in       the treatment of medically inoperable patients with limited-stage       non-small-cell lung cancer (NSCLC) in a Phase II trial. Methods and       Materials: Forty patients with Stage I NSCLC were treated with SBRT......%. At 2       years, 54% were without local or distant progression, and overall survival       was 47%. Within 6 months after treatment, one or more Grade >/=2 reactions       were observed in 48% of the patients. Conclusions: Stereotactic body       radiotherapy in patients with limited-stage NSCLC...

  20. Treatment toxicities in long-term survivors of limited small cell lung cancer

    International Nuclear Information System (INIS)

    Frytak, S.; Shaw, J.N.; Lee, R.E.; Eagan, R.T.; Shaw, E.G.; Richardson, R.L.; Creagan, E.T.; Coles, D.T.; Jett, J.R.

    1988-01-01

    A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients

  1. Intensity limitations of a gas cell for stopping, storing and guiding of radioactive ions

    CERN Document Server

    Huyse, M; Kudryavtsev, Yuri A; Van Duppen, P

    2002-01-01

    The possibility to use a gas cell filled by noble gas (He or Ar) for thermalizing, storing and transporting radioactive ions is explored by studying experimentally ion - electron recombination of stable Ni, resonantly ionized by laser light. Combined with a literature study on ionization chambers, especially developed for high-intensity applications, conclusions are drawn on the maximum intensity of the incoming ion beam. A practical limit is encountered when the space-charge induced voltage fully counteract the applied voltage on the electrodes collecting the electrons.

  2. Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity

    Directory of Open Access Journals (Sweden)

    Yanxia Guo

    2016-12-01

    Full Text Available Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4+CD8+ (DP thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCRα selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limitscell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.

  3. Vestibular schwannoma and cell-phones. Results, limits and perspectives of clinical studies.

    Science.gov (United States)

    Mornet, E; Kania, R; Sauvaget, E; Herman, P; Tran Ba Huy, P

    2013-11-01

    The widespread development of cell-phones entails novel user exposure to electromagnetic fields. Health impact is a public health issue and a source of anxiety in the population. Some clinical studies reported an association between cell and cordless phone use and vestibular schwannoma; others found none. A systematic review was performed of all published clinical studies (cohort, registry, case-control and validation studies), with analysis of results, to determine the nature of the association and the level of evidence. Cohort studies were inconclusive due to short exposure durations and poor representativeness. Registry studies showed no correlation between evolution of cell-phone use and incidence of vestibular schwannoma. Case-control studies reported contradictory results, with methodological flaws. Only a small number of subjects were included in long-term studies (>10 years), and these failed to demonstrate any indisputable causal relationship. Exposure assessment methods were debatable, and long-term assessment was lacking. An on-going prospective study should determine any major effect of electromagnetic fields; schwannoma being a rare pathology, absence of association will be difficult to prove. No clinical association has been demonstrated between cell and cordless phone use and vestibular schwannoma. Existing studies are limited by their retrospective assessment of exposure. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  4. Comparative Ability of Mesenchymal Stromal Cells from Different Tissues to Limit Neutrophil Recruitment to Inflamed Endothelium.

    Directory of Open Access Journals (Sweden)

    Hafsa Munir

    Full Text Available Mesenchymal stromal cells (MSC are tissue-resident stromal cells capable of modulating immune responses, including leukocyte recruitment by endothelial cells (EC. However, the comparative potency of MSC from different sources in suppressing recruitment, and the necessity for close contact with endothelium remain uncertain, although these factors have implications for use of MSC in therapy. We thus compared the effects of MSC isolated from bone marrow, Wharton's jelly, and trabecular bone on neutrophil recruitment to cytokine-stimulated EC, using co-culture models with different degrees of proximity between MSC and EC. All types of MSC suppressed neutrophil adhesion to inflamed endothelium but not neutrophil transmigration, whether directly incorporated into endothelial monolayers or separated from them by thin micropore filters. Further increase in the separation of the two cell types tended to reduce efficacy, although this diminution was least for the bone marrow MSC. Immuno-protective effects of MSC were also diminished with repeated passage; with BMMSC, but not WJMSC, completing losing their suppressive effect by passage 7. Conditioned media from all co-cultures suppressed neutrophil recruitment, and IL-6 was identified as a common bioactive mediator. These results suggest endogenous MSC have a homeostatic role in limiting inflammatory leukocyte infiltration in a range of tissues. Since released soluble mediators might have effects locally or remotely, infusion of MSC into blood or direct injection into target organs might be efficacious, but in either case, cross-talk between EC and MSC appears necessary.

  5. Limited Variation in BK Virus T-Cell Epitopes Revealed by Next-Generation Sequencing

    Science.gov (United States)

    Sahoo, Malaya K.; Tan, Susanna K.; Chen, Sharon F.; Kapusinszky, Beatrix; Concepcion, Katherine R.; Kjelson, Lynn; Mallempati, Kalyan; Farina, Heidi M.; Fernández-Viña, Marcelo; Tyan, Dolly; Grimm, Paul C.; Anderson, Matthew W.; Concepcion, Waldo

    2015-01-01

    BK virus (BKV) infection causing end-organ disease remains a formidable challenge to the hematopoietic cell transplant (HCT) and kidney transplant fields. As BKV-specific treatments are limited, immunologic-based therapies may be a promising and novel therapeutic option for transplant recipients with persistent BKV infection. Here, we describe a whole-genome, deep-sequencing methodology and bioinformatics pipeline that identify BKV variants across the genome and at BKV-specific HLA-A2-, HLA-B0702-, and HLA-B08-restricted CD8 T-cell epitopes. BKV whole genomes were amplified using long-range PCR with four inverse primer sets, and fragmentation libraries were sequenced on the Ion Torrent Personal Genome Machine (PGM). An error model and variant-calling algorithm were developed to accurately identify rare variants. A total of 65 samples from 18 pediatric HCT and kidney recipients with quantifiable BKV DNAemia underwent whole-genome sequencing. Limited genetic variation was observed. The median number of amino acid variants identified per sample was 8 (range, 2 to 37; interquartile range, 10), with the majority of variants (77%) detected at a frequency of <5%. When normalized for length, there was no statistical difference in the median number of variants across all genes. Similarly, the predominant virus population within samples harbored T-cell epitopes similar to the reference BKV strain that was matched for the BKV genotype. Despite the conservation of epitopes, low-level variants in T-cell epitopes were detected in 77.7% (14/18) of patients. Understanding epitope variation across the whole genome provides insight into the virus-immune interface and may help guide the development of protocols for novel immunologic-based therapies. PMID:26202116

  6. A set of nutrient limitations trigger yeast cell death in a nitrogen-dependent manner during wine alcoholic fermentation.

    Directory of Open Access Journals (Sweden)

    Camille Duc

    Full Text Available Yeast cell death can occur during wine alcoholic fermentation. It is generally considered to result from ethanol stress that impacts membrane integrity. This cell death mainly occurs when grape musts processing reduces lipid availability, resulting in weaker membrane resistance to ethanol. However the mechanisms underlying cell death in these conditions remain unclear. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a given nutrient limitation and thus survive starvation. We show here that a set of micronutrients (oleic acid, ergosterol, pantothenic acid and nicotinic acid in low, growth-restricting concentrations trigger cell death in alcoholic fermentation when nitrogen level is high. We provide evidence that nitrogen signaling is involved in cell death and that either SCH9 deletion or Tor inhibition prevent cell death in several types of micronutrient limitation. Under such limitations, yeast cells fail to acquire any stress resistance and are unable to store glycogen. Unexpectedly, transcriptome analyses did not reveal any major changes in stress genes expression, suggesting that post-transcriptional events critical for stress response were not triggered by micronutrient starvation. Our data point to the fact that yeast cell death results from yeast inability to trigger an appropriate stress response under some conditions of nutrient limitations most likely not encountered by yeast in the wild. Our conclusions provide a novel frame for considering both cell death and the management of nutrients during alcoholic fermentation.

  7. A set of nutrient limitations trigger yeast cell death in a nitrogen-dependent manner during wine alcoholic fermentation.

    Science.gov (United States)

    Duc, Camille; Pradal, Martine; Sanchez, Isabelle; Noble, Jessica; Tesnière, Catherine; Blondin, Bruno

    2017-01-01

    Yeast cell death can occur during wine alcoholic fermentation. It is generally considered to result from ethanol stress that impacts membrane integrity. This cell death mainly occurs when grape musts processing reduces lipid availability, resulting in weaker membrane resistance to ethanol. However the mechanisms underlying cell death in these conditions remain unclear. We examined cell death occurrence considering yeast cells ability to elicit an appropriate response to a given nutrient limitation and thus survive starvation. We show here that a set of micronutrients (oleic acid, ergosterol, pantothenic acid and nicotinic acid) in low, growth-restricting concentrations trigger cell death in alcoholic fermentation when nitrogen level is high. We provide evidence that nitrogen signaling is involved in cell death and that either SCH9 deletion or Tor inhibition prevent cell death in several types of micronutrient limitation. Under such limitations, yeast cells fail to acquire any stress resistance and are unable to store glycogen. Unexpectedly, transcriptome analyses did not reveal any major changes in stress genes expression, suggesting that post-transcriptional events critical for stress response were not triggered by micronutrient starvation. Our data point to the fact that yeast cell death results from yeast inability to trigger an appropriate stress response under some conditions of nutrient limitations most likely not encountered by yeast in the wild. Our conclusions provide a novel frame for considering both cell death and the management of nutrients during alcoholic fermentation.

  8. Impact of nutrient imbalance on wine alcoholic fermentations: nitrogen excess enhances yeast cell death in lipid-limited must.

    Directory of Open Access Journals (Sweden)

    Catherine Tesnière

    Full Text Available We evaluated the consequences of nutritional imbalances, particularly lipid/nitrogen imbalances, on wine yeast survival during alcoholic fermentation. We report that lipid limitation (ergosterol limitation in our model led to a rapid loss of viability during the stationary phase of fermentation and that the cell death rate is strongly modulated by nitrogen availability and nature. Yeast survival was reduced in the presence of excess nitrogen in lipid-limited fermentations. The rapidly dying yeast cells in fermentations in high nitrogen and lipid-limited conditions displayed a lower storage of the carbohydrates trehalose and glycogen than observed in nitrogen-limited cells. We studied the cell stress response using HSP12 promoter-driven GFP expression as a marker, and found that lipid limitation triggered a weaker stress response than nitrogen limitation. We used a SCH9-deleted strain to assess the involvement of nitrogen signalling pathways in the triggering of cell death. Deletion of SCH9 increased yeast viability in the presence of excess nitrogen, indicating that a signalling pathway acting through Sch9p is involved in this nitrogen-triggered cell death. We also show that various nitrogen sources, but not histidine or proline, provoked cell death. Our various findings indicate that lipid limitation does not elicit a transcriptional programme that leads to a stress response protecting yeast cells and that nitrogen excess triggers cell death by modulating this stress response, but not through HSP12. These results reveal a possibly negative role of nitrogen in fermentation, with reported effects referring to ergosterol limitation conditions. These effects should be taken into account in the management of alcoholic fermentations.

  9. The natural history of skin-limited Langerhans cell histiocytosis: a single-institution experience.

    Science.gov (United States)

    Ehrhardt, Matthew J; Humphrey, Stephen R; Kelly, Michael E; Chiu, Yvonne E; Galbraith, Sheila S

    2014-11-01

    Prior reports of Langerhans cell histiocytosis (LCH) suggest that isolated skin involvement is rare and often progresses to systemic disease. More rapid access to pediatric subspecialty care has likely led to more frequent representation of this condition. The purpose of this study is to characterize the natural history of skin-limited LCH in an era of increased access to pediatric subspecialty care. A retrospective chart review was performed on all patients newly diagnosed with LCH between 2001 and 2012 at the Children's Hospital of Wisconsin. Extensive review of laboratory, physical examination, and imaging reports was performed and data collected for patients with biopsy-proven skin LCH. Sixteen individuals with skin-limited LCH were identified. The median age at onset of skin eruption was birth (range, birth to 6 mo), and median duration of follow-up was 19.5 months (range, 2 wk to 10 y) from diagnosis. One patient (6%) developed pituitary disease and 1 patient (6%) had refractory skin involvement. All others experienced complete resolution. For patients without progressive or refractory disease, resolution of skin findings occurred within 7 months from onset. Progression of skin-limited to multisystem LCH likely may be less frequent than previously described.

  10. Limit power of nuclear fuel cells with biconcave cross sections; Potencia limite de celulas de combustivel nuclear cilindricas de secao biconcava

    Energy Technology Data Exchange (ETDEWEB)

    Alves, Thiago Antonini; Pelegrini, Marcelo Ferreira; Woiski, Emanuel Rocha; Maia, Cassio Roberto Macedo [UNESP, Ilha Solteira, SP (Brazil). Dept. de Engenharia Mecanica]. E-mail: antonini@dem.feis.unesp.br; woiski@dem.feis.unesp.br; cassio@dem.feis.unesp.br

    2004-07-01

    Diffusive media with distributed sources, such as the case of nuclear fuel cells, represent a major role in engineering. Due to the nuclear fission of the chemical element, fuel cells are capable of releasing an enormous amount of thermal energy in spite of their reduced dimensions, in such a way that the maximum power of the reactor is closely related to the fusion temperature of the fuel, and consequently to the maximum temperature in the cell. The cell maximum temperature is, therefore, a chief parameter in nuclear reactor design. Limiting power, of course, depends not only of the fuel thermo physical properties, but also of the cell shape and dimensions. The present work purports the study of the effects of some parameters of cell geometry on the limiting power, especially for cell with biconcave cross sections. Given the large temperature gradients in the cell, the thermal conductivity must be assumed as a generic function of temperature. Therefore, the problem has been modeled as a nonlinear 2 D Poisson-like PDE, with a nontrivial geometry of the boundary. For the analytical solution, Kirchhoff transform has been employed to turn the equation into a linear Poisson equation, a conformal transform brought it to a rectangular domain and Generalized Integral Transform method applied in order to solve the resulting equation. For the numerical solution of the linearized equation, a program has been developed in Python, reusing classes of Ellipt2d, an open-source elliptic solver. The domain has been divided into linear triangular finite elements, and the system of equations resulting of Galerkin method application has been solved, for each parameter set. The trend in critical power has been discussed, as well as the numerical results compared to the analytical solutions and to the literature. (author)

  11. Hydrogel limits stem cell dispersal in the deaf cochlea: implications for cochlear implants.

    Science.gov (United States)

    Nayagam, Bryony A; Backhouse, Steven S; Cimenkaya, Cengiz; Shepherd, Robert K

    2012-12-01

    Auditory neurons provide the critical link between a cochlear implant and the brain in deaf individuals, therefore their preservation and/or regeneration is important for optimal performance of this neural prosthesis. In cases where auditory neurons are significantly depleted, stem cells (SCs) may be used to replace the lost population of neurons, thereby re-establishing the critical link between the periphery (implant) and the brain. For such a therapy to be therapeutically viable, SCs must be differentiated into neurons, retained at their delivery site and damage caused to the residual auditory neurons minimized. Here we describe the transplantation of SC-derived neurons into the deaf cochlea, using a peptide hydrogel to limit their dispersal. The described approach illustrates that SCs can be delivered to and are retained within the basal turn of the cochlea, without a significant loss of endogenous auditory neurons. In addition, the tissue response elicited from this surgical approach was restricted to the surgical site and did not extend beyond the cochlear basal turn. Overall, this approach illustrates the feasibility of targeted cell delivery into the mammalian cochlea using hydrogel, which may be useful for future cell-based transplantation strategies, for combined treatment with a cochlear implant to restore function.

  12. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation.

    Science.gov (United States)

    Araujo, Lindsey; Khim, Phillip; Mkhikian, Haik; Mortales, Christie-Lynn; Demetriou, Michael

    2017-01-06

    Rapidly proliferating cells switch from oxidative phosphorylation to aerobic glycolysis plus glutaminolysis, markedly increasing glucose and glutamine catabolism. Although Otto Warburg first described aerobic glycolysis in cancer cells >90 years ago, the primary purpose of this metabolic switch remains controversial. The hexosamine biosynthetic pathway requires glucose and glutamine for de novo synthesis of UDP-GlcNAc, a sugar-nucleotide that inhibits receptor endocytosis and signaling by promoting N-acetylglucosamine branching of Asn (N)-linked glycans. Here, we report that aerobic glycolysis and glutaminolysis co-operatively reduce UDP-GlcNAc biosynthesis and N-glycan branching in mouse T cell blasts by starving the hexosamine pathway of glucose and glutamine. This drives growth and pro-inflammatory T H 17 over anti-inflammatory-induced T regulatory (iTreg) differentiation, the latter by promoting endocytic loss of IL-2 receptor-α (CD25). Thus, a primary function of aerobic glycolysis and glutaminolysis is to co-operatively limit metabolite supply to N-glycan biosynthesis, an activity with widespread implications for autoimmunity and cancer.

  13. Large Accumulation of Collagen and Increased Activation of Mast Cells in Hearts of Mice with Hyperlipidemia

    Directory of Open Access Journals (Sweden)

    Yunpeng Cheng

    2017-09-01

    Full Text Available Abstract Background: Hyperlipidemia, which is characterized by an elevation of lipids in the bloodstream, is a major risk factor for cardiac disease. Objectives: The present study investigated the role of fibrosis in the progression of hyperlipidemia in the mice heart, and whether mast cell activation was associated with the fibrosis process. Methods: Hyperlipidemia was produced in C57BL / 6 mice by feeding them on a high-fat diet for 8 weeks.To assess tissue fibrosis, picrosirius red staining was performed. Hematoxylin & eosin (H&E staining was performed to identify the histopathological changes in the hearts. Immunohistochemistry was also accomplished to determine the localization of transforming growth factor (TGF-β and α-smooth muscle actin (α-SMA. Western blotting was performed to analyze the expression of chymase, tryptase, TGF-β, α-SMA and activity of Wnt/β-catenin pathway. At the end, serum total cholesterol (TC and triglycerides (TG levels were measured. All the values were expressed as means ± SD, the statistical significance level adopted was 5%. Results: Hyperlipidemia mice showed significantly increased collagen deposition in the hearts compared with normal mice. In addition, H&E staining showed significant cellular degeneration. Cardiac muscle was arranged in disorder with fracture in mice of the model group. Immunohistochemistry and western blot analysis revealed that expression levels of tryptase, chymase, β-catenin, TGF-β and α-SMA were significantly increased in the hyperlipidemia mice compared with the control group. Conclusions: The results indicated that mast cell activation might induce cardiac fibrosis by tryptase and chymase in hyperlipidemia, which had a close relationship with the increased activity of TGF-β/Wnt/β-catenin pathway.

  14. Stimulators of mineralization limit the invasive phenotype of human osteosarcoma cells by a mechanism involving impaired invadopodia formation.

    Science.gov (United States)

    Cmoch, Anna; Podszywalow-Bartnicka, Paulina; Palczewska, Malgorzata; Piwocka, Katarzyna; Groves, Patrick; Pikula, Slawomir

    2014-01-01

    Osteosarcoma (OS) is a highly aggressive bone cancer affecting children and young adults. Growing evidence connects the invasive potential of OS cells with their ability to form invadopodia (structures specialized in extracellular matrix proteolysis). In this study, we tested the hypothesis that commonly used in vitro stimulators of mineralization limit the invadopodia formation in OS cells. Here we examined the invasive potential of human osteoblast-like cells (Saos-2) and osteolytic-like (143B) OS cells treated with the stimulators of mineralization (ascorbic acid and B-glycerophosphate) and observed a significant difference in response of the tested cells to the treatment. In contrast to 143B cells, osteoblast-like cells developed a mineralization phenotype that was accompanied by a decreased proliferation rate, prolongation of the cell cycle progression and apoptosis. On the other hand, stimulators of mineralization limited osteolytic-like OS cell invasiveness into collagen matrix. We are the first to evidence the ability of 143B cells to degrade extracellular matrix to be driven by invadopodia. Herein, we show that this ability of osteolytic-like cells in vitro is limited by stimulators of mineralization. Our study demonstrates that mineralization competency determines the invasive potential of cancer cells. A better understanding of the molecular mechanisms by which stimulators of mineralization regulate and execute invadopodia formation would reveal novel clinical targets for treating osteosarcoma.

  15. Conductive polymer layers to limit transfer of fuel reactants to catalysts of fuel cells to reduce reactant crossover

    Science.gov (United States)

    Stanis, Ronald J.; Lambert, Timothy N.

    2016-12-06

    An apparatus of an aspect includes a fuel cell catalyst layer. The fuel cell catalyst layer is operable to catalyze a reaction involving a fuel reactant. A fuel cell gas diffusion layer is coupled with the fuel cell catalyst layer. The fuel cell gas diffusion layer includes a porous electrically conductive material. The porous electrically conductive material is operable to allow the fuel reactant to transfer through the fuel cell gas diffusion layer to reach the fuel cell catalyst layer. The porous electrically conductive material is also operable to conduct electrons associated with the reaction through the fuel cell gas diffusion layer. An electrically conductive polymer material is coupled with the fuel cell gas diffusion layer. The electrically conductive polymer material is operable to limit transfer of the fuel reactant to the fuel cell catalyst layer.

  16. Immunocytochemical and ultrastructural evidence of glial cells and hyalocytes in internal limiting membrane specimens of idiopathic macular holes.

    Science.gov (United States)

    Schumann, Ricarda G; Eibl, Kirsten H; Zhao, Fei; Scheerbaum, Martin; Scheler, Renate; Schaumberger, Markus M; Wehnes, Helga; Walch, Axel K; Haritoglou, Christos; Kampik, Anselm; Gandorfer, Arnd

    2011-10-03

    To provide new information on epiretinal cell proliferation and the cells' origin in idiopathic macular holes and to overcome the effects of embedding and sectioning preparation procedures on cell-distribution patterns. Interference and phase-contrast microscopy, immunocytochemistry, and scanning and transmission electron microscopy were performed on surgically excised whole-mounted internal limiting membrane (ILM) specimens removed from 60 eyes with idiopathic macular holes. Cell distribution and cell morphology were correlated with immunocytochemical staining characteristics. Twelve cell type-specific antibodies were used to detect glial cells, hyalocytes, retinal pigment epithelial cells, retinal ganglion cells, and immune cells. Cell viability was analyzed. Epiretinal cell proliferation was found in all ILM specimens, irrespective of the stage of the macular hole. Cell density showed a broad variety. Immunocytochemistry frequently revealed simultaneous expression of GFAP/CD45, GFAP/CD64, GFAP/CD68, GFAP/CRALBP, and GFAP/CD90. Some cells presented with intracellular contractile filaments (anti-αSMA); others were not immunoreactive to any antibody examined. The percentage of viable cells showed a broad variety with a mean of 73% (SD 29%). Electron microscopy demonstrated glial cells, hyalocytes, and myofibroblast-like cells. The presence of epiretinal cells at the ILM in all macular hole stages strongly suggests a substantial involvement of cell migration and proliferation in the course of macular hole development. Glial cells and hyalocytes play the predominant role in epiretinal cell proliferation. Given the co-expression of glial cell and hyalocyte markers, transdifferentiation of epiretinal cells needs further elucidation, especially with respect to αSMA-positive cells leading to traction at the vitreoretinal interface.

  17. JNK mitogen-activated protein kinase limits calcium-dependent chloride secretion across colonic epithelial cells.

    LENUS (Irish Health Repository)

    Donnellan, Fergal

    2010-01-01

    Neuroimmune agonists induce epithelial Cl(-) secretion through elevations in intracellular Ca2+ or cAMP. Previously, we demonstrated that epidermal growth factor receptor (EGFR) transactivation and subsequent ERK MAPK activation limits secretory responses to Ca2+-dependent, but not cAMP-dependent, agonists. Although JNK MAPKs are also expressed in epithelial cells, their role in regulating transport function is unknown. Here, we investigated the potential role for JNK in regulating Cl(-) secretion in T(84) colonic epithelial cells. Western blot analysis revealed that a prototypical Ca2+-dependent secretagogue, carbachol (CCh; 100 microM), induced phosphorylation of both the 46-kDa and 54-kDa isoforms of JNK. This effect was mimicked by thapsigargin (TG), which specifically elevates intracellular Ca2+, but not by forskolin (FSK; 10 microM), which elevates cAMP. CCh-induced JNK phosphorylation was attenuated by the EGFR inhibitor, tyrphostin-AG1478 (1 microM). Pretreatment of voltage-clamped T(84) cells with SP600125 (2 microM), a specific JNK inhibitor, potentiated secretory responses to both CCh and TG but not to FSK. The effects of SP600125 on CCh-induced secretion were not additive with those of the ERK inhibitor, PD98059. Finally, in apically permeabilized T(84) cell monolayers, SP600125 potentiated CCh-induced K+ conductances but not Na+\\/K+ATPase activity. These data demonstrate a novel role for JNK MAPK in regulating Ca2+ but not cAMP-dependent epithelial Cl(-) secretion. JNK activation is mediated by EGFR transactivation and exerts its antisecretory effects through inhibition of basolateral K+ channels. These data further our understanding of mechanisms regulating epithelial secretion and underscore the potential for exploitation of MAPK-dependent signaling in treatment of intestinal transport disorders.

  18. Combined chemotherapy and radiation therapy in limited disease small-cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Moon Kyung; Ahn, Yong Chan; Park, Keun Chil; Lim Do Hoon; Huh, Seung Jae; Kim, Dae Yong; Shin, Kyung Hwan; Lee, Kyu Chan; Kwon, O Jung [College of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)

    1999-03-01

    This is a retrospective study to evaluate the response rate, acute toxicity, and survival rate of a combined chemotherapy and radiation therapy in limited disease small cell lung cancer. Forty six patients with limited disease small-cell lung cancer who underwent combined chemotherapy and radiation therapy between October 1994 and April 1998 were evaluated. Six cycles of chemotherapy were planned either using a VIP regimen (etoposide, ifosfamide, and cis-platin) or a EP regimen (etoposide and cis-platin). Thoracic radiation therapy was planned to deliver 44 Gy using 10MV X-ray, starting concurrently with chemotherapy. Response was evaluated 4 weeks after the completion of the planned chemotherapy and radiation therapy, and the prophylactic cranial irradiation was planned only for the patients with complete responses. Acute toxicity was evaluated using the SWOG toxicity criteria, and the overall survival and disease-free survival were calculated using the Kaplan-Meier Method. The median follow-up period was 16 months (range:2 to 41 months). Complete response was achieved in 30 (65%) patients, of which 22 patients received prophylactic cranial irradiations. Acute toxicities over grade III were granulocytopenia in 23 (50%), anemia in 17 (37%), thrombo-cytopenia in nine (20%), alopecia in nine (20%), nausea/vomiting in five (11%), and peripheral neuropathy in one (2%). Chemotherapy was delayed in one patient, and the chemotherapy doses were reduced in 58 (24%) out of the total 246 cycles. No radiation esophagitis over grade III was observed, while interruption during radiation therapy for a mean of 8.3 days occurred in 21 patients. The local recurrences were observed in 8 patients and local progressions were in 6 patients, and the distant metastases in 17 patients. Among these, four patients had both the local relapse and the distant metastasis. Brain was the most common metastatic site (10 patients), followed by the liver as the next common site (4 patients). The

  19. Effects of Photovoltaic and Fuel Cell Hybrid System on Distribution Network Considering the Voltage Limits

    Directory of Open Access Journals (Sweden)

    ABYANEH, H. A.

    2010-11-01

    Full Text Available Development of distribution network and power consumption growth, increase voltage drop on the line impedance and therefore voltage drop in system buses. In some cases consumption is so high that voltage in some buses exceed from standard. In this paper, effect of the fuel cell and photovoltaic hybrid system on distribution network for solving expressed problem is studied. For determining the capacity of each distributed generation source, voltage limitation on the bus voltages under different conditions is considered. Simulation is done by using DIgSILENT software on the part of the 20 kV real life Sirjan distribution system. In this article, optimum location with regard to system and environmental conditions are studied in two different viewpoints.

  20. Osteoprotegerin-Mediated Homeostasis of Rank+ Thymic Epithelial Cells Does Not Limit Foxp3+ Regulatory T Cell Development.

    Science.gov (United States)

    McCarthy, Nicholas I; Cowan, Jennifer E; Nakamura, Kyoko; Bacon, Andrea; Baik, Song; White, Andrea J; Parnell, Sonia M; Jenkinson, Eric J; Jenkinson, William E; Anderson, Graham

    2015-09-15

    In the thymus, medullary thymic epithelial cells (mTEC) regulate T cell tolerance via negative selection and Foxp3(+) regulatory T cell (Treg) development, and alterations in the mTEC compartment can lead to tolerance breakdown and autoimmunity. Both the receptor activator for NF-κB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis and expression of the transcriptional regulator Aire are involved in the regulation of thymus medullary microenvironments. However, their impact on the mechanisms controlling mTEC homeostasis is poorly understood, as are the processes that enable the thymus medulla to support the balanced production of mTEC-dependent Foxp3(+) Treg. In this study, we have investigated the control of mTEC homeostasis and examined how this process impacts the efficacy of Foxp3(+) Treg development. Using newly generated RANK Venus reporter mice, we identify distinct RANK(+) subsets that reside within both the mTEC(hi) and mTEC(lo) compartments and that represent direct targets of OPG-mediated control. Moreover, by mapping OPG expression to a subset of Aire(+) mTEC, our data show how cis- and trans-acting mechanisms are able to control the thymus medulla by operating on multiple mTEC targets. Finally, we show that whereas the increase in mTEC availability in OPG-deficient (Tnfrsf11b(-/-)) mice impacts the intrathymic Foxp3(+) Treg pool by enhancing peripheral Treg recirculation back to the thymus, it does not alter the number of de novo Rag2pGFP(+)Foxp3(+) Treg that are generated. Collectively, our study defines patterns of RANK expression within the thymus medulla, and it shows that mTEC homeostasis is not a rate-limiting step in intrathymic Foxp3(+) Treg production. Copyright © 2015 The Authors.

  1. Cellulose and lignin colocalization at the plant cell wall surface limits microbial hydrolysis of Populus biomass

    Energy Technology Data Exchange (ETDEWEB)

    Dumitrache, Alexandru [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Tolbert, Allison [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Georgia Inst. of Technology, Atlanta, GA (United States); Natzke, Jace [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Brown, Steven D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Davison, Brian H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ragauskas, Arthur J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)

    2017-04-20

    Biorefining of plant feedstocks into fuels and specialty chemicals, using biological conversion, requires the solubilization of lignocellulosics into simpler oligomeric compounds. However, non-pretreated woody biomass has shown high resistance to hydrolysis by cellulolytic microbes or purified cellulases. We investigate the limited solubilization of Populus deltoides by the cellulolytic thermophile Clostridium thermocellum in the absence of solute inhibitors. Compared to control samples, fermented poplar revealed that the hydrolysis of carbohydrates in secondary cell walls ceased prematurely as lignin presence increased at the surface. In quantitative fluorescence colocalization analysis by confocal laser scanning microscopy, the Manders’ coefficient of fractional overlap between lignin and cellulose signals increased from an average of 0.67 to a near-maximum 0.92 in fermented tissue. Chemical imaging by time-of-flight secondary ion mass spectrometry revealed a 49% decline in surface cellulose and a compensatory 30% and 11% increase in surface S- and G- lignin, respectively. Although 72% of the initial glucan was still present in the lignocellulose matrix of this feedstock, subsequent treatments with cell-free purified cellulases did not significantly restore hydrolysis. This confirmed that biomass surfaces had become non-productive for the C. thermocellum hydrolytic exoproteome. This study provides direct evidence for an explicit definition of feedstock recalcitrance, whereby depletion of surface carbohydrate increases lignin exposure which leads to inhibition of enzyme activity, while the bulk residual biomass retains significant undigested carbohydrate content. The analysis presented here establishes a novel method for the quantitation of lignocellulose recalcitrance.

  2. The limiting conditional probability distribution in a stochastic model of T cell repertoire maintenance.

    Science.gov (United States)

    Stirk, Emily R; Lythe, Grant; van den Berg, Hugo A; Hurst, Gareth A D; Molina-París, Carmen

    2010-04-01

    The limiting conditional probability distribution (LCD) has been much studied in the field of mathematical biology, particularly in the context of epidemiology and the persistence of epidemics. However, it has not yet been applied to the immune system. One of the characteristic features of the T cell repertoire is its diversity. This diversity declines in old age, whence the concepts of extinction and persistence are also relevant to the immune system. In this paper we model T cell repertoire maintenance by means of a continuous-time birth and death process on the positive integers, where the origin is an absorbing state. We show that eventual extinction is guaranteed. The late-time behaviour of the process before extinction takes place is modelled by the LCD, which we prove always exists for the process studied here. In most cases, analytic expressions for the LCD cannot be computed but the probability distribution may be approximated by means of the stationary probability distributions of two related processes. We show how these approximations are related to the LCD of the original process and use them to study the LCD in two special cases. We also make use of the large N expansion to derive a further approximation to the LCD. The accuracy of the various approximations is then analysed. (c) 2009 Elsevier Inc. All rights reserved.

  3. Statistical analysis of data from limiting dilution cloning to assess monoclonality in generating manufacturing cell lines.

    Science.gov (United States)

    Quiroz, Jorge; Tsao, Yung-Shyeng

    2016-07-08

    Assurance of monoclonality of recombinant cell lines is a critical issue to gain regulatory approval in biological license application (BLA). Some of the requirements of regulatory agencies are the use of proper documentations and appropriate statistical analysis to demonstrate monoclonality. In some cases, one round may be sufficient to demonstrate monoclonality. In this article, we propose the use of confidence intervals for assessing monoclonality for limiting dilution cloning in the generation of recombinant manufacturing cell lines based on a single round. The use of confidence intervals instead of point estimates allow practitioners to account for the uncertainty present in the data when assessing whether an estimated level of monoclonality is consistent with regulatory requirements. In other cases, one round may not be sufficient and two consecutive rounds are required to assess monoclonality. When two consecutive subclonings are required, we improved the present methodology by reducing the infinite series proposed by Coller and Coller (Hybridoma 1983;2:91-96) to a simpler series. The proposed simpler series provides more accurate and reliable results. It also reduces the level of computation and can be easily implemented in any spreadsheet program like Microsoft Excel. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1061-1068, 2016. © 2016 American Institute of Chemical Engineers.

  4. Subclassification of pulmonary non-small cell lung carcinoma in fine needle aspirates using a limited immunohistochemistry panel

    Directory of Open Access Journals (Sweden)

    Kusum Kapila

    2013-01-01

    Conclusion: Use of limited IHC panel helps categorize primary versus secondary tumors to the lung. The p63 is a useful marker for detecting squamous cell carcinoma. In countries where antibodies are not readily available, using a limited IHC panel of TTF-1, p63, and CK7 can help further type NSCLC lung tumors.

  5. Nitric oxide diffusion to red blood cells limits extracellular, but not intraphagosomal, peroxynitrite formation by macrophages.

    Science.gov (United States)

    Prolo, Carolina; Álvarez, María Noel; Ríos, Natalia; Peluffo, Gonzalo; Radi, Rafael; Romero, Natalia

    2015-10-01

    Macrophage-derived nitric oxide ((•)NO) participates in cytotoxic mechanisms against diverse microorganisms and tumor cells. These effects can be mediated by (•)NO itself or (•)NO-derived species such as peroxynitrite formed by its diffusion-controlled reaction with NADPH oxidase-derived superoxide radical anion (O(2)(•-)). In vivo, the facile extracellular diffusion of (•)NO as well as different competing consumption routes limit its bioavailability for the reaction with O(2)(•-) and, hence, peroxynitrite formation. In this work, we evaluated the extent by which (•)NO diffusion to red blood cells (RBC) can compete with activated macrophages-derived O(2)(•-) and affect peroxynitrite formation yields. Macrophage-dependent peroxynitrite production was determined by boron-based probes that react directly with peroxynitrite, namely, coumarin-7-boronic acid (CBA) and fluorescein-boronate (Fl-B). The influence of (•)NO diffusion to RBC on peroxynitrite formation was experimentally analyzed in co-incubations of (•)NO and O(2)(•-)-forming macrophages with erythrocytes. Additionally, we evaluated the permeation of (•)NO to RBC by measuring the intracellular oxidation of oxyhemoglobin to methemoglobin. Our results indicate that diluted RBC suspensions dose-dependently inhibit peroxynitrite formation, outcompeting the O(2)(•-) reaction. Computer-assisted kinetic studies evaluating peroxynitrite formation by its precursor radicals in the presence of RBC are in accordance with experimental results. Moreover, the presence of erythrocytes in the proximity of (•)NO and O(2)(•-)-forming macrophages prevented intracellular Fl-B oxidation pre-loaded in L1210 cells co-cultured with activated macrophages. On the other hand, Fl-B-coated latex beads incorporated in the macrophage phagocytic vacuole indicated that intraphagosomal probe oxidation by peroxynitrite was not affected by nearby RBC. Our data support that in the proximity of a blood vessel, (

  6. The rate-limiting reaction in phosphatidylcholine synthesis by alveolar type II cells isolated from fetal rat lung

    NARCIS (Netherlands)

    Post, M.; Batenburg, J.J.; Golde, L.M.G. van; Smith, B.T.

    1984-01-01

    1. 1. The rate-limiting reaction in the formation of phosphatidylcholine by type II cells isolated from fetal rat lung was examined. 2. 2. Studies on the uptake of [Me-3H]choline and its incorporation into its metabolites indicated that in these cells the choline phosphate pool was much larger

  7. Barriers to Combined-Modality Therapy for Limited-Stage Small-Cell Lung Cancer.

    Science.gov (United States)

    Pezzi, Todd A; Schwartz, David L; Mohamed, Abdallah S R; Welsh, James W; Komaki, Ritsuko U; Hahn, Stephen M; Sepesi, Boris; Pezzi, Christopher M; Fuller, Clifton D; Chun, Stephen G

    2018-01-04

    Combined-modality therapy with chemotherapy and radiation therapy plays a crucial role in the upfront treatment of patients with limited-stage small-cell lung cancer (SCLC), but there may be barriers to utilization in the United States. To estimate utilization rates and factors associated with chemotherapy and radiation therapy delivery for limited-stage SCLC using the National Cancer Database. Analysis of initial management of all limited-stage SCLC cases from 2004 through 2013 in the National Cancer Database. Utilization rates of chemotherapy and radiation therapy at time of initial treatment. Multivariable analysis identified independent clinical and socioeconomic factors associated with utilization and overall survival. A total of 70 247 cases met inclusion criteria (55.3% female; median age, 68 y [range, 19-90 y]). Initial treatment was 55.5% chemotherapy and radiation therapy, 20.5% chemotherapy alone, 3.5% radiation therapy alone, and 20.0% neither (0.5% not reported). Median survival was 18.2 (95% CI, 17.9-18.4), 10.5 (95% CI, 10.3-10.7), 8.3 (95% CI, 7.7-8.8), and 3.7 (95% CI, 3.5-3.8) months, respectively. Being uninsured was associated with a lower likelihood of both chemotherapy (odds ratio [OR], 0.65; 95% CI, 0.56-0.75; P therapy (OR, 0.75; 95% CI, 0.67-0.85; P therapy delivery. Lack of health insurance (HR, 1.19; 95% CI, 1.13-1.26; P therapy (HR, 0.62; 95% CI, 0.60-0.63; P therapy or chemotherapy as part of initial treatment for limited-stage SCLC, which, in turn, was associated with poor survival. Lack of radiation therapy delivery was uniquely associated with government insurance coverage, suggesting a need for targeted access improvement in this population. Additional work will be necessary to conclusively define exact population patterns, specific treatment deficiencies, and causative factors leading to heterogeneous care delivery.

  8. Twice daily radiation therapy plus concurrent chemotherapy for limited-stage small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yeo, Seung Gu; Cho, Moon June; Kim, Sun Young; Kim, Ki Whan; Kim, Jun Sang [Chungnam National University Hospital, Daejeon (Korea, Republic of)

    2006-06-15

    A retrospective study was performed to evaluate the efficiency and feasibility of twice daily radiation therapy plus concurrent chemotherapy for limited-stage small cell lung cancer in terms of treatment response, survival, patterns of failure, and acute toxicities. Between February 1993 and October 2002, 76 patients of histologically proven limited-stage small cell lung cancer (LS-SCLC) were treated with twice daily radiation therapy and concurrent chemotherapy. Male was in 84% (64/76), and median age was 57 years (range, 32 {approx} 75 years). Thoracic radiation therapy consisted of 120 or 150 cGy per fraction, twice a day at least 6 hours apart, 5 days a week. Median total dose was 50.4 Gy (range, 45 {approx} 51 Gy). Concurrent chemotherapy consisted of CAV (cytoxan 1000 mg/m{sup 2}, adriamycin 40 mg/m{sup 2}, vincristine 1 mg/m{sup 2}) alternating with PE (cisplatin 60 mg/m{sup 2}, etoposide 100 mg/m{sup 2}) or PE alone, every 3 weeks. The median cycle of chemotherapy was six (range, 1 {approx} 9 cycle). Prophylactic cranial irradiation (PCI) was recommended to the patients who achieved a complete response (CR). PCI scheme was 25 Gy/ 10 fractions. Median follow up was 18 months (range, 1 {approx} 136 months). Overall response rate was 86%; complete response in 39 (52%) and partial response in 26 (34%) patients. The median overall survival was 23 months. One, two, and three year overall survival rate was 72%, 50% and 30%, respectively. In univariate analysis, the treatment response was revealed as a significant favorable prognostic factor for survival ({rho} < 0.001). Grade 3 or worse acute toxicities were leukopenia in 46 (61%), anemia in 5 (6%), thrombocytopenia in 10 (13%), esophagitis in 5 (6%), and pulmonary toxicity in 2 (2%) patients. Of 73 evaluable patients, 40 (55%) patients subsequently had disease progression. The most frequent first site of distant metastasis was brain. Twice daily radiation therapy plus concurrent chemotherapy produced favorable

  9. Radiation therapy for elderly patients with limited non-small cell lung cancer

    International Nuclear Information System (INIS)

    Hayakawa, Kazushige; Mitsuhashi, Norio; Katano, Susumu

    1998-01-01

    The treatment results for 93 patients aged 75 years or older (elderly group) with limited non-small cell lung cancer (NSCLC) were retrospectively analyzed and compared with those for 193 patients younger than 75-years old (younger group). The elderly patients were classified into two groups: 64 patients aged 75-79 years (the elderly A) and 29 patients aged 80 years or older (the elderly B). All patients were treated with 10 MV X-rays using 2 Gy daily standard fractionation between 1976 and 1994. The total dose ranged from 60 Gy to 80 Gy. The overall two and five year survival rates were 31% and 12% for the elderly A group, and 28% and 6% for the elderly B group, respectively, compared with 34% and 12% for the younger group. In stage I-II NSCLC patients, the 2-year and 5-year disease-specific survival rates were 61% and 43% for the elderly A group, and 55% and 17% for the elderly B group, respectively, while the corresponding rates for younger group were 56% and 22%, respectively. In patients with stage III disease, however, the survival curves of the elderly B were inferior to those of the younger group and the elderly A group, although the difference was not statistically significant. Only two elderly patients died of late pulmonary insufficiency associated with high-dose irradiation of 80 Gy to the proximal bronchus. No other treatment-related event was observed except for mild acceptable acute complications in the elderly groups. The condition of two patients aged more than 80 years, however, deteriorated in mentality during hospitalization. Definitive radiation therapy is recommended to the elderly aged 75 years or older with limited NSCLC, especially early stage disease, as an acceptable choice or treatment. (K.H.)

  10. Increased expression of the renin-angiotensin system and mast cell density but not of angiotensin-converting enzyme II in late stages of human heart failure.

    Science.gov (United States)

    Batlle, Montserrat; Roig, Eulàlia; Perez-Villa, Fèlix; Lario, Sergio; Cejudo-Martin, Pilar; García-Pras, Ester; Ortiz, José; Roqué, Mercé; Orús, Josefina; Rigol, Montserrat; Heras, Magdalena; Ramírez, José; Jimenez, Wladimiro

    2006-09-01

    The activation of the renin-angiotensin system (RAS) contributes to the progression of left ventricular dysfunction. A novel human homologue of the angiotensin-converting enzyme (ACE), named ACE2, has been described but its role in human heart failure (HF) has not been elucidated. Besides, there is controversy as to whether the major angiotensin II-forming-activity in heart is ACE or chymase released from mast cells. Furthermore, long-term blockade of nitric oxide (NO) synthesis has been shown to increase ACE activity. To assess the locally activated vasoactive mediators that may contribute to the ventricular deterioration process, we sought to simultaneously analyze their expression in failing hearts. We analyzed left ventricular biopsies from 30 patients with heart failure undergoing heart transplantation and 12 organ donors. The mRNA levels of ACE, ACE2, chymase and endothelial nitric oxide synthase (eNOS), were quantified by real-time polymerase chain reaction and mast cell density was assessed by immunohistochemistry. The mRNA levels of the atrial natriuretic peptide (ANP) and the brain natriuretic peptide (BNP) were also quantified as controls. There was higher ACE and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in ACE2 expression were detected. eNOS mRNA levels were lower in failing hearts. Both ANP and BNP expression were higher in pathological than in control samples. These data document a decompensation of vasoactive systems that may contribute to the progressive impairment of the myocardial function in HF. On the other hand, ACE2 mRNA expression is not altered in human end-stage HF.

  11. Limiting-dilution analysis for the determination of leukemic cell frequencies after bone marrow decontamination with mafosfamide or merocyanine 540

    International Nuclear Information System (INIS)

    Porcellini, A.; Talevi, N.; Marchetti-Rossi, M.T.; Palazzi, M.; Manna, A.; Sparaventi, G.; Delfini, C.; Valentini, M.

    1987-01-01

    To stimulate a leukemia remission marrow, cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SF, Nalm-6, and K-562 lines. The cell mixtures were incubated in vitro with mafosfamide (AZ) or with the photoreactive dye merocyanine 540 (MC-540). A quantity of 10(4) cells of the treated suspensions was dispensed into microculture plates, and graded cell numbers of the line used to contaminate the normal marrow were added. Limiting-dilution analysis was used to estimate the frequency of leukemia cells persisting after treatment with the decontaminating agents. Treatment with AZ or MC-540 produced a total elimination (ie, 6 logs or 5.3 logs respectively) of B cell acute leukemia cells (CCRF-SB), whereas nearly 1.7 logs and 2 logs of K-562 acute myelogenous blasts were still present in the cell mixtures after treatment with MC-540 and AZ, respectively. Treatment of the Nalm-6-contaminated cell mixtures with AZ resulted in 100% elimination of clonogenic cells, whereas nearly 80% decontamination was obtained with MC-540. Our results suggest that treatment with AZ could be an effective method of eliminating clonogenic tumor cells from human bone marrow. MC-540, shown by previous studies to spare sufficient pluripotential stem cells to ensure hemopoietic reconstitution in the murine model and in clinical application, has comparable effects and merits trials for possible clinical use in autologous bone marrow transplantation

  12. Limiting-dilution analysis for the determination of leukemic cell frequencies after bone marrow decontamination with mafosfamide or merocyanine 540

    Energy Technology Data Exchange (ETDEWEB)

    Porcellini, A.; Talevi, N.; Marchetti-Rossi, M.T.; Palazzi, M.; Manna, A.; Sparaventi, G.; Delfini, C.; Valentini, M.

    1987-11-01

    To stimulate a leukemia remission marrow, cell suspensions of normal human bone marrow were mixed with human acute lymphoblastic or myelogenous leukemic cells of the CCRF-SF, Nalm-6, and K-562 lines. The cell mixtures were incubated in vitro with mafosfamide (AZ) or with the photoreactive dye merocyanine 540 (MC-540). A quantity of 10(4) cells of the treated suspensions was dispensed into microculture plates, and graded cell numbers of the line used to contaminate the normal marrow were added. Limiting-dilution analysis was used to estimate the frequency of leukemia cells persisting after treatment with the decontaminating agents. Treatment with AZ or MC-540 produced a total elimination (ie, 6 logs or 5.3 logs respectively) of B cell acute leukemia cells (CCRF-SB), whereas nearly 1.7 logs and 2 logs of K-562 acute myelogenous blasts were still present in the cell mixtures after treatment with MC-540 and AZ, respectively. Treatment of the Nalm-6-contaminated cell mixtures with AZ resulted in 100% elimination of clonogenic cells, whereas nearly 80% decontamination was obtained with MC-540. Our results suggest that treatment with AZ could be an effective method of eliminating clonogenic tumor cells from human bone marrow. MC-540, shown by previous studies to spare sufficient pluripotential stem cells to ensure hemopoietic reconstitution in the murine model and in clinical application, has comparable effects and merits trials for possible clinical use in autologous bone marrow transplantation.

  13. A 'fragile cell' sub-population revealed during cytometric assessment of Saccharomyces cerevisiae viability in lipid-limited alcoholic fermentation.

    Science.gov (United States)

    Delobel, P; Pradal, M; Blondin, B; Tesniere, C

    2012-11-01

    To show that in anaerobic fermentation with limiting lipid nutrients, cell preparation impacts the viability assessment of yeast cells, and to identify the factors involved. Saccharomyces cerevisiae viability was determined using propidium iodide staining and the flow cytometry. Analyses identified intact cells, dead cells and, under certain conditions, the presence of a third subpopulation of apparently damaged cells. This intermediate population could account for up to 40% of the entire cell population. We describe, analyse and discuss the effects of different solutions for cell resuspension on the respective proportion of these three populations, in particular that of the intermediate population. We show that this intermediate cell population forms in the absence of Ca(2+)/Mg(2+). Cell preparation significantly impacts population viability assessment by FCM. The intermediate population, revealed under certain conditions, could be renamed as 'fragile cells'. For these cells, Ca(2+) and Mg(2+) reduce cell membrane permeability to PI. This is the first study that analyses and discusses the factors influencing the formation of an intermediate population when studying viability in yeast alcoholic fermentation. With a wider application in biological research, this study provides important support to the relatively new questioning of propidium iodide staining as a universal cell death indicator. © 2012 The Authors. Letters in Applied Microbiology © 2012 The Society for Applied Microbiology.

  14. Prospective study of proton-beam radiation therapy for limited-stage small cell lung cancer.

    Science.gov (United States)

    Rwigema, Jean-Claude M; Verma, Vivek; Lin, Liyong; Berman, Abigail T; Levin, William P; Evans, Tracey L; Aggarwal, Charu; Rengan, Ramesh; Langer, Corey; Cohen, Roger B; Simone, Charles B

    2017-11-01

    Existing data supporting the use of proton-beam therapy (PBT) for limited-stage small cell lung cancer (LS-SCLC) are limited to a single 6-patient case series. This is the first prospective study to evaluate clinical outcomes and toxicities of PBT for LS-SCLC. This study prospectively analyzed patients with primary, nonrecurrent LS-SCLC definitively treated with PBT and concurrent chemotherapy from 2011 to 2016. Clinical backup intensity-modulated radiotherapy (IMRT) plans were generated for each patient and were compared with PBT plans. Outcome measures included local control (LC), recurrence-free survival (RFS), and overall survival (OS) rates and toxicities. Thirty consecutive patients were enrolled and evaluated. The median dose was 63.9 cobalt gray equivalents (range, 45-66.6 cobalt gray equivalents) in 33 to 37 fractions delivered daily (n = 18 [60.0%]) or twice daily (n = 12 [40.0%]). The concurrent chemotherapy was cisplatin/etoposide (n = 21 [70.0%]) or carboplatin/etoposide (n = 9 [30.0%]). In comparison with the backup IMRT plans, PBT allowed statistically significant reductions in the cord, heart, and lung mean doses and the volume receiving at least 5 Gy but not in the esophagus mean dose or the lung volume receiving at least 20 Gy. At a median follow-up of 14 months, the 1-/2-year LC and RFS rates were 85%/69% and 63%/42%, respectively. The median OS was 28.2 months, and the 1-/2-year OS rates were 72%/58%. There was 1 case each (3.3%) of grade 3 or higher esophagitis, pneumonitis, anorexia, and pericardial effusion. Grade 2 pneumonitis and esophagitis were seen in 10.0% and 43.3% of patients, respectively. In the first prospective registry study and largest analysis to date of PBT for LS-SCLC, PBT was found to be safe with a limited incidence of high-grade toxicities. Cancer 2017;123:4244-4251. © 2017 American Cancer Society. © 2017 American Cancer Society.

  15. Epiretinal cell proliferation in macular pucker and vitreomacular traction syndrome: analysis of flat-mounted internal limiting membrane specimens.

    Science.gov (United States)

    Zhao, Fei; Gandorfer, Arnd; Haritoglou, Christos; Scheler, Renate; Schaumberger, Markus M; Kampik, Anselm; Schumann, Ricarda G

    2013-01-01

    To describe new details of epiretinal cell proliferation in flat-mounted internal limiting membrane specimens. One hundred nineteen internal limiting membrane specimens were removed en bloc with epiretinal membranes from 79 eyes with macular pucker (MP) and 40 eyes with vitreomacular traction syndrome. Intraoperatively, posterior vitreous detachment was assessed as complete or incomplete. Whole specimens were flat-mounted on glass slides and processed for interference and phase-contrast microscopy, cell viability assay, and immunocytochemistry. Mean cell viability percentage was higher in MP than in vitreomacular traction syndrome. Two cell distribution patterns were found. Anti-CD163 labeling presented predominantly in MP with complete posterior vitreous detachment. CD45 expression was similar in all groups of diagnosis. Anti-glial fibrillary acidic protein (GFAP) labeling was found in MP irrespective of the extent of posterior vitreous detachment. Alpha-SMA (α-smooth muscle actin) labeling was mainly presented in MP with incomplete posterior vitreous detachment and in vitreomacular traction syndrome. Simultaneous antibody labeling included GFAP/CD45, GFAP/CD163, CD163/CD45, and CD163/α-SMA. Hyalocytes constitute a major cell type of epiretinal cell proliferation in eyes with MP and vitreomacular traction syndrome. Glial cells, notably retinal Muller cells, are involved as well. It appears that transdifferentiation of cells in vitreomacular traction might be more frequent than previously thought and that those cells possess a greater variability of immunocytochemical properties than expected.

  16. Methane rescues retinal ganglion cells and limits retinal mitochondrial dysfunction following optic nerve crush.

    Science.gov (United States)

    Wang, Ruobing; Sun, Qinglei; Xia, Fangzhou; Chen, Zeli; Wu, Jiangchun; Zhang, Yuelu; Xu, Jiajun; Liu, Lin

    2017-06-01

    Secondary degeneration is a common event in traumatic central nervous system disorders, which involves neuronal apoptosis and mitochondrial dysfunction. Exogenous methane exerts the therapeutic effects in many organ injury. Our study aims to investigate the potential neuroprotection of methane in a rat model of optic nerve crush (ONC). Adult male Sprague-Dawley rats were subjected to ONC and administrated intraperitoneally with methane-saturated or normal saline (10 ml/kg) once per day for one week after ONC. The retinal ganglion cells (RGCs) density was assessed by hematoxylin and eosin staining and Fluoro-Gold retrogradely labeling. Visual function was evaluated by flash visual evoked potentials (FVEP). The retinal apoptosis was measured by terminal-deoxy-transferase-mediated dUTP nick end labeling (TUNEL) assay and the expression of apoptosis-related factors, such as phosphorylated Bcl-2-associated death promoter (pBAD), phosphorylated glycogen synthase kinase-3β (pGSK-3β), Bcl-2 associated X protein (Bax) and Bcl-2 extra large (Bcl-xL). Retinal mitochondrial function was assessed by the mRNA expressions of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), the mitochondrial DNA (mtDNA) copy number, citrate synthase activity and ATP content. Methane treatment significantly improved the RGC loss and visual dysfunction following ONC. As expected, methane also remarkably inhibited the retinal neural apoptosis, such as the fewer TUNEL-positive cells in ganglion cell layer, accompanied by the up-regulations of anti-apoptotic factors (pGSK-3β, pBAD, Bcl-xL) and the down-regulation of pro-apoptotic factor (Bax). Furthermore, methane treatment suppressed up-regulations of critical mitochondrial components (PGC-1α, NRF1 and TFAM) mRNA and mtDNA copy number, as well as improved the reduction of functional mitochondria markers, including citrate synthase

  17. Bioanode as a limiting factor to biocathode performance in microbial electrolysis cells.

    Science.gov (United States)

    Lim, Swee Su; Yu, Eileen Hao; Daud, Wan Ramli Wan; Kim, Byung Hong; Scott, Keith

    2017-08-01

    The bioanode is important for a microbial electrolysis cell (MEC) and its robustness to maintain its catalytic activity affects the performance of the whole system. Bioanodes enriched at a potential of +0.2V (vs. standard hydrogen electrode) were able to sustain their oxidation activity when the anode potential was varied from -0.3 up to +1.0V. Chronoamperometric test revealed that the bioanode produced peak current density of 0.36A/m 2 and 0.37A/m 2 at applied potential 0 and +0.6V, respectively. Meanwhile hydrogen production at the biocathode was proportional to the applied potential, in the range from -0.5 to -1.0V. The highest production rate was 7.4L H 2 /(m 2 cathode area)/day at -1.0V cathode potential. A limited current output at the bioanode could halt the biocathode capability to generate hydrogen. Therefore maximum applied potential that can be applied to the biocathode was calculated as -0.84V without overloading the bioanode. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Chest radiotherapy in limited-stage small cell lung cancer: facts, questions, prospects

    International Nuclear Information System (INIS)

    De Ruysscher, D.; Vansteenkiste, J.

    2000-01-01

    Limited-disease small cell lung cancer (LD-SCLC) is initially very sensitive to both radiotherapy and chemotherapy. However, the 5-year survival is generally only 10-15%, with most patients failing with therapy refractory relapses, both locally and in distant sites. The addition of chest irradiation to chemotherapy increases the absolute survival by approximately 5%. We reviewed the many controversies regarding optimal timing and irradiation technique. No strong data support total radiation doses over 50 Gy. According to one phase III trial and several retrospective studies, increasing the volume of the radiation fields to the pre-chemotherapy turnout volume instead of the post-chemotherapy volume does not improve local control. The total time in which the entire combined-modality treatment is delivered may be important. From seven randomized trials, it can be concluded that the timing of the radiotherapy as such is not very important. Some phase III trials support the use of accelerated chest radiation together with cisplatin-etoposide chemotherapy, delivered from the first day of treatment, although no firm conclusions can be drawn from the available data. The best results are reported in studies in which the time from the start of treatment to the end of the radiotherapy was less than 30 days. This has to be taken into consideration when treatment modalities incorporating new chemotherapeutic agents and radiotherapy are considered. (author)

  19. Locoregional failures following thoracic irradiation in patients with limited-stage small cell lung carcinoma

    International Nuclear Information System (INIS)

    Giuliani, Meredith E.; Lindsay, Patricia E.; Sun, Alexander; Bezjak, Andrea; Le, Lisa W.; Brade, Anthony; Cho, John; Leighl, Natasha B.; Shepherd, Frances A.; Hope, Andrew J.

    2012-01-01

    Purpose: To determine the patterns of loco-regional (LR) and distant failure in patients with limited-stage small cell lung carcinoma (LS-SCLC) treated with curative intent. Methods: From 1997 to 2008, 253 LS-SCLC patients were treated with curative intent chemo-radiation at our institution. A retrospective review identified sites of failure. The cumulative LR failure (LRF) rate was calculated. Distant failure-free survival (FFS) and overall survival (OS) were calculated using the Kaplan–Meier method. Volumetric images of LR failures were delineated and registered with the original radiation treatment plans if available. Dosimetric parameters for the delineated failure volumes were calculated from the original treatment information. Results: The median follow-up was 19 months. The site of first failure was LR in 34, distant in 80 and simultaneous LR and distant in 31 patients. The cumulative LRF rate was 29% and 38% at 2 and 5 years. OS was 44% at 2 years. Seventy patients had electronically archived treatment plans of which there were 16 LR failures (7 local and 39 regional failure volumes). Of the local and regional failure volumes 29% and 31% were in-field, respectively. Conclusions: The predominant pattern of LR failure was marginal or out-of-field. LR failures may be preventable with improved radiotherapy target definition.

  20. Circulating activated innate lymphoid cells and mucosal-associated invariant T cells are associated with airflow limitation in patients with asthma

    Directory of Open Access Journals (Sweden)

    Ayako Ishimori

    2017-04-01

    Conclusions: For the first time, our data showed that activated NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other and may be associated with airflow limitation in patients with asthma.

  1. DAZL limits pluripotency, differentiation, and apoptosis in developing primordial germ cells

    NARCIS (Netherlands)

    Chen, Hsu-Hsin; Welling, Maaike; Bloch, Donald B; Muñoz, Javier; Mientjes, Edwin; Chen, Xinjie; Tramp, Cody; Wu, Jie; Yabuuchi, Akiko; Chou, Yu-Fen; Buecker, Christa; Krainer, Adrian; Willemsen, Rob; Heck, Albert J; Geijsen, Niels

    2014-01-01

    The scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro germ cell

  2. Early exposure to interleukin-21 limits rapidly generated anti-Epstein-Barr virus T-cell line differentiation.

    Science.gov (United States)

    Orio, Julie; Carli, Cédric; Janelle, Valérie; Giroux, Martin; Taillefer, Julie; Goupil, Mathieu; Richaud, Manon; Roy, Denis-Claude; Delisle, Jean-Sébastien

    2015-04-01

    The adoptive transfer of ex vivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation in vitro, but this remains to be demonstrated in anti-viral T-cell lines. We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation. We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation. Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Prospects and Limitations of Using Endogenous Neural Stem Cells for Brain Regeneration

    OpenAIRE

    Kaneko, Naoko; Kako, Eisuke; Sawamoto, Kazunobu

    2011-01-01

    Neural stem cells (NSCs) are capable of producing a variety of neural cell types, and are indispensable for the development of the mammalian brain. NSCs can be induced in vitro from pluripotent stem cells, including embryonic stem cells and induced-pluripotent stem cells. Although the transplantation of these exogenous NSCs is a potential strategy for improving presently untreatable neurological conditions, there are several obstacles to its implementation, including tumorigenic, immunologica...

  4. Immunoglobulin E is associated with markers of mast cell degranulation and microalbuminuria in obese subjects with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Olayiwola Popoola

    2016-01-01

    Full Text Available Background: Irrespective of the cause of kidney injury, development of renal fibrosis may likely result after prolong insult by the etiologic agent. Inflammatory process associated with an increase in number and activity of mast cell (MC has been implicated in the development of renal fibrosis. Renal fibrosis occurs through the activation of MC by immunoglobulin E (IgE binding to high-affinity receptor on its surface. After IgE binding, MC release inflammatory mediators such as histamine, MC protease, cytokines, and chemokines. Aim: This study was designed to investigate the possible role of IgE in the development of renal complication in subjects with Type 2 diabetes. Materials and Methods: A total number of 165 subjects comprising ninety obese diabetic cases (test group and 75 nondiabetic controls were recruited in this study. The test group was further divided into those with poor glycemic control (n = 45 and those with good glycemic control (n = 45 using glycated hemoglobin (HbA1c. Urine microalbumin was determine using turbidimetry immunoassay, C-reactive protein (CRP using latex-enhanced immunoturbidimetry assay, IgE, insulin, chymase, and tryptase were estimated using ELISA and HbA1c were estimated by high-performance liquid chromatography. Results: There was statistically significant difference in the mean values of microalbumin, IgE, CRP and HbA1c, chymase, and tryptase in the test group compared with controls (P < 0.01. We found a positive correlation between microalbumin excretion rate and IgE, HbA1c, tryptase, and chymase (P < 0.01. Conclusion: The findings of this study suggest that glycemic control associated inflammatory process involving MC degranulation may contribute to the development of diabetic nephropathy.

  5. Semi-automated limit-dilution assay and clonal expansion of all T-cell precursors of cytotoxic lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, A.; Chen, W.F.; Scollay, R.; Shortman, K. (Walter and Eliza Hall Inst. of Medical Research, Parkville (Australia))

    1982-08-13

    A limit-dilution microculture system is described, where almost all precursor T cells of the cytotoxic lineage (CTL-p) develop into extended clones of cytotoxic T cells (CTL), which are then detected with a new radio-autographic /sup 111/In-release assay. The principle is to polyclonally activate all T cells with concanavalin A, to expand the resultant clones over an 8-9 day period in cultures saturated with growth factors, then to detect all clones with cytotoxic function by phytohaemagglutinin mediated lysis of P815 tumour cells. The key variables for obtaining high cloning efficiency are the use of flat-bottomed 96-well culture trays, the use of appropriately irradiated spleen filler cells, and the inclusion of a T-cell growth factor supplement. Cultures are set up at input levels of around one T cell per well. Forty percent of T cells then form CTL clones readily detected by the cytotoxic assay. The lytic activity of the average clone is equivalent to 3000 CTL, but clone size appears to be much larger. The precursor cells are predominantly if not entirely from the Lyt 2/sup +/ T-cell subclass and almost all cells of this subclass form cytolytic clones. Analysis of the frequency of positive cultures shows a good fit to the expected Poisson distribution, with no evidence of the CTL-p frequency estimates being distorted by helper or suppressor effects.

  6. Semi-automated limit-dilution assay and clonal expansion of all T-cell precursors of cytotoxic lymphocytes

    International Nuclear Information System (INIS)

    Wilson, A.; Chen, W.-F.; Scollay, R.; Shortman, K.

    1982-01-01

    A limit-dilution microculture system is described, where almost all precursor T cells of the cytotoxic lineage (CTL-p) develop into extended clones of cytotoxic T cells (CTL), which are then detected with a new radio-autographic 111 In-release assay. The principle is to polyclonally activate all T cells with concanavalin A, to expand the resultant clones over an 8-9 day period in cultures saturated with growth factors, then to detect all clones with cytotoxic function by phytohaemagglutinin mediated lysis of P815 tumour cells. The key variables for obtaining high cloning efficiency are the use of flat-bottomed 96-well culture trays, the use of appropriately irradiated spleen filler cells, and the inclusion of a T-cell growth factor supplement. Cultures are set up at input levels of around one T cell per well. Forty percent of T cells then form CTL clones readily detected by the cytotoxic assay. The lytic activity of the average clone is equivalent to 3000 CTL, but clone size appears to be much larger. The precursor cells are predominantly if not entirely from the Lyt 2 + T-cell subclass and almost all cells of this subclass form cytolytic clones. Analysis of the frequency of positive cultures shows a good fit to the expected Poisson distribution, with no evidence of the CTL-p frequency estimates being distorted by helper or suppressor effects. (Auth.)

  7. Tim-3: An activation marker and activation limiter of innate immune cells

    Directory of Open Access Journals (Sweden)

    Gencheng eHan

    2013-12-01

    Full Text Available Tim-3 was initially identified on activated Th1, Th17, and Tc1 cells and induces T cell death or exhaustion after binding to its ligand, Gal-9. The observed relationship between dysregulated Tim-3 expression on T cells and the progression of many clinical diseases has identified this molecule as an important target for intervention in adaptive immunity. Recent data have shown that it also plays critical roles in regulating the activities of macrophages, monocytes, dendritic cells, mast cells, natural killer cells, and endothelial cells. Although the underlying mechanisms remain unclear, dysregulation of Tim-3 expression on these innate immune cells leads to an excessive or inhibited inflammatory response and subsequent autoimmune damage or viral or tumor evasion. In this review, we focus on the expression and function of Tim-3 on innate immune cells and discuss 1 how Tim-3 is expressed and regulated on different innate immune cells; 2 how it affects the activity of different innate immune cells; and 3 how dysregulated Tim-3 expression on innate immune cells affects adaptive immunity and disease progression. Tim-3 is involved in the optimal activation of innate immune cells through its varied expression. A better understanding of the physiopathological role of the Tim-3 pathway in innate immunity will shed new light on the pathogenesis of clinical diseases, such as autoimmune diseases, chronic viral infections, and cancer, and suggest new approaches to intervention.

  8. Retrospective Analysis of Chemoradiotherapy for Limited-Stage Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jong Hoon; Kim, Sung Hwan; Kim, Su Zy; Lee, Joo Hwan; Kim, Hoon Kyo; Shim, Byoung Yong [Catholic University St. Vincent' s Hospital, Suwon (Korea, Republic of)

    2009-09-15

    This study was designed to analyze the outcome and toxicity of thoracic radiation therapy (TRT) and chemotherapy for patients who suffer with limited-stage small-cell lung cancer (LS-SCLC). We retrospectively studied 35 patients with LS-SCLC. TRT was administered once daily (1.8 to 2 Gy per fraction) and it was directed to the primary tumor for a total 50 to 66 Gy in 6 to 7 weeks. The patients received four cycles of etoposide plus cisplatin. TRT was begun on day 1 of the first cycle of chemotherapy in the concurrent arm and after the fourth cycle in the sequential arm. The median progression-free survival time was 16.5 months (95% confidence interval [CI], 9.0 to 24.1 months) for the sequential arm, and 26.3 months (95% CI, 16.6 to 35.9 months) for the concurrent arm. The 2-year progression-free survival rate was 16.0 percent for the sequential arm and 50.0 percent for the concurrent arm (p=0.0950 by log-rank test). Leukopenia was more severe and more frequent in the concurrent arm than in the sequential arm. However, severe esophagitis was infrequent in both arms. The radiotherapy was interrupted more frequently in the concurrent arm than in the sequential arm due to hematologic toxicities (p=0.001). This study suggests that concurrent TRT with etoposide plus cisplatin is more effective for the treatment of LS-SCLC than sequential TRT. However, there is a significant increase in the risk of toxicities, and radiotherapy was frequently interrupted in the concurrent arm due to hematologic toxicities.

  9. Collection-limited theory interprets the extraordinary response of single semiconductor organic solar cells

    Science.gov (United States)

    Ray, Biswajit; Baradwaj, Aditya G.; Khan, Mohammad Ryyan; Boudouris, Bryan W.; Alam, Muhammad Ashraful

    2015-01-01

    The bulk heterojunction (BHJ) organic photovoltaic (OPV) architecture has dominated the literature due to its ability to be implemented in devices with relatively high efficiency values. However, a simpler device architecture based on a single organic semiconductor (SS-OPV) offers several advantages: it obviates the need to control the highly system-dependent nanoscale BHJ morphology, and therefore, would allow the use of broader range of organic semiconductors. Unfortunately, the photocurrent in standard SS-OPV devices is typically very low, which generally is attributed to inefficient charge separation of the photogenerated excitons. Here we show that the short-circuit current density from SS-OPV devices can be enhanced significantly (∼100-fold) through the use of inverted device configurations, relative to a standard OPV device architecture. This result suggests that charge generation may not be the performance bottleneck in OPV device operation. Instead, poor charge collection, caused by defect-induced electric field screening, is most likely the primary performance bottleneck in regular-geometry SS-OPV cells. We justify this hypothesis by: (i) detailed numerical simulations, (ii) electrical characterization experiments of functional SS-OPV devices using multiple polymers as active layer materials, and (iii) impedance spectroscopy measurements. Furthermore, we show that the collection-limited photocurrent theory consistently interprets typical characteristics of regular SS-OPV devices. These insights should encourage the design and OPV implementation of high-purity, high-mobility polymers, and other soft materials that have shown promise in organic field-effect transistor applications, but have not performed well in BHJ OPV devices, wherein they adopt less-than-ideal nanostructures when blended with electron-accepting materials. PMID:26290582

  10. Prognostic factors for limited-stage small cell lung cancer: a study of 284 patients.

    Science.gov (United States)

    Chen, Jun; Jiang, Ruoxiang; Garces, Yolanda I; Jatoi, Aminah; Stoddard, Shawn M; Sun, Zhifu; Marks, Randolph S; Liu, Yunpeng; Yang, Ping

    2010-02-01

    Combined modality therapy is the standard care for limited stage-small cell lung cancer (LS-SCLC) and has led to a significant improvement in patients' survival. This study sought to investigate and define the importance of prognostic effects of known and controversial factors especially the impact of smoking status and treatment strategies. A total of 284 patients with LS-SCLC were diagnosed and prospectively followed from 1997 to 2008 at Mayo Clinic; their characteristics and survival outcome were assessed on the basis of age, gender, smoking history, performance status (PS), tumor recurrence or progression, and treatment using Cox proportional hazards models. Our main results are as follows: (1) Although neither smoking status (former or current smokers) nor intensity (pack-years smoked) at the time of SCLC diagnosis were significant survival predictors, compared to continued smokers (who never quit smoking), patients who quit at or after diagnosis cut the risk of death by 45% (HR=0.55, 95% CI 0.38-0.79); patients who quit before lung cancer diagnosis also experienced survival benefit (HR=0.72, 95% CI 0.52-1.00). (2) Thoracic radiotherapy and platinum-based chemotherapy could significantly improve survival but the timing (within or after one month of diagnosis) of starting chemotherapy or radiation therapy did not. (3) After adjusting for other known factors, a lower PS did not predict poorer survival, suggesting that PS should not be the only factor for making treatment decisions. In conclusion, this study demonstrated the negative impact of continued cigarette smoking on survival; therefore, clinicians and all care providers should strongly encourage smoking cessation at diagnosis of LS-SCLC. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  11. Effect of early chemoradiotherapy in patients with limited stage small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ha, In Bong; Jeong, Bae Kwon; Jeong, Ho Jin; Choi, Hoon Sik; Chai, Gyu Young; Kang, Myoung Hee; Kim, Hoon Gu; Lee, Gyeong Won; Na, Jae Beom; Kang, Ki Mun [Gyeongsang National University School of Medicine, Jinju (Korea, Republic of)

    2013-12-15

    We evaluated the effect of early chemoradiotherapy on the treatment of patients with limited stage small cell lung cancer (LS-SCLC). Between January 2006 and December 2011, thirty-one patients with histologically proven LS-SCLC who were treated with two cycles of chemotherapy followed by concurrent chemoradiotherapy and consolidation chemotherapy were retrospectively analyzed. The chemotherapy regimen was composed of etoposide and cisplatin. Thoracic radiotherapy consisted of 50 to 60 Gy (median, 54 Gy) given in 5 to 6.5 weeks. The follow-up period ranged from 5 to 53 months (median, 22 months). After chemoradiotherapy, 35.5% of the patients (11 patients) showed complete response, 61.3% (19 patients) showed partial response, 3.2% (one patient) showed progressive disease, resulting in an overall response rate of 96.8% (30 patients). The 1-, 2-, and 3-year overall survival (OS) rates were 66.5%, 41.0%, and 28.1%, respectively, with a median OS of 21.3 months. The 1-, 2-, and 3-year progression free survival (PFS) rates were 49.8%, 22.8%, and 13.7%, respectively, with median PFS of 12 months. The patterns of failure were: locoregional recurrences in 29.0% (nine patients), distant metastasis in 9.7% (three patients), and both locoregional and distant metastasis in 9.7% (three patients). Grade 3 or 4 toxicities of leukopenia, anemia, and thrombocytopenia were observed in 32.2%, 29.0%, and 25.8%, respectively. Grade 3 radiation esophagitis and radiation pneumonitis were shown in 12.9% and 6.4%, respectively. We conclude that early chemoradiotherapy for LS-SCLC provides feasible and acceptable local control and safety.

  12. Collection-limited theory interprets the extraordinary response of single semiconductor organic solar cells.

    Science.gov (United States)

    Ray, Biswajit; Baradwaj, Aditya G; Khan, Mohammad Ryyan; Boudouris, Bryan W; Alam, Muhammad Ashraful

    2015-09-08

    The bulk heterojunction (BHJ) organic photovoltaic (OPV) architecture has dominated the literature due to its ability to be implemented in devices with relatively high efficiency values. However, a simpler device architecture based on a single organic semiconductor (SS-OPV) offers several advantages: it obviates the need to control the highly system-dependent nanoscale BHJ morphology, and therefore, would allow the use of broader range of organic semiconductors. Unfortunately, the photocurrent in standard SS-OPV devices is typically very low, which generally is attributed to inefficient charge separation of the photogenerated excitons. Here we show that the short-circuit current density from SS-OPV devices can be enhanced significantly (∼100-fold) through the use of inverted device configurations, relative to a standard OPV device architecture. This result suggests that charge generation may not be the performance bottleneck in OPV device operation. Instead, poor charge collection, caused by defect-induced electric field screening, is most likely the primary performance bottleneck in regular-geometry SS-OPV cells. We justify this hypothesis by: (i) detailed numerical simulations, (ii) electrical characterization experiments of functional SS-OPV devices using multiple polymers as active layer materials, and (iii) impedance spectroscopy measurements. Furthermore, we show that the collection-limited photocurrent theory consistently interprets typical characteristics of regular SS-OPV devices. These insights should encourage the design and OPV implementation of high-purity, high-mobility polymers, and other soft materials that have shown promise in organic field-effect transistor applications, but have not performed well in BHJ OPV devices, wherein they adopt less-than-ideal nanostructures when blended with electron-accepting materials.

  13. Bioactive food components, cancer cell growth limitation and reversal of glycolytic metabolism

    NARCIS (Netherlands)

    Keijer, J.; Bekkenkamp-Grovestein, M.; Venema, D.P.; Dommels, Y.E.M.

    2011-01-01

    Cancer cells are resistant to apoptosis and show a shift in energy production from mitochondrial oxidative phosphorylation to cytosolic glycolysis. Apoptosis resistance and metabolic reprogramming are linked in many cancer cells and both processes center on mitochondria. Clearly, mutated cancer

  14. Langerhans cells favor skin flora tolerance through limited presentation of bacterial antigens and induction of regulatory T cells

    NARCIS (Netherlands)

    van der Aar, Angelic M. G.; Picavet, Daisy I.; Muller, Femke J.; de Boer, Leonie; van Capel, Toni M. M.; Zaat, Sebastian A. J.; Bos, Jan D.; Janssen, Hans; George, Thaddeus C.; Kapsenberg, Martien L.; van Ham, S. Marieke; Teunissen, Marcel B. M.; de Jong, Esther C.

    2013-01-01

    The mechanisms preventing detrimental T-cell responses against commensal skin bacteria remain elusive. Using monocyte-derived and skin-derived dendritic cells (DCs), we demonstrate that epidermal Langerhans cells (LCs), the DCs in the most superficial layer of the skin, have a poor capacity to

  15. The Upper Limit to the Theoretical Efficiency of P-N Homojunction and Interfacial Layer Heterojunction Solar Cells.

    Science.gov (United States)

    Spitzer, Mark Bradley

    The physical mechanisms governing photovoltaic energy conversion in p-n homojunction and interfacial layer heterojunction (ILH) solar cells are examined. The usefulness of minority carrier mirrors (MCM) in such cells is studied by solving the minority carrier diffusion equation in the n- and p-type quasi-neutral regions of the cell, with boundary conditions representing MCM's at the ends of these regions. In this formalism, the MCM is considered to be an interfacial plane having zero surface recombination velocity. Non -zero values are also considered. It is shown that the MCM improves the open circuit voltage of the solar cell when it is located within a diffusion length of the junction between the n- and p-type regions. The effect of the MCM diminishes as the distance between it and the junction increases. The above analysis is applied to the direct gap materials CuInSe(,2) (E = 1.0eV) and GaAs (E = 1.43eV). It is shown that the theoretical upper limit to the conversion efficiency for devices employing MCM's on the front and back is approximately 26% for a CuInSe(,2) cell of width 2 microns. The analysis is also applied to cells made from silicon. A cell thickness of approximately 300 microns is necessary to absorb all the light owing to the indirect bandgap of silicon, yet the solar cell must be made thin in order to attain the maximum effect of the MCM's. A concept of internal light trapping is discussed; this trapping causes the light to undergo multiple reflections within the thin cell. By solving the minority carrier diffusion equation with appropriate generation function, it is shown that the upper limit to the efficiency is approximately 27%, for a cell of 15 microns in width. The ILH solar cell is examined. A model describing current transport in the ILH cell is discussed and applied to the MIS solar cell. A new type of solar cell, the back surface MIS cell, is considered. The model is applied to this type of cell and the efficiency is calculated. The ILH

  16. Once vs. twice daily thoracic irradiation in limited stage small cell lung cancer

    International Nuclear Information System (INIS)

    Kim, Jun Sang; Kim, Jae Sung; Kim, Ju Ock; Kim, Sun Young; Cho, Moon June

    1998-01-01

    A retrospective study was conducted comparing single dally fraction (SDF) thoracic radiotherapy (TRT) with twice daily (BID) TRT to determine the potential benefit of BID TRT in limited-stage small cell lung cancer (SCLC). Endpoints of the study were response, survival, pattern of failure, and acute toxicity. Between November 1989 to December 1996, 78 patients with histologically proven limited-stage SCLC were treated at the Department of Therapeutic Radiology, Chungnam National University Hospital. Of these, 9 were irradiated for palliative intent, and 1 had recurrent disease. Remaining 68 patients were enrolled in this study. There were 26 patients with a median age of 58 years, and 22 (85%) ECOG performance score of less than 1 in SDF TRT. There were 42 patients with a median age of 57 years, and 36 (86%) ECOG performance score of less than 1 in BID TRT. By radiation fractionation regimen, there were 26 in SDF TRT and 42 in BID TRT. SDF TRT consisted of 180 cGy, 5 days a week. BID TRT consisted of 150 cGY BID, 5 days a week in 13 of 42 and 120 cGy BID, in 29 of 42. And the twice daily fractions were separated by at least 4 hours. Total radiotherapy doses were between 5040 and 6940 cGy (median, 5040 cGy) in SDF TRT and was between 4320 and 5100 cGy (median, 4560 cGy) in BID TRT. Prophylactic cranial irradiation (PCI) was recommended for patients who achieved a CR. The recommended PCI dose was 2500 cGy/10 fractions. Chemotherapy consisted of CAV (cytoxan 1000 mg/m 2 , adriamycin 40 mg/m 2 , vincristine 1 mg/m 2 ) alternating with VPP (cisplatin 60 mg/m 2 , etoposide 100 mg/m 2 ) every 3 weeks in 25 (96%) of SDF TRT and in 40 (95%) of BID TRT. Median cycle of chemotherapy was six in both group. Timing for chemotherapy was sequential in 23 of SDF TRT and in 3 BID TRT, and concurrent in 3 of SDF TRT and in 39 of BID TRT. Follow-up ranged from 2 of 99 months (median, 14 months) in both groups. Of the 26 SDF TRT, 9 (35%) achieved a complete response (CR) and 14 (54

  17. DAZL limits pluripotency, differentiation, and apoptosis in developing primordial germ cells

    NARCIS (Netherlands)

    H.H. Chen; M. Welling (Maaike); D.B. Bloch (Donald B.); J. Muñoz (Javier); E.J. Mientjes (Edwin); X. Chen (Xinjie); C. Tramp (Cody); J. Wu (Jie); A. Yabuuchi (Akiko); Y.F. Chou; C. Buecker (Christa); A. Krainer (Adrian); R. Willemsen (Rob); A.J.R. Heck (Albert); N. Geijsen (Niels)

    2014-01-01

    textabstractThe scarcity of primordial germ cells (PGCs) in the developing mammalian embryo hampers robust biochemical analysis of the processes that underlie early germ cell formation. Here, we demonstrate that DAZL, a germ cell-specific RNA binding protein, is a robust PGC marker during in vitro

  18. 'Green mice' display limitations in enhanced green fluorescent protein expression in retina and optic nerve cells.

    Science.gov (United States)

    Caminos, Elena; Vaquero, Cecilia F; García-Olmo, Dolores C

    2014-12-01

    Characterization of retinal cells, cell transplants and gene therapies may be helped by pre-labeled retinal cells, such as those transfected with vectors for green fluorescent protein expression. The aim of this study was to analyze retinal cells and optic nerve components from transgenic green mice (GM) with the 'enhanced' green fluorescent protein (EGFP) gene under the control of the CAG promoter (a chicken β-actin promoter and a cytomegalovirus enhancer). The structural analysis and electroretinography recordings showed a normal, healthy retina. Surprisingly, EGFP expression was not ubiquitously located in the retina and optic nerve. Epithelial cells, photoreceptors and bipolar cells presented high green fluorescence levels. In contrast, horizontal cells, specific amacrine cells and ganglion cells exhibited a null EGFP expression level. The synaptic terminals of rod bipolar cells displayed a high green fluorescence level when animals were kept in the dark. Immature retinas exhibited different EGFP expression patterns to those noted in adults. Axons and glial cells in the optic nerve revealed a specific regional EGFP expression pattern, which correlated with the presence of myelin. These results suggest that EGFP expression might be related to the activity of both the CAG promoter and β-actin in mature retinal neurons and oligodendrocytes. Moreover, EGFP expression might be regulated by light in both immature and adult animals. Since GM are used in numerous retina bioassays, it is essential to know the differential EGFP expression in order to select cells of interest for each study.

  19. Transgenic suppression of cell death limits penetration success of the soybean rust fungus Phakopsora pachyrhizi into epidermal cells of barley.

    Science.gov (United States)

    Hoefle, Caroline; Loehrer, Marco; Schaffrath, Ulrich; Frank, Markus; Schultheiss, Holger; Hückelhoven, Ralph

    2009-03-01

    The basidiomycete Phakopsora pachyrhizi (P. pachyrhizi) causes Asian soybean rust, one of the most devastating plant diseases on soybean. When inoculated on the nonhost barley P. pachyrhizi caused only very small necrotic spots, typical for an incompatible interaction, which involves a hypersensitive cell death reaction. A microscopic inspection of the interaction of barley with P. pachyrhizi revealed that the fungus germinated on barley and formed functional appressoria on epidermal cells. The fungus attempted to directly penetrate through periclinal cell walls but often failed, arrested in plant cell wall appositions that stained positively for callose. Penetration resistance depends on intact ROR1(REQUIRED FOR mlo-SPECIFIED RESISTANCE 1) and ROR2 genes of barley. If the fungus succeeded in penetration, epidermal cell death took place. Dead epidermal cells did not generally restrict fungal development but allowed for mesophyll invasion, which was followed by mesophyll cell death and fungal arrest. Transient or stable over expression of the barley cell death suppressor BAX inhibitor-1 reduced both epidermal cell death and fungal penetration success. Data suggest that P. pachyrhizi provokes a programmed cell death facilitating fungal entry into epidermal cells of barley.

  20. Concise Review: Optimized Strategies for Stem Cell-Based Therapy in Myocardial Repair: Clinical Translatability and Potential Limitation.

    Science.gov (United States)

    Wu, Rongrong; Hu, Xinyang; Wang, Jian'an

    2018-01-13

    Ischemic heart diseases (IHDs) remain major public health problems with high rates of morbidity and mortality worldwide. Despite significant advances, current therapeutic approaches are unable to rescue the extensive and irreversible loss of cardiomyocytes caused by severe ischemia. Over the past 16 years, stem cell-based therapy has been recognized as an innovative strategy for cardiac repair/regeneration and functional recovery after IHDs. Although substantial preclinical animal studies using a variety of stem/progenitor cells have shown promising results, there is a tremendous degree of skepticism in the clinical community as many stem cell trials do not confer any beneficial effects. How to accelerate stem cell-based therapy toward successful clinical application attracts considerate attention. However, many important issues need to be fully addressed. In this Review, we have described and compared the effects of different types of stem cells with their dose, delivery routes, and timing that have been routinely tested in recent preclinical and clinical findings. We have also discussed the potential mechanisms of action of stem cells, and explored the role and underlying regulatory components of stem cell-derived secretomes/exosomes in myocardial repair. Furthermore, we have critically reviewed the different strategies for optimizing both donor stem cells and the target cardiac microenvironments to enhance the engraftment and efficacy of stem cells, highlighting their clinical translatability and potential limitation. Stem Cells 2018. © AlphaMed Press 2018.

  1. Limited energy supply in Müller cells alters glutamate uptake

    DEFF Research Database (Denmark)

    Toft-Kehler, Anne Katrine; Skytt, Dorte Marie; Poulsen, Kristian Arild

    2014-01-01

    evaluates if glucose-deprivation of Müller cells interferes with their ability to remove glutamate from the extracellular space. The human Müller glial cell line, Moorfields/Institute of Ophthalmology-Müller 1, was used to study changes in glutamate uptake. Excitatory amino acid transporter (EAAT) proteins...... were up-regulated in glucose-deprived Müller cells and glutamate uptake was significantly increased in the absence of glucose. The present findings revealed an up-regulation of EAAT1 and EAAT2 in glucose-deprived Müller cells as well as an increased ability to take up glutamate. Hence, glucose...... deprivation may result in an increased ability to protect RGCs from glutamate-induced excitotoxicity, whereas malfunction of glutamate uptake in Müller cells may contribute to retinal neurodegeneration....

  2. IKKα Promotes Intestinal Tumorigenesis by Limiting Recruitment of M1-like Polarized Myeloid Cells

    Directory of Open Access Journals (Sweden)

    Serkan I. Göktuna

    2014-06-01

    Full Text Available The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC therapy.

  3. Studies of Antibiotic Resistance of Beta-Lactamase Bacteria under Different Nutrition Limitations at the Single-Cell Level.

    Science.gov (United States)

    Wang, Ying; Ran, Min; Wang, Jun; Ouyang, Qi; Luo, Chunxiong

    2015-01-01

    Drug resistance involves many biological processes, including cell growth, cell communication, and cell cooperation. In the last few decades, bacterial drug resistance studies have made substantial progress. However, a major limitation of the traditional resistance study still exists: most of the studies have concentrated on the average behavior of enormous amounts of cells rather than surveying single cells with different phenotypes or genotypes. Here, we report our study of beta-lactamase bacterial drug resistance in a well-designed microfluidic device, which allows us to conduct more controllable experiments, such as controlling the nutrient concentration, switching the culture media, performing parallel experiments, observing single cells, and acquiring time-lapse images. By using GFP as a beta-lactamase indicator and acquiring time-lapse images at the single-cell level, we observed correlations between the bacterial heterogeneous phenotypes and their behavior in different culture media. The feedback loop between the growth rate and the beta-lactamase production suggests that the beta-lactamase bacteria are more resistant in a rich medium than in a relatively poor medium. In the poorest medium, the proportion of dormant cells may increase, which causes a lower death rate in the same generation. Our work may contribute to assaying the antibiotic resistance of pathogenic bacteria in heterogeneous complex media.

  4. Studies of Antibiotic Resistance of Beta-Lactamase Bacteria under Different Nutrition Limitations at the Single-Cell Level.

    Directory of Open Access Journals (Sweden)

    Ying Wang

    Full Text Available Drug resistance involves many biological processes, including cell growth, cell communication, and cell cooperation. In the last few decades, bacterial drug resistance studies have made substantial progress. However, a major limitation of the traditional resistance study still exists: most of the studies have concentrated on the average behavior of enormous amounts of cells rather than surveying single cells with different phenotypes or genotypes. Here, we report our study of beta-lactamase bacterial drug resistance in a well-designed microfluidic device, which allows us to conduct more controllable experiments, such as controlling the nutrient concentration, switching the culture media, performing parallel experiments, observing single cells, and acquiring time-lapse images. By using GFP as a beta-lactamase indicator and acquiring time-lapse images at the single-cell level, we observed correlations between the bacterial heterogeneous phenotypes and their behavior in different culture media. The feedback loop between the growth rate and the beta-lactamase production suggests that the beta-lactamase bacteria are more resistant in a rich medium than in a relatively poor medium. In the poorest medium, the proportion of dormant cells may increase, which causes a lower death rate in the same generation. Our work may contribute to assaying the antibiotic resistance of pathogenic bacteria in heterogeneous complex media.

  5. Transcription Factor IRF4 Promotes CD8+T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection.

    Science.gov (United States)

    Man, Kevin; Gabriel, Sarah S; Liao, Yang; Gloury, Renee; Preston, Simon; Henstridge, Darren C; Pellegrini, Marc; Zehn, Dietmar; Berberich-Siebelt, Friederike; Febbraio, Mark A; Shi, Wei; Kallies, Axel

    2017-12-19

    During chronic stimulation, CD8 + T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  6. Moving stem cells to the clinic: potential and limitations for brain repair.

    Science.gov (United States)

    Steinbeck, Julius A; Studer, Lorenz

    2015-04-08

    Stem cell-based therapies hold considerable promise for many currently devastating neurological disorders. Substantial progress has been made in the derivation of disease-relevant human donor cell populations. Behavioral data in relevant animal models of disease have demonstrated therapeutic efficacy for several cell-based approaches. Consequently, cGMP grade cell products are currently being developed for first in human clinical trials in select disorders. Despite the therapeutic promise, the presumed mechanism of action of donor cell populations often remains insufficiently validated. It depends greatly on the properties of the transplanted cell type and the underlying host pathology. Several new technologies have become available to probe mechanisms of action in real time and to manipulate in vivo cell function and integration to enhance therapeutic efficacy. Results from such studies generate crucial insight into the nature of brain repair that can be achieved today and push the boundaries of what may be possible in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Parasitic worms stimulate host NADPH oxidases to produce reactive oxygen species that limit plant cell death and promote infection.

    Science.gov (United States)

    Siddique, Shahid; Matera, Christiane; Radakovic, Zoran S; Hasan, M Shamim; Gutbrod, Philipp; Rozanska, Elzbieta; Sobczak, Miroslaw; Torres, Miguel Angel; Grundler, Florian M W

    2014-04-08

    Plants and animals produce reactive oxygen species (ROS) in response to infection. In plants, ROS not only activate defense responses and promote cell death to limit the spread of pathogens but also restrict the amount of cell death in response to pathogen recognition. Plants also use hormones, such as salicylic acid, to mediate immune responses to infection. However, there are long-lasting biotrophic plant-pathogen interactions, such as the interaction between parasitic nematodes and plant roots during which defense responses are suppressed and root cells are reorganized to specific nurse cell systems. In plants, ROS are primarily generated by plasma membrane-localized NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidases, and loss of NADPH oxidase activity compromises immune responses and cell death. We found that infection of Arabidopsis thaliana by the parasitic nematode Heterodera schachtii activated the NADPH oxidases RbohD and RbohF to produce ROS, which was necessary to restrict infected plant cell death and promote nurse cell formation. RbohD- and RbohF-deficient plants exhibited larger regions of cell death in response to nematode infection, and nurse cell formation was greatly reduced. Genetic disruption of SID2, which is required for salicylic acid accumulation and immune activation in nematode-infected plants, led to the increased size of nematodes in RbohD- and RbohF-deficient plants, but did not decrease plant cell death. Thus, by stimulating NADPH oxidase-generated ROS, parasitic nematodes fine-tune the pattern of plant cell death during the destructive root invasion and may antagonize salicylic acid-induced defense responses during biotrophic life stages.

  8. Long term observations in combined modality therapy for limited stage small cell lung cancer

    International Nuclear Information System (INIS)

    Colletier, Philip J.; Komaki, Ritsuko; Schea, Randi A.; Allen, Pamela; Cox, James D.

    1997-01-01

    Purpose/Objective: With the discovery that patients with small cell lung cancer (SCLC) exhibit a high level of sensitivity to both chemotherapy and radiotherapy, the treatment of SCLC became a model for the success of combined modality treatment. In this retrospective review, we analyze the outcomes and patterns of failure when patients are treated with chemotherapy and thoracic irradiation. The relative values of sequential and concurrent chemotherapy, in conjunction with chest irradiation, are assessed. The potential benefit of prophylactic cranial irradiation is explored. The impact of prognostic factors for long term survival of SCLC patients are examined to identify pretreatment patient characteristics and treatment parameters which might predict for a favorable outcome. Materials and Methods: We identified 190 patients treated at M.D. Anderson Cancer Center from January 1985 to December 1992 with curative intent for limited stage SCLC. Prognostic factors were determined using univariate and multivariate analysis. The significant covariates for each outcome endpoint were evaluated. Probabilities of local failure, overall survival, relapse-free survival, and distant metastasis-free survival were calculated from the time of treatment using actuarial life table analysis. Results: The median age was 61, with 51% males. There were 119 patients treated sequentially, and 71 concurrently. The Karnofsky Performance Status was >= 90 in 48% of patients in the concurrent cohort, vs. 35% of the sequential group. Prophylactic cranial irradiation (PCI) was delivered in 117 cases (62%). There were 51 long term survivors, defined as survival >=36 months. The median follow-up in surviving patients was 75 months. At the time of the analysis, 166 patients (87%) had expired. The crude 2 and 3 year survival rate for the entire group was 38.4% and 26.8%, respectively. The actuarial 2-year survival was 39.9%, and at 3 years the actuarial survival was 27.8%. The median actuarial

  9. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.

    Science.gov (United States)

    Lin, Tara L; Wang, Qiuju H; Brown, Patrick; Peacock, Craig; Merchant, Akil A; Brennan, Sarah; Jones, Evan; McGovern, Karen; Watkins, D Neil; Sakamoto, Kathleen M; Matsui, William

    2010-12-28

    Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.

  10. Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.

    Directory of Open Access Journals (Sweden)

    Tara L Lin

    Full Text Available Conserved embryonic signaling pathways such as Hedgehog (Hh, Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL. We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.

  11. Phthalates Are Metabolised by Primary Thyroid Cell Cultures but Have Limited Influence on Selected Thyroid Cell Functions In Vitro.

    Directory of Open Access Journals (Sweden)

    Juliana Frohnert Hansen

    Full Text Available Phthalates are plasticisers added to a wide variety of products, resulting in measurable exposure of humans. They are suspected to disrupt the thyroid axis as epidemiological studies suggest an influence on the peripheral thyroid hormone concentration. The mechanism is still unknown as only few in vitro studies within this area exist. The aim of the present study was to investigate the influence of three phthalate diesters (di-ethyl phthalate, di-n-butyl phthalate (DnBP, di-(2-ethylhexyl phthalate (DEHP and two monoesters (mono-n-butyl phthalate and mono-(2-ethylhexyl phthalate (MEHP on the differentiated function of primary human thyroid cell cultures. Also, the kinetics of phthalate metabolism were investigated. DEHP and its monoester, MEHP, both had an inhibitory influence on 3'-5'-cyclic adenosine monophosphate secretion from the cells, and MEHP also on thyroglobulin (Tg secretion from the cells. Results of the lactate dehydrogenase-measurements indicated that the MEHP-mediated influence was caused by cell death. No influence on gene expression of thyroid specific genes (Tg, thyroid peroxidase, sodium iodine symporter and thyroid stimulating hormone receptor by any of the investigated diesters could be demonstrated. All phthalate diesters were metabolised to the respective monoester, however with a fall in efficiency for high concentrations of the larger diesters DnBP and DEHP. In conclusion, human thyroid cells were able to metabolise phthalates but this phthalate-exposure did not appear to substantially influence selected functions of these cells.

  12. NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis.

    Directory of Open Access Journals (Sweden)

    Yan-fei Liu

    Full Text Available Gastric cancer is one of the most common malignancies and has a high rate of metastasis. We hypothesize that NME2 (Nucleoside Diphosphate Kinase 2, which has previously been considered as an anti-metastatic gene, plays a role in the invasiveness of gastric cancer cells. Using a tissue chip technology and immunohistochemistry, we demonstrated that NME2 expression was associated with levels of differentiation of gastric cancer cells and their metastasis into the lymph nodes. When the NME2 gene product was over-expressed by ;in vitro stable transfection, cells from BGC823 and MKN45 gastric cancer cell lines had reduced rates of proliferation, migration, and invasion through the collagen matrix, suggesting an inhibitory activity of NME2 in the propagation and invasion of gastric cancer. NME2 could, therefore, severe as a risk marker for gastric cancer invasiveness and a potential new target for gene therapy to enhance or induce NME2 expression.

  13. Asynchronous Inflammation and Myogenic Cell Migration Limit Muscle Tissue Regeneration Mediated by a Cellular Scaffolds

    Science.gov (United States)

    2015-02-11

    such as duchenne muscular dystrophy) results in impaired regeneration, increased atrophy and fibrosis of skeletal muscle [24-27]. It has also been...2005; 122:289-301. 24. Cohn RDCampbell KP. Molecular basis of muscular dystrophies. Muscle Nerve 2000; 23:1456-1471. 25. Morgan JEZammit PS. Direct...effects of the pathogenic mutation on satellite cell function in muscular dystrophy. Exp Cell Res 2010; 316:3100-3108. 26. Conboy IMRando TA

  14. Limitations of Ber-EP4 for distinction of Bowen disease from basal cell carcinoma.

    Science.gov (United States)

    Kogut, Marta; Toberer, Ferdinand; Enk, Alexander H; Hassel, Jessica C

    2016-04-01

    Diagnostic differentiation between Bowen disease a variant of squamous cell carcinoma in situ (SCCIS) and basal cell carcinoma (BCC) can be difficult on the basis of hematoxylin and eosin (routine) staining in small or fragmented biopsy samples. Ber-EP4 staining is diagnostically reliable for differentiation between BCC and cutaneous squamous cell carcinoma [Dasgeb et al. Biomark Cancer, 5: 7, (2013); Tellechea et al. Am J Dermatopathol, 15: 452 (1993)]. The objective of this study was to determine the usefulness of Ber-EP4 staining for differentiation of SCCIS from BCC. Here, we performed immunohistochemistry with a Ber-EP4 antibody in 76 cases of Bowen type of SCCIS. As positive controls we selected 16 cases of BCC. A positive reaction was obtained for Ber-EP4 in the secretory portion of eccrine and apocrine glands and in follicular germinative cells at the lower end of catagen hairs of normal skin tissue. All BCC samples tested were positive. Of the Bowen type SCCIS samples, 26.3% reacted positively (at least 5% positive staining of neoplastic cells). In 3/76 cases (3.9%) more than 50% of the tumor cells expressed Ber-EP4. We conclude that Ber-EP4 expression is not always helpful to distinguish between Bowen type of SCCIS and BCC, as Ber-EP4 expression in Bowen type SCCIS is not infrequent. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. DNA polymerase ζ limits chromosomal damage and promotes cell survival following aflatoxin exposure.

    Science.gov (United States)

    Lin, Ying-Chih; Owen, Nichole; Minko, Irina G; Lange, Sabine S; Tomida, Junya; Li, Liang; Stone, Michael P; Wood, Richard D; McCullough, Amanda K; Lloyd, R Stephen

    2016-11-29

    Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B 1 (AFB 1 ) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB 1 -N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB 1 (AFB 1 -Fapy-dG). Because this latter adduct is known to persist in human tissues and contributes to the high frequency G-to-T mutation signature associated with many hepatocellular carcinomas, we sought to establish the identity of the polymerase(s) involved in processing this lesion. Although our previous biochemical analyses demonstrated the ability of polymerase ζ (pol ζ) to incorporate an A opposite AFB 1 -Fapy-dG and extend from this mismatch, biological evidence supporting a unique role for this polymerase in cellular tolerance following aflatoxin exposure has not been established. Following challenge with AFB 1 , survival of mouse cells deficient in pol ζ (Rev3L -/- ) was significantly reduced relative to Rev3L +/- cells or Rev3L -/- cells complemented through expression of the wild-type human REV3L. Furthermore, cell-cycle progression of Rev3L -/- mouse embryo fibroblasts was arrested in late S/G2 following AFB 1 exposure. These Rev3L -/- cells showed an increase in replication-dependent formation of γ-H2AX foci, micronuclei, and chromosomal aberrations (chromatid breaks and radials) relative to Rev3L +/- cells. These data suggest that pol ζ is essential for processing AFB 1 -induced DNA adducts and that, in its absence, cells do not have an efficient backup polymerase or a repair/tolerance mechanism facilitating survival.

  16. Changes in phosphorus magnetic resonance spectra during the cell cycle of phosphorus limited phased culture of Candida utilis

    International Nuclear Information System (INIS)

    Dawson, P.S.S.; MacDonald, J.C.

    1987-01-01

    Cell extracts, serially obtained from Candida utilis grown in continuous (synchrony) culture under phosphate limitation during an 8-h cycle and examined by NMR spectroscopy, revealed changes in polyphosphate content during the cycle period: other phosphorus containing components showed relatively little change. Initially zero, the polyphosphate content increased rapidly to a maximum after 30 min that coincided with exhaustion of phosphate from the culture, and then decreased slowly back to zero at the end of the cycle. The results suggest that polyphosphate, usually considered to function as a reserve material, actively participates during the cell cycle. 12 refs.; 1 figure; 1 table

  17. Limiting Current of Oxygen Reduction on Gas-Diffusion Electrodes for Phosphoric Acid Fuel Cells

    DEFF Research Database (Denmark)

    Li, Qingfeng; Gang, Xiao; Hjuler, Hans Aage

    1994-01-01

    on polytetrafluorine-ethyl bonded gas-diffusion electordes in phosphoric acid with and without fluorinated additives. This provides an alternative to estimate the film thickness by combining it with the acid-adsorption measurements and the porosity analysis of the catalyst layer. It was noticed that the limiting...... expression for the limiting current density. The acid-film thickness estimated this way was found to be of 0.1 mum order of magnitude for the two types of electrodes used in phosphoric acid with and without fluorinated additives at 150-degrees-C....

  18. Secretory expression of functional barley limit dextrinase by Pichia pastoris using high cell-density fermentation

    DEFF Research Database (Denmark)

    Vester-Christensen, Malene Bech; Abou Hachem, Maher; Næsted, Henrik

    2010-01-01

    Heterologous production of large multidomain proteins from higher plants is often cumbersome. Barley limit dextrinase (LD), a 98 kDa multidomain starch and alpha-limit dextrin debranching enzyme, plays a major role in starch mobilization during seed germination and is possibly involved in starch....... Kinetic constants of LD catalyzed pullulan hydrolysis were found to K-m,K-app = 0.16 +/- 0.02 mg/mL and k(cat,app) = 79 +/- 10 s(-1) by fitting the uncompetitive substrate inhibition Michaelis-Menten equation, which reflects significant substrate inhibition and/or transglycosylation. The resulting...

  19. Shedding of APP limits its synaptogenic activity and cell adhesion properties

    Science.gov (United States)

    Stahl, Ronny; Schilling, Sandra; Soba, Peter; Rupp, Carsten; Hartmann, Tobias; Wagner, Katja; Merdes, Gunter; Eggert, Simone; Kins, Stefan

    2014-01-01

    The amyloid precursor protein (APP) plays a central role in Alzheimer’s disease (AD) and has essential synapse promoting functions. Synaptogenic activity as well as cell adhesion properties of APP presumably depend on trans-cellular dimerization via its extracellular domain. Since neuronal APP is extensively processed by secretases, it raises the question if APP shedding affects its cell adhesion and synaptogenic properties. We show that inhibition of APP shedding using cleavage deficient forms of APP or a dominant negative α-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by α-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules. PMID:25520622

  20. Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells

    Directory of Open Access Journals (Sweden)

    Pedro Sousa-Victor

    2017-09-01

    Full Text Available Sophisticated mechanisms that preserve genome integrity are critical to ensure the maintenance of regenerative capacity while preventing transformation of somatic stem cells (SCs, yet little is known about mechanisms regulating genome maintenance in these cells. Here, we show that intestinal stem cells (ISCs induce the Argonaute family protein Piwi in response to JAK/STAT signaling during acute proliferative episodes. Piwi function is critical to ensure heterochromatin maintenance, suppress retrotransposon activation, and prevent DNA damage in homeostasis and under regenerative pressure. Accordingly, loss of Piwi results in the loss of actively dividing ISCs and their progenies by apoptosis. We further show that Piwi expression is sufficient to allay age-related retrotransposon expression, DNA damage, apoptosis, and mis-differentiation phenotypes in the ISC lineage, improving epithelial homeostasis. Our data identify a role for Piwi in the regulation of somatic SC function, and they highlight the importance of retrotransposon control in somatic SC maintenance.

  1. Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells

    Science.gov (United States)

    Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and...

  2. Digestion of isolated legume cells in a stomach-duodenum model: three mechanisms limit starch and protein hydrolysis.

    Science.gov (United States)

    Bhattarai, Rewati R; Dhital, Sushil; Wu, Peng; Chen, Xiao Dong; Gidley, Michael J

    2017-07-19

    Retention of intact plant cells to the end of the small intestine leads to transport of entrapped macronutrients such as starch and protein for colonic microbial fermentation, and is a promising mechanism to increase the content of resistant starch in diets. However, the effect of gastro-intestinal bio-mechanical processing on the intactness of plant cells and the subsequent resistance to enzymatic digestion of intracellular starch and protein are not well understood. In this study, intact cells isolated from legume cotyledons are digested in a laboratory model which mimics the mechanical and biochemical conditions of the rat stomach and duodenum. The resulting digesta are characterised in terms of cell (wall) integrity as well as intracellular starch and protein hydrolysis. The cells remained essentially intact in the model with negligible (ca. 2-3%) starch or protein digestion; however when the cells were mechanically broken and digested in the model, the hydrolysis was increased to 45-50% suggesting that intact cellular structures could survive the mixing regimes in the model stomach and duodenum sufficiently to prevent digestive enzyme access. Apart from intact cell walls providing effective barrier properties, they also limit digestibility by restricting starch gelatinisation during cooking, and significant non-specific binding of α-amylase is observed to both intact and broken cell wall components, providing a third mechanism hindering starch hydrolysis. The study suggests that the preservation of intactness of plant cells, such as from legumes, could be a viable approach to achieve the targeted delivery of resistant starch to the colon.

  3. Inhibition of breast cancer-cell glutamate release with sulfasalazine limits cancer-induced bone pain.

    Science.gov (United States)

    Ungard, Robert G; Seidlitz, Eric P; Singh, Gurmit

    2014-01-01

    Cancer in bone is frequently a result of metastases from distant sites, particularly from the breast, lung, and prostate. Pain is a common and often severe pathological feature of cancers in bone, and is a significant impediment to the maintenance of quality of life of patients living with bone metastases. Cancer cell lines have been demonstrated to release significant amounts of the neurotransmitter and cell-signalling molecule l-glutamate via the system xC(-) cystine/glutamate antiporter. We have developed a novel mouse model of breast cancer bone metastases to investigate the impact of inhibiting cancer cell glutamate transporters on nociceptive behaviour. Immunodeficient mice were inoculated intrafemorally with the human breast adenocarcinoma cell line MDA-MB-231, then treated 14days later via mini-osmotic pumps inserted intraperitoneally with sulfasalazine, (S)-4-carboxyphenylglycine, or vehicle. Both sulfasalazine and (S)-4-carboxyphenylglycine attenuated in vitro cancer cell glutamate release in a dose-dependent manner via the system xC(-) transporter. Animals treated with sulfasalazine displayed reduced nociceptive behaviours and an extended time until the onset of behavioural evidence of pain. Animals treated with a lower dose of (S)-4-carboxyphenylglycine did not display this reduction in nociceptive behaviour. These results suggest that a reduction in glutamate secretion from cancers in bone with the system xC(-) inhibitor sulfasalazine may provide some benefit for treating the often severe and intractable pain associated with bone metastases. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Acetylsalicylic acid differentially limits the activation and expression of cell death markers in human platelets exposed to Staphylococcus aureus strains.

    Science.gov (United States)

    Chabert, Adrien; Damien, Pauline; Verhoeven, Paul O; Grattard, Florence; Berthelot, Philippe; Zeni, Fabrice; Panicot-Dubois, Laurence; Robert, Stéphane; Dignat-George, Françoise; Eyraud, Marie-Ange; Pozzetto, Bruno; Payrastre, Bernard; Cognasse, Fabrice; Garraud, Olivier; Hamzeh-Cognasse, Hind

    2017-07-17

    Beyond their hemostatic functions, platelets alter their inflammatory response according to the bacterial stimulus. Staphylococcus aureus is associated with exacerbated inflammation and thrombocytopenia, which is associated with poor prognosis during sepsis. Acetylsalicylic acid and statins prevent platelet aggregation and decrease the mortality rate during sepsis. Therefore, we assessed whether these two molecules could reduce in vitro platelet activation and the inflammatory response to S. aureus. Platelets were exposed to clinical strains of S. aureus in the presence or absence of acetylsalicylic acid or fluvastatin. Platelet activation, aggregation, and release of soluble sCD62P, sCD40 Ligand, RANTES and GROα were assessed. Platelet cell death was evaluated by analyzing the mitochondrial membrane potential, phosphatidylserine exposure, platelet microparticle release and caspase-3 activation. All S. aureus strains induced platelet activation but not aggregation and decreased the platelet count, the expression of cell death markers and the release of RANTES and GROα. Acetylsalicylic acid but not fluvastatin limited platelet activation and inflammatory factor release and restored the platelet count by protecting platelets from Staphylococcus-induced expression of cell death markers. This study demonstrates that acetylsalicylic acid limits S. aureus-induced effects on platelets by reducing cell death, revealing new strategies to reduce the platelet contribution to bacteremia-associated inflammation.

  5. Phthalates Are Metabolised by Primary Thyroid Cell Cultures but Have Limited Influence on Selected Thyroid Cell Functions In Vitro

    DEFF Research Database (Denmark)

    Hansen, Juliana Frohnert; Brorson, Marianne Møller; Boas, Malene

    2016-01-01

    Phthalates are plasticisers added to a wide variety of products, resulting in measurable exposure of humans. They are suspected to disrupt the thyroid axis as epidemiological studies suggest an influence on the peripheral thyroid hormone concentration. The mechanism is still unknown as only few...... in vitro studies within this area exist. The aim of the present study was to investigate the influence of three phthalate diesters (di-ethyl phthalate, di-n-butyl phthalate (DnBP), di-(2-ethylhexyl) phthalate (DEHP)) and two monoesters (mono-n-butyl phthalate and mono-(2-ethylhexyl) phthalate (MEHP......)) on the differentiated function of primary human thyroid cell cultures. Also, the kinetics of phthalate metabolism were investigated. DEHP and its monoester, MEHP, both had an inhibitory influence on 3'-5'-cyclic adenosine monophosphate secretion from the cells, and MEHP also on thyroglobulin (Tg) secretion from...

  6. A Cell-Enriched Engineered Myocardial Graft Limits Infarct Size and Improves Cardiac Function

    Directory of Open Access Journals (Sweden)

    Isaac Perea-Gil, MS

    2016-08-01

    Full Text Available Myocardial infarction (MI remains a dreadful disease around the world, causing irreversible sequelae that shorten life expectancy and reduce quality of life despite current treatment. Here, the authors engineered a cell-enriched myocardial graft, composed of a decellularized myocardial matrix refilled with adipose tissue-derived progenitor cells (EMG-ATDPC. Once applied over the infarcted area in the swine MI model, the EMG-ATDPC improved cardiac function, reduced infarct size, attenuated fibrosis progression, and promoted neovascularization of the ischemic myocardium. The beneficial effects exerted by the EMG-ATDPC and the absence of identified adverse side effects should facilitate its clinical translation as a novel MI therapy in humans.

  7. Practical Application Limits of Fuel Cells and Batteries for Zero Emission Vessels

    Energy Technology Data Exchange (ETDEWEB)

    Minnehan, John J. [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Energy Innovation Dept.; Pratt, Joseph William [Sandia National Lab. (SNL-CA), Livermore, CA (United States). Energy Innovation Dept.

    2017-11-01

    Batteries and hydrogen fuel cells provide zero emission power at the point of use. They are studied as an alternative powerplant for maritime vessels by considering 14 case studies of various ship sizes and routes varying from small passenger vessels to the largest cargo ships. The method used was to compare the mass and volume of the required zero emission solution to the available mass and volume on an existing vessel considering its current engine and fuel storage systems. The results show that it is practically feasible to consider these zero emission technologies for most vessels in the world's fleet. Hydrogen fuel cells proved to be the most capable while battery systems showed an advantage for high power, short duration missions. The results provide a guide to ship designers to determine the most suitable types of zero emission powerplants to fit a ship based on its size and energy requirements.

  8. Understanding the cancer cell phenotype beyond the limitations of current omics analyses.

    Science.gov (United States)

    Moreno-Sánchez, Rafael; Saavedra, Emma; Gallardo-Pérez, Juan Carlos; Rumjanek, Franklin D; Rodríguez-Enríquez, Sara

    2016-01-01

    Efforts to understand the mechanistic principles driving cancer metabolism and proliferation have been lately governed by genomic, transcriptomic and proteomic studies. This paper analyzes the caveats of these approaches. As molecular biology's central dogma proposes a unidirectional flux of information from genes to mRNA to proteins, it has frequently been assumed that monitoring the changes in the gene sequences and in mRNA and protein contents is sufficient to explain complex cellular processes. Such a stance commonly disregards that post-translational modifications can alter the protein function/activity and also that regulatory mechanisms enter into action, to coordinate the protein activities of pathways/cellular processes, in order to keep the cellular homeostasis. Hence, the actual protein activities (as enzymes/transporters/receptors) and their regulatory mechanisms ultimately dictate the final outcomes of a pathway/cellular process. In this regard, it is here documented that the mRNA levels of many metabolic enzymes and transcriptional factors have no correlation with the respective protein contents and activities. The validity of current clinical mRNA-based tests and proposed metabolite biomarkers for cancer detection/prognosis is also discussed. Therefore, it is proposed that, to achieve a thorough understanding of the modifications undergone by proliferating cancer cells, it is mandatory to experimentally analyze the cellular processes at the functional level. This could be achieved (a) locally, by examining the actual protein activities in the cell and their kinetic properties (or at least kinetically characterize the most controlling steps of the pathway/cellular process); (b) systemically, by analyzing the main fluxes of the pathway/cellular process, and how they are modulated by metabolites, all which should contribute to comprehending the regulatory mechanisms that have been altered in cancer cells. By adopting a more holistic approach it may

  9. Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations

    Czech Academy of Sciences Publication Activity Database

    Lunov, Oleg; Zablotskyy, Vitaliy A.; Churpita, Olexandr; Chánová, Eliška; Syková, Eva; Dejneka, Alexandr; Kubinová, Šárka

    2014-01-01

    Roč. 4, NOV (2014), "7129-1"-"7129-11" ISSN 2045-2322 R&D Projects: GA MŠk LO1309 Grant - others:AV ČR(CZ) M100101219 Institutional support: RVO:68378271 ; RVO:61389013 ; RVO:68378041 Keywords : cell death * non-thermal plasma * therapeutic perspectives Subject RIV: BO - Biophysics; FH - Neurology (UEM-P); CD - Macromolecular Chemistry (UMCH-V) Impact factor: 5.578, year: 2014

  10. Regenerative potential of the cartilaginous tissue in mesenchymal stem cells: update, limitations, and challenges.

    Science.gov (United States)

    Cruz, Ivana Beatrice Mânica da; Severo, Antônio Lourenço; Azzolin, Verônica Farina; Garcia, Luiz Filipe Machado; Kuhn, André; Lech, Osvandré

    2017-01-01

    Advances in the studies with adult mesenchymal stem cells (MSCs) have turned tissue regenerative therapy into a promising tool in many areas of medicine. In orthopedics, one of the main challenges has been the regeneration of cartilage tissue, mainly in diarthroses. In the induction of the MSCs, in addition to cytodifferentiation, the microenvironmental context of the tissue to be regenerated and an appropriate spatial arrangement are extremely important factors. Furthermore, it is known that MSC differentiation is fundamentally determined by mechanisms such as cell proliferation (mitosis), biochemical-molecular interactions, movement, cell adhesion, and apoptosis. Although the use of MSCs for cartilage regeneration remains at a research level, there are important questions to be resolved in order to make this therapy efficient and safe. It is known, for instance, that the expansion of chondrocytes in cultivation, needed to increase the number of cells, could end up producing fibrocartilage instead of hyaline cartilage. However, the latest results are promising. In 2014, the first stage I/II clinical trial to evaluate the efficacy and safety of the intra-articular injection of MSCs in femorotibial cartilage regeneration was published, indicating a decrease in injured areas. One issue to be explored is how many modifications in the articulate inflammatory environment could induce differentiation of MSCs already allocated in that region. Such issue arose from studies that suggested that the suppression of the inflammation may increase the efficiency of tissue regeneration. Considering the complexity of the events related to the chondrogenesis and cartilage repair, it can be concluded that the road ahead is still long, and that further studies are needed.

  11. Water Extract of Ashwagandha Leaves Limits Proliferation and Migration, and Induces Differentiation in Glioma Cells

    Directory of Open Access Journals (Sweden)

    Hardeep Kataria

    2011-01-01

    Full Text Available Root extracts of Withania somnifera (Ashwagandha are commonly used as a remedy for a variety of ailments and a general tonic for overall health and longevity in the Indian traditional medicine system, Ayurveda. We undertook a study to investigate the anti-proliferative and differentiation-inducing activities in the water extract of Ashwagandha leaves (ASH-WEX by examining in glioma cells. Preliminary detection for phytochemicals was performed by thin-layer chromatography. Cytotoxicity was determined using trypan blue and MTT assays. Expression level of an hsp70 family protein (mortalin, glial cell differentiation marker [glial fibrillary acidic protein (GFAP] and neural cell adhesion molecule (NCAM were analyzed by immunocytochemistry and immunoblotting. Anti-migratory assay was also done using wound-scratch assay. Expression levels of mortalin, GFAP and NCAM showed changes, subsequent to the treatment with ASH-WEX. The data support the existence of anti-proliferative, differentiation-inducing and anti-migratory/anti-metastasis activities in ASH-WEX that could be used as potentially safe and complimentary therapy for glioma.

  12. Gold Nanoparticles Promote Proliferation of Human Periodontal Ligament Stem Cells and Have Limited Effects on Cells Differentiation

    Directory of Open Access Journals (Sweden)

    Chen Li

    2016-01-01

    Full Text Available Gold nanoparticles (AuNPs had been widely applied in the practice and advancement of chemistry, biology, and medicine due to facility of synthesis and versatility in surface functionalization. Recent studies had shown that AuNPs can be applied to cells, affecting cellular physiological processes such as proliferation and differentiation. In this study, four diameters of AuNPs (20, 40, 60, and 80 nm were cocultured with human periodontal ligament cells (hPDLCs at six different concentrations. The optimal size and concentration of AuNPs were selected to treat human periodontal ligament stem cells (hPDLSCs to evaluate proliferation. Moreover, the influence of AuNPs on multiple differentiation capacity of hPDLSCs was clarified. The results revealed that AuNPs (60 nm, 56 μM can effectively promote the proliferation of hPDLCs/hPDLSCs in vitro, slightly enhance osteoblastic differentiation, and have no effect on adipogenic differentiation. In addition, the expression of COL-1, Runx2, BSP, and OCN was upregulated in the presence of AuNPs (60 nm, 56 μM. These results indicated that AuNPs (60 nm, 56 μM can effectively promote the proliferation of hPDLCs/hPDLSCs and have no significant effect on the differentiation of hPDLSCs. These results provide an insight on the advantage of implementing of AuNPs on hPDLSCs culture and expose the influence of these materials on periodontal tissue engineering.

  13. Diabetes Limits Stem Cell Mobilization Following G-CSF but Not Plerixafor.

    Science.gov (United States)

    Fadini, Gian Paolo; Fiala, Mark; Cappellari, Roberta; Danna, Marianna; Park, Soo; Poncina, Nicol; Menegazzo, Lisa; Albiero, Mattia; DiPersio, John; Stockerl-Goldstein, Keith; Avogaro, Angelo

    2015-08-01

    Previous studies suggest that diabetes impairs hematopoietic stem cell (HSC) mobilization in response to granulocyte colony-stimulating factor (G-CSF). In this study, we tested whether the CXCR4 antagonist plerixafor, differently from G-CSF, is effective in mobilizing HSCs in patients with diabetes. In a prospective study, individuals with and without diabetes (n = 10/group) were administered plerixafor to compare CD34(+) HSC mobilization; plerixafor was equally able to mobilize CD34(+) HSCs in the two groups, whereas in historical data, G-CSF was less effective in patients with diabetes. In a retrospective autologous transplantation study conducted on 706 patients, diabetes was associated with poorer mobilization in patients who received G-CSF with/without chemotherapy, whereas it was not in patients who received G-CSF plus plerixafor. Similarly in an allogeneic transplantation study (n = 335), diabetes was associated with poorer mobilization in patients who received G-CSF. Patients with diabetes who received G-CSF without plerixafor had a lower probability of reaching >50/μL CD34(+) HSCs, independent from confounding variables. In conclusion, diabetes negatively impacted HSC mobilization after G-CSF with or without chemotherapy but had no effect on mobilization induced by G-CSF with plerixafor. This finding has major implications for the care of patients with diabetes undergoing stem cell mobilization and transplantation and for the vascular regenerative potential of bone marrow stem cells. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  14. Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Regulate the Phenotype of Smooth Muscle Cells to Limit Intimal Hyperplasia.

    Science.gov (United States)

    Liu, Rong; Shen, Hong; Ma, Jian; Sun, Leiqing; Wei, Meng

    2016-04-01

    Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) play important roles in the reduction of inflammation in multiple disease models. However, their role in vein graft (VG) remodeling is undefined. We aimed to investigate the effect of EVs from adipose MSCs (ADMSC-EVs) on VG intimal hyperplasia and to explore the possible mechanisms. After generation and characterization of control-EVs and ADMSC-EVs in vitro, we investigated their effect on the proliferation and migration of vascular smooth muscle cells (VSMCs) in vitro. Next, we established a mouse model of VG transplantation. Mice underwent surgery and received control-EVs or ADMSC-EVs by intraperitoneal injection every other day for 20 days. VG remodeling was evaluated after 4 weeks. We also assessed the effect of ADMSC-EVs on macrophage migration and inflammatory cytokine expression. Significant inhibitory effects of ADMSC-EVs on in vitro VSMC proliferation (p < 0.05) and migration (p < 0.05) were observed compared with control-EVs. The extent of intimal hyperplasia was significantly decreased in ADMSC-EV-treated mice compared with control-EV-treated mice (26 ± 8.4 vs. 45 ± 9.0 μm, p < 0.05). A reduced presence of macrophages was observed in ADMSC-EV-treated mice (p < 0.05). Significantly decreased expression of inflammatory cytokines interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was also found in the ADMSC-EV-treated group (both p < 0.05). In addition, phosphorylation of Akt, Erk1/2, and p38 in VGs was decreased in the ADMSC-EV-treated group. We demonstrated that ADMSC-EVs exert an inhibitory effect on VG neointima formation by regulating VSMC proliferation and migration, macrophage migration, inflammatory cytokine expression, and the related signaling pathways.

  15. Thin Silicon Solar Cells: A Path to 35% Shockley-Queisser Limits

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Laura; Boccard, Mathieu; Williams, Joshua; Jeffries, April; Gangam, Srikanth; Ghosh, Kunal; Honsberg, Christiana; Bowden, Stuart; Holman, Zachary; Atwater, Harry; Buonassisi, Tonio; Bremner, Stephen; Green, Martin; Balif, Christoph; Bertoni, Mariana

    2014-06-08

    Crystalline silicon technology is expected to remain the leading photovoltaic industry workhorse for decades. We present here the objectives and workplan of a recently launched project funded by the U.S. Department of Energy through the Foundational Program to Advance Cell Efficiency II (FPACE II), which aims at leading crystalline silicon to an efficiency breakthrough. The project will tackle fundamental approach of materials design, defect engineering, device simulations and materials growth and characterization. Among the main novelties, the implementation of carrier selective contacts made of wide bandgap material or stack of materials is investigated for improved passivation, carrier extraction and carrier transport. Based on an initial selection of candidate materials, preliminary experiments are conducted to verify the suitability of their critical parameters as well as preservation of the silicon substrate surface and bulk properties. The target materials include III-V and metal-oxide materials.

  16. Comparison of treatment outcomes between involved-field and elective nodal irradiation in limited-stage small cell lung cancer

    International Nuclear Information System (INIS)

    Han, Tae-Jin; Kim, Hak-Jae; Wu, Hong-Gyun; Heo, Dae-Seog; Kim, Young-Whan; Lee, Se-Hoon

    2012-01-01

    The present study was performed to assess the usefulness of involved-field irradiation and the impact of 18 F-fluorodeoxyglucose-positron emission tomography-based staging on treatment outcomes in limited-stage small cell lung cancer. Eighty patients who received definitive chemoradiotherapy for limited-stage small cell lung cancer were retrospectively analyzed. Fifty patients were treated with involved-field irradiation, which means that the radiotherapy portal includes only clinically identifiable tumors. The other 30 patients were irradiated with a comprehensive portal, including uninvolved mediastinal and/or supraclavicular lymph nodes, so-called elective nodal irradiation. No significant difference was seen in clinical factors between the two groups. At a median follow-up of 27 months (range, 5-75 months), no significant differences were observed in 3 year overall survival (44.6 vs. 54.1%, P=0.220) and 3 year progression-free survival (24.4 vs. 42.8%, P=0.133) between the involved-field irradiation group and the elective nodal irradiation group, respectively. For patients who did not undergo positron emission tomography scans, 3 year overall survival (29.3 vs. 56.3%, P=0.022) and 3 year progression-free survival (11.0 vs. 50.0%, P=0.040) were significantly longer in the elective nodal irradiation group. Crude incidences of isolated nodal failure were 6.0% in the involved-field irradiation group and 0% in the elective nodal irradiation group, respectively. All isolated nodal failures were developed in patients who had not undergone positron emission tomography scans in their initial work-ups. If patients did not undergo positron emission tomography-based staging, the omission of elective nodal irradiation resulted in impaired survival outcomes and raised the risk of isolated nodal failure. Therefore, involved-field irradiation for limited-stage small cell lung cancer might be reasonable only with positron emission tomography scan implementation. (author)

  17. Prevention of melanin formation during aryl alcohol oxidase production under growth-limited conditions using an Aspergillus nidulans cell factory.

    Science.gov (United States)

    Pardo-Planas, Oscar; Prade, Rolf A; Müller, Michael; Atiyeh, Hasan K; Wilkins, Mark R

    2017-11-01

    An Aspergillus nidulans cell factory was genetically engineered to produce an aryl alcohol oxidase (AAO). The cell factory initiated production of melanin when growth-limited conditions were established using stationary plates and shaken flasks. This phenomenon was more pronounced when the strain was cultured in a trickle bed reactor (TBR). This study investigated different approaches to reduce melanin formation in fungal mycelia and liquid medium in order to increase the enzyme production yield. Removal of copper from the medium recipe reduced melanin formation in agar cultures and increased enzyme activities by 48% in agitated liquid cultures. Copper has been reported as a key element for tyrosinase, an enzyme responsible for melanin production. Ascorbic acid (0.44g/L) stopped melanin accumulation, did not affect growth parameters and resulted in AAO activity that was more than two-fold greater than a control treatment with no ascorbic acid. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Benefits and Limitations of Protein Hydrolysates as Components of Serum-Free Media for Animal Cell Culture Applications

    Science.gov (United States)

    Lobo-Alfonso, Juliet; Price, Paul; Jayme, David

    Increased understanding of influential factors for the cultivation of animal cells, combined with heightened regulatory concern over potential transmission of adventitious contaminants associated with serum and other animal-derived components, has elevated interest in using protein hydrolysates as serum replacements or nutrient supplements. This paper reviews the chemistry and biology of various hydrolysates derived from animal, plant and microbial sources. It provides specific examples of a beneficial selection of plant and yeast hydrolysates as ingredients of serum-free nutrient formulations for bioproduction applications of cultured mammalian and insect cells. Strategies for customizing and optimizing nutrients for specialized applications and general benefits and limitations of protein hydrolysates for biopharmaceutical production are also discussed.

  19. Prognostic factors for patients with inoperable non-small cell lung cancer, limited disease

    International Nuclear Information System (INIS)

    Kaasa, S.; Mastekaasa, A.; Lund, E.

    1989-01-01

    In a prospective controlled clinical trial, 102 patients with inoperable non-small lung cancer (NSCLC), limited disease, stage II and III were treated with combination chemotherapy, cisplatin 70 mg/m 2 i.v. on day one and etoposide 100 mg/m 2 i.v. on day one, and etoposide 200 mg/m 2 orally on days 2 and 3, or radiotherapy given in 15 fractions of 2.8 Gy with two anterior/posterior fields during a period of three weeks. The patients completed a validated self-administered questionnaire before the start of treatment that assessed their psychosocial well-being, disease-related symptoms, personal functioning, and every day activity. These subjective varibles were evaluated together with treatment modality, WHO performance status, weight loss, and stage of disease, with regard to their value in predicting survival. Univariate survival analyses were undertaken for each individual factor, median survival was calculated according to life-table analyses. A step-wise multiple regression analysis was used to measure the prognostic value of the various factors. In the univariate analysis, general symptons (p=0.0006) psychosocial well-being (p=0.0002) and stage of disease (p=0.007) were the best predictive factors. In the multiple regression analyses the subjective variables, general symptons (p<0.01) and psychosocial well-being (p<0.05) were shown to have the best predictive value for the patients' survival. (author). 20 refs.; 4 figs.; 3 tabs

  20. Autophagy Limits Endotoxemic Acute Kidney Injury and Alters Renal Tubular Epithelial Cell Cytokine Expression.

    Directory of Open Access Journals (Sweden)

    Jeremy S Leventhal

    Full Text Available Sepsis related acute kidney injury (AKI is a common in-hospital complication with a dismal prognosis. Our incomplete understanding of disease pathogenesis has prevented the identification of hypothesis-driven preventive or therapeutic interventions. Increasing evidence in ischemia-reperfusion and nephrotoxic mouse models of AKI support the theory that autophagy protects renal tubular epithelial cells (RTEC from injury. However, the role of RTEC autophagy in septic AKI remains unclear. We observed that lipopolysaccharide (LPS, a mediator of gram-negative bacterial sepsis, induces RTEC autophagy in vivo and in vitro through TLR4-initiated signaling. We modeled septic AKI through intraperitoneal LPS injection in mice in which autophagy-related protein 7 was specifically knocked out in the renal proximal tubules (ATG7KO. Compared to control littermates, ATG7KO mice developed more severe renal dysfunction (24hr BUN 100.1mg/dl +/- 14.8 vs 54.6mg/dl +/- 11.3 and parenchymal injury. After injection with LPS, analysis of kidney lysates identified higher IL-6 expression and increased STAT3 activation in kidney lysates from ATG7KO mice compared to controls. In vitro experiments confirmed an altered response to LPS in RTEC with genetic or pharmacological impairment of autophagy. In conclusion, RTEC autophagy protects against endotoxin induced injury and regulates downstream effects of RTEC TLR4 signaling.

  1. Overcoming the efficiency limitations of SnS2 nanoparticle-based bulk heterojunction solar cells

    Science.gov (United States)

    Tam Nguyen Truong, Nguyen; Kieu Trinh, Thanh; Thanh Hau Pham, Viet; Smith, Ryan P.; Park, Chinho

    2018-04-01

    This study examined the effects of heat treatment, the electron transport layer, and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) incorporation on the performance of hybrid bulk heterojunction (BHJ) solar cells composed of tin disulfide (SnS2) nanoparticles (NPs) and low band gap energy polymers poly[2,6-(4,4-bis(2-ethylhexyl)-4H-cyclopenta[2,1-b3,4-b‧]dithiophene)-alt-4,7(2,1,3-benzothiadiazole)] (PCPDTBT) or poly({4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b‧]dithiophene-2,6-diyl}{3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl}) (PBT7). Inserting an electron transport layer (ETL) (i.e., ZnO) on the top of the photoactive layer improved the surface morphology of the photoactive layer, which led to an improvement in charge transport. Moreover, adding a suitable amount of PCBM to the SnS2/polymer active layer enhanced the device performance, such as short circuit current density (J sc) and power conversion efficiency (PCE). In particular, adding 0.5 mg of PCBM to the composite solution led to a 25% and 1.5% improvement in the J sc value and PCE, respectively. The enhanced performance was due mainly to the improvements in the surface morphology of the photoactive layer, charge carrier mobility within the donor-acceptor interface, and carrier collection efficiency at the cathode.

  2. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    KAUST Repository

    Marcatili, P.

    2013-05-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  3. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships.

    Science.gov (United States)

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-05-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. © 2014 John Wiley & Sons Ltd.

  4. PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells

    Science.gov (United States)

    Ferraresi, Alessandra; Morani, Federica; Follo, Carlo; Isidoro, Ciro

    2016-01-01

    GLUT1 is the facilitative transporter playing the major role in the internalization of glucose. Basally, GLUT1 resides on vesicles located in a para-golgian area, and is translocated onto the plasmamembrane upon activation of the PI3KC1-AKT pathway. In proliferating cancer cells, which demand a high quantity of glucose for their metabolism, GLUT1 is permanently expressed on the plasmamembrane. This is associated with the abnormal activation of the PI3KC1-AKT pathway, consequent to the mutational activation of PI3KC1 and/or the loss of PTEN. The latter, in fact, could antagonize the phosphorylation of AKT by limiting the availability of Phosphatidylinositol (3,4,5)-trisphosphate. Here, we asked whether PTEN could control the plasmamembrane expression of GLUT1 also through its protein-phosphatase activity on AKT. Experiments of co-immunoprecipitation and in vitro de-phosphorylation assay with homogenates of cells transgenically expressing the wild type or knocked-down mutants (lipid-phosphatase, protein-phosphatase, or both) isoforms demonstrated that indeed PTEN physically interacts with AKT and drives its dephosphorylation, and so limiting the expression of GLUT1 at the plasmamembrane. We also show that growth factors limit the ability of PTEN to dephosphorylate AKT. Our data emphasize the fact that PTEN acts in two distinct steps of the PI3k/AKT pathway to control the expression of GLUT1 at the plasmamembrane and, further, add AKT to the list of the protein substrates of PTEN. PMID:27829222

  5. Study of quality and field limitation of superconducting 1.3 GHz 9-Cell RF-cavities at DESY

    Energy Technology Data Exchange (ETDEWEB)

    Schlander, Felix

    2013-01-15

    The European XFEL and the International Linear Collider are based on superconducting rf cavities made of niobium. Their advantages are low ohmic losses which allow high duty cycles and the possibility to use a large beam aperture which is substantial to prevent wake fields at high current accelerators. To reach the theoretical limits of superconducting cavities, it is required to understand the present performance limitations. These are field emission, thermal breakdown (quench) and the ohmic losses dependent on the accelerating field, which are expressed in the quality factor. As the limiting mechanisms themselves are understood in general, the origin of the quench is often unclear. To determine the quench locations, a localisation tool for thermal breakdown using the second sound in superfluid helium has been installed at the cavity test facility at DESY and the results for a sample of about 30 cavities have been examined. The features of the distribution of the quench locations have been analysed and it has been found that the quench locations are in the area of the highest surface magnetic field and not necessarily at the equator of the cells. The data sample has been extended in an attempt to characterise the average behaviour of the quality factor related to the accelerating field. An analysis of the surface resistance of individual cavities shows that a recently developed model for the surface resistance of niobium is not able to describe the measurement in all detail, but the application of an additional mechanism showed promising results.

  6. Quantitative imaging of green fluorescent protein in cultured cells: comparison of microscopic techniques, use in fusion proteins and detection limits.

    Science.gov (United States)

    Niswender, K D; Blackman, S M; Rohde, L; Magnuson, M A; Piston, D W

    1995-11-01

    To determine the application limits of green fluorescent protein (GFP) as a reporter gene or protein tag, we expressed GFP by itself and with fusion protein partners, and used three different imaging methods to identify GFP fluorescence. In conventional epifluorescence photomicroscopy, GFP expressed in cells could be distinguished as a bright green signal over a yellow-green autofluorescence background. In quantitative fluorescence microscopy, however, the GFP signal is contaminated by cellular autofluorescence. Improved separation of GFP signal from HeLa cell autofluorescence was achieved by the combination of confocal scanning laser microscopy using 488-nm excitation, a rapid cut-on dichroic mirror and a narrow-bandpass emission filter. Two-photon excitation of GFP fluorescence at the equivalent of approximately 390 nm provided better absorption than did 488-nm excitation. This resulted in increased signal/background but also generated a different autofluorescence pattern and appeared to increase GFP photobleaching. Fluorescence spectra similar to those of GFP alone were observed when GFP was expressed as a fusion protein either with glutathione-S-transferase (GST) or with glucokinase. Furthermore, purified GST.GFP fusion protein displayed an extinction coefficient and quantum yield consistent with values previously reported for GFP alone. In HeLa cells, the cytoplasmic GFP concentration must be greater than approximately 1 microM to allow quantifiable discrimination over autofluorescence. However, lower expression levels may be detectable if GFP is targeted to discrete subcellular compartments, such as the plasma membrane, organelles or nucleus.

  7. Cell Phone-Based and Adherence Device Technologies for HIV Care and Treatment in Resource-Limited Settings: Recent Advances.

    Science.gov (United States)

    Campbell, Jeffrey I; Haberer, Jessica E

    2015-12-01

    Numerous cell phone-based and adherence monitoring technologies have been developed to address barriers to effective HIV prevention, testing, and treatment. Because most people living with HIV and AIDS reside in resource-limited settings (RLS), it is important to understand the development and use of these technologies in RLS. Recent research on cell phone-based technologies has focused on HIV education, linkage to and retention in care, disease tracking, and antiretroviral therapy adherence reminders. Advances in adherence devices have focused on real-time adherence monitors, which have been used for both antiretroviral therapy and pre-exposure prophylaxis. Real-time monitoring has recently been combined with cell phone-based technologies to create real-time adherence interventions using short message service (SMS). New developments in adherence technologies are exploring ingestion monitoring and metabolite detection to confirm adherence. This article provides an overview of recent advances in these two families of technologies and includes research on their acceptability and cost-effectiveness when available. It additionally outlines key challenges and needed research as use of these technologies continues to expand and evolve.

  8. Overcoming the Range Limitation of Medium-Duty Battery Electric Vehicles through the use of Hydrogen Fuel-Cells

    Energy Technology Data Exchange (ETDEWEB)

    Wood, E.; Wang, L.; Gonder, J.; Ulsh, M.

    2013-10-01

    Battery electric vehicles possess great potential for decreasing lifecycle costs in medium-duty applications, a market segment currently dominated by internal combustion technology. Characterized by frequent repetition of similar routes and daily return to a central depot, medium-duty vocations are well positioned to leverage the low operating costs of battery electric vehicles. Unfortunately, the range limitation of commercially available battery electric vehicles acts as a barrier to widespread adoption. This paper describes the National Renewable Energy Laboratory's collaboration with the U.S. Department of Energy and industry partners to analyze the use of small hydrogen fuel-cell stacks to extend the range of battery electric vehicles as a means of improving utility, and presumably, increasing market adoption. This analysis employs real-world vocational data and near-term economic assumptions to (1) identify optimal component configurations for minimizing lifecycle costs, (2) benchmark economic performance relative to both battery electric and conventional powertrains, and (3) understand how the optimal design and its competitiveness change with respect to duty cycle and economic climate. It is found that small fuel-cell power units provide extended range at significantly lower capital and lifecycle costs than additional battery capacity alone. And while fuel-cell range-extended vehicles are not deemed economically competitive with conventional vehicles given present-day economic conditions, this paper identifies potential future scenarios where cost equivalency is achieved.

  9. Use of Limiting Dilution Method for Isolation of Nucleus Pulposus Mesenchymal Stem/Progenitor Cells and Effects of Plating Density on Biological Characteristics and Plasticity

    Directory of Open Access Journals (Sweden)

    Linghan Lin

    2017-01-01

    Full Text Available Objectives. To evaluate the effects of the limiting dilution method and plating density in rat nucleus pulposus mesenchymal stem/progenitor cells (NPMSCs. Materials and Methods. Nucleus pulposus tissues were isolated from 12-week-old male Sprague-Dawley rats and NPMSCs were isolated using limiting dilution method. Cells were then classified into 3 groups according to plating density. Cell morphologies were observed, and colony-forming units, migration abilities, proliferative capacities, cell cycle percentages, multilineage differentiation capacities, stem cell biomarker expression levels, and immunophenotyping were also examined in each group. Results. Low density group (LD had higher morphological homogeneity, stronger colony-forming ability, higher cell proliferation capacity, and enhanced cell migration ability relative to the other two groups (p<0.05. Moreover, LD had more cells entering S phase, with fewer cells arrested in G0/G1 phase (p<0.05. While all three density groups showed a multilineage differentiation potential, LD showed a higher degree of observed and semiquantified lineage specific staining (p<0.05. Furthermore, LD displayed higher expression levels of stem cell biomarkers (Nanog, Oct4, and Sox2 and showed higher percentages of CD29+, CD44+, and CD90+ cells (p<0.05 following flow cytometry analysis. Conclusions. Limiting dilution method is suggested when isolating NPMSCs as a means of improving cell activity and plasticity.

  10. Mast cells are key mediators of cathelicidin initiated skin inflammation in rosacea

    Science.gov (United States)

    Muto, Yumiko; Wang, Zhenping; Vanderberghe, Matthieu; Two, Aimee; Gallo, Richard L.; Di Nardo, Anna

    2014-01-01

    Rosacea is a chronic inflammatory skin disease whose pathophysiological mechanism is still unclear. However, it is known that mast cell (MC) numbers is increased in the dermis of rosacea patients. MC proteases not only recruit other immune cells, which amplify the inflammatory response, but also cause vasodilation and angiogenesis. MCs are also one of the primary sources of cathelicidin LL-37 (Cath LL-37), an antimicrobial peptide that has been shown to be an enabler of rosacea pathogenesis. Here, we demonstrate that MCs are key mediators of cathelicidin initiated skin inflammation. Following Cath LL-37 injection into the dermis, MC deficient B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh) mice did not develop rosacea-like features. Conversely, chymase (prosacea subjects that showed a decrease in MMP activity (prosacea treatment. PMID:24844861

  11. A randomized trial of chest irradiation alone versus chest irradiation plus Lentinan in squamous cell lung cancer in limited stage

    International Nuclear Information System (INIS)

    Kimura, Ikuro; Ohnoshi, Taisuke; Konno, Kiyoshi

    1993-01-01

    In an attempt to evaluate the effect of Lentinan, polysaccharides from Lentinusedodes, in combination with chest irradiation for limited-stage squamous cell lung cancer, we conducted a randomized trial between January 1987 and July 1989. Patients were randomly allocated to receive either a definitive chest irradiation of 60 Gy alone (RT) or the chest irradiation plus Lentinan (RT+L). Patients allocated to the RT+L group received iv infusion of Lentinan, 1 mg twice a week or 2 mg once a week, as long as possible. Of 201 patients enrolled, 183 (94 for RT, and 89 for RT+L) were eligible for analysis of survival time, and 169 (86 for RT, and 83 for RT+L) were evaluated for tumor response, survival time and quality of life. The response rate to the treatments showed a trend favoring the RT+L group (65% vs. 51%, p=0.142). The median survival time was 455 days for the RT+L group and 371 days for the RT group. The difference was not statistically significant. In the subset of patients with cancer of hilar origin, however, RT+L group patients lived significantly longer than RT group patients: Progression-free interval from symptoms and quality of life were evaluated for the both groups based on manual records of an individual patient. RT+L group patients had a significantly longer progression-free interval from dyspneic feeling than the RT group patients. The RT+L group tended to have a feeling of well-being. We conclude that Lentinan in combination with chest irradiation is useful for patients with limited-stage squamous cell lung cancer in terms of prolongation of life and maintenance of a favorable quality of life as well. (author)

  12. Adaptive interference-aware multichannel assignment for shared overloaded small-cell access points under limited feedback

    KAUST Repository

    Radaydeh, Redha Mahmoud

    2014-02-01

    This paper proposes a reduced-complexity multichannel assignment scheme for short-range cellular systems. It treats the scenario when a number of small-cell (e.g., femtocell) access points (APs) can be shared to serve active scheduled users. The APs employ isotropic antenna arrays and operate using an open-access control strategy. To improve the reuse ratio of physical resources, the APs are assumed to occupy a single physical channel, wherein coordination among them is infeasible. On the other hand, to improve the spatial coverage, a scheduled user can be served by a single transmit channel from an AP at a time. For the case of overloaded APs and when the feedback links are capacity limited, the scheme attempts to identify the suitable transmit channels from the deployed APs in an adaptive manner such that certain performance and/or processing load limits are satisfied. The effects of some system and design parameters on the outcomes of the scheme are thoroughly discussed. Novel results for the statistics of the resulting interference power are presented, from which results for some performance measures and processing loads are obtained. Numerical and simulations results are provided to clarify the achieved gains, as compared with related models under different operating conditions. © 2013 IEEE.

  13. Evaluation of cognitive function in patients with limited small cell lung cancer prior to and shortly following prophylactic cranial irradiation

    International Nuclear Information System (INIS)

    Komaki, Ritsuko; Meyers, Christina A.; Shin, Dong M.; Garden, Adam S.; Byrne, Kevin; Nickens, Judy A.; Cox, James D.

    1995-01-01

    Purpose: Cognitive deficits after treatment for small cell lung cancer (SCLC) have been attributed to prophylactic cranial irradiation (PCI). A prospective study of neuropsychological function was undertaken to document the evolution and magnitude of neuropsychologic deficits. Methods and Materials: Thirty patients with limited stage SCLC who responded well (29 complete response (CR), 1 partial response (PR)) to combination chemotherapy plus thoracic irradiation or resection were studied with neuropsychological tests in the cognitive domains of intelligence, frontal lobe function, language, memory, visual-perception, and motor dexterity prior to a planned course of PCI. Nine patients had a neurologic history that could influence testing. Results: An unexpected 97% (29 out of 30) of patients had evidence of cognitive dysfunction prior to PCI. The most frequent impairment was verbal memory, followed by frontal lobe dysfunction, and fine motor incoordination. Of the patients with no prior neurologic or substance abuse history, 20 out of 21 (95%) had impairments on neuropsychological assessment. This neurologically normal group was just as impaired as the group with such a history with respect to delayed verbal memory and frontal lobe executive function. Eleven patients had neuropsychological testing 6 to 20 months after PCI; no significant differences were found from their pretreatment tests. Conclusions: A high proportion of neurologically normal patients with limited SCLC and favorable responses to combination chemotherapy have specific cognitive deficits before receiving PCI. Short-term (6 to 20 months) observations after PCI have shown no significant deterioration

  14. Assaying embryotoxicity in the test tube: current limitations of the embryonic stem cell test (EST) challenging its applicability domain.

    Science.gov (United States)

    Riebeling, Christian; Hayess, Katrin; Peters, Annelieke K; Steemans, Margino; Spielmann, Horst; Luch, Andreas; Seiler, Andrea E M

    2012-05-01

    Testing for embryotoxicity in vitro is an attractive alternative to animal experimentation. The embryonic stem cell test (EST) is such a method, and it has been formally validated by the European Centre for the Validation of Alternative Methods. A number of recent studies have underscored the potential of this method. However, the EST performed well below the 78% accuracy expected from the validation study using a new set of chemicals and pharmaceutical compounds, and also of toxicity criteria, tested to enlarge the database of the validated EST as part of the Work Package III of the ReProTect Project funded within the 6th Framework Programme of the European Union. To assess the performance and applicability domain of the EST we present a detailed review of the substances and their effects in the EST being nitrofen, ochratoxin A, D-penicillamine, methylazoxymethanol, lovastatin, papaverine, warfarin, β-aminopropionitrile, dinoseb, furosemide, doxylamine, pravastatin, and metoclopramide. By delineation of the molecular mechanisms of the substances we identify six categories of reasons for misclassifications. Some of these limitations might also affect other in vitro methods assessing embryotoxicity. Substances that fall into these categories need to be included in future validation sets and in validation guidelines for embryotoxicity testing. Most importantly, we suggest conceivable improvements and additions to the EST which will resolve most of the limitations.

  15. Correlations Between the Density of Tryptase Positive Mast Cells (DMCT and that of New Blood Vessels (CD105+ in Patients with Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Micu Gianina Viorica

    2016-06-01

    Full Text Available Mast cells proteases, tryptase and chymase are directly involved in the growth and progression of solid tumors due to their important role in tumor angiogenesis. We examined the density of tryptase positive mast cells and the mean density of new blood vessels in gastric malignant tumors of patients with and without Helicobacter pylori infection, using immunohistochemical staining for tryptase (for mast cells and CD 105 (for new vessels. Tryptase and CD 105 expression was detected in gastrectomy specimens. In this study, mast cell density correlates with angiogenesis and the growth and progression of gastric cancer. It also shows that the participation of Helicobacter pylori infection in the growth and progress of gastric neoplasia is due to an increase of peritumoral angiogenesis, with subsequent local and distant tumor spread and perivascular growth, but without perineural and nodal involvement.

  16. A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres.

    Directory of Open Access Journals (Sweden)

    Ignacio Flores

    Full Text Available Telomere maintenance is essential to ensure proper size and function of organs with a high turnover. In particular, a dwarf phenotype as well as phenotypes associated to premature loss of tissue regeneration, including the skin (hair loss, hair graying, decreased wound healing, are found in mice deficient for telomerase, the enzyme responsible for maintaining telomere length. Coincidental with the appearance of these phenotypes, p53 is found activated in several tissues from these mice, where is thought to trigger cellular senescence and/or apoptotic responses. Here, we show that p53 abrogation rescues both the small size phenotype and restitutes the functionality of epidermal stem cells (ESC of telomerase-deficient mice with dysfunctional telomeres. In particular, p53 ablation restores hair growth, skin renewal and wound healing responses upon mitogenic induction, as well as rescues ESCmobilization defects in vivo and defective ESC clonogenic activity in vitro. This recovery of ESC functions is accompanied by a downregulation of senescence markers and an increased proliferation in the skin and kidney of telomerase-deficient mice with critically short telomeres without changes in apoptosis rates. Together, these findings indicate the existence of a p53-dependent senescence response acting on stem/progenitor cells with dysfunctional telomeres that is actively limiting their contribution to tissue regeneration, thereby impinging on tissue fitness.

  17. Weight Loss and Decrease of Body Mass Index during Allogeneic Stem Cell Transplantation Are Common Events with Limited Clinical Impact.

    Directory of Open Access Journals (Sweden)

    Christina T Rieger

    Full Text Available Weight loss in cancer patients has been attributed with significant morbidity and mortality. During allogeneic stem cell transplantation (SCT, oral nutrition is often hampered and hence total parenteral nutrition (TPN is necessary. We therefore investigated the course of weight during stem cell transplantation and the clinical consequences of weight change.180 consecutive patients who received allogeneic SCT between January 2010 and December 2011 at our center were analyzed for weight loss, laboratory and clinical parameters.During SCT, a median decrease of 6.6% of body mass index (BMI was observed for the whole population (from 25.3 at admission to 23.6 at discharge, and a 1.6fold increase of malnutrition despite use of TPN (28.3% to 45.0%. 55.6% of patients experienced a significant weight loss of ≥5% with a median decrease of 9.2% in BMI. Serum levels of albumin, total protein and cholesterol rapidly decreased during conditioning therapy. After a median of 2.4 years, the median BMI was still only 23.4 (not different from discharge. However, we did not observe a meaningful difference in side effects and survival between patients that did or did not lose weight.Weight loss is commonly observed during allogeneic SCT despite TPN, but the clinical consequences thereof seem limited: we observed no significant impact on patients with a decrease ≥ 5% in BMI on transplant outcome, side effects or survival.

  18. From Au to Pt via surface limited redox replacement of Pb UPD in one-cell configuration.

    Science.gov (United States)

    Fayette, M; Liu, Y; Bertrand, D; Nutariya, J; Vasiljevic, N; Dimitrov, N

    2011-05-03

    This work is aimed at developing a protocol based on surface limited redox replacement (SLRR) of underpotentially deposited (UPD) Pb layers for the growth of epitaxial and continuous Pt thin films on polycrystalline and single crystalline Au surfaces. Different from previously reported papers using SLRR in multiple immersion or flow cell setups, this work explores the one-cell configuration setup as an alternative to improve the efficiency and quality of the growth. Open circuit chronopotentiometry and quartz-crystal microbalance experiments demonstrate steady displacement kinetics and a yield that is higher than the stoichiometric Pt(II)-Pb exchange ratio (1:1). This high yield is attributed to oxidative adsorption of OH(ad) taking place on Pt along with the displacement process. Also, ex situ scanning tunneling microscopy surface characterization reveals after the first replacement event the formation of a dense Pt cluster network that homogenously covers the Au surface. The Pt films grow homogenously with no significant changes in the cluster distribution and surface roughness observed up to 10 successive replacement events. X-ray diffraction analysis shows distinct (111) crystallographic orientation of thicker Pt films deposited on (111) textured Au thin films. Coarse energy dispersive spectroscopy measurements and finer X-ray photoelectron spectroscopy suggest at least 4 atom % Pb incorporating into the Pt layer compared to 13 atom % alloyed Cu when the growth is carried out by SLRR of Cu UPD.

  19. Dealing with initial chemotherapy doses: a new basis for treatment optimization in limited small-cell lung cancer

    International Nuclear Information System (INIS)

    Le Chevalier, T.; Le Cesne, A.; Arriagada, R.

    1995-01-01

    Treatment of patients with small-cell lung cancer (SCLC) remains disappointing despite high initial complete response rates. The dramatic initial chemosensitivity of tumor cells is frustrated by the early emergence of chemoresistant clonogenic cells, regardless of front line treatments. Although the dose relationship is fairly well established regarding the response rate, its effect on survival is inconclusive. From 1980 to 1988, 202 patients with limited SCLC were included in four consecutive protocols using an alternating schedule of thoracic radiotherapy and chemotherapy. Despite an increase of chemotherapy and/or total radiation doses, no significant difference was observed between the four protocols in terms of response rate, disease free and overall survival. However, a retrospective analysis performed on a total of 131 consecutive patients led us to propose the hypothesis that a moderate increase in the initial dose, ie first course, of cisplatin and cyclophosphamide could improve overall survival. From 1988 to 1991, 105 patients were subsequently included in a large randomized trial raising this question. The treatment difference only concerned the initial doses of cisplatin (80 vs 100 mg/m 2 ) and cyclophosphamide (900 vs 1200 mg/m 2 ). The trial was closed after inclusion of 105 patients, 32 months after the start of the study because at that time overall survival was significantly better in the higher-dose group (p = 0.001). The emergence of this debatable concept opens new directions in the therapeutic strategy of SCLC and the contribution of hematopoietic growth factors may be a great interest in the management of this disease. (authors). 27 refs., 1 tab

  20. Disease-specific survival for limited-stage small-cell lung cancer affected by statistical method of assessment

    Directory of Open Access Journals (Sweden)

    Yuan Fei

    2007-02-01

    Full Text Available Abstract Background In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model, or log-normal survival analysis. Methods Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS. DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors. Results The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0–2% at 1 year, 0–12% at 3 years, and 0–1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10–12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1–6% at 1 year, 15–26% at 3 years, and 0–12% at 5 years; multivariate 95% confidence limits were overlapping in all instances. Conclusion Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the

  1. The extracellular membrane-proximal domain of membrane-bound IgE restricts B cell activation by limiting B cell antigen receptor surface expression.

    Science.gov (United States)

    Vanshylla, Kanika; Opazo, Felipe; Gronke, Konrad; Wienands, Jürgen; Engels, Niklas

    2018-03-01

    Immunoglobulin E (IgE) antibodies are key mediators of allergic reactions. Due to their potentially harmful anaphylactic properties, their production is tightly regulated. The membrane-bound isoform of IgE (mIgE), which is an integral component of the B cell antigen receptor, has been shown to be critical for the regulation of IgE responses in mice. In primate species including humans, mIgE can be expressed in two isoforms that are produced by alternative splicing of the primary ε Ig heavy chain transcript, and differ in the absence or presence of an extracellular membrane-proximal domain (EMPD) consisting of 52 amino acids. However, the function of the EMPD remains unclear. Here, we demonstrate that the EMPD restricts surface expression of mIgE-containing BCRs in human and murine B cells. The EMPD does not interfere with BCR assembly but acts as an autonomous endoplasmic reticulum retention domain. Limited surface expression of EMPD-containing mIgE-BCRs caused impaired activation of intracellular signaling cascades and hence represents a regulatory mechanism that may control the production of potentially anaphylactic IgE antibodies in primate species. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Increased expressions of NKp44, NKp46 on NK/NKT-like cells are associated with impaired cytolytic function in self-limiting hepatitis E infection.

    Science.gov (United States)

    Das, Rumki; Tripathy, Anuradha

    2014-10-01

    We have characterized the NK/NKT-like cells in patients with self-limiting hepatitis E infection. The distribution of peripheral NK/NKT-like cells, expressions of activation receptors, cytotoxic potential and effector function of NK/NKT-like cells from fresh peripheral blood mononuclear cells of 86 acute patients, 101 recovered and 54 control individuals were assessed. Activated NKT-like (CD16(+) CD56(+) CD3(+)) cells were high in the patient groups. On CD56(+) CD3(-) cells, NKp44 and NKp46 expressions were high in the acute patients, whereas NKp30, NKp44, NKp46 and NKG2D were high in the recovered individuals. On CD56(+) CD3(+) cells, NKp44, NKp46 and NKG2D expressions were high in the recovered but NKp30 was low in both the patient groups. Collectively, the current study elucidates the role of NK/NKT-like cells demonstrating phenotypic alterations of activated NKT-like cells and activation receptors, lack of CD107a expression and functional impairment of peripheral NK/NKT-like cells in self-limiting hepatitis E infection.

  3. Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.

    Science.gov (United States)

    Liu, T; Kishton, R J; Macintyre, A N; Gerriets, V A; Xiang, H; Liu, X; Abel, E D; Rizzieri, D; Locasale, J W; Rathmell, J C

    2014-10-16

    The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting

  4. The effect of X-rays on the precursors of antibody forming cells (B cells) as measured with the in vitro limiting dilution assay

    NARCIS (Netherlands)

    Lubbe, F.H.; Hooijkaas, H.; Preesman, A.A.

    1982-01-01

    The effect of X-irradiation upon murine antibody-forming cell precursors (B cells) was established in cultures of spleen cells stimulated with the B cell mitogen lipopolysaccharide (LPS). At day 5 and 7 the numbers of IgM- and IgG2-secreting cells were determined in cultures of irradiated and

  5. Triage of Limited Versus Extensive Disease on 18F-FDG PET/CT Scan in Small Cell lung Cancer

    Directory of Open Access Journals (Sweden)

    Saima Riaz

    2017-06-01

    Full Text Available Objective(s: Small cell lung cancer (SCLC is an aggressive neuroendocrine carcinoma, which accounts for 10-15% of pulmonary cancers and exhibits early metastatic spread. This study aimed to determine the added value of 18F-FDG PET/CT imaging in tumor, node, and metastasis (TNM staging of SCLC, compared to the conventional computed tomography (CT scan and its potential role as a prognosticator.Methods: This retrospective review was conducted on 23 patients, who were histopathologically diagnosed to have SCLC and referred for undergoing 18F-FDG PET/CT scanning during October 2009-December 2015. The rate of agreement between the CT and 18F-FDG PET/CT findings for TNM staging was calculated using the Cohen’s kappa (κ. The median follow-up time was eight months, ranging 27-3 months. The overall and disease-free survival rates were calculated based on the extent of disease.Results: 19 cases were male and four female with the mean age of 58±9 years. The 18F-FDG PET/CT identified limited and extensive diseases in 2 (8.7% and 21 (91.3% patients, respectively. In addition, the results of the Cohen’s kappa demonstrated a strong (κ=0.82, fair (κ=0.24, and poor (κ=0.12 agreement between the PET/CT and CT findings for determining tumor, node, and metastasis stages, respectively. The 18F-FDG PET/CT scans upstaged disease in 47% of the cases with visceral and osseous metastasis. The disease-free survival rates for the limited and extensive diseases were 100% and 23% within the 12-month follow-up. In addition, 8 (35% patients expired during the follow-up period.Conclusion: Improved nodal and metastatic disease identification highlights the role of 18F-FDG PET/CT scanning in initial staging of SCLC with prognostic implications.

  6. Role of prophylactic brain irradiation in limited stage small cell lung cancer: clinical, neuropsychologic, and CT sequelae

    International Nuclear Information System (INIS)

    Laukkanen, E.; Klonoff, H.; Allan, B.; Graeb, D.; Murray, N.

    1988-01-01

    Ninety-four patients with limited stage small cell lung cancer treated between 1981 and 1985 with a regimen including prophylactic brain irradiation (PBI) after combination chemotherapy were assessed for compliance with PBI, brain relapse, and neurologic morbidity. Seventy-seven percent of patients had PBI and of these, 22% developed brain metastases after a median time of 11 months post treatment. The brain was the apparent unique initial site of relapse in 10% of PBI cases but more commonly brain relapse was preceded or accompanied by failure at other sites, especially the chest. Brain metastases were the greatest cause of morbidity in 50% of PBI failures. Twelve of 14 PBI patients alive 2 years after treatment had oncologic, neurologic, and neuropsychological evaluation, and brain CT. All long-term survivors were capable of self care and none fulfilled diagnostic criteria for dementia, with three borderline cases. One third had pretreatment neurologic dysfunction and two thirds post treatment neurologic symptoms, most commonly recent memory loss. Fifty percent had subtle motor findings. Intellectual functioning was at the 38th percentile with most patients having an unskilled occupational history. Neuropsychologic impairment ratings were borderline in three cases and definitely impaired in seven cases. CT scans showed brain atrophy in all cases with mild progression in those having a pre-treatment baseline. Periventricular and subcortical low density lesions identical to the CT appearance of subcortical arteriosclerotic encephalopathy were seen in 82% of posttreatment CT studies, and lacunar infarcts in 54%. Neuropsychologic impairment scores and the extent of CT periventricular low density lesions were strongly associated

  7. Prognostic role of patient gender in limited-disease small-cell lung cancer treated with chemoradiotherapy

    International Nuclear Information System (INIS)

    Roengvoraphoj, Olarn; Eze, Chukwuka; Niyazi, Maximilian; Li, Minglun; Belka, Claus; Manapov, Farkhad; Hildebrandt, Guido; Fietkau, Rainer

    2017-01-01

    Previous studies have demonstrated that female gender could be a prognostic factor in limited-disease (LD) small-cell lung cancer (SCLC), but the correlation between patient gender and survival parameters remains unclear. Data from 179 LD SCLC patients treated with definitive chemoradiotherapy (CRT) were reviewed. Influence of patient gender on time to progression (TTP), local control (LC), brain metastasis-free (BMFS), distant metastasis-free (DMFS) and overall survival (OS) was analysed. Definitive CRT was completed by 179 (110 men/69 women) patients. Of these, 68 (38%; 34 men/34 women) patients were treated in concurrent and 111 (62%; 76 men/35 women) in sequential mode. Prophylactic cranial irradiation (PCI) was subsequently applied in 70 (39%; 36 men/34 women) patients with partial or complete response after CRT. Median OS was 20 (95% confidence interval [CI] 10-22) and 14 (95% CI 10-18) months in female and male patients, respectively (p = 0.021). In subgroups defined by remission status (complete and partial response) after CRT, an OS benefit for females compared to males was also detected. There was no correlation between patient gender and TTP, LC or DMFS, and no difference in OS in the female and male subgroups treated with PCI. The incidence of metachronous brain metastases (BMs) in the male and female subgroups differed significantly (40/110 men vs. 18/69 women, p = 0.03). Also, mean BMFS was significantly longer in women (p = 0.023). Patient gender also significantly correlated with OS on multivariate analysis after adjustment for other prognostic factors (p = 0.04, HR 1.38, 95% CI 1.08-1.92). In this heterogeneous LD SCLC patient cohort treated with definitive CRT, female gender was significantly associated with longer BMFS and OS, as well as with a lower incidence of metachronous brain failure. (orig.) [de

  8. A rapid method for the differentiation of yeast cells grown under carbon and nitrogen-limited conditions by means of partial least squares discriminant analysis employing infrared micro-spectroscopic data of entire yeast cells

    OpenAIRE

    Kuligowski, Julia; Quintás, Guillermo; Herwig, Christoph; Lendl, Bernhard

    2012-01-01

    This paper shows the ease of application and usefulness of mid-IR measurements for the investigation of orthogonal cell states on the example of the analysis of Pichia pastoris cells. A rapid method for the discrimination of entire yeast cells grown under carbon and nitrogen-limited conditions based on the direct acquisition of mid-IR spectra and partial least squares discriminant analysis (PLS-DA) is described. The obtained PLS-DA model was extensively validated employing two different valid...

  9. Prognostic role of patient gender in limited-disease small-cell lung cancer treated with chemoradiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Roengvoraphoj, Olarn; Eze, Chukwuka; Niyazi, Maximilian; Li, Minglun; Belka, Claus; Manapov, Farkhad [LMU Munich, Department of Radiation Oncology, Munich (Germany); Hildebrandt, Guido [University of Rostock, Department of Radiation Oncology, Rostock (Germany); Fietkau, Rainer [University Hospital Erlangen, Department of Radiation Oncology, Erlangen (Germany)

    2017-02-15

    Previous studies have demonstrated that female gender could be a prognostic factor in limited-disease (LD) small-cell lung cancer (SCLC), but the correlation between patient gender and survival parameters remains unclear. Data from 179 LD SCLC patients treated with definitive chemoradiotherapy (CRT) were reviewed. Influence of patient gender on time to progression (TTP), local control (LC), brain metastasis-free (BMFS), distant metastasis-free (DMFS) and overall survival (OS) was analysed. Definitive CRT was completed by 179 (110 men/69 women) patients. Of these, 68 (38%; 34 men/34 women) patients were treated in concurrent and 111 (62%; 76 men/35 women) in sequential mode. Prophylactic cranial irradiation (PCI) was subsequently applied in 70 (39%; 36 men/34 women) patients with partial or complete response after CRT. Median OS was 20 (95% confidence interval [CI] 10-22) and 14 (95% CI 10-18) months in female and male patients, respectively (p = 0.021). In subgroups defined by remission status (complete and partial response) after CRT, an OS benefit for females compared to males was also detected. There was no correlation between patient gender and TTP, LC or DMFS, and no difference in OS in the female and male subgroups treated with PCI. The incidence of metachronous brain metastases (BMs) in the male and female subgroups differed significantly (40/110 men vs. 18/69 women, p = 0.03). Also, mean BMFS was significantly longer in women (p = 0.023). Patient gender also significantly correlated with OS on multivariate analysis after adjustment for other prognostic factors (p = 0.04, HR 1.38, 95% CI 1.08-1.92). In this heterogeneous LD SCLC patient cohort treated with definitive CRT, female gender was significantly associated with longer BMFS and OS, as well as with a lower incidence of metachronous brain failure. (orig.) [German] Studien haben gezeigt, dass weibliches Geschlecht ein prognostischer Faktor beim kleinzelligen Lungenkarzinom (SCLC) im Stadium ''limited

  10. Detector cell based on plastic liquid-core waveguides suitable for aqueous solutions: one-to-two decades improved detection limits in

    NARCIS (Netherlands)

    Gooijer, C.; de Beer, T.; Bader, A.N.; van Iperen, D.J.; Brinkman, U.A.T.; Hoornweg, G.Ph.

    1998-01-01

    A new type of detector cell is presented, which is designed to improve concentration detection limits in conventional-size reversed-phase column liquid chromatography (LC) with ultraviolet (UV)-visible absorption detection. It is based on a recently developed plastic liquid-core waveguide (LCW),

  11. Optimal labeling dose, labeling time, and magnetic resonance imaging detection limits of ultrasmall superparamagnetic iron-oxide nanoparticle labeled mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Mathiasen, Anders Bruun; Hansen, Louise; Friis, Tina

    2013-01-01

    Background. Regenerative therapy is an emerging treatment modality. To determine migration and retention of implanted cells, it is crucial to develop noninvasive tracking methods. The aim was to determine ex vivo magnetic resonance imaging (MRI) detection limits of ultrasmall superparamagnetic iron...

  12. Glucose oxidase as a biocatalytic enzyme-based bio-fuel cell using Nafion membrane limiting crossover

    International Nuclear Information System (INIS)

    Naidoo, S; Blottnitz, H; Naidoo, Q; Vaivars, G

    2013-01-01

    A novel combination for an Enzyme-based Biofuel cell included a Nafion membrane as an ion transporter that maintained a working cell charge and inhibited membrane degradation. The prototype cell chamber used oxygen (O 2 ) in the cathode cell and glucose in the anode. The Nafion membrane stability studied here was evidently in the region of 0% loss of conductivity as the charge was constant and increased after the addition of glucose. The prototype cell chamber used NaCl in the cathode cell and glucose oxidase (GOx) in the anodic chamber was successfully studied for membrane stability showed in this study no evidence of poisoning from membrane leakage in a controlled pH environment. There was no crossover at the anaerobic operating ambient temperatures and under physiological pH 5 – 7 conditions. In this research we have successfully used a Nafion membrane together with GOx and under controlled conditions produced respectable power densities

  13. Stable T-bet+GATA-3+ Th1/Th2 Hybrid Cells Arise In Vivo, Can Develop Directly from Naive Precursors, and Limit Immunopathologic Inflammation

    Science.gov (United States)

    Peine, Michael; Fröhlich, Anja; Hegazy, Ahmed N.; Kühl, Anja A.; Grevelding, Christoph G.; Höfer, Thomas; Hartmann, Susanne; Löhning, Max

    2013-01-01

    Differentiated T helper (Th) cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN)-γ and interleukin (IL)-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet+GATA-3+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation. PMID:23976880

  14. Stable T-bet(+GATA-3(+ Th1/Th2 hybrid cells arise in vivo, can develop directly from naive precursors, and limit immunopathologic inflammation.

    Directory of Open Access Journals (Sweden)

    Michael Peine

    Full Text Available Differentiated T helper (Th cell lineages are thought to emerge from alternative cell fate decisions. However, recent studies indicated that differentiated Th cells can adopt mixed phenotypes during secondary immunological challenges. Here we show that natural primary immune responses against parasites generate bifunctional Th1 and Th2 hybrid cells that co-express the lineage-specifying transcription factors T-bet and GATA-3 and co-produce Th1 and Th2 cytokines. The integration of Th1-promoting interferon (IFN-γ and interleukin (IL-12 signals together with Th2-favoring IL-4 signals commits naive Th cells directly and homogeneously to the hybrid Th1/2 phenotype. Specifically, IFN-γ signals are essential for T-bet(+GATA-3(+ cells to develop in vitro and in vivo by breaking the dominance of IL-4 over IL-12 signals. The hybrid Th1/2 phenotype is stably maintained in memory cells in vivo for months. It resists reprogramming into classic Th1 or Th2 cells by Th1- or Th2-promoting stimuli, which rather induce quantitative modulations of the combined Th1 and Th2 programs without abolishing either. The hybrid phenotype is associated with intermediate manifestations of both Th1 and Th2 cell properties. Consistently, hybrid Th1/2 cells support inflammatory type-1 and type-2 immune responses but cause less immunopathology than Th1 and Th2 cells, respectively. Thus, we propose the self-limitation of effector T cells based on the stable cell-intrinsic balance of two opposing differentiation programs as a novel concept of how the immune system can prevent excessive inflammation.

  15. A meta-analysis of the Timing of Chest Radiotherapy in Patients with Limited-stage Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hui ZHAO

    2010-09-01

    Full Text Available Background and objective Although evidence for a significant survival benefit of chest radiotherapy has been proven, no conclusion could be drawn regarding the optimal timing of chest radiation. The aim of this study is to explore whether the timing of chest radiation may influence the survival of the patients with limited-stage small-cell lung cancer (LSSCLC by performing a literature-based meta-analysis. Methods By searching Medline, CENTRAL (the Cochrane central register of controlled trials, CBM, and CNKI, et al, we collected both domestic and overseas published documents about randomized trials comparing different timing chest radiotherapy in patients with LS-SCLC. Early chest radiation was regarded as beginning within 30 days after the start of chemotherapy. Random or fixed effect models were applied to conduct meta-analysis on the trials. The combined odds ratio (OR and the 95% confidence interval (CI were calculated to estimate the mortality in 2 or 3 years and toxicity of the two treatments. The statistical heterogeneity was determined by cochran’s Chi-square test (Q test. The Begg’ test was used to determine the publication bias. Results Six trials that included a total of 1 189 patients were analyzed in the meta-analysis 587 patients were in the early radiation group and 602 patients were in the late radiation group. Considering all 6 eligible trials, the overall survival at 2/3 years was not significantly different between early and late chest radiation (OR=0.78, 95%CI: 0.55-1.05, Z=1.68, P=0.093. For the toxicity, no obvious difference was observed for early chest radiotherapy compared with late irradiation in pneumonitis (OR=1.93, 95%CI: 0.97-3.86, P=0.797, esophagitis (OR=1.43, 95%CI: 0.95-2.13, P=0.572 and thrombocytopenia (OR=1.23, 95%CI: 0.88-1.77, P=0.746, respectively. Conclusion No statistical difference was observed in 2/3 years survival and toxicity, including pneumonitis, esophagitis and thrombocytopenia, between

  16. A Prospective Randomized Study of the Radiotherapy Volume for Limited-stage Small Cell Lung Cancer: A Preliminary Report

    Directory of Open Access Journals (Sweden)

    Xiao HU

    2010-07-01

    Full Text Available Background and objective Controversies exists with regard to target volumes as far as thoracic radiotherapy (TRT is concerned in the multimodality treatment for limited-stage small cell lung cancer (LSCLC. The aim of this study is to prospectively compare the local control rate, toxicity profiles, and overall survival (OS between patients received different target volumes irradiation after induction chemotherapy. Methods LSCLC patients received 2 cycles of etoposide and cisplatin (EP induction chemotherapy and were randomly assigned to receive TRT to either the post- or pre-chemotherapy tumor extent (GTV-T as study arm and control arm, CTV-N included the positive nodal drainage area for both arms. One to 2 weeks after induction chemotherapy, 45 Gy/30 Fx/19 d TRT was administered concurrently with the third cycle of EP regimen. After that, additional 3 cycles of EP consolidation were administered. Prophylactic cranial irradiation (PCI was administered to patients with a complete response. Results Thirty-seven and 40 patients were randomly assigned to study arm and control arm. The local recurrence rates were 32.4% and 28.2% respectively (P=0.80; the isolated nodal failure (INF rate were 3.0% and 2.6% respectively (P=0.91; all INF sites were in the ipsilateral supraclavicular fossa. Medastinal N3 disease was the risk factor for INF (P=0.02, OR=14.13, 95%CI: 1.47-136.13. During radiotherapy, grade I, II weight loss was observed in 29.4%, 5.9% and 56.4%, 7.7% patients respectively (P=0.04. Grade 0-I and II-III late pulmonary injury was developed in 97.1%, 2.9% and 86.4%, 15.4% patients respectively (P=0.07. Median survival time was 22.1 months and 26.9 months respectively. The 1 to 3-year OS were 77.9%, 44.4%, 37.3% and 75.8%, 56.3%, 41.7% respectively (P=0.79. Conclusion The preliminary results of this study indicate that irradiant the post-chemotherapy tumor extent (GTV-T and positive nodal drainage area did not decrease local control and overall

  17. Nephron progenitor cell death elicits a limited compensatory response associated with interstitial expansion in the neonatal kidney

    Directory of Open Access Journals (Sweden)

    Sree Deepthi Muthukrishnan

    2018-01-01

    Full Text Available The final nephron number in an adult kidney is regulated by nephron progenitor cell availability and collecting duct branching in the fetal period. Fetal environmental perturbations that cause reductions in cell numbers in these two compartments result in low nephron endowment. Previous work has shown that maternal dietary factors influence nephron progenitor cell availability, with both caloric restriction and protein deprivation leading to reduced cell numbers through apoptosis. In this study, we evaluate the consequences of inducing nephron progenitor cell death on progenitor niche dynamics and on nephron endowment. Depletion of approximately 40% of nephron progenitor cells by expression of diphtheria toxin A at embryonic day 15 in the mouse results in 10-20% nephron reduction in the neonatal period. Analysis of cell numbers within the progenitor cell pool following induction of apoptosis reveals a compensatory response in which surviving progenitor cells increase their proliferation and replenish the niche. The proliferative response is temporally associated with infiltration of macrophages into the nephrogenic zone. Colony stimulating factor 1 (CSF1 has a mitogenic effect on nephron progenitor cells, providing a potential explanation for the compensatory proliferation. However, CSF1 also promotes interstitial cell proliferation, and the compensatory response is associated with interstitial expansion in recovering kidneys which can be pharmacologically inhibited by treatment with clodronate liposomes. Our findings suggest that the fetal kidney employs a macrophage-dependent compensatory regenerative mechanism to respond to acute injury caused by death of nephron progenitor cells, but that this regenerative response is associated with neonatal interstitial expansion.

  18. Endogenous neural stem cells in central canal of adult rats acquired limited ability to differentiate into neurons following mild spinal cord injury

    Science.gov (United States)

    Liu, Yuan; Tan, Botao; Wang, Li; Long, Zaiyun; Li, Yingyu; Liao, Weihong; Wu, Yamin

    2015-01-01

    Endogenous neural stem cells in central canal of adult mammalian spinal cord exhibit stem cell properties following injury. In the present study, the endogenous neural stem cells were labeled with Dil to track the differentiation of cells after mild spinal cord injury (SCI). Compared with 1 and 14 days post mild injury, the number of endogenous neural stem cells significantly increased at the injured site of spinal cord on 3 and 7 days post-injury. Dil-labeled βIII-tublin and GFAP expressing cells could be detected on 7 days post-injury, which indicated that the endogenous neural stem cells in central canal of spinal cord differentiated into different type of neural cells, but there were more differentiated astrocytes than the neurons after injury. Furthermore, after injury the expression of inhibitory Notch1 and Hes1 mRNA began to increase at 6 hours and was evident at 12 and 24 hours, which maintained high levels up to 7 days post-injury. These results indicated that a mild SCI in rat is sufficient to induce endogenous neural stem cells proliferation and differentiation. However, the ability to differentiate into neurons is limited, which may be, at least in part, due to high expression of inhibitory Notch1 and Hes1 genes after injury. PMID:26097566

  19. A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability

    Science.gov (United States)

    Ball, David A.

    2016-01-01

    The cell division cycle of eukaryotes is governed by a complex network of cyclin-dependent protein kinases (CDKs) and auxiliary proteins that govern CDK activities. The control system must function reliably in the context of molecular noise that is inevitable in tiny yeast cells, because mistakes in sequencing cell cycle events are detrimental or fatal to the cell or its progeny. To assess the effects of noise on cell cycle progression requires not only extensive, quantitative, experimental measurements of cellular heterogeneity but also comprehensive, accurate, mathematical models of stochastic fluctuations in the CDK control system. In this paper we provide a stochastic model of the budding yeast cell cycle that accurately accounts for the variable phenotypes of wild-type cells and more than 20 mutant yeast strains simulated in different growth conditions. We specifically tested the role of feedback regulations mediated by G1- and SG2M-phase cyclins to minimize the noise in cell cycle progression. Details of the model are informed and tested by quantitative measurements (by fluorescence in situ hybridization) of the joint distributions of mRNA populations in yeast cells. We use the model to predict the phenotypes of ~30 mutant yeast strains that have not yet been characterized experimentally. PMID:27935947

  20. B cell-derived transforming growth factor-β1 expression limits the induction phase of autoimmune neuroinflammation.

    Science.gov (United States)

    Bjarnadóttir, Kristbjörg; Benkhoucha, Mahdia; Merkler, Doron; Weber, Martin S; Payne, Natalie L; Bernard, Claude C A; Molnarfi, Nicolas; Lalive, Patrice H

    2016-10-06

    Studies in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), have shown that regulatory B cells modulate the course of the disease via the production of suppressive cytokines. While data indicate a role for transforming growth factor (TGF)-β1 expression in regulatory B cell functions, this mechanism has not yet been tested in autoimmune neuroinflammation. Transgenic mice deficient for TGF-β1 expression in B cells (B-TGF-β1 -/- ) were tested in EAE induced by recombinant mouse myelin oligodendrocyte glycoprotein (rmMOG). In this model, B-TGF-β1 -/- mice showed an earlier onset of neurologic impairment compared to their littermate controls. Exacerbated EAE susceptibility in B-TGF-β1 -/- mice was associated with augmented CNS T helper (Th)1/17 responses. Moreover, selective B cell TGF-β1-deficiency increased the frequencies and activation of myeloid dendritic cells, potent professional antigen-presenting cells (APCs), suggesting that B cell-derived TGF-β1 can constrain Th1/17 responses through inhibition of APC activity. Collectively our data suggest that B cells can down-regulate the function of APCs, and in turn encephalitogenic Th1/17 responses, via TGF-β1, findings that may be relevant to B cell-targeted therapies.

  1. SF Treg cells transcribing high levels of Bcl-2 and microRNA-21 demonstrate limited apoptosis in RA

    NARCIS (Netherlands)

    van der Geest, Kornelis S. M.; Smigielska, Katarzyna; Park, Ji-Ah; Abdulahad, Wayel H.; Kim, Hye-Won; Kroesen, Bart-Jan; van den Berg, Anke; Boots, Annemieke M. H.; Lee, Eun-Bong; Brouwer, Elisabeth

    Objective. The aim of this study was to investigate the turnover of Treg cells in the SF of RA patients. Methods. Treg cells were enumerated in peripheral blood and SF of RA patients and analysed by flow cytometry for expression of the proliferation marker Ki-67 and binding of the apoptosis marker

  2. A MYC-Driven Change in Mitochondrial Dynamics Limits YAP/TAZ Function in Mammary Epithelial Cells and Breast Cancer.

    Science.gov (United States)

    von Eyss, Björn; Jaenicke, Laura A; Kortlever, Roderik M; Royla, Nadine; Wiese, Katrin E; Letschert, Sebastian; McDuffus, Leigh-Anne; Sauer, Markus; Rosenwald, Andreas; Evan, Gerard I; Kempa, Stefan; Eilers, Martin

    2015-12-14

    In several developmental lineages, an increase in MYC expression drives the transition from quiescent stem cells to transit-amplifying cells. We show that MYC activates a stereotypic transcriptional program of genes involved in cell growth in mammary epithelial cells. This change in gene expression indirectly inhibits the YAP/TAZ co-activators, which maintain the clonogenic potential of these cells. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. MYC-dependent growth strains cellular energy resources and stimulates AMP-activated kinase (AMPK). PLD6 alters mitochondrial fusion and fission dynamics downstream of MYC. This change activates AMPK, which in turn inhibits YAP/TAZ. Mouse models and human pathological data show that MYC enhances AMPK and suppresses YAP/TAZ activity in mammary tumors. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Rarity of human T helper 17 cells is due to retinoic acid orphan receptor-dependent mechanisms that limit their expansion.

    Science.gov (United States)

    Santarlasci, Veronica; Maggi, Laura; Capone, Manuela; Querci, Valentina; Beltrame, Luca; Cavalieri, Duccio; D'Aiuto, Elena; Cimaz, Rolando; Nebbioso, Angela; Liotta, Francesco; De Palma, Raffaele; Maggi, Enrico; Cosmi, Lorenzo; Romagnani, Sergio; Annunziato, Francesco

    2012-02-24

    The reason why CD4(+) T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated expression of IL-4-induced gene 1 (IL4I1) mRNA, a secreted L-phenylalanine oxidase, which associated with a decrease in CD3ζ chain expression and consequent abnormalities in the molecular pathway that allows IL-2 production and cell proliferation. High IL4I1 mRNA expression was detectable in Th17 cell precursors and was strictly dependent on Th17 cell master gene, the retinoid acid related orphan receptor (RORC). Th17 cells also exhibited RORC-dependent CD28 hyperexpression and the ability to produce IL-17A after CD28 stimulation without CD3 triggering. Our findings suggest that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms limiting their expansion. Copyright © 2012 Elsevier Inc. All rights reserved.

  4. Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals.

    Directory of Open Access Journals (Sweden)

    Nichole R Klatt

    2014-08-01

    Full Text Available A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP, remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated ("putative progressors", PP, thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001, which was associated with decreased HIV infection of these cells in VNPs (r = -0.649, p = 0.019. In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM cells (p = 0.035, and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01. Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.

  5. A Quasi-Steady-State Approximation to the Basic Target-Cell-Limited Viral Dynamics Model with a Non-Cytopathic Effect

    Directory of Open Access Journals (Sweden)

    Richard A. Cangelosi

    2018-01-01

    Full Text Available Analysis of previously published target-cell limited viral dynamic models for pathogens such as HIV, hepatitis, and influenza generally rely on standard techniques from dynamical systems theory or numerical simulation. We use a quasi-steady-state approximation to derive an analytic solution for the model with a non-cytopathic effect, that is, when the death rates of uninfected and infected cells are equal. The analytic solution provides time evolution values of all three compartments of uninfected cells, infected cells, and virus. Results are compared with numerical simulation using clinical data for equine infectious anemia virus, a retrovirus closely related to HIV, and the utility of the analytic solution is discussed.

  6. Vasomotion dynamics following calcium spiking depend on both cell signalling and limited constriction velocity in rat mesenteric small arteries

    NARCIS (Netherlands)

    VanBavel, Ed; van der Meulen, Esther T.; Spaan, Jos A. E.

    2008-01-01

    Vascular smooth muscle cell contraction depends on intracellular calcium. However, calcium-contraction coupling involves a complex array of intracellular processes. Quantitating the dynamical relation between calcium perturbations and resulting changes in tone may help identifying these processes.

  7. Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen

    Directory of Open Access Journals (Sweden)

    Haiech Jacques

    2009-08-01

    Full Text Available Abstract Background Pharmacological high-throughput screening (HTS represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA. FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay. Methods Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA. Results The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model. Conclusion Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive

  8. Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Wenting Guo

    2017-12-01

    Full Text Available Amyotrophic lateral sclerosis (ALS and frontotemporal dementia (FTD are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.

  9. The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells.

    Science.gov (United States)

    Iwata, Shigeru; Mikami, Yohei; Sun, Hong-Wei; Brooks, Stephen R; Jankovic, Dragana; Hirahara, Kiyoshi; Onodera, Atsushi; Shih, Han-Yu; Kawabe, Takeshi; Jiang, Kan; Nakayama, Toshinori; Sher, Alan; O'Shea, John J; Davis, Fred P; Kanno, Yuka

    2017-06-20

    Host defense requires the specification of CD4 + helper T (Th) cells into distinct fates, including Th1 cells that preferentially produce interferon-γ (IFN-γ). IFN-γ, a member of a large family of anti-pathogenic and anti-tumor IFNs, induces T-bet, a lineage-defining transcription factor for Th1 cells, which in turn supports IFN-γ production in a feed-forward manner. Herein, we show that a cell-intrinsic role of T-bet influences how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-γ aberrantly induced a type I IFN transcriptomic program. T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, in addition to promoting Th1 effector commitment, T-bet acts as a repressor in differentiated Th1 cells to prevent abberant autocrine type I IFN and downstream signaling. Published by Elsevier Inc.

  10. Interference Alignment-based Precoding and User Selection with Limited Feedback in Two-cell Downlink Multi-user MIMO Systems

    Directory of Open Access Journals (Sweden)

    Yin Zhu

    2016-05-01

    Full Text Available Interference alignment (IA is a new approach to address interference in modern multiple-input multiple-out (MIMO cellular networks in which interference is an important factor that limits the system throughput. System throughput in most IA implementation schemes is significantly improved only with perfect channel state information and in a high signal-to-noise ratio (SNR region. Designing a simple IA scheme for the system with limited feedback and investigating system performance at a low-to-medium SNR region is important and practical. This paper proposed a precoding and user selection scheme based on partial interference alignment in two-cell downlink multi-user MIMO systems under limited feedback. This scheme aligned inter-cell interference to a predefined direction by designing user’s receive antenna combining vectors. A modified singular value decomposition (SVD-based beamforming method and a corresponding user-selection algorithm were proposed for the system with low rate limited feedback to improve sum rate performance. Simulation results show that the proposed scheme achieves a higher sum rate than traditional schemes without IA. The modified SVD-based beamforming scheme is also superior to the traditional zero-forcing beamforming scheme in low-rate limited feedback systems. The proposed partial IA scheme does not need to collaborate between transmitters and joint design between the transmitter and the users. The scheme can be implemented with low feedback overhead in current MIMO cellular networks.

  11. An understanding of potential and limitations of alginate/PLL microcapsules as a cell retention system for perfusion cultures.

    Science.gov (United States)

    Demont, Aurelie; Cole, Harriet; Marison, Ian W

    2016-02-01

    Microcapsules for high cell density culture of mammalian cells have found an increasing interest, however, the poor stability of the microcapsules and the lack of characterisation methods led to few quantitative results. Alginate-poly-L-lysine (PLL) microcapsules have been studied in detail in order to form a basis for comparison of capsules made from different polymers. Since the microcapsules can be easily retained in the bioreactor without the need for a cell separation device, high cell densities were achieved with a maximum of 4 × 10(7) cell/ml(microcapsules), corresponding to a colonisation of 5% of the internal capsule volume. Measurement of microcapsule integrity and mechanical resistance showed that alginate-PLL microcapsules are not suitable for perfusion cultures since they are very sensitive to media composition, mainly the presence of non-gelling ions that have a higher affinity for alginate than PLL and Ca(2+), leading to the leakage of PLL and Ca(2+), and to microcapsule rupture.

  12. Feasibility and Limits of Magnetically Labeling Primary Cultured Rat T Cells with Ferumoxides Coupled with Commonly Used Transfection Agents

    Directory of Open Access Journals (Sweden)

    Cedric Berger

    2006-04-01

    Full Text Available Visualization and quantification of inflammatory processes is of high importance for early diagnosis of a multitude of diseases. Magnetic resonance imaging (MRI using iron oxide (FeO nanoparticles as contrast agents allows the study of macrophage infiltration during inflammation in a variety of tissues. Macrophages are effectors of the immune response, their appearance being orchestrated by activated T lymphocytes. Therefore, tracking of labeled T lymphocytes, which initiate the immune process, should enable earlier detection of tissue inflammation. In this study, we investigate the feasibility of specifically labeling harvested T cells by using dextran-coated FeO nanoparticles and commonly available transfection agents (TAs. Physicochemical properties of the newly formed FeO/TA vesicles were determined as well as their cell toxicity and their T cell activation potential. The labeling efficiency of each FeO/TA combination was evaluated by measuring the transverse MRI relaxation rate R2 by X-ray spectroscopy and magnetic selection. Toxicity and labeling efficacy differed significantly among TAs. The best results were achieved by using polyamine TAs and in particular by using poly-l-lysine at a concentration of 1.5 µg/mL administered in combination with 22.5 µg iron/mL. By using this protocol, up to 60% of harvested T cells could be labeled. Microscopic investigation revealed FeO/TA nanoparticles not only localized within the cytoplasma of the cells but also sticking to the outer membrane surface.

  13. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving ILC3

    Science.gov (United States)

    Withers, David R.; Hepworth, Matthew R.; Wang, Xinxin; Mackley, Emma C.; Halford, Emily E.; Dutton, Emma E.; Marriott, Clare L.; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N.; Sonnenberg, Gregory F.

    2016-01-01

    RAR-related orphan receptor γt (ROR-γt) directs differentiation of pro-inflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases1–3. However, ROR-γt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine4–11, suggesting that targeting ROR-γt could also result in impaired host defense to infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 cells but not ILC3s in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Transient genetic deletion of ROR-γt in mature ILC3s also did not impair cytokine responses in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation, and reduced the frequencies of TH17 cells but not ILC3s isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell versus ILC3 responses, and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation. PMID:26878233

  14. Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells.

    Science.gov (United States)

    Foxman, Ellen F; Storer, James A; Fitzgerald, Megan E; Wasik, Bethany R; Hou, Lin; Zhao, Hongyu; Turner, Paul E; Pyle, Anna Marie; Iwasaki, Akiko

    2015-01-20

    Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33-35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I-like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature.

  15. The benefits and limitations of cell-free DNA screening for 22q11.2 deletion syndrome.

    Science.gov (United States)

    Dugoff, Lorraine; Mennuti, Michael T; McDonald-McGinn, Donna M

    2017-01-01

    Cell-free DNA testing is increasingly being used to screen pregnant women for fetal aneuploidy. This technology may also identify microdeletion syndromes, including 22q11.2 deletion syndrome, the most common microdeletion syndrome, and the 22q11.2 duplication syndrome. The purpose of this paper is to provide an overview of the 22q11.2 deletion syndrome, to review the early experience with cell-free DNA screening for this deletion and to consider the potential benefits that may be associated with prenatal detection of the deletion. © 2016 John Wiley & Sons, Ltd. © 2016 John Wiley & Sons, Ltd.

  16. A biological study establishing the endotoxin limit for in vitro proliferation of human mesenchymal stem cells

    Directory of Open Access Journals (Sweden)

    Yusuke Nomura

    2017-12-01

    Conclusions: Since endotoxins can affect various cellular functions, an endotoxin limit should be set for in vitro MSC cultures. The lowest observed adverse effect level was determined to be 0.1 ng/ml based on the effect on MSC proliferation.

  17. A phase II study of VP-16-ifosfamide-cisplatin combination chemotherapy plus early concurrent thoracic irradiation for previously untreated limited small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Woo, In Sook; Park, Young Suk; Kwon, Sung Hee [Hallym Univ., Seoul (Korea, Republic of). Coll. of Medicine] [and others

    2000-12-01

    At present the addition of thoracic irradiation to combination chemotherapy is a standard treatment for limited staged small cell ling cancer. However, there is still controversy about the optimum timing of chest irradiation. We conducted a phase II study of etoposide (VP-16)-ifosfamide-cisplatin (VIP) combination chemotherapy plus early concurrent thoracic irradiation for the patients with previously untreated limited small cell lung cancer in order to assess if the treatment modality could improve the response rate and the toxicity. Forty-four patients with limited small cell lung cancer were treated with etoposide-ifosfamide-cisplatin and concurrent thoracic irradiation. Combination chemotherapy consisted of etoposide 100 mg/m{sup 2} (on day 1-3), ifosfamide 1000 mg/m{sup 2} (on days 1 and 2) and cisplatin 100 mg/m{sup 2} (on day 1). Concurrent thoracic irradiation consisted of a total of 4000 cGy over 4 weeks starting on the first day of the first chemotherapy. All patients who showed a complete response were given prophylactic cranial irradiation for 2.5 weeks. Forty-four of the 49 patients who entered the study from May 1994 to August 1998 were evaluable. The median age was 59 years and 40 patients had a performance status of 0 or 1. The median survival time was 22.5 months. Twenty-eight patients (62%) showed a complete response and 16 (38%) a partial response. Twenty-four patients (54%) developed grade 3 or 4 neutropenia; there was a 9% RTOG score 3 or 4 esophagitis. VIP combination chemotherapy and early concurrent thoracic irradiation for patients with limited stage small cell lung cancer revealed excellent antitumor response with tolerable toxicity. (author)

  18. Limited regression of central giant cell granuloma by interferon alpha after failed calcitonin therapy: a report of 2 cases

    NARCIS (Netherlands)

    de Lange, J.; van den Akker, H.P.; van den Berg, H.; Richel, D.J.; Gortzak, R.A.T.

    2006-01-01

    Central giant cell granuloma (CGCG) is a benign lesion of the jaws with a sometimes locally aggressive behaviour. The most common therapy is surgical curettage which has a high recurrence rate, especially in lesions with aggressive signs and symptoms (i.e. pain, paresthesia, root-resorption and

  19. Limitations of using aggrecan and type X collagen as markers of chondrogenesis in mesenchymal stem cell differentiation.

    Science.gov (United States)

    Mwale, Fackson; Stachura, Dorothy; Roughley, Peter; Antoniou, John

    2006-08-01

    The study was initially designed to differentiate human bone marrow-derived mesenchymal stem cells (MSC) into chondrocyte-like cells, for use in tissue engineering. We cultured MSCs in defined chondrogenic medium as pellet cultures supplemented with transforming growth factor (TGF)-beta1 or -beta3 and dexamethazone, as they are commonly used to promote in vitro chondrogenesis. Markers of chondrogenesis used were type II collagen and aggrecan, with type X collagen being used as a marker of late-stage chondrocyte hypertrophy (associated with endochondral ossification). Our results show that aggrecan is constitutively expressed by MSCs and that type X collagen is expressed as an early event. Furthermore, we found that type X collagen was expressed before type II collagen in some cases. This is surprising because it is understood that stem cells have to be differentiated into chondrocytes before they can become hypertrophic. Thus, caution must be exercised when using aggrecan and type X collagen as markers for chondrogenesis and chondrocyte hypertrophy, respectively, in association with stem cell differentiation from this source.

  20. Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis

    OpenAIRE

    Henique, Carole; Bollée, Guillaume; Loyer, Xavier; Grahammer, Florian; Dhaun, Neeraj; Camus, Marine; Vernerey, Julien; Guyonnet, Léa; Gaillard, François; Lazareth, Hélène; Meyer, Charlotte; Bensaada, Imane; Legrès, Luc; Satoh, Takashi; Akira, Shizuo

    2017-01-01

    Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differenti...

  1. Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis.

    NARCIS (Netherlands)

    Bon, L. van; Popa, C.; Huibens, R.J.F.; Vonk, M.C.; York, M.; Simms, R.; Hesselstrand, R.; Wuttge, D.M.; Lafyatis, R.; Radstake, T.R.D.J.

    2010-01-01

    BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). OBJECTIVE: To map TLR-mediated cytokine responses of DCs from patients with SSc. METHODS: 45 patients with SSc were

  2. Effects of glucose, lactate and basic FGF as limiting factors on the expansion of human induced pluripotent stem cells.

    Science.gov (United States)

    Horiguchi, Ikki; Urabe, Yusuke; Kimura, Keiichi; Sakai, Yasuyuki

    2018-01-01

    Pluripotent stem cells (PSCs) are one of the promising cell sources for tissue engineering and drug screening. However, mass production of induced pluripotent stem cells (iPSCs) is still developing. Especially, a huge amount of culture medium usage causes expensive cost in the mass production process. In this report, we reduced culture medium usage by extending interval of changing culture medium. In parallel, we also increased glucose concentration and supplied heparan sulfate to avoid depletion of glucose and bFGF, respectively. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses showed that reducing medium change frequency increased differentiation marker expressions but high glucose concentration downregulated these expressions. In contrast, heparan sulfate did not prevent differentiation marker expressions. According to analyses of growth rate, cell growth with extended medium change interval was decreased in later stage of log growth phase despite the existence of high glucose concentration and heparan sulfate. This result and culturing iPSCs with lactate showed that the accumulation of excreted lactate decreased the growth rate regardless of pH control. Conclusively, these experiments show that adding glucose and removing lactate are important to expand iPSCs with reduced culture medium usage. This knowledge should be useful to design economical iPSC mass production and differentiation system. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  3. T cell-mediated cytotoxicity against p53-protein derived peptides in bulk and limiting dilution cultures of healthy donors

    DEFF Research Database (Denmark)

    Röpke, M; Regner, M; Claesson, M H

    1995-01-01

    -I restricted epitopes for T cell recognition and p53-derived peptides have been suggested as targets for tumour-specific cytotoxic T lymphocytes (CTL). Our primary aim was to estimate the frequencies of p53-peptide reactive CTL precursors (CTLp) in peripheral blood from healthy young individuals. We selected...

  4. Role of eicosanoids and white blood cells in the beneficial effects of limited reperfusion after ischemia-reperfusion injury in skeletal muscle

    International Nuclear Information System (INIS)

    Anderson, R.J.; Cambria, R.A.; Dikdan, G.; Lysz, T.W.; Hobson, R.W. II

    1990-01-01

    Limiting the rate of reperfusion blood flow has been shown to be beneficial locally in models of ischemia-reperfusion injury. We investigated the effects of this on eicosanoids (thromboxane B2, 6-keto-PGF1 alpha, and leukotriene B4), white blood cell activation, and skeletal muscle injury as quantitated by triphenyltetrazolium chloride and technetium-99m pyrophosphate after ischemia-reperfusion injury in an isolated gracilis muscle model in 16 anesthetized dogs. One gracilis muscle in each dog was subjected to 6 hours of ischemia followed by 1 hour of limited reperfusion and then by a second hour of normal reperfusion. The other muscle was subjected to 6 hours of ischemia followed by 2 hours of normal reperfusion. Six dogs each were used as normal reperfusion controls (NR) and limited reperfusion controls (LR), with 5 dogs being treated with a thromboxane synthetase inhibitor (LR/TSI) and another five with a leukotriene inhibitor (LR/LI). LR in all three groups (LR, LR/TSI, and LR/LI) showed a benefit in skeletal muscle injury as measured by triphenyltetrazolim chloride and technetium-99m pyrophosphate when compared with NR. However, there was no significant difference between the groups with LR regarding eicosanoid levels and white blood cell activation when compared with NR. These results demonstrate that LR produces benefits by mechanisms other than those dependent upon thromboxane A2, prostacyclin, or white blood cell activation

  5. Limitations and relative utility of screening assays to assess engineered nanoparticle toxicity in a human cell line

    International Nuclear Information System (INIS)

    Monteiro-Riviere, N.A.; Inman, A.O.; Zhang, L.W.

    2009-01-01

    Single-walled carbon nanotubes (SWCNT), fullerenes (C 60 ), carbon black (CB), nC 60 , and quantum dots (QD) have been studied in vitro to determine their toxicity in a number of cell types. Here, we report that classical dye-based assays such as MTT and neutral red (NR) that determine cell viability produce invalid results with some NM (nanomaterials) due to NM/dye interactions and/or NM adsorption of the dye/dye products. In this study, human epidermal keratinocytes (HEK) were exposed in vitro to CB, SWCNT, C 60 , nC 60 , and QD to assess viability with calcein AM (CAM), Live/Dead (LD), NR, MTT, Celltiter 96 AQueous One (96 AQ), alamar Blue (aB), Celltiter-Blue (CTB), CytoTox One TM (CTO), and flow cytometry. In addition, trypan blue (TB) was quantitated by light microscopy. Assay linearity (R 2 value) was determined with HEK plated at concentrations from 0 to 25,000 cells per well in 96-well plates. HEK were treated with serial dilutions of each NM for 24 h and assessed with each of the viability assays. TB, CAM and LD assays, which depend on direct staining of living and/or dead cells, were difficult to interpret due to physical interference of the NM with cells. Results of the dye-based assays varied a great deal, depending on the interactions of the dye/dye product with the carbon nanomaterials (CNM). Results show the optimal high throughput assay for use with carbon and noncarbon NM was 96 AQ. This study shows that, unlike small molecules, CNM interact with assay markers to cause variable results with classical toxicology assays and may not be suitable for assessing nanoparticle cytotoxicity. Therefore, more than one assay may be required when determining nanoparticle toxicity for risk assessment

  6. Mast cell subsets and neuropeptides in leprosy reactions

    Directory of Open Access Journals (Sweden)

    Antunes Sérgio Luiz Gomes

    2003-01-01

    Full Text Available The immunohistochemical identification of neuropeptides (calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P, alpha-melanocyte stimulating hormone and gamma-melanocyte stimulating hormone quantification of mast cells and their subsets (tryptase/chymase-immunoreactive mast cells = TCMC and tryptase-immunoreactive mast cells = TMC were determined in biopsies of six patients with leprosy reactions (three patients with type I reaction and three with type II. Biopsies were compared with those taken from the same body site in the remission stage of the same patient. We found a relative increase of TMC in the inflammatory infiltrate of the reactional biopsies compared to the post-reactional biopsy. Also, the total number of mast cells and the TMC/TCMC ratio in the inflammatory infiltrate was significantly higher than in the intervening dermis of the biopsies of both periods. No significant difference was found regarding neuroptide expression in the reactional and post-reactional biopsies. The relative increase of TMC in the reactional infiltrates could implicate this mast cell subset in the reported increase of the immune response in leprosy reactions.

  7. Efficient secretory expression of functional barley limit dextrinase inhibitor by high cell-density fermentation of Pichia pastoris

    DEFF Research Database (Denmark)

    Jensen, Johanne Mørch; Vester-Christensen, Malene Bech; Møller, Marie Sofie

    2011-01-01

    The limit dextrinase inhibitor (LDI) from barley seeds acts specifically on limit dextrinase (LD), an endogenous starch debranching enzyme. LDI is a 14kDa hydrophobic protein containing four disulfide bonds and one unpaired thiol group previously found to be either glutathionylated or cysteinylated...... the identity of the produced glutathionylated LDI-His6. At a 1:1M ratio the recombinant LDI completely inhibited hydrolysis of pullulan catalyzed by 5–10nM LD. LDI retained stability in the pH 2–12 range and at pH 6.5 displayed a half-life of 53 and 33min at 90 and 93°C, respectively. The efficient...

  8. Limited B cell repertoire in severe combined immunodeficient mice engrafted with peripheral blood mononuclear cells derived from immunodeficient or normal humans.

    Science.gov (United States)

    Saxon, A; Macy, E; Denis, K; Tary-Lehmann, M; Witte, O; Braun, J

    1991-02-01

    The ability to engraft human PBMC or fetal tissue immune cells in the severe combined immunodeficient (SCID) mouse has created a need for characterization of these systems and their application to disease models. We demonstrate that SCID mice reconstituted with PBMC support the growth and differentiation of a restricted set of B cells. Human IgG levels of 1-2 mg/ml (10-20% of normal human serum levels) were routinely achieved in spite of a serum half life of only 12 d. Ig levels peaked around 50 d and Ig production was maintained for greater than 100 d. The Ig was greater than 85% IgG though some IgM, IgA, IgD, and even IgE could be detected. However, the human IgG produced in hu-PBL-SCID mice was pauci-clonal when analyzed by isoelectric focusing and by kappa/lambda light chain usage. Using a new polymerase chain reaction based analysis capable of monitoring individual VH family utilization, we found that the engrafted B cells showed skewed and restricted human VH subfamily utilization. These parameters were markedly variable among hu-PBL-SCID mice reconstituted from the same donor cell population at both early (21-50 d) and late stages (greater than 100 d). Hu-PBL/CVI-SCID mice constructed with cells from patients with common variable immunodeficiency with an in vitro block in terminal B cell differentiation produced human Ig responses that were quantitatively the same as those produced by hu-PBL-SCID mice from normal donors. The hu-PBL-SCID system using PBMC appears to lead to growth and Ig production by a small number of B cells and results in a restricted B cell repertoire.

  9. Influence of grain boundary modification on limited performance of wide bandgap Cu(In,Ga)Se2 solar cells

    International Nuclear Information System (INIS)

    Raghuwanshi, M.; Cadel, E.; Pareige, P.; Duguay, S.; Couzinie-Devy, F.; Arzel, L.; Barreau, N.

    2014-01-01

    The reason why so-called wide-bandgap CuIn 1−x Ga x Se 2 (CIGSe with x > 0.4) based solar cells show hindered performance compared with theoretical expectations is still a matter of debate. In the present Letter, atom probe tomography studies of CuIn 1−x Ga x Se 2 polycrystalline thin films with x varying from 0 to 1 are reported. These investigations confirm that the grain boundaries (GBs) of low gallium containing (x   0.8) are Cu-enriched compared with GI. For intermediate gallium contents (0.4 < x < 0.8), both types of GBs are detected. This threshold value of 0.4 surprisingly coincides with solar cells output voltage deviation from theoretical expectations, which suggests modifications of GBs properties could participate in the loss of photovoltaic performance.

  10. Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART.

    Directory of Open Access Journals (Sweden)

    Ahmad R Sedaghat

    2007-08-01

    Full Text Available Whereas cells productively infected with human immunodeficiency virus type 1 (HIV-1 decay rapidly in the setting of highly active antiretroviral therapy (HAART, latently infected resting CD4(+ T cells decay very slowly, persisting for the lifetime of the patient and thus forming a stable reservoir for HIV-1. It has been suggested that the stability of the latent reservoir is due to low-level viral replication that continuously replenishes the reservoir despite HAART. Here, we offer the first quantitative study to our knowledge of inflow of newly infected cells into the latent reservoir due to viral replication in the setting of HAART. We make use of a previous observation that in some patients on HAART, the residual viremia is dominated by a predominant plasma clone (PPC of HIV-1 not found in the latent reservoir. The unique sequence of the PPC serves as a functional label for new entries into the reservoir. We employ a simple mathematical model for the dynamics of the latent reservoir to constrain the inflow rate to between 0 and as few as 70 cells per day. The magnitude of the maximum daily inflow rate is small compared to the size of the latent reservoir, and therefore any inflow that occurs in patients on HAART is unlikely to significantly influence the decay rate of the reservoir. These results suggest that the stability of the latent reservoir is unlikely to arise from ongoing replication during HAART. Thus, intensification of standard HAART regimens should have minimal effects on the decay of the latent reservoir.

  11. Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis.

    Science.gov (United States)

    Henique, Carole; Bollée, Guillaume; Loyer, Xavier; Grahammer, Florian; Dhaun, Neeraj; Camus, Marine; Vernerey, Julien; Guyonnet, Léa; Gaillard, François; Lazareth, Hélène; Meyer, Charlotte; Bensaada, Imane; Legrès, Luc; Satoh, Takashi; Akira, Shizuo; Bruneval, Patrick; Dimmeler, Stefanie; Tedgui, Alain; Karras, Alexandre; Thervet, Eric; Nochy, Dominique; Huber, Tobias B; Mesnard, Laurent; Lenoir, Olivia; Tharaux, Pierre-Louis

    2017-11-28

    Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57 Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57 Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.

  12. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use.

    Science.gov (United States)

    Sethi, Aisha; Jain, Dhanpat; Roland, Bani Chander; Kinzel, Jason; Gibson, Joanna; Schrader, Ronald; Hanson, Joshua Anspach

    2015-02-01

    Mastocytic enterocolitis is a recently described entity defined by chronic diarrhea of unknown etiology and normal colon biopsy results with increased mast cells (MCs) seen on special stains. These patients may benefit from mast cell stabilizers; however, the clinical utility of MC counts remains unknown. To determine the clinical utility of colonic MC counts on normal biopsies in patients with chronic diarrhea of unknown etiology. Blinded MC counts using a c-Kit stain were performed in 76 consecutive patients with chronic diarrhea of unknown etiology who had normal colon biopsy results and in 89 consecutive control patients presenting for screening colonoscopy. Mast cells were counted per single high-power field in the highest-density area. A t test was used to compare the counts, and receiver operating characteristic curves were generated to examine sensitive and specific cutoff values. Overall, MC counts averaged 31 MCs per high-power field in the study group versus 24 MCs per high-power field in the control group (P chronic diarrhea of unknown etiology, primarily in the left colon. However, receiver operating characteristic analysis demonstrates no discriminatory cutoff values. Quantitative MC stains yield little useful diagnostic information, and further studies are necessary to determine whether mastocytic enterocolitis truly represents a distinct entity.

  13. Effects of Kapton Sample Cell Windows on the Detection Limit of Smectite: Implications for CheMin on the Mars Science Laboratory Mission

    Science.gov (United States)

    Achilles, C. N.; Ming, Douglas W.; Morris, R. V.; Blake, D. F.

    2012-01-01

    The CheMin instrument on the Mars Science Laboratory (MSL) rover Curiosity is an X-ray diffraction (XRD) and X-ray fluorescence (XRF) instrument capable of providing the mineralogical and chemical compositions of rocks and soils on the surface of Mars. CheMin uses a microfocus X-ray tube with a Co target, transmission geometry, and an energy-discriminating X-ray sensitive CCD to produce simultaneous 2-D XRD patterns and energy-dispersive X-ray histograms from powdered samples. CheMin has two different window materials used for sample cells -- Mylar and Kapton. Instrument details are provided elsewhere. Fe/Mg-smectite (e.g., nontronite) has been identified in Gale Crater, the MSL future landing site, by CRISM spectra. While large quantities of phyllosilicate minerals will be easily detected by CheMin, it is important to establish detection limits of such phases to understand capabilities and limitations of the instrument. A previous study indicated that the (001) peak of smectite at 15 Ang was detectable in a mixture of 1 wt.% smectite with olivine when Mylar is the window material for the sample cell. Complications arise when Kapton is the window material because Kapton itself also has a diffraction peak near 15 Ang (6.8 deg 2 Theta). This study presents results of mineral mixtures of smectite and olivine to determine smectite detection limits for Kapton sample cells. Because the intensity and position of the smectite (001) peak depends on the hydration state, we also analyzed mixtures with "hydrated" and "dehydrated"h smectite to examine the effects of hydration state on detection limits.

  14. Empagliflozin Limits Myocardial Infarction in Vivo and Cell Death in Vitro: Role of STAT3, Mitochondria, and Redox Aspects

    Directory of Open Access Journals (Sweden)

    Ioanna Andreadou

    2017-12-01

    Full Text Available Empagliflozin (EMPA, a drug approved for type 2 diabetes management, reduced cardiovascular death but is unknown if it reduces myocardial infarction. We sought to investigate: (i the effect of EMPA on myocardial function and infarct size after ischemia/reperfusion in mice fed with western diet (WD, (ii the underlying signaling pathways, (iii its effects on cell survival in rat embryonic-heart-derived cardiomyoblasts (H9C2 and endothelial cells (ECs. To facilitate the aforementioned aims, mice were initially randomized in Control and EMPA groups and were subjected to 30 min ischemia and 2 h reperfusion. EMPA reduced body weight, blood glucose levels, and mean arterial pressure. Cholesterol, triglyceride, and AGEs remained unchanged. Left ventricular fractional shortening was improved (43.97 ± 0.92 vs. 40.75 ± 0.61% and infarct size reduced (33.2 ± 0.01 vs. 17.6 ± 0.02%. In a second series of experiments, mice were subjected to the above interventions up to the 10th min of reperfusion and myocardial biopsies were obtained for assessment of the signaling cascade. STAT3 was increased in parallel with reduced levels of malondialdehyde (MDA and reduced expression of myocardial iNOS and interleukin-6. Cell viability and ATP content were increased in H9C2 and in ECs. While, STAT3 phosphorylation is known to bestow infarct sparing properties through interaction with mitochondria, we observed that EMPA did not directly alter the mitochondrial calcium retention capacity (CRC; therefore, its effect in reducing myocardial infarction is STAT3 dependent. In conclusion, EMPA improves myocardial function and reduces infarct size as well as improves redox regulation by decreasing iNOS expression and subsequently lipid peroxidation as shown by its surrogate marker MDA. The mechanisms of action implicate the activation of STAT3 anti-oxidant and anti-inflammatory properties.

  15. Carboxylation of multiwalled carbon nanotube attenuated the cytotoxicity by limiting the oxidative stress initiated cell membrane integrity damage, cell cycle arrestment, and death receptor mediated apoptotic pathway.

    Science.gov (United States)

    Liu, Zhenbao; Liu, Yanfei; Peng, Dongming

    2015-08-01

    In this study, the effects of carboxylated multiwalled carbon nanotubes (MWCNTs-COOH) on human normal liver cell line L02 was compared with that of pristine multiwalled carbon nanotubes (p-MWCNTs). It was shown that compared with MWCNTs-COOH, p-MWCNTs induced apoptosis, reduced the level of intracellular antioxidant glutathione more significantly, and caused severer cell membrane damage as demonstrated by lactate dehydrogenase leakage. Cell cycles were arrested by both MWCNTs, while p-MWCNTs induced higher ratio of G0/G1 phase arrestment as compared with MWCNTs-COOH. Caspase-8 was also activated after both MWCNTs exposure, indicating extrinsic apoptotic pathway was involved in the apoptosis induced by MWCNTs exposure, more importantly, MWCNTs-COOH significantly reduced the activation of caspase-8 as compared with p-MWCNTs. All these results suggested that MWCNTs-COOH might be safer for in vivo application as compared with p-MWCNTs. © 2015 Wiley Periodicals, Inc.

  16. Development and validation of non-integrative, self-limited, and replicating minicircles for safe reporter gene imaging of cell-based therapies.

    Directory of Open Access Journals (Sweden)

    John A Ronald

    Full Text Available Reporter gene (RG imaging of cell-based therapies provides a direct readout of therapeutic efficacy by assessing the fate of implanted cells. To permit long-term cellular imaging, RGs are traditionally required to be integrated into the cellular genome. This poses a potential safety risk and regulatory bottleneck for clinical translation as integration can lead to cellular transformation. To address this issue, we have developed non-integrative, replicating minicircles (MCs as an alternative platform for safer monitoring of cells in living subjects. We developed both plasmids and minicircles containing the scaffold/matrix attachment regions (S/MAR of the human interferon-beta gene, driven by the CMV promoter, and expressing the bioluminescence RG firefly luciferase. Constructs were transfected into breast cancer cells, and expanded S/MAR minicircle clones showed luciferase signal for greater than 3 months in culture and minicircles remained as episomes. Importantly, luciferase activity in clonal populations was slowly lost over time and this corresponded to a loss of episome, providing a way to reversibly label cells. To monitor cell proliferation in vivo, 1.5 × 10(6 cells carrying the S/MAR minicircle were implanted subcutaneously into mice (n = 5 and as tumors developed significantly more bioluminescence signal was noted at day 35 and 43 compared to day 7 post-implant (p<0.05. To our knowledge, this is the first work examining the use of episomal, self-limited, replicating minicircles to track the proliferation of cells using non-invasive imaging in living subjects. Continued development of S/MAR minicircles will provide a broadly applicable vector platform amenable with any of the numerous RG technologies available to allow therapeutic cell fate to be assessed in individual patients, and to achieve this without the need to manipulate the cell's genome so that safety concerns are minimized. This will lead to safe tools to assess treatment

  17. Mediators of Mast Cells in Bullous Pemphigoid and Dermatitis Herpetiformis

    Directory of Open Access Journals (Sweden)

    Agnieszka Zebrowska

    2014-01-01

    Full Text Available Bullous pemphigoid (BP and dermatitis herpetiformis (DH are skin diseases associated with inflammation. However, few findings exist concerning the role of mast cells in autoimmune blistering disease. Skin biopsies were taken from 27 BP and 14 DH patients, as well as 20 healthy individuals. Immunohistochemistry was used to identify the localization and mast cell expression of TNFα and MMP9 in skin lesions and perilesional skin. The serum concentrations of TNFα, MMP9, chymase, tryptase, PAF, and IL-4 were measured by immunoassay. TNFα and MMP9 expression in the epidermis and in inflammatory influxed cells in the dermis was detected in skin biopsies from patients. Although these mediators were found to be expressed in the perilesional skin of all patients, the level was much lower than that in lesional skin. Increased serum PAF levels were observed in BP patients. Mast cells may play an essential role in activating inflammation, which ultimately contributes to the tissue damage observed in BP and DH. Our findings suggest that differences in the pattern of cytokine expression directly contribute to variations in cellular infiltration in DH and BP.

  18. Experimental Investigation and Discussion on the Mechanical Endurance Limit of Nafion Membrane Used in Proton Exchange Membrane Fuel Cell

    Directory of Open Access Journals (Sweden)

    Yang Xiao

    2014-10-01

    Full Text Available As a solution of high efficiency and clean energy, fuel cell technologies, especially proton exchange membrane fuel cell (PEMFC, have caught extensive attention. However, after decades of development, the performances of PEMFCs are far from achieving the target from the Department of Energy (DOE. Thus, further understanding of the degradation mechanism is needed to overcome this obstacle. Due to the importance of proton exchange membrane in a PEMFC, the degradation of the membrane, such as hygrothermal aging effect on its properties, are particularly necessary. In this work, a thick membrane (Nafion N117, which is always used as an ionic polymer for the PEMFCs, has been analyzed. Experimental investigation is performed for understanding the mechanical endurance of the bare membranes under different loading conditions. Tensile tests are conducted to compare the mechanical property evolution of two kinds of bare-membrane specimens including the dog-bone and the deeply double edge notched (DDEN types. Both dog-bone and DDEN specimens were subjected to a series of degradation tests with different cycling times and wide humidity ranges. The tensile tests are repeated for both kinds of specimens to assess the strain-stress relations. Furthermore, Fourier transform infrared spectroscopy (FT-IR, X-ray diffraction (XRD and Scanning electron microscope (SEM observation and water absorption measurement were conducted to speculate the cause of this variation. The initial cracks along with the increasing of bound water content were speculated as the primary cause.

  19. Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies.

    Science.gov (United States)

    Tipton, Thomas R W; Roghanian, Ali; Oldham, Robert J; Carter, Matthew J; Cox, Kerry L; Mockridge, C Ian; French, Ruth R; Dahal, Lekh N; Duriez, Patrick J; Hargreaves, Philip G; Cragg, Mark S; Beers, Stephen A

    2015-03-19

    Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas obinutuzumab, a type II mAb, lacks the ability to redistribute into lipid rafts and is glycoengineered for augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that type I mAbs such as rituximab have a propensity to undergo enhanced antigenic modulation compared with type II. Here we assessed the key effector mechanisms affected, comparing type I and II antibodies of various isotypes in ADCC and antibody-dependent cellular-phagocytosis (ADCP) assays. Rituximab and ofatumumab depleted both normal and leukemic human CD20-expressing B cells in the mouse less effectively than glycoengineered and wild-type forms of obinutuzumab, particularly when human immunoglobulin G1 (hIgG1) mAbs were compared. In contrast to mouse IgG2a, hIgG1 mAbs were ineffective in ADCC assays with murine natural killer cells as effectors, whereas ADCP was equivalent for mouse IgG2a and hIgG1. However, rituximab's ability to elicit both ADCC and ADCP was reduced by antigenic modulation, whereas type II antibodies remained unaffected. These data demonstrate that ADCP and ADCC are impaired by antigenic modulation and that ADCP is the main effector function employed in vivo. © 2015 by The American Society of Hematology.

  20. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells.

    Science.gov (United States)

    Withers, David R; Hepworth, Matthew R; Wang, Xinxin; Mackley, Emma C; Halford, Emily E; Dutton, Emma E; Marriott, Clare L; Brucklacher-Waldert, Verena; Veldhoen, Marc; Kelsen, Judith; Baldassano, Robert N; Sonnenberg, Gregory F

    2016-03-01

    RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, ROR-γt-dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

  1. Quorum Sensing-Regulated Phenol-Soluble Modulins Limit Persister Cell Populations in Staphylococcus aureus

    DEFF Research Database (Denmark)

    Bojer, Martin S; Lindemose, Søren; Vestergaard, Martin

    2018-01-01

    Incomplete killing of bacterial pathogens by antibiotics is an underlying cause of treatment failure and accompanying complications. Among those avoiding chemotherapy are persisters being individual cells in a population that for extended periods of time survive high antibiotic concentrations...... proposedly by being in a quiescent state refractory to antibiotic killing. While investigating the human pathogenStaphylococcus aureusand the influence of growth phase on persister formation, we noted that spent supernatants of stationary phase cultures ofS. aureusorS. epidermidis, but not of distantly...... properties; however, the persister reducing activity was specifically linked to synthesis of the PSMα family. Correspondingly, a high-persister phenotype of a PSMα mutant was observed upon fluoroquinolone or aminoglycoside challenge, demonstrating that the persister reducing activity of PSMs can...

  2. From invasion to latency: intracellular noise and cell motility as key controls of the competition between resource-limited cellular populations

    KAUST Repository

    Guerrero, Pilar

    2015-04-02

    © 2015, Springer-Verlag Berlin Heidelberg. In this paper we analyse stochastic models of the competition between two resource-limited cell populations which differ in their response to nutrient availability: the resident population exhibits a switch-like response behaviour while the invading population exhibits a bistable response. We investigate how noise in the intracellular regulatory pathways and cell motility influence the fate of the incumbent and invading populations. We focus initially on a spatially homogeneous system and study in detail the role of intracellular noise. We show that in such well-mixed systems, two distinct regimes exist: In the low (intracellular) noise limit, the invader has the ability to invade the resident population, whereas in the high noise regime competition between the two populations is found to be neutral and, in accordance with neutral evolution theory, invasion is a random event. Careful examination of the system dynamics leads us to conclude that (i) even if the invader is unable to invade, the distribution of survival times, PS(t), has a fat-tail behaviour (PS(t)∼t-1) which implies that small colonies of mutants can coexist with the resident population for arbitrarily long times, and (ii) the bistable structure of the invading population increases the stability of the latent population, thus increasing their long-term likelihood of survival, by decreasing the intensity of the noise at the population level. We also examine the effects of spatial inhomogeneity. In the low noise limit we find that cell motility is positively correlated with the aggressiveness of the invader as defined by the time the invader takes to invade the resident population: the faster the invasion, the more aggressive the invader.

  3. Performance limitations in thieno[3,4-c]pyrrole-4,6-dione-based polymer:ITIC solar cells

    KAUST Repository

    Yang, Fan

    2017-08-15

    We report a systematic study of the efficiency limitations of non-fullerene organic solar cells that exhibit a small energy loss (Eloss) between the polymer donor and the non-fullerene acceptor. To clarify the impact of Eloss on the performance of the solar cells, three thieno[3,4-c]pyrrole-4,6-dione-based conjugated polymers (PTPD3T, PTPD2T, and PTPDBDT) are employed as the electron donor, which all have complementary absorption spectra compared with the ITIC acceptor. The corresponding photovoltaic devices show that low Eloss (0.54 eV) in PTPDBDT:ITIC leads to a high open-circuit voltage (Voc) of 1.05 V, but also to a small quantum efficiency, and in turn photocurrent. The high Voc or small energy loss in the PTPDBDT-based solar cells is a consequence of less non-radiative recombination, whereas the low quantum efficiency is attributed to the unfavorable micro-phase separation, as confirmed by the steady-state and time-resolved photoluminescence experiments, grazing-incidence wide-angle X-ray scattering, and resonant soft X-ray scattering (R-SoXS) measurements. We conclude that to achieve high performance non-fullerene solar cells, it is essential to realize a large Voc with small Eloss while simultaneously maintaining a high quantum efficiency by manipulating the molecular interaction in the bulk-heterojunction.

  4. Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence.

    Science.gov (United States)

    Steffens, H P; Kurz, S; Holtappels, R; Reddehase, M J

    1998-03-01

    In the immunocompetent host, primary cytomegalovirus (CMV) infection is resolved by the immune response without causing overt disease. The viral genome, however, is not cleared but is maintained in a latent state that entails a risk of virus recurrence and consequent organ disease. By using murine CMV as a model, we have shown previously that multiple organs harbor latent CMV and that reactivation occurs with an incidence that is determined by the viral DNA load in the respective organ (M. J. Reddehase, M. Balthesen, M. Rapp, S. Jonjic, I. Pavic, and U. H. Koszinowski. J. Exp. Med. 179:185-193, 1994). This predicts that a therapeutic intervention capable of limiting the load of latent viral genome should also reduce the risk of virus recurrence. Here we demonstrate the benefits and the limits of a preemptive CD8 T-cell immunotherapy of CMV infection in the immunocompromised bone marrow transplantation recipient. Antiviral CD8 T cells prevented CMV disease and accelerated the resolution of productive infection. The therapy also resulted in a lower load of latent CMV DNA in organs and consequently reduced the incidence of recurrence. The data thus provide a further supporting argument for clinical trials of preemptive cytoimmunotherapy of human CMV disease with CD8 T cells. However, CD8 T cells failed to clear the viral DNA. The therapy-susceptible portion of the DNA load differed between organs and was highest in the lungs. The existence of an invariant, therapy-resistant load suggests a role for immune system evasion mechanisms in the establishment of CMV latency.

  5. Current limiters

    Energy Technology Data Exchange (ETDEWEB)

    Loescher, D.H. [Sandia National Labs., Albuquerque, NM (United States). Systems Surety Assessment Dept.; Noren, K. [Univ. of Idaho, Moscow, ID (United States). Dept. of Electrical Engineering

    1996-09-01

    The current that flows between the electrical test equipment and the nuclear explosive must be limited to safe levels during electrical tests conducted on nuclear explosives at the DOE Pantex facility. The safest way to limit the current is to use batteries that can provide only acceptably low current into a short circuit; unfortunately this is not always possible. When it is not possible, current limiters, along with other design features, are used to limit the current. Three types of current limiters, the fuse blower, the resistor limiter, and the MOSFET-pass-transistor limiters, are used extensively in Pantex test equipment. Detailed failure mode and effects analyses were conducted on these limiters. Two other types of limiters were also analyzed. It was found that there is no best type of limiter that should be used in all applications. The fuse blower has advantages when many circuits must be monitored, a low insertion voltage drop is important, and size and weight must be kept low. However, this limiter has many failure modes that can lead to the loss of over current protection. The resistor limiter is simple and inexpensive, but is normally usable only on circuits for which the nominal current is less than a few tens of milliamperes. The MOSFET limiter can be used on high current circuits, but it has a number of single point failure modes that can lead to a loss of protective action. Because bad component placement or poor wire routing can defeat any limiter, placement and routing must be designed carefully and documented thoroughly.

  6. Immunization with Neospora caninum profilin induces limited protection and a regulatory T-cell response in mice.

    Science.gov (United States)

    Mansilla, Florencia Celeste; Quintana, María Eugenia; Langellotti, Cecilia; Wilda, Maximiliano; Martinez, Andrea; Fonzo, Adriana; Moore, Dadín Prando; Cardoso, Nancy; Capozzo, Alejandra Victoria

    2016-01-01

    Profilins are actin-binding proteins that regulate the polymerization of actin filaments. In apicomplexan parasites, they are essential for invasion. Profilins also trigger the immune response of the host by activating TLRs on dendritic cells (DCs), inducing the production of pro-inflammatory cytokines. In this study we characterized for the first time the immune response and protection elicited by a vaccine based on Neospora caninum profilin in mice. Groups of eight BALB/c mice received either two doses of a recombinant N. caninum profilin expressed in Escherichia coli. (rNcPRO) or PBS, both formulated with an aqueous soy-based adjuvant enriched in TLR-agonists. Specific anti-profilin antibodies were detected in rNcPRO-vaccinated animals, mainly IgM and IgG3, which were consumed after infection. Splenocytes from rNcPRO-immunized animals proliferated after an in vitro stimulation with rNcPRO before and after challenge. An impairment of the cellular response was observed in NcPRO vaccinated and infected mice following an in vitro stimulation with native antigens of N. caninum, related to an increase in the percentage of CD4+CD25+FoxP3+. Two out of five rNcPRO-vaccinated challenged mice were protected; they were negative for parasite DNA in the brain and showed no histopathological lesions, which were found in all PBS-vaccinated animals. As a whole, our results provide evidence of a regulatory response elicited by immunization with rNcPRO, and suggest a role of profilin in the modulation and/or evasion of immune responses against N. caninum. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Quench limits

    International Nuclear Information System (INIS)

    Sapinski, M.

    2012-01-01

    With thirteen beam induced quenches and numerous Machine Development tests, the current knowledge of LHC magnets quench limits still contains a lot of unknowns. Various approaches to determine the quench limits are reviewed and results of the tests are presented. Attempt to reconstruct a coherent picture emerging from these results is taken. The available methods of computation of the quench levels are presented together with dedicated particle shower simulations which are necessary to understand the tests. The future experiments, needed to reach better understanding of quench limits as well as limits for the machine operation are investigated. The possible strategies to set BLM (Beam Loss Monitor) thresholds are discussed. (author)

  8. Evaluation of Ganglion Cell-Inner Plexiform Layer Thickness after Vitreoretinal Surgery with Internal Limiting Membrane Peeling in Cases with Idiopathic Macular Hole

    Directory of Open Access Journals (Sweden)

    Sibel Demirel

    2017-06-01

    Full Text Available Objectives: To evaluate macular retinal ganglion cell-inner plexiform layer (GCIPL thickness after vitrectomy with internal limiting membrane (ILM peeling for idiopathic macular holes using spectral domain optical coherence tomography (SD-OCT. Materials and Methods: Eighteen eyes of 18 patients with unilateral idiopathic macular hole who underwent vitrectomy with ILM peeling were retrospectively analyzed. Healthy fellow eyes of the patients and 18 eyes of 18 age-matched healthy individuals constituted the control group. The patients were evaluated at 1 day, 1 week, 1 month, and 3 months after surgery. The best corrected visual acuity (BCVA measurements, biomicroscopic examination findings and SD-OCT measurements were recorded. Ganglion cell-inner plexiform layer thickness was evaluated with ganglion cell analysis software of Cirrus HD-OCT before surgery and at 1 month and 3 months after surgery and compared with control groups. Presence of dissociated optic nerve fiber layer (DONFL was evaluated with C-scan mode. Results: Of the 18 patients, 9 were male and 9 were female with a mean age of 65.6±5.6 (55-77 years. Preoperative BCVA was 0.75±0.19 logMAR, while it was 0.44±0.17 logMAR and 0.36±0.15 logMAR at postoperative 1 and 3 months, respectively (p0.05. Conclusion: Internal limiting membrane peeling during macular hole surgery may cause functional and /or structural changes that may be associated with visual acuity. Significant GCIPL thinning and DONLF appearance may occur postoperatively.

  9. Evaluation of Macular Retinal Ganglion Cell-Inner Plexiform Layer Thickness after Vitrectomy with Internal Limiting Membrane Peeling for Idiopathic Macular Holes

    Directory of Open Access Journals (Sweden)

    Alfonso L. Sabater

    2014-01-01

    Full Text Available Purpose. To evaluate macular retinal ganglion cell-inner plexiform layer (GCIPL thickness changes after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole repair using a high-resolution spectral-domain optical coherence tomography (SD-OCT. Methods. 32 eyes from 32 patients with idiopathic macular holes who underwent vitrectomy with internal limiting membrane peeling between January 2011 and July 2012 were retrospectively analyzed. GCIPL thickness was measured before surgery, and at one month and at six months after surgery. Values obtained from automated and semimanual SD-OCT segmentation analysis were compared (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA. Results. No significant differences were found between average GCIPL thickness values between preoperative and postoperative analysis. However, statistical significant differences were found in GCIPL thickness at the temporal macular quadrants at six months after surgery. Quality measurement analysis performed by automated segmentation revealed a significant number of segmentation errors. Semimanual segmentation slightly improved the quality of the results. Conclusion. SD-OCT analysis of GCIPL thickness found a significant reduction at the temporal macular quadrants at 6 months after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole.

  10. Evaluation of Macular Retinal Ganglion Cell-Inner Plexiform Layer Thickness after Vitrectomy with Internal Limiting Membrane Peeling for Idiopathic Macular Holes

    Science.gov (United States)

    Velázquez-Villoria, Álvaro; Zapata, Miguel A.; Figueroa, Marta S.; Suárez-Leoz, Marta; Arrevola, Luis; Teijeiro, María-Ángeles; García-Layana, Alfredo

    2014-01-01

    Purpose. To evaluate macular retinal ganglion cell-inner plexiform layer (GCIPL) thickness changes after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole repair using a high-resolution spectral-domain optical coherence tomography (SD-OCT). Methods. 32 eyes from 32 patients with idiopathic macular holes who underwent vitrectomy with internal limiting membrane peeling between January 2011 and July 2012 were retrospectively analyzed. GCIPL thickness was measured before surgery, and at one month and at six months after surgery. Values obtained from automated and semimanual SD-OCT segmentation analysis were compared (Cirrus HD-OCT, Carl Zeiss Meditec, Dublin, CA). Results. No significant differences were found between average GCIPL thickness values between preoperative and postoperative analysis. However, statistical significant differences were found in GCIPL thickness at the temporal macular quadrants at six months after surgery. Quality measurement analysis performed by automated segmentation revealed a significant number of segmentation errors. Semimanual segmentation slightly improved the quality of the results. Conclusion. SD-OCT analysis of GCIPL thickness found a significant reduction at the temporal macular quadrants at 6 months after Brilliant Blue G-assisted internal limiting membrane peeling for idiopathic macular hole. PMID:25110679

  11. Moderate hypofractionated image-guided thoracic radiotherapy for locally advanced node-positive non-small cell lung cancer patients with very limited lung function: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Manapov, Farkhad; Roengvoraphoj, Olarn; Li, Ming Lun; Eze, Chukwuka [Dept. of Radiation Oncology, Ludwig-Maximilian University of Munich, Munich (Germany)

    2017-06-15

    Patients with locally advanced lung cancer and very limited pulmonary function (forced expiratory volume in 1 second [FEV1] ≤ 1 L) have dismal prognosis and undergo palliative treatment or best supportive care. We describe two cases of locally advanced node-positive non-small cell lung cancer (NSCLC) patients with very limited lung function treated with induction chemotherapy and moderate hypofractionated image-guided radiotherapy (Hypo-IGRT). Hypo-IGRT was delivered to a total dose of 45 Gy to the primary tumor and involved lymph nodes. Planning was based on positron emission tomography-computed tomography (PET/ CT) and four-dimensional computed tomography (4D-CT). Internal target volume (ITV) was defined as the overlap of gross tumor volume delineated on 10 phases of 4D-CT. ITV to planning target volume margin was 5 mm in all directions. Both patients showed good clinical and radiological response. No relevant toxicity was documented. Hypo-IGRT is feasible treatment option in locally advanced node-positive NSCLC patients with very limited lung function (FEV1 ≤ 1 L)

  12. Limitations of the hCMEC/D3 cell line as a model for Aβ clearance by the human blood-brain barrier.

    Science.gov (United States)

    Biemans, Elisanne A L M; Jäkel, Lieke; de Waal, Robert M W; Kuiperij, H Bea; Verbeek, Marcel M

    2017-07-01

    Alzheimer's disease and cerebral amyloid angiopathy are characterized by accumulation of amyloid-β (Aβ) at the cerebrovasculature due to decreased clearance at the blood-brain barrier (BBB). However, the exact mechanism of Aβ clearance across this barrier has not been fully elucidated. The hCMEC/D3 cell line has been characterized as a valid model for the BBB. In this study we evaluated the use of this model to study Aβ clearance across the BBB, with an emphasis on brain-to-blood directional permeability. Barrier integrity of hCMEC/D3 monolayers was confirmed for large molecules in both the apical to basolateral and the reverse direction. However, permeability for smaller molecules was substantially higher, especially in basolateral to apical direction, and barrier formation for Aβ was completely absent in this direction. In addition, hCMEC/D3 cells failed to develop a high TEER, possibly caused by incomplete formation of tight junctions. We conclude that the hCMEC/D3 model has several limitations to study the cerebral clearance of Aβ. Therefore, the model needs further characterization before this cell system can be generally applied as a model to study cerebral Aβ clearance. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc. © 2016 The Authors Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

  13. Dose limits

    International Nuclear Information System (INIS)

    Fitoussi, L.

    1987-12-01

    The dose limit is defined to be the level of harmfulness which must not be exceeded, so that an activity can be exercised in a regular manner without running a risk unacceptable to man and the society. The paper examines the effects of radiation categorised into stochastic and non-stochastic. Dose limits for workers and the public are discussed

  14. Phenylalanine and tyrosine levels are rate-limiting factors in production of health promoting metabolites in Vitis vinifera cv. Gamay Red cell suspension

    Directory of Open Access Journals (Sweden)

    Neta eManela

    2015-07-01

    Full Text Available Environmental stresses such as high light intensity and temperature cause induction of the shikimate pathway, aromatic amino acids (AAA pathways, and of pathways downstream from AAAs. The induction leads to production of specialized metabolites that protect the cells from oxidative damage. The regulation of the diverse AAA derived pathways is still not well understood. To gain insight on that regulation, we increased AAA production in red grape Vitis vinifera cv. Gamay Red cell suspension, without inducing external stress on the cells, and characterized the metabolic effect of this induction. Increased AAA production was achieved by expressing a feedback-insensitive bacterial form of 3-deoxy- D-arabino-heptulosonate 7-phosphate synthase enzyme (AroG* of the shikimate pathway under a constitutive promoter. The presence of AroG* protein led to elevated levels of primary metabolites in the shikimate and AAA pathways including phenylalanine and tyrosine, and to a dramatic increase in phenylpropanoids. The AroG* transformed lines accumulated up to 20 and 150 fold higher levels of resveratrol and dihydroquercetin, respectively. Quercetin, formed from dihydroquercetin, and resveratrol, are health promoting metabolites that are induced due to environmental stresses. Testing the expression level of key genes along the stilbenoids, benzenoids and phenylpropanoid pathways showed that transcription was not affected by AroG*. This suggests that concentrations of AAAs, and of phenylalanine in particular, are rate-limiting in production of these metabolites. In contrast, increased phenylalanine production did not lead to elevated concentrations of anthocyanins, even though they are also phenylpropanoid metabolites. This suggests a control mechanism of this pathway that is independent of AAA concentration. Interestingly, total anthocyanin concentrations were slightly lower in AroG* cells, and the relative frequencies of the different anthocyanins changed as

  15. Inverse Limits

    CERN Document Server

    Ingram, WT

    2012-01-01

    Inverse limits provide a powerful tool for constructing complicated spaces from simple ones. They also turn the study of a dynamical system consisting of a space and a self-map into a study of a (likely more complicated) space and a self-homeomorphism. In four chapters along with an appendix containing background material the authors develop the theory of inverse limits. The book begins with an introduction through inverse limits on [0,1] before moving to a general treatment of the subject. Special topics in continuum theory complete the book. Although it is not a book on dynamics, the influen

  16. The use of NH4+rather than NO3-affects cell stoichiometry, C allocation, photosynthesis and growth in the cyanobacterium Synechococcus sp. UTEX LB 2380, only when energy is limiting.

    Science.gov (United States)

    Ruan, Zuoxi; Giordano, Mario

    2017-02-01

    The assimilation of N-NO 3 - requires more energy than that of N-NH 4 + . This becomes relevant when energy is limiting and may impinge differently on cell energy budget depending on depth, time of the day and season. We hypothesize that N-limited and energy-limited cells of the oceanic cyanobacterium Synechococcus sp. differ in their response to the N source with respect to growth, elemental stoichiometry and carbon allocation. Under N limitation, cells retained almost absolute homeostasis of elemental and organic composition, and the use of NH 4 + did not stimulate growth. When energy was limiting, however, Synechococcus grew faster in NH 4 + than in NO 3 - and had higher C (20%), N (38%) and S (30%) cell quotas. Furthermore, more C was allocated to protein, whereas the carbohydrate and lipid pool size did not change appreciably. Energy limitation also led to a higher photosynthetic rate relative to N limitation. We interpret these results as an indication that, under energy limitation, the use of the least expensive N source allowed a spillover of the energy saved from N assimilation to the assimilation of other nutrients. The change in elemental stoichiometry influenced C allocation, inducing an increase in cell protein, which resulted in a stimulation of photosynthesis and growth. © 2016 John Wiley & Sons Ltd.

  17. Stimulated mast cells promote maturation of myocardial microvascular endothelial cell neovessels by modulating the angiopoietin-Tie-2 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Z.H. [Division of Cardiology, Shanghai Sixth People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, Division of Cardiology, Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China); Yancheng People' s First Hospital, Division of Cardiology, Yancheng, Jiangsu, China, Division of Cardiology, Yancheng People’s First Hospital, Yancheng, Jiangsu (China); Zhu, W.; Tao, J.P.; Zhang, Q.Y.; Wei, M. [Division of Cardiology, Shanghai Sixth People' s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China, Division of Cardiology, Shanghai Sixth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai (China)

    2013-10-22

    Angiopoietin (Ang)-1 and Ang-2 interact in angiogenesis to activate the Tie-2 receptor, which may be involved in new vessel maturation and regression. Mast cells (MCs) are also involved in formation of new blood vessels and angiogenesis. The present study was designed to test whether MCs can mediate angiogenesis in myocardial microvascular endothelial cells (MMVECs). Using a rat MMVEC and MC co-culture system, we observed that Ang-1 protein levels were very low even though its mRNA levels were increased by MCs. Interestingly, MCs were able to enhance migration, proliferation, and capillary-like tube formation, which were associated with suppressed Ang-2 protein expression, but not Tie-2 expression levels. These MCs induced effects that could be reversed by either tryptase inhibitor [N-tosyl-L-lysine chloromethyl ketone (TLCK)] or chymase inhibitor (N-tosyl-L-phenylalanyl chloromethyl ketone), with TLCK showing greater effects. In conclusion, our data indicated that MCs can interrupt neovessel maturation via suppression of the Ang-2/Tie-2 signaling pathway.

  18. Validation of a short questionnaire to measure symptoms and functional limitations associated with hand-foot syndrome and mucositis in patients with metastatic renal cell carcinoma.

    Science.gov (United States)

    Lai, Jin-Shei; Beaumont, Jennifer L; Diaz, Jose; Khan, Sadya; Cella, David

    2016-01-15

    Hand-foot syndrome and mucositis/stomatitis are frequent adverse events (AEs) of treatment with tyrosine kinase inhibitors in cancer therapy. Quality-of-life instruments that measure the functional consequences of these AEs are needed to assess the impact of therapeutic interventions and to guide patient care. The Hand-Foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ [formerly the Supplementary Quality of Life Questionnaire]) was used in the COMPARZ trial (Pazopanib vs Sunitinib in the Treatment of Locally Advanced and/or Metastatic Renal Cell Carcinoma [national clinical trial no. NCT00720941]) and the PISCES study (Patient Preference Study of Pazopanib vs Sunitinib in Advanced or Metastatic Kidney Cancer [clinicaltrials.gov NCT01064310]) to assess mouth/throat and hand/foot soreness symptoms and subsequent limitations in patients receiving pazopanib or sunitinib for metastatic renal cell carcinoma. The objective of the current analysis was to validate the HAMSIQ using data from the PISCES study. The HAMSIQ was administered in the PISCES study at baseline and every 2 weeks over two 10-week periods to patients who were receiving pazopanib or sunitinib. Data from the first 10-week period were used to assess the feasibility, validity, and responsiveness of the HAMSIQ. In total, ≥85% of 169 patients completed the HAMSIQ (excluding the item concerning days off work). Correlations among items within the same limitation subscale generally were high (Cronbach α ≥ .80). HAMSIQ limitation scores differentiated patients according to their baseline performance status and severity of soreness. Small-to-moderate correlations were observed for the symptoms/limitation scores and for changes from baseline scores between the HAMSIQ and the Functional Assessment of Chronic Illness Therapy fatigue survey. The HAMSIQ demonstrated responsiveness to changes in clinical status and the development of hand-foot syndrome AEs over time. The HAMSIQ is a feasible, valid

  19. Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting

    Directory of Open Access Journals (Sweden)

    Lawn Stephen D

    2008-07-01

    Full Text Available Abstract Background Viral load monitoring is not available for the vast majority of patients receiving antiretroviral therapy in resource-limited settings. However, the practical utility of CD4 cell count measurements as an alternative monitoring strategy has not been rigorously assessed. Methods In this study, we used a novel modelling approach that accounted for all CD4 cell count and VL values measured during follow-up from the first date that VL suppression was achieved. We determined the associations between CD4 counts (absolute values and changes during ART, VL measurements and risk of virological failure (VL > 1,000 copies/ml following initial VL suppression in 330 patients in South Africa. CD4 count changes were modelled both as the difference from baseline (ΔCD4 count and the difference between consecutive values (CD4 count slope using all 3-monthly CD4 count measurements during follow-up. Results During 7093.2 patient-months of observation 3756 paired CD4 count and VL measurements were made. In patients who developed virological failure (n = 179, VL correlated significantly with absolute CD4 counts (r = - 0.08, P = 0.003, ΔCD4 counts (r = - 0.11, P P P = 0.99, P = 0.92 and P = 0.75, respectively. Moreover, in a receiver operating characteristic (ROC curve, the association between a negative CD4 count slope and virological failure was poor (area under the curve = 0.59; sensitivity = 53.0%; specificity = 63.6%; positive predictive value = 10.9%. Conclusion CD4 count changes correlated significantly with VL at group level but had very limited utility in identifying virological failure in individual patients. CD4 count is an inadequate alternative to VL measurement for early detection of virological failure.

  20. Successful treatment of limited-stage small-cell lung cancer in the right mainstem bronchus by a combination of chemotherapy and argon plasma coagulation

    Directory of Open Access Journals (Sweden)

    Takayuki Takeda

    2017-01-01

    Full Text Available The current standard-of-care treatment for patients with limited-stage small-cell lung cancer (SCLC is concurrent chemoradiotherapy for local and systemic control. However, standard-of-care treatment strategies have not been established for those with limited-stage SCLC who have a history of thoracic radiotherapy due to concerns with complications associated with radiation overdose. A 37-year-old male developed an aspergilloma in the postoperative left thoracic space after he was treated with concurrent chemoradiotherapy for mediastinal type lung adenocarcionoma and subsequent left upper lobectomy for heterochronous dual adenocarcinoma. Fiberoptic bronchoscopy was performed to examine the status of the suspected bronchopleural fistula when a polypoid mass was observed in the right mainstem bronchus. A histological examination showed that the mass was SCLC at a clinical stage of cTisN0M0, stageIA, without local invasion. Since thoracic radiotherapy was not an option due to a previous history of thoracic irradiation, a combination treatment of carboplatin and etoposide was administered for 4 cycles and resulted in good partial response. In addition, argon plasma coagulation (APC was performed as an alternative to curative radiotherapy on day 22 of the 4th cycle. The 5th cycle was administered 7 days after APC at which the anticancer therapy was completed. The patient remains disease-free 60 months after the completion of treatment, which suggests that this combination therapy may resolve very early-stage SCLC.

  1. Triumphing over Charge Transfer Limitations of PEDOT Nanofiber Reduction Catalyst by 1,2-Ethanedithiol Doping for Quantum Dot Solar Cells.

    Science.gov (United States)

    Kim, Tea-Yon; Lee, Tae Kyung; Kim, Byung Su; Park, Seul Chan; Lee, Sungjin; Im, Seung Soon; Bisquert, Juan; Kang, Yong Soo

    2017-01-18

    Charge transfer between a conducting polymer-based counter electrode (CE) and a polysulfide (S 2- /S n 2- ) electrolyte mediator is a key limitation to improvements of solar energy conversion efficiency (ECE) in quantum-dot-sensitized solar cells (QDSCs). In this paper, 1,2-ethanedithiol (EDT) was doped into nanofibrous poly(3,4-ethylenedioxythiophene) (PEDOT NF) to overcome the charge transfer limitation between PEDOT NF and S 2- /S n 2- . EDT not only helps to reduce the aggregation and thus enhance the linearization of the PEDOT chains but also changes the molecular conformation of the PEDOT chains from a benzoid to a quinoid structure. EDT-doped PEDOT NF-based CEs showed almost 3.7 times higher conductivity, better electrocatalytic activity, and improved compatibility with S 2- /S n 2- in an aqueous electrolyte. As a result, the charge transfer resistance between the polymer-based CE and the S 2- /S n 2- electrolyte was significantly reduced, resulting in over 3% ECE in QDSCs, more than double that of a bare PEDOT NF-based CE.

  2. Limitations of the HOMA-B score for assessment of beta-cell functionality in interventional trials-results from the PIOglim study.

    Science.gov (United States)

    Pfützner, Andreas; Derwahl, Michael; Jacob, Stephan; Hohberg, Cloth; Blümner, Ernst; Lehmann, Ute; Fuchs, Winfried; Forst, Thomas

    2010-08-01

    Drugs with unspecific stimulating effects on beta-cell secretion increase the homeostasis model assessment (HOMA)-B score, indicating improved beta-cell "function." We investigated whether the beta-cell protection provided by adding pioglitazone (PIO) to glimepiride (GLIM) in comparison to up-titrating the GLIM dose alone is reflected by appropriate changes in several measures of beta-cell function, including HOMA-B score. This double-blind, parallel prospective 6-month study was performed with 82 patients (47 men, 35 women; age, 61 +/- 9 years; duration of disease, 5.3 +/- 4.4 years; body mass index, 32.6 +/- 6.0 kg/m(2); hemoglobin A1c [HbA1c], 7.3 +/- 0.7%) with GLIM monotherapy (1-3 mg). They were randomized to receive a GLIM + PIO combination with up-titration (2 mg + 30 mg/4 mg + 30 mg/4 mg + 4 mg) or to remain on GLIM (up-titration 4/5/6 mg). Observation parameters determined at baseline and end point included HOMA-B, HOMA-IR, HbA1c, glucose, insulin, and intact proinsulin. There was a slight increase in the HOMA-B score in the GLIM group but not in the GLIM + PIO arm (baseline/end point: for GLIM, 71 +/- 48/88 +/- 64; for PIO + GLIM, 74 +/- 56/69 +/- 52). Improvements in the other observation parameters were predominantly detected in the PIO + GLIM group (HbA1c, 7.20 +/- 0.61%/6.36 +/- 0.90%; HOMA-IR, 7.0 +/- 4.5/4.1 +/- 2.1; intact proinsulin, 12.4 +/- 10.3/7.6 +/- 4.8 pmol/L [all P HOMA-IR, 7.4 +/- 4.5/7.5 +/- 4.3 [not significant]; intact proinsulin, 17.3 +/- 21.6/16.3 +/- 15.5 pmol/L [not significant]). The PIO + GLIM combination led to overall improvement of laboratory biomarkers for beta-cell function, except for HOMA-B. Glimepiride up-titration had no such effects but increased the HOMA-B score. HOMA-B seems to provide misleading results when used as a diagnostic tool in patients treated with sulfonylurea drugs. A corrective term for consideration of proinsulin in the HOMA-B equation may address this limitation.

  3. Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Massimo Dal Monte

    2018-03-01

    Full Text Available Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON and is an initial symptom of multiple sclerosis (MS. Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG, were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM, a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro-FAG (nFAG®, a balanced mixture of fatty acids (FAs, counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role.

  4. Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Jeanny [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Il Han, E-mail: ihkim@snu.ac.kr [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of); Institute of Radiation Medicine, Medical Research Center, Seoul National University, Seoul (Korea, Republic of); Kim, Byoung Hyuck [Department of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Tae Min; Heo, Dae Seog [Department of Internal Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2015-05-01

    Purpose: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. Methods and Materials: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8% had bulky tumors (≥7 cm); and 75.3% underwent ≥6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). Results: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). Conclusions: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.

  5. Testing the limits of the Maxwell distribution of velocities for atoms flying nearly parallel to the walls of a thin cell

    Science.gov (United States)

    Todorov, Petko; Bloch, Daniel

    2017-11-01

    For a gas at thermal equilibrium, it is usually assumed that the velocity distribution follows an isotropic 3-dimensional Maxwell-Boltzmann (M-B) law. This assumption classically implies the assumption of a "cos θ" law for the flux of atoms leaving the surface. Actually, such a law has no grounds in surface physics, and experimental tests of this assumption have remained very few. In a variety of recently developed sub-Doppler laser spectroscopy techniques for gases one-dimensionally confined in a thin cell, the specific contribution of atoms moving nearly parallel to the boundary of the vapor container becomes essential. We report here on the implementation of an experiment to probe effectively the distribution of atomic velocities parallel to the windows for a thin (60 μm) Cs vapor cell. The principle of the setup relies on a spatially separated pump-probe experiment, where the variations of the signal amplitude with the pump-probe separation provide the information on the velocity distribution. The experiment is performed in a sapphire cell on the Cs resonance line, which benefits from a long-lived hyperfine optical pumping. Presently, we can analyze specifically the density of atoms with slow normal velocities ˜5-20 m/s, already corresponding to unusual grazing flight—at ˜85°-88.5° from the normal to the surface—and no deviation from the M-B law is found within the limits of our elementary setup. Finally we suggest tracks to explore more parallel velocities, when surface details—roughness or structure—and the atom-surface interaction should play a key role to restrict the applicability of an M-B-type distribution.

  6. Current approaches for avoiding the limitations of circulating tumor cells detection methods-implications for diagnosis and treatment of patients with solid tumors.

    Science.gov (United States)

    Kowalik, Artur; Kowalewska, Magdalena; Góźdź, Stanisław

    2017-07-01

    Eight million people die of cancer each year and 90% of deaths are caused by systemic disease. Circulating tumor cells (CTCs) contribute to the formation of metastases and thus are the subject of extensive research and an abiding interest to biotechnology and pharmaceutical companies. Recent technological advances have resulted in greatly improved CTC detection, enumeration, expansion, and culture methods. However, despite the fact that nearly 150 years have passed since the first detection and description of CTCs in human blood and enormous technological progress that has taken place in this field, especially within the last decade, few CTC detection methods have been approved for routine clinical use. This reflects the substantial methodological problems related to the nature of these cells, their heterogeneity, and diverse metastatic potential. Here, we provide an overview of CTC phenotypes, including the plasticity of CTCs and the relevance of inflammation and cell fusion phenomena for CTC biology. We also review the literature on CTC detection methodology-its recent improvements, clinical significance, and efforts of its clinical application in cancer patients management. At present, CTC detection remains a challenging diagnostic approach as a result of numerous current methodological limitations. This is especially problematic during the early stages of the disease due to the small numbers of CTCs released into the blood of cancer patients. Nonetheless, the rapid development of novel techniques of CTC detection and enumeration in peripheral blood is expected to expedite their implementation in the clinical setting. It is of utmost importance to understand the biology of CTCs and their distinct populations as a prerequisite for achieving this ultimate goal. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Irinotecan and cisplatin with concurrent thoracic radiotherapy in a once-every-three-weeks schedule in patients with limited-disease small-cell lung cancer : A phase I study

    NARCIS (Netherlands)

    de Jong, W. X.; de Jonge, M. J. A.; van der Leest, A. H. D.; van Meerbeeck, J. P.; Groen, H. J. M.

    Background: Irinotecan and cisplatin with concurrent radiotherapy is a powerful treatment combination for patients with limited-disease small-cell lung cancer (LD-SCLC). The objective was to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of irinotecan and cisplatin with

  8. Process of care and preliminary outcome in limited-stage small-cell lung cancer: results of the 1995-1997 patterns of care study in Japan

    International Nuclear Information System (INIS)

    Uno, Takashi; Sumi, Minako; Sawa, Yoshihide M.S.; Teshima, Teruki; Hara, Ryusuke; Ikeda, Hiroshi; Inoue, Toshihiko

    2003-01-01

    Purpose: To evaluate the practice process using the national average (Na); to compare differences in the process of care by age group; and to provide a preliminary outcome data for limited-stage small-cell lung cancer in Japan. Methods and Materials: The Patterns of Care Study conducted a nationwide survey of the care process for Stage I-III small-cell lung cancer in Japan. Patients were divided into three age groups: <65 years (younger group, n = 73); between 65 and 74 years (intermediate group, n = 81); and ≥75 years (elderly group, n = 20). Results: The NA for the total dose was 49.0 Gy, and for use of photon energy ≥6 MV, chemotherapy, and prophylactic cranial irradiation was 77.3%, 93.2%, and 1.69%, respectively. Age stratification had no impact on the variables of radiotherapy (RT) such as total dose and field size. Only 37% of patients received chemotherapy and thoracic RT concurrently. The proportion of patients who received chemotherapy and RT concurrently was 44%, 27%, and 25% of the younger, intermediate, and elderly groups, respectively (p = 0.029). Etoposide and cisplatin were less frequently used in the elderly group (≥75 years old). Overall survival at 3 years for the entire group was 26%. The 3-year survival rate was 30% in the younger group, 28% in the intermediate group, and 9% in the elderly group. Variables found to have a significant impact on survival by multivariate analysis were the use of chemotherapy (p = 0.030), age (p 0.032), and T stage (p = 0.042). Conclusion: Calculated NAs showed that the results of clinical study had favorably penetrated into the practice process in Japan. The results demonstrated that patient age significantly influenced the process of chemotherapy such as the use of etoposide and cisplatin for limited-stage small-cell lung cancer in Japan. More concurrent chemotherapy and thoracic RT and the application of prophylactic cranial irradiation for complete responders need to be investigated in the future

  9. A rapid method for the differentiation of yeast cells grown under carbon and nitrogen-limited conditions by means of partial least squares discriminant analysis employing infrared micro-spectroscopic data of entire yeast cells

    Science.gov (United States)

    Kuligowski, Julia; Quintás, Guillermo; Herwig, Christoph; Lendl, Bernhard

    2012-01-01

    This paper shows the ease of application and usefulness of mid-IR measurements for the investigation of orthogonal cell states on the example of the analysis of Pichia pastoris cells. A rapid method for the discrimination of entire yeast cells grown under carbon and nitrogen-limited conditions based on the direct acquisition of mid-IR spectra and partial least squares discriminant analysis (PLS-DA) is described. The obtained PLS-DA model was extensively validated employing two different validation strategies: (i) statistical validation employing a method based on permutation testing and (ii) external validation splitting the available data into two independent sub-sets. The Variable Importance in Projection scores of the PLS-DA model provided deeper insight into the differences between the two investigated states. Hence, we demonstrate the feasibility of a method which uses IR spectra from intact cells that may be employed in a second step as an in-line tool in process development and process control along Quality by Design principles. PMID:22967595

  10. Xenotransplantation: Perspectives and limits

    OpenAIRE

    Hammer, Claus

    2001-01-01

    Xenotransplantation faces the dilemma of an unlimited supply of cells, tissues and organs on the one hand and severe obstacles and limits on the other. One reason for the limitations is that the source animal of choice, the pig, and the human recipient separated 90 million years ago during evolution, a time in which biological characteristics such as anatomy, physiology and immunology have had much time to drift far apart. The acceptance of such an evolutionary widely divergent organ, especia...

  11. Age Limits

    OpenAIRE

    Jan Antfolk

    2017-01-01

    Whereas women of all ages prefer slightly older sexual partners, men—regardless of their age—have a preference for women in their 20s. Earlier research has suggested that this difference between the sexes’ age preferences is resolved according to women’s preferences. This research has not, however, sufficiently considered that the age range of considered partners might change over the life span. Here we investigated the age limits (youngest and oldest) of considered and actual sex partners in...

  12. Dosimetric rationale and early experience at UFPTI of thoracic proton therapy and chemotherapy in limited-stage small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Colaco, Rovel J.; Huh, Soon; Nichols, Romaine; Morris, Christopher G.; Flampouri, Stella; Li, Zuofeng; Hoppe, Bradford S. [Univ. of Florida Proton Therapy Inst., Jacksonville (United States)], e-mail: bhoppe@floridaproton.org; D' Agostino, Harry [Dept. of Thoracic Surgery, Univ. of Florida Coll. of Medicine, Gainesville (United States); Pham, Dat C. [Dept. of Hematology and Medical Oncology, Univ. of Florida Coll. of Medicine, Gainesville (United States); Bajwa, Abubakr A. [Dept. of Medicine, Univ. of Florida Coll. of Medicine, Gainesville (United States)

    2013-04-15

    Background: Concurrent chemoradiotherapy (CRT) is the standard of care in patients with limited-stage small cell lung cancer (SCLC). Treatment with conventional x-ray therapy (XRT) is associated with high toxicity rates, particularly acute grade 3+ esophagitis and pneumonitis. We present outcomes for the first known series of limited-stage SCLC patients treated with proton therapy and a dosimetric comparison of lung and esophageal doses with intensity-modulated radiation therapy (IMRT). Material and methods: Six patients were treated; five concurrently and one sequentially. Five patients received 60-66 CGE in 30-34 fractions once daily and one patient received 45 CGE in 30 fractions twice daily. All six patients received prophylactic cranial irradiation. Common Terminology Criteria for Adverse Events, v3.0, was used to grade toxicity. IMRT plans were also generated and compared with proton plans. Results: The median follow-up was 12.0 months. The one-year overall and progression-free survival rates were 83% and 66%, respectively. There were no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis, and no other acute grade 3+ non-hematological toxicities were seen. One patient with a history of pulmonary fibrosis and atrial fibrillation developed worsening symptoms four months after treatment requiring oxygen. Three patients died; two of progressive disease and one after a fall. The latter patient was disease-free at 36 months after treatment. Another patient recurred and is alive, while two patients remain disease-free at 12 months of follow-up. Proton therapy proved superior to IMRT across all esophageal and lung dose volume points. Conclusion. In this small series of SCLC patients treated with proton therapy with radical intent, treatment was well tolerated with no cases of acute grade 3+ esophagitis or acute grade 2+ pneumonitis. Dosimetric comparison showed better sparing of lung and esophagus with proton therapy. Proton therapy merits further

  13. Value and limits of non-robotic transoral oropharyngectomy for local control of T1-2 invasive squamous cell carcinoma of the tonsillar fossa.

    Science.gov (United States)

    Laccourreye, O; Malinvaud, D; Holostenco, V; Ménard, M; Garcia, D; Bonfils, P

    2015-06-01

    An analysis of the value and limits of non-robotic transoral oropharyngectomy for local control of T1-2 squamous cell carcinoma of the tonsillar fossa. A retrospective series of 111 T1 and 133 T2 (N0: 129; N1: 52; N2: 53; N3: 10). Induction chemotherapy and postoperative radiation therapy were used in 63.5% and 29.5% of cases, respectively. Actuarial analysis of local failure, impact of various variables upon local failure and consequences of local failure upon other oncological events and survival are documented. The 5-year actuarial local failure estimate was 10.4% and 14.2% for T1 and T2 tumors, respectively. The 5-year actuarial local failure estimate was significantly reduced when resection margins were safe or yielded dysplasia (P=0.008) and when induction chemotherapy achieved complete histologic regression (P=0.013). Salvage treatment achieved a 97.2% and 93.2% overall local control rate in T1 and T2 tumors, respectively. The 5-year actuarial nodal failure estimate was 35.1% in patients with local failure versus 10.8% without (P=0.0001). The 5-year actuarial metachronous second primary estimate was 7% in patients with local failure versus 33.2% without (P=0.016). The impact of local failure on survival (5-year actuarial survival estimate: 67.3% without and 46.4% with local failure) was not significant. In T1-2 squamous cell carcinoma of the tonsillar fossa, non-robotic transoral oropharyngectomy appeared to be highly effective in terms of local control. The high incidence of head and neck metachronous second primaries further advocates the use of this treatment option in order to reserve radiation therapy to such cases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  14. Limits of ZnO Electrodeposition in Mesoporous Tin Doped Indium Oxide Films in View of Application in Dye-Sensitized Solar Cells

    Directory of Open Access Journals (Sweden)

    Christian Dunkel

    2014-04-01

    Full Text Available Well-ordered 3D mesoporous indium tin oxide (ITO films obtained by a templated sol-gel route are discussed as conductive porous current collectors. This paper explores the use of such films modified by electrochemical deposition of zinc oxide (ZnO on the pore walls to improve the electron transport in dye-sensitized solar cells (DSSCs. Mesoporous ITO film were dip-coated with pore sizes of 20–25 nm and 40–45 nm employing novel poly(isobutylene-b-poly(ethylene oxide block copolymers as structure-directors. After electrochemical deposition of ZnO and sensitization with the indoline dye D149 the films were tested as photoanodes in DSSCs. Short ZnO deposition times led to strong back reaction of photogenerated electrons from non-covered ITO to the electrolyte. ITO films with larger pores enabled longer ZnO deposition times before pore blocking occurred, resulting in higher efficiencies, which could be further increased by using thicker ITO films consisting of five layers, but were still lower compared to nanoporous ZnO films electrodeposited on flat ITO. The major factors that currently limit the application are the still low thickness of the mesoporous ITO films, too small pore sizes and non-ideal geometries that do not allow obtaining full coverage of the ITO surface with ZnO before pore blocking occurs.

  15. Developmental hypothyroxinaemia and hypothyroidism limit dendritic growth of cerebellar Purkinje cells in rat offspring: involvement of microtubule-associated protein 2 (MAP2) and stathmin.

    Science.gov (United States)

    Wang, Yuan; Wang, Yi; Dong, Jing; Wei, Wei; Song, Binbin; Min, Hui; Teng, Weiping; Chen, Jie

    2014-06-01

    Iodine is essential for the synthesis of thyroid hormone. Iodine deficiency (ID)-induced hypothyroxinaemia and hypothyroidism during developmental period contribute to impairments of function in the brain, such as psychomotor and motor alterations. However, the mechanisms are still unclear. Therefore, the present research is to study the effects of developmental hypothyroxinaemia caused by mild ID and developmental hypothyroidism caused by severe ID or methimazole (MMZ) on dendritic growth in filial cerebellar Purkinje cells (PCs) and the underlying mechanisms. A maternal hypothyroxinaemia model was established in Wistar rats using a mild ID diet, and two maternal hypothyroidism models were developed with either severe ID diet or MMZ water. We examined the total dendritic length using immunofluorescence, and Western blot analysis was conducted to investigate the activity of microtubule-associated protein 2 (MAP2), stathmin and calcium/calmodulin-dependent protein kinase II (CaMKII). Hypothyroxinaemia and hypothyroidism reduced the total dendritic length of cerebellar PCs, decreased MAP2 and its phosphorylation, increased stathmin but reduced its phosphorylation and down-regulated the activity of CaMKII and its phosphorylation in cerebellar PCs on postnatal day (PN) 7, PN14 and PN21. Developmental hypothyroxinaemia induced by mild ID and hypothyroidism induced by severe ID or MMZ limit PCs dendritic growth, which may involve in the disturbance of MAP2 and stathmin in a CaMKII-dependent manner. It suggests a potential mechanism of motor coordination impairments caused by developmental hypothyroxinaemia and hypothyroidism. © 2013 British Neuropathological Society.

  16. Silicon photomultiplier (SPM) detection of low-level bioluminescence for the development of deployable whole-cell biosensors: possibilities and limitations.

    Science.gov (United States)

    Li, Huaqing; Lopes, Nicholas; Moser, Scott; Sayler, Gary; Ripp, Steven

    2012-03-15

    Whole-cell bacterial bioreporters await miniaturized photon counting modules with high sensitivity and robust compatible hardware to fulfill their promise of versatile, on-site biosensor functionality. In this study, we explore the photon counting readout properties of the silicon photomultiplier (SPM) with a thermoelectric cooler and the possibilities of detecting low-level bioluminescent signals. Detection performance was evaluated through a simulated LED light source and the bioluminescence produced by the genetically engineered Pseudomonas fluorescens bacterial bioreporter 5RL. Compared with the conventional photomultiplier tube (PMT), the results revealed that the cooled SPM exhibits a wider linear response to inducible substrate concentrations (salicylate) ranging from 250 to 5000 ppb. Although cooling of the SPM lowered dark count rates and improved the minimum detectable signal, and the application of a digital filter enhanced the signal-to-noise ratio, the detection of very low light signals is still limited and remains a challenge in the design of compact photon counting systems. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Long-term persistence of limited HTLV-I Tax-specific cytotoxic T cell clones in a patient with adult T cell leukemia/lymphoma after allogeneic stem cell transplantation.

    Science.gov (United States)

    Tanaka, Yukie; Nakasone, Hideki; Yamazaki, Rie; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Machishima, Tomohito; Sato, Miki; Terasako, Kiriko; Kimura, Shun-ichi; Kikuchi, Misato; Okuda, Shinya; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

    2012-12-01

    Adult T cell leukemia/lymphoma (ATL) is a highly aggressive malignancy of T cells caused by human T cell lymphotropic virus type 1 (HTLV-1). Recent clinical studies have suggested that allogeneic stem cell transplantation (HSCT) improves the clinical course of ATL by harnessing a graft-versus-ATL effect, and that donor-derived HTLV-1 Tax-specific CD8(+) cytotoxic T cells (CTLs) contribute to the graft-versus-ATL effect after HSCT. However, little is known about the immunological characteristics of Tax-specific CTLs in ATL patients who underwent HSCT. We serially analyzed frequencies, differentiation, functions and clonal dynamics of Tax-specific CTLs in paired samples of peripheral blood (PB) and bone marrow (BM) from an ATL patient after HSCT at the single-cell level. We used flowcytometric and single-cell T cell receptor (TCR) repertoire analysis methods without culture steps. Donor-derived Tax-specific CTLs effectively suppressed HTLV-1 replication in both PB and BM at least during chronic graft-versus-host disease after HSCT. Furthermore, Tax-specific CTLs had comparable properties between BM and PB, except for preferential accumulation in BM rather than PB. Tax-specific CTLs persistently existed as less-differentiated CD45RA(-)CCR7(-) effector memory CTLs based on predominant phenotypes of CD27(+), CD28(+/-) and CD57(+/-). Our approach using single-cell TCR repertoire analysis method showed highly restricted oligoclonal responses of Tax-specific CTLs, and TCR BV7- or BV30- expressing two predominant CTL clones persistently existed and maintained strong cytotoxic activities against HTLV-1 in both PB and BM over three years after HSCT. These findings about Tax-specific CTLs provide insights into future directions for studies on immunotherapy against ATL.

  18. Limited Impact of Setup and Range Uncertainties, Breathing Motion, and Interplay Effects in Robustly Optimized Intensity Modulated Proton Therapy for Stage III Non-small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Inoue, Tatsuya [Department of Radiology, Juntendo University Urayasu Hospital, Chiba (Japan); Widder, Joachim; Dijk, Lisanne V. van [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Takegawa, Hideki [Department of Radiation Oncology, Kansai Medical University Hirakata Hospital, Osaka (Japan); Koizumi, Masahiko; Takashina, Masaaki [Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Osaka (Japan); Usui, Keisuke; Kurokawa, Chie; Sugimoto, Satoru [Department of Radiation Oncology, Juntendo University Graduate School of Medicine, Tokyo (Japan); Saito, Anneyuko I. [Department of Radiology, Juntendo University Urayasu Hospital, Chiba (Japan); Department of Radiation Oncology, Juntendo University Graduate School of Medicine, Tokyo (Japan); Sasai, Keisuke [Department of Radiation Oncology, Juntendo University Graduate School of Medicine, Tokyo (Japan); Veld, Aart A. van' t; Langendijk, Johannes A. [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands); Korevaar, Erik W., E-mail: e.w.korevaar@umcg.nl [Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen (Netherlands)

    2016-11-01

    Purpose: To investigate the impact of setup and range uncertainties, breathing motion, and interplay effects using scanning pencil beams in robustly optimized intensity modulated proton therapy (IMPT) for stage III non-small cell lung cancer (NSCLC). Methods and Materials: Three-field IMPT plans were created using a minimax robust optimization technique for 10 NSCLC patients. The plans accounted for 5- or 7-mm setup errors with ±3% range uncertainties. The robustness of the IMPT nominal plans was evaluated considering (1) isotropic 5-mm setup errors with ±3% range uncertainties; (2) breathing motion; (3) interplay effects; and (4) a combination of items 1 and 2. The plans were calculated using 4-dimensional and average intensity projection computed tomography images. The target coverage (TC, volume receiving 95% of prescribed dose) and homogeneity index (D{sub 2} − D{sub 98}, where D{sub 2} and D{sub 98} are the least doses received by 2% and 98% of the volume) for the internal clinical target volume, and dose indexes for lung, esophagus, heart and spinal cord were compared with that of clinical volumetric modulated arc therapy plans. Results: The TC and homogeneity index for all plans were within clinical limits when considering the breathing motion and interplay effects independently. The setup and range uncertainties had a larger effect when considering their combined effect. The TC decreased to <98% (clinical threshold) in 3 of 10 patients for robust 5-mm evaluations. However, the TC remained >98% for robust 7-mm evaluations for all patients. The organ at risk dose parameters did not significantly vary between the respective robust 5-mm and robust 7-mm evaluations for the 4 error types. Compared with the volumetric modulated arc therapy plans, the IMPT plans showed better target homogeneity and mean lung and heart dose parameters reduced by about 40% and 60%, respectively. Conclusions: In robustly optimized IMPT for stage III NSCLC, the setup and range

  19. Age Limits.

    Science.gov (United States)

    Antfolk, Jan

    2017-03-01

    Whereas women of all ages prefer slightly older sexual partners, men-regardless of their age-have a preference for women in their 20s. Earlier research has suggested that this difference between the sexes' age preferences is resolved according to women's preferences. This research has not, however, sufficiently considered that the age range of considered partners might change over the life span. Here we investigated the age limits (youngest and oldest) of considered and actual sex partners in a population-based sample of 2,655 adults (aged 18-50 years). Over the investigated age span, women reported a narrower age range than men and women tended to prefer slightly older men. We also show that men's age range widens as they get older: While they continue to consider sex with young women, men also consider sex with women their own age or older. Contrary to earlier suggestions, men's sexual activity thus reflects also their own age range, although their potential interest in younger women is not likely converted into sexual activity. Compared to homosexual men, bisexual and heterosexual men were more unlikely to convert young preferences into actual behavior, supporting female-choice theory.

  20. Age Limits

    Directory of Open Access Journals (Sweden)

    Jan Antfolk

    2017-01-01

    Full Text Available Whereas women of all ages prefer slightly older sexual partners, men—regardless of their age—have a preference for women in their 20s. Earlier research has suggested that this difference between the sexes’ age preferences is resolved according to women’s preferences. This research has not, however, sufficiently considered that the age range of considered partners might change over the life span. Here we investigated the age limits (youngest and oldest of considered and actual sex partners in a population-based sample of 2,655 adults (aged 18-50 years. Over the investigated age span, women reported a narrower age range than men and women tended to prefer slightly older men. We also show that men’s age range widens as they get older: While they continue to consider sex with young women, men also consider sex with women their own age or older. Contrary to earlier suggestions, men’s sexual activity thus reflects also their own age range, although their potential interest in younger women is not likely converted into sexual activity. Compared to homosexual men, bisexual and heterosexual men were more unlikely to convert young preferences into actual behavior, supporting female-choice theory.

  1. The yeast three-hybrid system as an experimental platform to identify proteins interacting with small signaling molecules in plant cells: potential and limitations.

    Science.gov (United States)

    Cottier, Stéphanie; Mönig, Timon; Wang, Zheming; Svoboda, Jiří; Boland, Wilhelm; Kaiser, Markus; Kombrink, Erich

    2011-01-01

    Chemical genetics is a powerful scientific strategy that utilizes small bioactive molecules as experimental tools to unravel biological processes. Bioactive compounds occurring in nature represent an enormous diversity of structures that can be used to dissect functions of biological systems. Once the bioactivity of a natural or synthetic compound has been critically evaluated the challenge remains to identify its molecular target and mode of action, which usually is a time-consuming and labor-intensive process. To facilitate this task, we decided to implement the yeast three-hybrid (Y3H) technology as a general experimental platform to scan the whole Arabidopsis proteome for targets of small signaling molecules. The Y3H technology is based on the yeast two-hybrid system and allows direct cloning of proteins that interact in vivo with a synthetic hybrid ligand, which comprises the biologically active molecule of interest covalently linked to methotrexate (Mtx). In yeast nucleus the hybrid ligand connects two fusion proteins: the Mtx part binding to dihydrofolate reductase fused to a DNA-binding domain (encoded in the yeast strain), and the bioactive molecule part binding to its potential protein target fused to a DNA-activating domain (encoded on a cDNA expression vector). During cDNA library screening, the formation of this ternary, transcriptional activator complex leads to reporter gene activation in yeast cells, and thereby allows selection of the putative targets of small bioactive molecules of interest. Here we present the strategy and experimental details for construction and application of a Y3H platform, including chemical synthesis of different hybrid ligands, construction of suitable cDNA libraries, the choice of yeast strains, and appropriate screening conditions. Based on the results obtained and the current literature we discuss the perspectives and limitations of the Y3H approach for identifying targets of small bioactive molecules.

  2. The yeast three-hybrid system as an experimental platform to identify proteins interacting with small signaling molecules in plant cells: Potential and limitations

    Directory of Open Access Journals (Sweden)

    Stéphanie eCottier

    2011-12-01

    Full Text Available Chemical genetics is a powerful scientific strategy that utilizes small bioactive molecules as experimental tools to unravel biological processes. Bioactive compounds occurring in nature represent an enormous diversity of structures that can be used to dissect functions of biological systems. Once the bioactivity of a natural or synthetic compound has been critically evaluated the challenge remains to identify its molecular target and mode of action, which usually is a time consuming and labor-intensive process. To facilitate this task, we decided to implement the yeast three-hybrid (Y3H technology as a general experimental platform to scan the whole Arabidopsis proteome for targets of small signaling molecules. The Y3H technology is based on the yeast two-hybrid system and allows direct cloning of proteins that interact in vivo with a synthetic hybrid ligand, which comprises the biologically active molecule of interest covalently linked to methotrexate (Mtx. In yeast nucleus the hybrid ligand connects two fusion proteins: the Mtx part binding to dihydrofolate reductase fused to a DNA binding domain (encoded in the yeast strain, and the bioactive molecule part binding to its potential protein target fused to a DNA activating domain (encoded on a cDNA expression vector. During cDNA library screening, the formation of this ternary, transcriptional activator complex leads to reporter gene activation in yeast cells, and thereby allows selection of the putative targets of small bioactive molecules of interest. Here we present the strategy and experimental details for construction and application of a Y3H platform, including chemical synthesis of different hybrid ligands, construction of suitable cDNA libraries, the choice of yeast strains, and appropriate screening conditions. Based on the results obtained and the current literature we discussed the perspectives and limitations of the Y3H approach for identifying targets of small bioactive molecules.

  3. A retrospective analysis of survival outcomes for two different radiotherapy fractionation schedules given in the same overall time for limited stage small cell lung cancer

    International Nuclear Information System (INIS)

    Bettington, Catherine S.; Bryant, Guy; Hickey, Brigid; Tripcony, Lee; Pratt, Gary; Fay, Michael

    2013-01-01

    To compare survival outcomes for two fractionation schedules of thoracic radiotherapy, both given over 3 weeks, in patients with limited stage small cell lung cancer (LS-SCLC). At Radiation Oncology Mater Centre (ROMC) and the Royal Brisbane and Women's Hospital (RBWH), patients with LS-SCLC treated with curative intent are given radiotherapy (with concurrent chemotherapy) to a dose of either 40Gy in 15 fractions ('the 40Gy/15⧣group') or 45Gy in 30 fractions ('the 45Gy/30⧣group'). The choice largely depends on institutional preference. Both these schedules are given over 3 weeks, using daily and twice-daily fractionation respectively. The records of all such patients treated from January 2000 to July 2009 were retrospectively reviewed and survival outcomes between the two groups compared. Of 118 eligible patients, there were 38 patients in the 40Gy/15⧣ group and 41 patients in the 45Gy/30⧣ group. The median relapse-free survival time was 12 months in both groups. Median overall survival was 21 months (95% CI 2–37 months) in the 40Gy/15⧣ group and 26 months (95% CI 1–48 months) in the 45Gy/30⧣ group. The 5-year overall survival rates were 20% and 25%, respectively (P=0.24). On multivariate analysis, factors influencing overall survival were: whether prophylactic cranial irradiation (PCI) was given (P=0.01) and whether salvage chemotherapy was given at the time of relapse (P=0.057). Given the small sample size, the potential for selection bias and the retrospective nature of our study it is not possible to draw firm conclusions regarding the efficacy of hypofractionated thoracic radiotherapy compared with hyperfractionated accelerated thoracic radiotherapy however hypofractionated radiotherapy may result in equivalent relapse-free survival.

  4. Influence of Interfraction Interval on Local Tumor Control in Patients With Limited-Disease Small-Cell Lung Cancer Treated With Radiochemotherapy

    International Nuclear Information System (INIS)

    Jeremic, Branislav; Milicic, Biljana

    2007-01-01

    Purpose: To investigate the influence of interfraction interval (IFI) on local recurrence-free survival (LRFS) in patients with limited-disease small-cell lung cancer (LD SCLC) treated with accelerated hyperfractionated radiotherapy (Acc Hfx RT) and concurrent cisplatin and etoposide (PE). Methods and Materials: A total of 103 patients were treated with either 'early' (Cycle 1) or 'late' (Cycle 4) concurrent Acc Hfx RT/PE. Two daily fractions were nonrandomly given using an IFI of either 4.5-5.0 h ('shorter') (n = 52) or 5.5-6.0 h ('longer') (n = 51). Results: The median LRFS and 5-year LRFS rate for all 103 patients were 52 months and 48%, respectively. Besides gender, Karnofsky performance status, and treatment group, IFI also influenced LRFS, whereas age and weight loss did not. When a multivariate model was used, IFI was marginally insignificant (p = 0.0770) as a predictor of LRFS. In terms of individual treatment groups, IFI was not significant in 'early' Acc Hfx RT/PE but showed a strong trend in a 'late' Acc Hfx RT/PE regimen. Although a shorter IFI led to a higher incidence of high-grade (≥3) esophagitis, leukopenia, and infection, a correlation analysis of toxicities with all potential prognostic factors showed that a shorter IFI was not an independent predictor of any acute high-grade toxicity. Conclusion: 'Shorter' IFI had a marginally insignificant influence on LRFS. A strong trend favoring it was observed in patients treated with 'late' concurrent Acc Hfx RT/PE. This may be of interest because it could contribute to further understanding of potential biologic parameters influencing treatment outcome

  5. Cambial activity and xylem cell development inPinus cembraandPinus sylvestrisat their climatic limits in the Eastern Alps in 2007.

    Science.gov (United States)

    Swidrak, Irene; Gruber, Andreas; Oberhuber, Walter

    2011-12-20

    It has been frequently stressed that at distributional boundaries, like at the Alpine timberline and within dry inner Alpine environments, tree growth will be affected first by changing climate conditions. Climate in 2007 was characterized by the occurrence of exceptionally mild temperatures in spring (3.4 and 2.7 °C above long-term mean (LTM) at timberline and the valley sites, respectively) with an almost continuous drought period recorded in April and slightly warmer than average temperatures throughout summer (1.3 °C above LTM at both sites). We compared temporal dynamics of cambial activity and xylem cell development in Pinus cembra at the Alpine timberline (1950 m a.s.l.) and Pinus sylvestris at a xeric inner Alpine site (750 m a.s.l.) by repeated cellular analyses of micro-cores (n = 5 trees/site). While onset of wood formation in P. sylvestris and P. cembra differed by about two weeks (12 and 27 April, respectively), maximum daily growth rates peaked on 6 May at the valley site and on 23 June at timberline. At both sites maximum tracheid production was reached prior to occurrence of more favourable climatic conditions during summer, i.e. an increase in precipitation and temperature. Xylem formation ended on 31 August and 28 October at the xeric site and at timberline, respectively. This study demonstrates the plasticity of tree-ring formation along an altitudinal transect in response to water availability and temperature. Whether early achievement of maximum growth rates is an adaptation to cope with extreme environmental conditions prevailing at limits of tree growth needs to be analysed more closely by taking belowground carbon allocation into account.

  6. Cambial activity and xylem cell development in Pinus cembra and Pinus sylvestris at their climatic limits in the Eastern Alps in 2007

    Science.gov (United States)

    Swidrak, Irene; Gruber, Andreas; Oberhuber, Walter

    2013-01-01

    Summary It has been frequently stressed that at distributional boundaries, like at the Alpine timberline and within dry inner Alpine environments, tree growth will be affected first by changing climate conditions. Climate in 2007 was characterized by the occurrence of exceptionally mild temperatures in spring (3.4 and 2.7 °C above long-term mean (LTM) at timberline and the valley sites, respectively) with an almost continuous drought period recorded in April and slightly warmer than average temperatures throughout summer (1.3 °C above LTM at both sites). We compared temporal dynamics of cambial activity and xylem cell development in Pinus cembra at the Alpine timberline (1950 m a.s.l.) and Pinus sylvestris at a xeric inner Alpine site (750 m a.s.l.) by repeated cellular analyses of micro-cores (n = 5 trees/site). While onset of wood formation in P. sylvestris and P. cembra differed by about two weeks (12 and 27 April, respectively), maximum daily growth rates peaked on 6 May at the valley site and on 23 June at timberline. At both sites maximum tracheid production was reached prior to occurrence of more favourable climatic conditions during summer, i.e. an increase in precipitation and temperature. Xylem formation ended on 31 August and 28 October at the xeric site and at timberline, respectively. This study demonstrates the plasticity of tree-ring formation along an altitudinal transect in response to water availability and temperature. Whether early achievement of maximum growth rates is an adaptation to cope with extreme environmental conditions prevailing at limits of tree growth needs to be analysed more closely by taking belowground carbon allocation into account. PMID:24273354

  7. Early treatment volume reduction rate as a prognostic factor in patients treated with chemoradiotherapy for limited stage small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo Hwan; Lee, Jeong Shin; Lee, Chang Geol; Cho, Jae Ho [Dept. of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (Korea, Republic of); Choi, Jin Hyun; Kim, Jun Won [Dept. of Radiation Oncology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2015-06-15

    To investigate the relationship between early treatment response to definitive chemoradiotherapy (CRT) and survival outcome in patients with limited stage small cell lung cancer (LS-SCLC). We retrospectively reviewed 47 patients with LS-SCLC who received definitive CRT between January 2009 and December 2012. Patients were treated with systemic chemotherapy regimen of etoposide/carboplatin (n = 15) or etoposide/cisplatin (n = 32) and concurrent thoracic radiotherapy at a median dose of 54 Gy (range, 46 to 64 Gy). Early treatment volume reduction rate (ETVRR) was defined as the percentage change in gross tumor volume between diagnostic computed tomography (CT) and simulation CT for adaptive RT planning and was used as a parameter for early treatment response. The median dose at adaptive RT planning was 36 Gy (range, 30 to 43 Gy), and adaptive CT was performed in 30 patients (63.8%). With a median follow-up of 27.7 months (range, 5.9 to 75.8 months), the 2-year locoregional progression-free survival (LRPFS) and overall survival (OS) rates were 74.2% and 56.5%, respectively. The mean diagnostic and adaptive gross tumor volumes were 117.9 mL (range, 5.9 to 447 mL) and 36.8 mL (range, 0.3 to 230.6 mL), respectively. The median ETVRR was 71.4% (range, 30 to 97.6%) and the ETVRR >45% group showed significantly better OS (p < 0.0001) and LRPFS (p = 0.009) than the other group. ETVRR as a parameter for early treatment response may be a useful prognostic factor to predict treatment outcome in LS-SCLC patients treated with CRT.

  8. Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998-2004

    Energy Technology Data Exchange (ETDEWEB)

    Hallqvist, Andreas; Rylander, Hillevi; Bjoerk-Eriksson, Thomas; Nyman, Jan [ Dept. of Oncology, Sahlgrenska Univ. Hospital, Goeteborg (Sweden)

    2007-10-15

    Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska Univ. Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide)+TRT{+-}prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and 'good' partial remission (PR) at response evaluation. Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I-II in 10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.

  9. Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo

    Directory of Open Access Journals (Sweden)

    Littman Dan R

    2009-01-01

    Full Text Available Abstract Background Cells derived from native rodents have limits at distinct steps of HIV replication. Rat primary CD4 T-cells, but not macrophages, display a profound transcriptional deficit that is ameliorated by transient trans-complementation with the human Tat-interacting protein Cyclin T1 (hCycT1. Results Here, we generated transgenic rats that selectively express hCycT1 in CD4 T-cells and macrophages. hCycT1 expression in rat T-cells boosted early HIV gene expression to levels approaching those in infected primary human T-cells. hCycT1 expression was necessary, but not sufficient, to enhance HIV transcription in T-cells from individual transgenic animals, indicating that endogenous cellular factors are critical co-regulators of HIV gene expression in rats. T-cells from hCD4/hCCR5/hCycT1-transgenic rats did not support productive infection of prototypic wild-type R5 HIV-1 strains ex vivo, suggesting one or more significant limitation in the late phase of the replication cycle in this primary rodent cell type. Remarkably, we identify a replication-competent HIV-1 GFP reporter strain (R7/3 YU-2 Env that displays characteristics of a spreading, primarily cell-to-cell-mediated infection in primary T-cells from hCD4/hCCR5-transgenic rats. Moreover, the replication of this recombinant HIV-1 strain was significantly enhanced by hCycT1 transgenesis. The viral determinants of this so far unique replicative ability are currently unknown. Conclusion Thus, hCycT1 expression is beneficial to de novo HIV infection in a transgenic rat model, but additional genetic manipulations of the host or virus are required to achieve full permissivity.

  10. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    Energy Technology Data Exchange (ETDEWEB)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-03-15

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ({sup 14}C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). {sup 14}C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA {sup 14}C content relative to a well-established {sup 14}C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA {sup 14}C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  11. Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating.

    Science.gov (United States)

    Perl, S; Kushner, J A; Buchholz, B A; Meeker, A K; Stein, G M; Hsieh, M; Kirby, M; Pechhold, S; Liu, E H; Harlan, D M; Tisdale, J F

    2010-10-01

    Diabetes mellitus results from an absolute or relative deficiency of insulin-producing pancreatic β-cells. The turnover rate of adult human β-cells remains unknown. We employed two techniques to examine adult human islet β-cell turnover and longevity in vivo. Subjects enrolled in National Institutes of Health clinical trials received thymidine analogs [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8 d to 4 yr prior to death. Archival autopsy samples from 10 patients (aged 17-74 yr) were employed to assess β-cell turnover by scoring nuclear analog labeling within insulin-staining cells. Human adult β-cell longevity was determined by estimating the cells' genomic DNA integration of atmospheric (14)C. DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15-yr-old donor, and purified β-cell DNA was obtained from two donors (ages 48 and 80 yr). (14)C levels were then determined using accelerator mass spectrometry. Cellular "birth date" was determined by comparing the subject's DNA (14)C content relative to a well-established (14)C atmospheric prevalence curve. In the two subjects less than 20 yr of age, 1-2% of the β-cell nuclei costained for BrdU/IdU. No β-cell nuclei costained in the eight patients more than 30 yr old. Consistent with the BrdU/IdU turnover data, β-cell DNA (14)C content indicated that the "birth date" of cells occurred within the subject's first 30 yr of life. Under typical circumstances, human β-cells and their cellular precursors are established by young adulthood.

  12. Adult Human Pancreatic Islet Beta-Cells Display Limited Turnover and Long Lifespan as Determined by In-Vivo Thymidine Analog Incorporation and Radiocarbon Dating

    International Nuclear Information System (INIS)

    Perl, S.; Kushner, J.A.; Buchholz, B.A.; Meeker, A.K.; Stein, G.M.; Hsieh, M.; Kirby, M.; Pechhold, S.; Liu, E.H.; Harlan, D.M.; Tisdale, J.F.

    2010-01-01

    Diabetes mellitus results from an absolute or relative deficiency of insulin producing pancreatic beta-cells. The adult human beta-cell's turnover rate remains unknown. We employed novel techniques to examine adult human islet beta-cell turnover and longevity in vivo. Subjects enrolled in NIH clinical trials received thymidine analogues [iododeoxyuridine (IdU) or bromodeoxyuridine (BrdU)] 8-days to 4-years prior to death. Archival autopsy samples from ten patients (aged 17-74 years) were employed to assess beta-cell turnover by scoring nuclear analog labeling within insulin staining cells. Human adult beta-cell longevity was determined by estimating the cells genomic DNA integration of atmospheric carbon-14 ( 14 C). DNA was purified from pancreatic islets isolated from cadaveric donors; whole islet prep DNA was obtained from a 15 year old donor, and purified beta-cell DNA was obtained from two donors (age 48 and 80 years). 14 C levels were then determined using accelerator mass spectrometry (AMS). Cellular 'birth date' was determined by comparing the subject's DNA 14 C content relative to a well-established 14 C atmospheric prevalence curve. In the two subjects less than age 20 years, 1-2% of the beta-cell nuclei co-stained for BrdU/IdU. No beta-cell nuclei co-stained in the eight patients more than 30 years old. Consistent with the BrdU/IdU turnover data, beta-cell DNA 14 C content indicated the cells 'birth date' occurred within the subject's first 30 years of life. Under typical circumstances, adult human beta-cells and their cellular precursors are established by young adulthood.

  13. Neonatal human retinal pigment epithelial cells secrete limited trophic factors in vitro and in vivo following striatal implantation in parkinsonian rats

    DEFF Research Database (Denmark)

    Russ, Kaspar; Flores, Joseph; Brudek, Tomasz

    2015-01-01

    Human retinal pigment epithelial (hRPE) cell implants into the striatum have been investigated as a potential cell-based treatment for Parkinson's disease in a Phase II clinical trial that recently failed. We hypothesize that the trophic factor potential of the hRPE cells could potentially...... influence the function and/or survival of the implants and may be involved in an alternative mechanism of action. However, it is unclear if hRPE cells secreted trophic factors when handled in the manner used in the clinical Phase II trial. To address these questions, we investigated two neonatal hRPE cell...... lesioned rats compared to sham (GM-only). The data suggest that trophic factors from neonatal hRPE cell implants likely did not participate in an alternative mechanism of action, which adds supports to a hypothesis that additional factors may have been necessary for the survival and/or function of h...

  14. Pilot study of dose intensive weekly chemotherapy followed by cisplatin plus etoposide with concurrent thoracic irradiation for limited-disease small-cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Isobe, Takeshi [Hiroshima Univ. (Japan). School of Medicine; Fukuoka, Masahiro; Negoro, Shyunichi [and others

    2000-07-01

    It was reported from a previous randomized trial (NEJM 329: 1848, 1993) that a moderate increase in the initial dose of cyclophosphamide and cisplatin improves the survival of patients with limited-disease small-cell lung cancer (LDSCLC). Rapid administration of several active agents over a short treatment period, such as the CODE regimen, is a potentially useful strategy for increasing the initial dose intensity. Based on these findings, we conducted a pilot study of CODE (C: 25 mg/m{sup 2}, day 1, weeks 1-4, O: 1 mg/m{sup 2}, day 1, weeks 2, 4, D: 40 mg/m{sup 2}, day 1, weeks 1, 3, E: 80 mg/m{sup 2}, days 1-3, weeks 1, 3) chemotherapy for the first 4 weeks followed by PE therapy (P: 80 mg/m{sup 2}, day 1, E: 100 mg/m{sup 2}, days 1-3, for 3 cycles) with concurrent TRT (1.5 Gy bid x 30 fr., total 45 Gy) to treat LDSCLC. From June 1996 through September 1996, 23 patients (pts) were enrolled, among whom 22 were eligible. The patients' characteristics were as follows: median age 65; M/F, 15/7; PS, 0/1/2, 9/9/4; stage II/IIIA/IIIB, 3/8/11. The relative dose intensities in the CODE phase for patients who received this treatment were 107% for P and 156% for E, compared with standard PE therapy. No treatment-related death occurred in this series. Myelosuppression was the most frequent toxicity in both treatments. Grade 3 and 4 leukopenia and neutropenia occurred in 73% and 86% of patients in the CODE phase, and in 83% and 91% in the PE phase, respectively. Thrombocytopenia occurred in 14% of the patients in the CODE phase and in 37% in the cisplatin-etoposide phase. Other non-hematological toxicities were mild. There was no severe esophagitis or pneumonitis following radiation therapy. CR was observed in 13 (59%) of the 22 patients, and 9 (41%) patients showed PR, giving an overall response rate of 100%. A median survival time has not yet been ascertained. Our preliminary results indicate that CODE therapy followed by PE therapy with concurrent TRT has very high

  15. Impact of thoracic radiotherapy timing in limited-stage small-cell lung cancer: usefulness of the individual patient data meta-analysis.

    Science.gov (United States)

    De Ruysscher, D; Lueza, B; Le Péchoux, C; Johnson, D H; O'Brien, M; Murray, N; Spiro, S; Wang, X; Takada, M; Lebeau, B; Blackstock, W; Skarlos, D; Baas, P; Choy, H; Price, A; Seymour, L; Arriagada, R; Pignon, J-P

    2016-10-01

    Chemotherapy (CT) combined with radiotherapy is the standard treatment of 'limited-stage' small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and CT. We carried out a meta-analysis of individual patient data in randomized trials comparing earlier versus later radiotherapy, or shorter versus longer radiotherapy duration, as defined in each trial. We combined the results from trials using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival. Twelve trials with 2668 patients were eligible. Data from nine trials comprising 2305 patients were available for analysis. The median follow-up was 10 years. When all trials were analysed together, 'earlier or shorter' versus 'later or longer' thoracic radiotherapy did not affect overall survival. However, the HR for overall survival was significantly in favour of 'earlier or shorter' radiotherapy among trials with a similar proportion of patients who were compliant with CT (defined as having received 100% or more of the planned CT cycles) in both arms (HR 0.79, 95% CI 0.69-0.91), and in favour of 'later or longer' radiotherapy among trials with different rates of CT compliance (HR 1.19, 1.05-1.34, interaction test, P < 0.0001). The absolute gain between 'earlier or shorter' versus 'later or longer' thoracic radiotherapy in 5-year overall survival for similar and for different CT compliance trials was 7.7% (95% CI 2.6-12.8%) and -2.2% (-5.8% to 1.4%), respectively. However, 'earlier or shorter' thoracic radiotherapy was associated with a higher incidence of severe acute oesophagitis than 'later or longer' radiotherapy. 'Earlier or shorter' delivery of thoracic radiotherapy with planned CT significantly improves 5-year overall survival at the expense of more acute toxicity, especially oesophagitis. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights

  16. Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Bing [Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai (China); Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou (China); Hong, Ling-Zhi [Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing (China); Cai, Xu-Wei; Zhu, Zheng-Fei; Liu, Qi; Zhao, Kuai-Le; Fan, Min; Mao, Jing-Fang; Yang, Huan-Jun; Wu, Kai-Liang [Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai (China); Fu, Xiao-Long, E-mail: xlfu1964@hotmail.com [Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai (China)

    2015-03-01

    Purpose: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. Methods and Materials: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. Results: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. Conclusion: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

  17. The cotyledon cell wall of the common bean (phaseolus vulgaris) resists digestion in the upper intestine and thus may limit iron bioavailability

    Science.gov (United States)

    Strategies that enhance the Fe bioavailability from the bean are of keen interest to nutritionists, bean breeders and growers. In beans, the cotyledon contains 75-80% of the total seed Fe, most of which appears to be located within the cotyledon cell. The cotyledon cell wall is known to be resistan...

  18. Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARγ/RORγt Pathway.

    Science.gov (United States)

    Zhang, Kai; Guo, Yawei; Ge, Zhenzhen; Zhang, Zhihui; Da, Yurong; Li, Wen; Zhang, Zimu; Xue, Zhenyi; Li, Yan; Ren, Yinghui; Jia, Long; Chan, Koon-Ho; Yang, Fengrui; Yan, Jun; Yao, Zhi; Xu, Aimin; Zhang, Rongxin

    2017-09-01

    T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor γ (PPARγ) and inhibited retinoid-related orphan receptor-γt (RORγt); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell-mediated autoimmune CNS inflammation.

  19. The Arabidopsis CDK inhibitor ICK3/KRP5 is rate limiting for primary root growth and promotes growth through cell elongation and endoreduplication.

    Science.gov (United States)

    Wen, Bo; Nieuwland, Jeroen; Murray, James A H

    2013-02-01

    The coordination of plant cell division and expansion controls plant morphogenesis, development, and growth. Cyclin-dependent kinases (CDKs) are not only key regulators of cell division but also play an important role in cell differentiation. In plants, CDK activity is modulated by the binding of INHIBITOR OF CDK/KIP-RELATED PROTEIN (ICK/KRP). Previously, ICK2/KRP2 has been shown to mediate auxin responses in lateral root initiation. Here are analysed the roles of all ICK/KRP genes in root growth. Analysis of ick/krp null-mutants revealed that only ick3/krp5 was affected in primary root growth. ICK3/KRP5 is strongly expressed in the root apical meristem (RAM), with lower expression in the expansion zone. ick3/krp5 roots grow more slowly than wildtype controls, and this results not from reduction of division in the proliferative region of the RAM but rather reduced expansion as cells exit the meristem. This leads to shorter final cell lengths in different tissues of the ick3/krp5 mutant root, particularly the epidermal non-hair cells, and this reduction in cell size correlates with reduced endoreduplication. Loss of ICK3/KRP5 also leads to delayed germination and in the mature embryo ICK3/KRP5 is specifically expressed in the transition zone between root and hypocotyl. Cells in the transition zone were smaller in the ick3/krp5 mutant, despite the absence of endoreduplication in the embryo suggesting a direct effect of ICK3/KRP5 on cell growth. It is concluded that ICK3/KRP5 is a positive regulator of both cell growth and endoreduplication.

  20. The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.

    Science.gov (United States)

    Thistlethwaite, Fiona C; Gilham, David E; Guest, Ryan D; Rothwell, Dominic G; Pillai, Manon; Burt, Deborah J; Byatte, Andrea J; Kirillova, Natalia; Valle, Juan W; Sharma, Surinder K; Chester, Kerry A; Westwood, Nigel B; Halford, Sarah E R; Nabarro, Stephen; Wan, Susan; Austin, Eric; Hawkins, Robert E

    2017-11-01

    The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5 + malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5 + -specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies.

  1. Interferon Regulator Factor 8 (IRF8 Limits Ocular Pathology during HSV-1 Infection by Restraining the Activation and Expansion of CD8+ T Cells.

    Directory of Open Access Journals (Sweden)

    Lin Sun

    Full Text Available Interferon Regulatory Factor-8 (IRF8 is constitutively expressed in monocytes and B cell lineages and plays important roles in immunity to pathogens and cancer. Although IRF8 expression is induced in activated T cells, the functional relevance of IRF8 in T cell-mediated immunity is not well understood. In this study, we used mice with targeted deletion of Irf8 in T-cells (IRF8KO to investigate the role of IRF8 in T cell-mediated responses during herpes simplex virus 1 (HSV-1 infection of the eye. In contrast to wild type mice, HSV-1-infected IRF8KO mice mounted a more robust anti-HSV-1 immune response, which included marked expansion of HSV-1-specific CD8+ T cells, increased infiltration of inflammatory cells into the cornea and trigeminal ganglia (TG and enhanced elimination of virus within the trigeminal ganglion. However, the consequence of the enhanced immunological response was the development of ocular inflammation, limbitis, and neutrophilic infiltration into the cornea of HSV-1-infected IRF8KO mice. Surprisingly, we observed a marked increase in virus-specific memory precursor effector cells (MPEC in IRF8KO mice, suggesting that IRF8 might play a role in regulating the differentiation of effector CD8+ T cells to the memory phenotype. Together, our data suggest that IRF8 might play a role in restraining excess lymphocyte proliferation. Thus, modulating IRF8 levels in T cells can be exploited therapeutically to prevent immune-mediated ocular pathology during autoimmune and infectious diseases of the eye.

  2. Imaging of VSOP labeled stem cells in agarose phantoms with susceptibility weighted and T2* weighted MR Imaging at 3T: determination of the detection limit.

    Directory of Open Access Journals (Sweden)

    Donald Lobsien

    Full Text Available OBJECTIVES: This study aimed to evaluate the detectability of stem cells labeled with very small iron oxide particles (VSOP at 3T with susceptibility weighted (SWI and T2* weighted imaging as a methodological basis for subsequent examinations in a large animal stroke model (sheep. MATERIALS AND METHODS: We examined ovine mesenchymal stem cells labeled with VSOP in agarose layer phantoms. The experiments were performed in 2 different groups, with quantities of 0-100,000 labeled cells per layer. 15 different SWI- and T2*-weighted sequences and 3 RF coils were used. All measurements were carried out on a clinical 3T MRI. Images of Group A were analyzed by four radiologists blinded for the number of cells, and rated for detectability according to a four-step scale. Images of Group B were subject to a ROI-based analysis of signal intensities. Signal deviations of more than the 0.95 confidence interval in cell containing layers as compared to the mean of the signal intensity of non cell bearing layers were considered significant. RESULTS: GROUP A: 500 or more labeled cells were judged as confidently visible when examined with a SWI-sequence with 0.15 mm slice thickness. Group B: 500 or more labeled cells showed a significant signal reduction in SWI sequences with a slice thickness of 0.25 mm. Slice thickness and cell number per layer had a significant influence on the amount of detected signal reduction. CONCLUSION: 500 VSOP labeled stem cells could be detected with SWI imaging at 3 Tesla using an experimental design suitable for large animal models.

  3. JA, a new type of polyunsaturated fatty acid isolated from Juglans mandshurica Maxim, limits the survival and induces apoptosis of heptocarcinoma cells.

    Science.gov (United States)

    Gao, Xiu-Li; Lin, Hua; Zhao, Wei; Hou, Ya-Qin; Bao, Yong-Li; Song, Zhen-Bo; Sun, Lu-Guo; Tian, Shang-Yi; Liu, Biao; Li, Yu-Xin

    2016-03-01

    Juglans mandshurica Maxim (Juglandaceae) is a famous folk medicine for cancer treatment and some natural compounds isolated from it have been studied extensively. Previously we isolated a type of ω-9 polyunsaturated fatty acid (JA) from the bark of J. mandshurica, however little is known about its activity and the underlying mechanisms. In this study, we studied anti-tumor activity of JA on several human cancer cell lines. Results showed that JA is cytotoxic to HepG2, MDA-MB-231, SGC-7901, A549 and Huh7 cells at a concentration exerting minimal toxic effects on L02 cells. The selective toxicity of JA was better than other classical anti-cancer drugs. Further investigation indicated that JA could induce cell apoptosis, characterized by chromatin condensation, DNA fragmentation and activation of the apoptosis-associated proteins such as Caspase-3 and PARP-1. Moreover, we investigated the cellular apoptosis pathway involved in the apoptosis process in HepG2 cells. We found that proteins involved in mitochondrion (cleaved-Caspase-9, Apaf-1, HtrA2/Omi, Bax, and Mitochondrial Bax) and endocytoplasmic reticulum (XBP-1s, GRP78, cleaved-Caspase-7 and cleaved-Caspase-12) apoptotic pathways were up-regulated when cells were treated by JA. In addition, a morphological change in the mitochondrion was detected. Furthermore, we found that JA could inhibit DNA synthesis and induce G2/M cell cycle arrest. The expression of G2-to-M transition related proteins, such as CyclinB1 and phosphorylated-CDK1, were reduced. In contrast, the G2-to-M inhibitor p21 was increased in JA-treated cells. Overall, our results suggest that JA can induce mitochondrion- and endocytoplasmic reticulum-mediated apoptosis, and G2/M phase arrest in HepG2 cells, making it a promising therapeutic agent against hepatoma.

  4. Perspective: Understanding of ripening growth model for minimum residual PbI2 and its limitation in the planar perovskite solar cells

    Directory of Open Access Journals (Sweden)

    Se-Yun Kim

    2016-10-01

    Full Text Available The power conversion efficiency of lead halide perovskite solar cells recently surpassed 22.1%. In this study, we suggest the perovskite absorber growth mechanism of the two-step process could be explained by an Ostwald ripening growth model for planar-structure perovskite solar cells. We attempt to find out the source of two main problems such as unreacted PbI2 and non-uniformed morphology by the proposed ripening growth mechanism and experimental results. This growth mechanism opens the way toward understanding a key aspect of the photovoltaic operation of high-efficiency, two-step perovskite solar cells.

  5. Analysis of risk factors for pulmonary complications in patients with limited-stage small cell lung cancer. A single-centre retrospective study

    Energy Technology Data Exchange (ETDEWEB)

    Sas-Korczynska, Beata; Kamzol, Wojciech [Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Cracow Branch, Clinic of Oncology and Department of Radiotherapy, Cracow (Poland); Luczynska, Elzbieta [Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Cracow Branch, Department of Diagnostic Radiology, Cracow (Poland); Sokolowski, Andrzej [Cracow University of Economics, Department of Statistics, Cracow (Poland)

    2017-02-15

    The most effective therapy in patients with limited-stage small cell lung cancer (LS SCLC) seems to be chemotherapy (using platinum-based regimens) and thoracic radiotherapy (TRT), which is followed by prophylactic cranial irradiation. The analysed group comprised 217 patients who received combined treatment for LS SCLC, i.e. chemotherapy (according to cisplatin and etoposide schedule) and TRT (concurrent in 101 and sequential in 116 patients). The influence of chemoradiotherapy (ChT-RT) schedule on treatment results (frequency of complete response, survival rates, and incidence of treatment failure and complications) was evaluated, and the frequency and severity of pulmonary complications were analysed to identify risk factors. The 5-year survival rates in concurrent vs. sequential ChT-RT schedules were 27.3 vs. 11.7% (overall) and 28 vs. 14.3% (disease-free). The frequencies of adverse events in relation to concurrent vs. sequential therapy were 85.1 vs. 9.5% (haematological complications) and 58.4 vs. 38.8% (pulmonary fibrosis), respectively. It was found that concurrent ChT-RT (hazard ratio, HR 2.75), a total dose equal to or more than 54 Gy (HR 2.55), the presence of haematological complications (HR 1.89) and a lung volume receiving a dose equal to or greater than 20 Gy exceeding 31% (HR 1.06) were the risk factors for pulmonary complications. Pulmonary complications after ChT-RT developed in 82% of patients treated for LS SCLC. In comparison to the sequential approach, concurrent ChT-RT had a positive effect on treatment outcome. However, this is a factor that can impair treatment tolerance, which manifests in the appearance of side effects. (orig.) [German] Die wirksamste Therapie bei einem kleinzelligen Lungenkrebs im limitierten Stadium (LS SCLC) scheinen Chemotherapie (platinbasierte Regime) und thorakale Strahlentherapie (TRT) zu sein, begleitet von der prophylaktischen Schaedelbestrahlung. Analysiert wurden 217 Patienten, die eine kombinierte Behandlung

  6. IFN-γ-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: Paradoxical post-transplantation effects of IFN-γ.

    Science.gov (United States)

    Xu, Xiaoguang; Huang, Haiyan; Wang, Qiang; Cai, Ming; Qian, Yeyong; Han, Yong; Wang, Xinying; Gao, Yu; Yuan, Ming; Xu, Liang; Yao, Chen; Xiao, Li; Shi, Bingyi

    2017-02-01

    IFN-γ is a protypical proinflammatory cytokine that plays a central role in inflammation and acute graft rejection. Accumulating evidence indicates that IFN-γ can exert previously unexpected immunoregulatory activities. However, little is known about the role of IFN-γ secreted by Th1-like regulatory T cells in human kidney transplantation. To determine the function of IFN-γ in acute T cell-mediated renal allograft rejection (ACR), we examined serum cytokine expression profiles in ACR patients by human cytokine multiplex immunoassay and analyzed the cellular origins of IFN-γ in peripheral blood and renal allograft biopsies from ACR cases and controls by flow cytometry and immunohistochemistry, respectively. The results showed significant reduction in serum concentrations of Th1-inducing cytokines IL-12p70 and IFN-γ as well as Th2-related cytokine IL-4 in ACR patients compared with stable controls. However, levels of several Th1-, Th2- and Th17-related cytokines, such as IL-2, TNF-α, TNF-β, IL-12 (p40), IL-10, IL-15, IL-17, IL-21, and IL-23, as well as the frequencies of Th1 and Th17 cell, did not differ between ACR cases and stable controls. Moreover, we found the levels of IFN-γ were correlated with those of the anti-inflammatory factor, IL-1 receptor antagonist (IL-1Ra) in ACR. Notably, the Th1-like Treg cell-to-Foxp3 - Th1 cell ratio was significantly lower in ACR patients compared with that in stable controls. In graft biopsies from ACR patients, Treg cells and Th1-like Treg cells were less abundant than those without ACR. Our study indicates that IFN-γ secreted from Th1-like Treg cells negatively modulates ACR. Copyright © 2016 Elsevier GmbH. All rights reserved.

  7. Circulating Cxcr5-Expressing Cd8+T-Cells are Major Producers of Il-21 and Associate with Limited Hiv Replication.

    Science.gov (United States)

    Perdomo-Celis, Federico; Taborda, Natalia A; Rugeles, Maria T

    2018-04-10

    Despite advances made with the highly active anti-retroviral therapy (HAART) in the control of the human immunodeficiency virus 1 (HIV) infection, a cure has not been achieved due to the persistence of viral reservoirs. The major HIV reservoirs remain in the lymphoid follicles due to, among other factors, the partial absence of CD8T-cells in these structures. Recently, lymphoid follicle-confined and circulating CD8T-cells expressing the C-X-C chemokine receptor type 5 (CXCR5) were described, possessing antiviral mechanisms which could help to control HIV replication. and methods: By flow cytometry, we characterized the phenotype and function of circulating CXCR5-expressing CD8T-cells in HIV-infected patients with natural or HAART-induced control of HIV replication. Circulating CXCR5-expressing CD8T-cells exhibited low or null expression of the C-C chemokine receptor type 7 (CCR7) and had a transitional memory phenotype. Particular redistributions of CXCR5-expressing CD8T-cells were found in HIV-infected patients, and they were partially restored by HAART. The frequency of CXCR5CCR7CD8T-cells was higher in spontaneous HIV controllers and negatively correlated with plasma HIV RNA levels. Total and HIV-specific CXCR5CD8T-cells were major producers of interleukin-21, and this function was positively associated with their interferon-γ production. Circulating CXCR5-expressing CD8T-cells are associated with low level HIV replication, could be novel correlates of protection and potentially useful in the eradication of HIV reservoirs.

  8. CD147/basigin limits lupus nephritis and Th17 cell differentiation in mice by inhibiting the interleukin-6/STAT-3 pathway.

    Science.gov (United States)

    Maeda, Kayaho; Kosugi, Tomoki; Sato, Waichi; Kojima, Hiroshi; Sato, Yuka; Kamimura, Daisuke; Kato, Noritoshi; Tsuboi, Naotake; Yuzawa, Yukio; Matsuo, Seiichi; Murakami, Masaaki; Maruyama, Shoichi; Kadomatsu, Kenji

    2015-05-01

    Interleukin-17 (IL-17)-producing T cells (Th17 cells) play critical roles in the pathogenesis of immune-related diseases, including systemic lupus erythematosus. However, the fundamental mechanism regulating Th17 cell differentiation is not fully understood. Recently, we demonstrated that plasma levels of CD147/basigin (Bsg) in patients with lupus nephritis (LN) were closely associated with disease activity. but the molecular mechanism involving Bsg has been elusive. Here, we addressed the role of Bsg in the pathogenesis of LN. Injections of pristane (2,6,10,14-tetramethylpentadecane [TMPD]) were administered to Bsg(-/-) or Bsg(+/+) mice to induce LN. The mice were killed 6 months after being injected, for histologic and biochemical analyses of the kidneys and spleens. Pristane induced LN more strikingly in Bsg(-/-) mice than in Bsg(+/+) mice, even though humoral autoimmunity was similarly increased in both genotypes. The increased number of Th17, but not Th1, Treg cells, was augmented in Bsg(-/-) mice. The expression of IL-17 was also increased in the kidneys of Bsg(-/-) mice, in proportion to LN disease activity. Furthermore, treatment with anti-IL-17 antibody reduced LN disease activity in Bsg(-/-) mice. Complementary to these phenotypes of Bsg(-/-) mice, Bsg expression was enhanced in activated CD4+ T cells in vivo and in vitro. Bsg deficiency selectively augmented in vitro differentiation of naive CD4+ T cells to Th17 cells and STAT-3 phosphorylation during this differentiation. Moreover, STAT-3 phosphorylation was suppressed by crosslinking of Bsg with its antibody. Bsg plays an indispensable role in Th17 cell differentiation as a negative regulator by suppressing the IL-6/STAT-3 pathway. © 2015, American College of Rheumatology.

  9. Production of proteolytic enzymes in mast cells, fibroblasts, vascular smooth muscle and endothelial cells cultivated under normoxic or hypoxic conditions

    Czech Academy of Sciences Publication Activity Database

    Maxová, H.; Bačáková, Lucie; Lisá, Věra; Novotná, J.; Tomášová, H.; Vízek, M.; Herget, J.

    2010-01-01

    Roč. 59, č. 5 (2010), s. 711-719 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/08/0108; GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : hypoxia * metalloproteinases * tryptase * chymase * immunofluorescence Subject RIV: EI - Biotechnology ; Bionics Impact factor: 1.646, year: 2010

  10. c-Kit Expression is Rate-Limiting for Stem Cell Factor-Mediated Disease Progression in Adenoid Cystic Carcinoma of the Salivary Glands

    Directory of Open Access Journals (Sweden)

    Janyaporn Phuchareon

    2014-10-01

    Full Text Available Adenoid cystic carcinoma (ACC is an aggressive malignant neoplasm of the salivary glands in which c-Kit is overexpressed and activated, although the mechanism for this is as yet unclear. We analyzed 27 sporadic ACC tumor specimens to examine the biologic and clinical significance of c-Kit activation. Mutational analysis revealed expression of wild-type c-Kit in all, eliminating gene mutation as a cause of activation. Because stem cell factor (SCF is c-Kit's sole ligand, we analyzed its expression in the tumor cells and their environment. Immunohistochemistry revealed its presence in c-Kit–positive tumor cells, suggesting an activation of autocrine signaling. We observed a significant induction of ERK1/2 in the cells. SCF staining was also found in other types of non-cancerous cells adjacent to tumors within salivary glands, including stromal fibroblasts, neutrophils, peripheral nerve, skeletal muscle, vascular endothelial cells, mucous acinar cells, and intercalated ducts. Quantitative PCR showed that the top quartile of c-Kit mRNA expression distinguished ACCs from normal salivary tissues and was cross-correlated with short-term poor prognosis. Expression levels of SCF and c-Kit were highly correlated in the cases with perineural invasion. These observations suggest that c-Kit is potentially activated by receptor dimerization upon stimulation by SCF in ACC, and that the highest quartile of c-Kit mRNA expression could be a predictor of poor prognosis. Our findings may support an avenue for c-Kit-targeted therapy to improve disease control in ACC patients harboring the top quartile of c-Kit mRNA expression.

  11. Kinetics of 13N-ammonia uptake in myocardial single cells indicating potential limitations in its applicability as a marker of myocardial blood flow

    International Nuclear Information System (INIS)

    Rauch, B.; Helus, F.; Grunze, M.; Braunwell, E.; Mall, G.; Hasselbach, W.; Kuebler, W.

    1985-01-01

    To study kinetics and principles of cellular uptake of 13 N-ammonia, a marker of coronary perfusion in myocardial scintigraphy, heart muscle cells of adult rats were isolated by perfusion with collagenase and hyaluronidase. Net uptake of 13 N, measured by flow dialysis, reached equilibrium within 20 sec in the presence of sodium bicarbonate and carbon dioxide (pH 7.4, 37 degrees C). Total extraction, 80 sec after the reaction start, was 786 +/- 159 mumol/ml cell volume. Cells destroyed by calcium overload were unable to extract 13 N-ammonia. Omission of bicarbonate and carbon dioxide reduced total extraction to 36% of control. 13 N-Ammonia uptake could also be reduced by 50 muM 4,4' diisothiocyanostilbene 2,2' disulfonic acid, by 100 micrograms/ml 1-methionine sulfoximine, and by preincubation with 5 muM free oleic acid. These results indicate that in addition to metabolic trapping by glutamine synthetase, the extraction of 13 N-ammonia by myocardial cells is influenced by cell membrane integrity, intracellular-extracellular pH gradient, and possibly an anion exchange system for bicarbonate. For this reason, the uptake of 13 N-ammonia may not always provide a valid measurement of myocardial perfusion

  12. Outcomes from monitoring of patients on antiretroviral therapy in resource-limited settings with viral load, CD4 cell count, or clinical observation alone: a computer simulation model

    DEFF Research Database (Denmark)

    Phillips, Andrew N; Pillay, Deenan; Miners, Alec H

    2008-01-01

    BACKGROUND: In lower-income countries, WHO recommends a population-based approach to antiretroviral treatment with standardised regimens and clinical decision making based on clinical status and, where available CD4 cell count, rather than viral load. Our aim was to study the potential consequences...... strategies-based on viral load, CD4 cell count, or clinical observation alone-for determining when to switch people starting antiretroviral treatment with the WHO-recommended first-line regimen of stavudine, lamivudine, and nevirapine to second-line antiretroviral treatment. FINDINGS: Over 5 years......, the predicted proportion of potential life-years survived was 83% with viral load monitoring (switch when viral load >500 copies per mL), 82% with CD4 cell count monitoring (switch at 50% drop from peak), and 82% with clinical monitoring (switch when two new WHO stage 3 events or a WHO stage 4 event occur...

  13. Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD).

    Science.gov (United States)

    Mori, Ken; Kitayama, Joji; Aoki, Junken; Kishi, Yasuhiro; Shida, Dai; Yamashita, Hiroharu; Arai, Hiroyuki; Nagawa, Hirokazu

    2007-07-01

    Lysophosphatidic acid (LPA) is involved in a broad spectrum of biological activities, including wound healing and cancer metastasis. Autotaxin (ATX), originally isolated from a melanoma supernatant as a tumor cell motility-stimulating factor, has been shown to be molecularly identical to lysophospholipase D (lysoPLD), which is the main enzyme in the production of LPA. Although ATX/lysoPLD is known to be widely expressed in normal human tissues, the exact distribution of ATX-producing cells has not been fully investigated. In this study, we evaluated ATX/lysoPLD expression by immunohistochemical staining using a rat anti-ATX mAb in the human gastrointestinal tract and found that submucosal mast cells (MC) highly expressed this enzyme. This was confirmed by immunofluorescent double staining using mAbs to tryptase and chymase. Then, we isolated MC from human gastric tissue by an immunomagnetic method using CD117-microbeads and showed that a subpopulation of CD203c-positive MC showed positive staining for intracellular ATX/lysoPLD on flowcytometry. This was confirmed by Western blotting of the isolated cells. Moreover, a significant level of ATX/lysoPLD release could be detected in the culture supernatants of human MC by Western blot analysis. Our data suggest that submucosal MC play significant roles in various aspects of pathophysiology in the gastrointestinal tract by locally providing bioactive LPA through the production of ATX/lysoPLD.

  14. Detection of T and B cells specific complement-fixing alloantibodies using flow cytometry: A diagnostic approach for a resource limited laboratory

    Directory of Open Access Journals (Sweden)

    Dharmendra Jain

    2017-01-01

    Conclusions: We postulate that this method incorporates most of the features of all the available modalities (i.e., National Institute of Health-complement dependent lymphocytotoxicity, FCXM, cytotoxic FCXM and C4d-flowPRA yet cost-effective and best suited for resource-limited laboratory/ies which is a common scenario in developing countries.

  15. Cell Death of Gamma Interferon-Stimulated Human Fibroblasts upon Toxoplasma gondii Infection Induces Early Parasite Egress and Limits Parasite Replication

    NARCIS (Netherlands)

    Niedelman, Wendy; Sprokholt, Joris K.; Clough, Barbara; Frickel, Eva-Maria; Saeij, Jeroen P. J.

    2013-01-01

    The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate

  16. Cell death of gamma interferon-stimulated human fibroblasts upon toxoplasma gondii infection induces early parasite egress and limits parasite replication

    NARCIS (Netherlands)

    Niedelman, W.; Sprokholt, J.K.; Clough, B.; Frickel, E.; Saeij, J.P.J.

    2013-01-01

    The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-¿) activation of both hematopoietic and nonhematopoietic cells. Although IFN-¿-induced innate

  17. 17-AAG mediated targeting of Hsp90 limits tert activity in peritoneal sarcoma related malignant ascites by downregulating cyclin D1 during cell cycle entry.

    Science.gov (United States)

    Chaklader, M; Das, P; Pereira, J A; Law, A; Chattopadhyay, S; Chatterjee, R; Mondal, A; Law, S

    2012-07-01

    Peritoneal or retro-peritoneal sarcomatosis related malignant ascites formation is a rare but serious consequence of the locoregional metastatic event. The present work aimed to study the effect of the Hsp90 inhibitor (17-AAG), an ansamycin analog, on cell cycle and DNA replication specific chaperone-clients interaction in the event of peritoneal sarcoma related malignant ascites formation in mouse model at the late stage of malignant growth. We administered 17-AAG, an Hsp90 inhibitor, divided doses (330 μg/kg b.w./day for first five days then next ten days with166 μg/kg b.w./day) through intra-peritoneal route of inbred Swiss albino mice bearing full grown peritoneal malignant ascites of sarcoma-180. Our study was evaluated by peripheral blood hemogram analysis, malignant ascitic cytology, cell viability test, survival time and mitotic indexing. Furthermore, flowcytometric HSP90, TERT, CyclinD1, PCNA and GM-CSF expression analysis has been considered for special objective of the study. Our experimental efforts reduced the aggressive proliferation of malignant ascites by drastic downregulation of TERT and cyclin D1 on the verge of cell cycle entry along with DNA replication processivity factor PCNA by directly modulating their folding machinery - heat shock protein 90. Consequently, we observed that malignant ascitic cells became error prone during the event of karyokinesis and produced micronucleus containing malignant cells with low viability. Peripheral neutrophilia due to over-expression of GM-CSF by the peritoneal malignant ascites were also controlled by the treatment with 17-AAG and overall, the treatment modality improved the median survival time. Finally we can conclude that 17AAG administration might serve as a prospective pharmacological agent for the management of peritoneal sarcoma related malignant ascites and throws light towards prolonged survival of the patients concerned.

  18. Determination of thermodynamic properties and stability limit from fluorite phase of uranium and lanthanide mixed oxides, using galvanic cells with solid electrolytes

    International Nuclear Information System (INIS)

    Santiago, T.N.

    1980-10-01

    A method for thermodynamic properties determination for oxygen solubility in oxide systems at temperature interval 973 ≤ T [K] ≤ 1773 is described. A galvanic cell using as solid electrolytes zircon dioxide doped with 15% of calcium oxide is presented. This method was used for determining the phase change, temperature dependent, of uranium-lanthanides-oxygen Ln U O 4 stoichiometric system. (C.G.C.)

  19. The utility and limitations of current web-available algorithms to predict peptides recognized by CD4 T cells in response to pathogen infection #

    Science.gov (United States)

    Chaves, Francisco A.; Lee, Alvin H.; Nayak, Jennifer; Richards, Katherine A.; Sant, Andrea J.

    2012-01-01

    The ability to track CD4 T cells elicited in response to pathogen infection or vaccination is critical because of the role these cells play in protective immunity. Coupled with advances in genome sequencing of pathogenic organisms, there is considerable appeal for implementation of computer-based algorithms to predict peptides that bind to the class II molecules, forming the complex recognized by CD4 T cells. Despite recent progress in this area, there is a paucity of data regarding their success in identifying actual pathogen-derived epitopes. In this study, we sought to rigorously evaluate the performance of multiple web-available algorithms by comparing their predictions and our results using purely empirical methods for epitope discovery in influenza that utilized overlapping peptides and cytokine Elispots, for three independent class II molecules. We analyzed the data in different ways, trying to anticipate how an investigator might use these computational tools for epitope discovery. We come to the conclusion that currently available algorithms can indeed facilitate epitope discovery, but all shared a high degree of false positive and false negative predictions. Therefore, efficiencies were low. We also found dramatic disparities among algorithms and between predicted IC50 values and true dissociation rates of peptide:MHC class II complexes. We suggest that improved success of predictive algorithms will depend less on changes in computational methods or increased data sets and more on changes in parameters used to “train” the algorithms that factor in elements of T cell repertoire and peptide acquisition by class II molecules. PMID:22467652

  20. ATR-p53 restricts homologous recombination in response to replicative stress but does not limit DNA interstrand crosslink repair in lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Bianca M Sirbu

    Full Text Available Homologous recombination (HR is required for the restart of collapsed DNA replication forks and error-free repair of DNA double-strand breaks (DSB. However, unscheduled or hyperactive HR may lead to genomic instability and promote cancer development. The cellular factors that restrict HR processes in mammalian cells are only beginning to be elucidated. The tumor suppressor p53 has been implicated in the suppression of HR though it has remained unclear why p53, as the guardian of the genome, would impair an error-free repair process. Here, we show for the first time that p53 downregulates foci formation of the RAD51 recombinase in response to replicative stress in H1299 lung cancer cells in a manner that is independent of its role as a transcription factor. We find that this downregulation of HR is not only completely dependent on the binding site of p53 with replication protein A but also the ATR/ATM serine 15 phosphorylation site. Genetic analysis suggests that ATR but not ATM kinase modulates p53's function in HR. The suppression of HR by p53 can be bypassed under experimental conditions that cause DSB either directly or indirectly, in line with p53's role as a guardian of the genome. As a result, transactivation-inactive p53 does not compromise the resistance of H1299 cells to the interstrand crosslinking agent mitomycin C. Altogether, our data support a model in which p53 plays an anti-recombinogenic role in the ATR-dependent mammalian replication checkpoint but does not impair a cell's ability to use HR for the removal of DSB induced by cytotoxic agents.

  1. Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells

    Science.gov (United States)

    Zent, Clive S.; Taylor, Ronald P.; Lindorfer, Margaret A.; Beum, Paul V.; LaPlant, Betsy; Wu, Wenting; Call, Timothy G.; Bowen, Deborah A.; Conte, Michael J.; Frederick, Lori A.; Link, Brian K.; Blackwell, Sue E.; Veeramani, Suresh; Baig, Nisar A.; Viswanatha, David S.; Weiner, George J.; Witzig, Thomas E.

    2014-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  2. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    Science.gov (United States)

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. © 2014 Wiley Periodicals, Inc.

  3. Endogenous CD317/Tetherin limits replication of HIV-1 and murine leukemia virus in rodent cells and is resistant to antagonists from primate viruses.

    Science.gov (United States)

    Goffinet, Christine; Schmidt, Sarah; Kern, Christian; Oberbremer, Lena; Keppler, Oliver T

    2010-11-01

    Human CD317 (BST-2/tetherin) is an intrinsic immunity factor that blocks the release of retroviruses, filoviruses, herpesviruses, and arenaviruses. It is unclear whether CD317 expressed endogenously in rodent cells has the capacity to interfere with the replication of the retroviral rodent pathogen murine leukemia virus (MLV) or, in the context of small-animal model development, contributes to the well-established late-phase restriction of human immunodeficiency virus type 1 (HIV-1). Here, we show that small interfering RNA (siRNA)-mediated knockdown of CD317 relieved a virion release restriction and markedly enhanced the egress of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) in rat cells, including primary macrophages. Moreover, rodent CD317 potently inhibited MLV release, and siRNA-mediated depletion of CD317 in a mouse T-cell line resulted in the accelerated spread of MLV. Several virus-encoded antagonists have recently been reported to overcome the restriction imposed by human or monkey CD317, including HIV-1 Vpu, envelope glycoproteins of HIV-2 and Ebola virus, Kaposi's sarcoma-associated herpesvirus K5, and SIV Nef. In contrast, both rat and mouse CD317 showed a high degree of resistance to these viral antagonists. These data suggest that CD317 is a broadly acting and conserved mediator of innate control of retroviral infection and pathogenesis that restricts the release of retroviruses and lentiviruses in rodents. The high degree of resistance of the rodent CD317 restriction factors to antagonists from primate viruses has implications for HIV-1 small-animal model development and may guide the design of novel antiviral interventions.

  4. Limited impact of the thymus on immunological recovery during and after chemotherapy in patients with diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Vedel, S J; Tholstrup, D; Kolte, L

    2009-01-01

    To investigate the impact of thymus on immunological recovery after dose-dense chemotherapy a prospective study of 17 patients diagnosed with diffuse large B-cell lymphoma (DLBCL) was conducted. Patients were monitored before, during and until 3 months after chemotherapy. The thymus was visualized...... using computer tomographic scans. Patients were divided into two groups according to thymic size, one group comprising of patients without detectable thymus and one group of patients with detectable thymus. Naïve CD4 and CD8 counts were measured by flow cytometry, and to measure thymic output...

  5. Limited density of an antigen presented by RMA-S cells requires B7-1/CD28 signaling to enhance T-cell immunity at the effector phase.

    Directory of Open Access Journals (Sweden)

    Xiao-Lin Li

    Full Text Available The association of B7-1/CD28 between antigen presenting cells (APCs and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide.

  6. Evaluating the impact of WaterCell® Technology on pressure redistribution and comfort/discomfort of adults with limited mobility.

    Science.gov (United States)

    Bartley, Carol; Stephens, Melanie

    2017-05-01

    The aim of the study was to evaluate the effect of WaterCell ® Technology on pressure redistribution and self-reported comfort and discomfort scores of adults with mobility problems who remain seated for extended periods of time. Twelve participants, were recruited and ranged in gender, age, height, weight, and body mass index. Five were male, seven were female, and five were permanent wheelchair users. Each participant was randomly allocated a chair, whose seat comprised of visco-elastic memory foam, high-elastic reflex foam, and watercells, to trial for a week. Data collected at day one and day seven included: interface pressure measurements taken across the gluteal region (peak and average); physiological observations of respiratory rate, pulse rate, and blood pressure; skin inspection and comfort and discomfort scores. Watercell ® technology was found to offer lower average pressures than those reported to cause potential skin injury. Peak pressure index findings were comparative to other studies. No correlation was found between discomfort intensity rating and pressure redistribution. Discomfort intensity rating was low for all participants and general discomfort ranged from very low to medium. Physiological observations decreased for 50% of participants over the seven days. From our study we have found that WaterCell ® technology offers comparable pressure redistribution for people with a disability who need to sit for prolonged periods of time and the chairs were found to be comfortable. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  7. Limited genetic diversity and purifying selection in Iranian Plasmodium falciparum Generative Cell Specific 1 (PfGCS1), a potential target for transmission-blocking vaccine.

    Science.gov (United States)

    Mehrizi, Akram Abouie; Zakeri, Sedigheh; Djadid, Navid Dinparast

    2014-03-01

    Among vaccines, those that have an impact on transmission are in priority for malaria elimination and eradication. One of the new identified transmission-blocking vaccine (TBV) candidate antigens is Generative Cell Specific 1 (GCS1) located on the male gametocytes of Plasmodium species. Since the antigenic diversity could hamper vaccine development, it is essential to determine the gene diversity of gcs1 in global malaria-endemic areas in order to develop efficient TBVs. Therefore, in this study, nucleotide diversity and selection in the Plasmodium falciparum GCS1 (PfGCS1) antigen were analyzed in 36 Iranian clinical isolates by using PCR sequencing in order to provide useful information on this TBV candidate antigen. For this purpose, successful sequence analysis was carried out in 36 isolates. The results showed three single-nucleotide polymorphisms including one synonymous (G1475A) and two non-synonymous (A697G and G1479A) mutations leading to 3 distinct haplotypes with different frequencies: GCS1-A (N184/D445, 16.7%), GCS1-B (S184/D445, 63.9%), and GCS1-C (N184/N445, 19.4%). The overall nucleotide diversity (π) for all 36 sequences of Iranian pfgcs1 was 0.00066±0.00012, and the dN-dS value (-0.00028) was negative, suggesting the possible action of purifying selection in this gene. Epitope mapping prediction of PfGCS1 antigen showed that most of the potential linear and conformational B-cell epitopes are located in conserved regions. However, N184S and D445N mutations were also involved in linear and conformational B-cell epitopes, respectively that should be considered in vaccine design. In conclusion, the present study showed a very low genetic diversity of pfgcs1 gene among Iranian isolates. Considering PfGCS1 as a conserved TBV candidate, our data provides valuable information to develop a PfGCS1-based TBV. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L)

    International Nuclear Information System (INIS)

    Nakamura, Kenichi; Shibata, Taro; Saji, Hisashi; Nakajima, Ryu; Tada, Hirohito; Okada, Morihito; Asamura, Hisao; Nakamura, Shinichiro; Tsuboi, Masahiro

    2010-01-01

    A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter ≤2 cm) peripheral non-small cell lung cancer, excluding radiologically determined non-invasive cancer. This study began in August 2009, and a total of 1100 patients will be accrued from 71 institutions within 3 years. The primary endpoint is overall survival. The secondary endpoints are post-operative respiratory function, relapse-free survival, proportion of local recurrence, adverse events, proportion of patients who complete segmentectomy, duration of hospitalization, duration of chest tube placement, operation time, blood loss and number of auto-sutures used. This study is one of the first intergroup studies in Japan between the Japan Clinical Oncology Group and the West Japan Oncology Group. (author)

  9. [A Phase I/II Study of Chemotherapy Concurrent with Twice-daily Radiotherapy 
Schedules by Intensity Modulated Radiation Therapy Using Simultaneous Integrated Boost for Limited-stage Small Cell Lung Cancer].

    Science.gov (United States)

    You, Jing; Yu, Huiming; Song, Maxiaowei; Shi, Chen; Wang, Xiaohang; Zheng, Ye; Yu, Rong; Shi, Anhui; Zhu, Guangying

    2017-01-20

    Twice-daily radiation concurrent with chemotherapy is one of the standard methods for limited-stage small cell lung cancer. The study was to evaluate the feasibility of chemotherapy concurrent with dose-escalating twice-daily radiotherapy by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) approach in patients with limited-stage small cell lung cancer. Patients with limited-stage small cell lung cancer were included, treated with twice-daily radiotherapy by SIB-IMRT concurrent with chemotherapy of etoposide plus cisplatin. Dose escalation was conducted by "classical" 3+3 methods with three patients enrolled in each dose level. The therapeutic gross tumor volume (GTV) was treated according to three consecutive dose levels i.e., 45 Gy at 1.5 Gy twice daily, 50 Gy at 1.67 Gy twice daily and 54 Gy at 1.8 Gy twice daily. The planning target volume (PTV) received a dose of 45 Gy delivered in 30 fractions of 1.5 Gy. The primary endpoints were acute toxicities. The secondary endpoints included overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) at 1-year of follow-up. Twenty men and six women were included. The median age was 52 (30-68) months. 12 patients experienced grade 2 acute esophagitis, and 1 patient developed grade 3 acute esophagitis. Only 3 patients developed Grade 2 pneumonitis. Grade 3 or higher radiation-related pneumonia was not observed. None died of treatment-related causes. With median follow-up of 11.2 months (3.2-36.2 months), 1-year OS, PFS and LRFFS were 89.0%, 51.0% and 85.0%, respectively. Dose escalation for twice-daily radiation concurrent with chemotherapy in LS-SCLC has been safely achieved up to 54 Gy for GTV using SIB-IMRT technique.

  10. What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Breaking through Immunity's Glass Ceiling.

    Science.gov (United States)

    Kelsoe, Garnett; Haynes, Barton F

    2017-06-19

    A key goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs) targeted to the vulnerable regions of the HIV envelope. BnAbs develop over time in ∼50% of HIV-1-infected individuals. However, to date, no vaccines have induced bnAbs and few or none of these vaccine-elicited HIV-1 antibodies carry the high frequencies of V(D)J mutations characteristic of bnAbs. Do the high frequencies of mutations characteristic of naturally induced bnAbs represent a fundamental barrier to the induction of bnAbs by vaccines? Recent studies suggest that high frequencies of V(D)J mutations can be achieved by serial vaccination strategies. Rather, it appears that, in the absence of HIV-1 infection, physiologic immune tolerance controls, including a germinal center process termed affinity reversion, may limit vaccine-driven bnAb development by clonal elimination or selecting for mutations incompatible with bnAb activity. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

  11. Surpassing the current limitations of high purity H2production in microbial electrolysis cell (MECs): Strategies for inhibiting growth of methanogens.

    Science.gov (United States)

    Kadier, Abudukeremu; Kalil, Mohd Sahaid; Chandrasekhar, Kuppam; Mohanakrishna, Gunda; Saratale, Ganesh Dattatraya; Saratale, Rijuta Ganesh; Kumar, Gopalakrishnan; Pugazhendhi, Arivalagan; Sivagurunathan, Periyasamy

    2018-02-01

    Microbial electrolysis cells (MECs) are perceived as a potential and promising innovative biotechnological tool that can convert carbon-rich waste biomass or wastewater into hydrogen (H 2 ) or other value-added chemicals. Undesired methane (CH 4 ) producing H 2 sinks, including methanogens, is a serious challenge faced by MECs to achieve high-rate H 2 production. Methanogens can consume H 2 to produce CH 4 in MECs, which has led to a drop of H 2 production efficiency, H 2 production rate (HPR) and also a low percentage of H 2 in the produced biogas. Organized inference related to the interactions of microbes and potential processes has assisted in understanding approaches and concepts for inhibiting the growth of methanogens and profitable scale up design. Thus, here in we review the current developments and also the improvements constituted for the reduction of microbial H 2 losses to methanogens. Firstly, the greatest challenge in achieving practical applications of MECs; undesirable microorganisms (methanogens) growth and various studied techniques for eliminating and reducing methanogens activities in MECs were discussed. Additionally, this extensive review also considers prospects for stimulating future research that could help to achieve more information and would provide the focus and path towards MECs as well as their possibilities for simultaneously generating H 2 and waste remediation. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Efficiency-limiting processes in cyclopentadithiophene-bridged donor-acceptor-type dyes for solid-state dye-sensitized solar cells

    KAUST Repository

    Hinkel, Felix

    2018-01-26

    The charge generation and recombination processes in three novel push-pull photosensitizers for dye-sensitized solar cells (DSSCs) are studied by ps–μs transient absorption (TA) and quasi-steady-state photoinduced absorption (PIA) spectroscopy. The three cyclopentadithiophene-based photosensitizer dye molecules exhibit comparably low power conversion efficiencies ranging from 0.8% to 1.7% in solid-state DSSCs. We find that the photocurrents increase in the presence of Li-salt additives. Both TA and PIA measurements observe long-lived dye cations created by electron injection from the dyes’ excited state for two dyes from the series. However, the third dye shows significantly lower performance as a consequence of the less efficient electron injection even after the addition of Li-salts and faster electron-hole recombination on the ns-μs time scale. In essence, the prerequisites for this class of donor-π bridge-acceptor photosensitizers to reach higher charge generation efficiencies are a combination of strong dipole moments and fine tuning of the electronic landscape at the titania-dye interface by Li-salt addition.

  13. Is immediate chest radiotherapy obligatory for any or all patients with limited-stage non-small cell carcinoma of the lung. Yes

    International Nuclear Information System (INIS)

    Cox, J.D.; Komaki, R.; Byhardt, R.W.

    1983-01-01

    External irradiation with the greatest technical sophistication available is indicated in all patients with inoperable non-small cell carcinoma of the lung confined to the primary site and to regional lymph nodes including the ipsilateral supraclavicular nodes. Irradiation with moderately high doses results in responses in 40%-65% of all patients. With irradiation to a level of at least 6000 rad in 30 fractions in 6 weeks, greater than 60% of patients never fail in the chest. Some of these patients become long-term, disease-free survivors. Until it is possible clearly to predict those patients who do not respond and thereby to justify an approach other than thoracic irradiation, it is necessary to offer radiation therapy to all of these patients. Since local control is far from satisfactory, one can certainly justify investigating new approaches, including further increases of the total dose, altered fractionation schemes, addition of radiosensitizers, and high linear energy transfer radiations. Since distant metastases frequently appear in spite of thorough pretreatment evaluations, one can also justify investigating the addition of systemic agents, both cytotoxic drugs and biologic response modifiers. Benefit from these systemic approaches may be completely masked, even in patients with disseminated disease, by failure to prevent complications and death due to the intrathoracic tumor

  14. The Conserved ATM Kinase RAG2-S365 Phosphorylation Site Limits Cleavage Events in Individual Cells Independent of Any Repair Defect

    Directory of Open Access Journals (Sweden)

    Susannah L. Hewitt

    2017-10-01

    Full Text Available Many DNA lesions associated with lymphoid malignancies are linked to off-target cleavage by the RAG1/2 recombinase. However, off-target cleavage has mostly been analyzed in the context of DNA repair defects, confounding any mechanistic understanding of cleavage deregulation. We identified a conserved SQ phosphorylation site on RAG2 365 to 366 that is involved in feedback control of RAG cleavage. Mutation of serine 365 to a non-phosphorylatable alanine permits bi-allelic and bi-locus RAG-mediated breaks in the same cell, leading to reciprocal translocations. This phenomenon is analogous to the phenotype we described for ATM kinase inactivation. Here, we establish deregulated cleavage itself as a driver of chromosomal instability without the associated repair defect. Intriguingly, a RAG2-S365E phosphomimetic rescues the deregulated cleavage of ATM inactivation, reducing the incidence of reciprocal translocations. These data support a model in which feedback control of cleavage and maintenance of genome stability involves ATM-mediated phosphorylation of RAG2.

  15. Reconstitution of T Cell Proliferation under Arginine Limitation: Activated Human T Cells Take Up Citrulline via L-Type Amino Acid Transporter 1 and Use It to Regenerate Arginine after Induction of Argininosuccinate Synthase Expression

    Directory of Open Access Journals (Sweden)

    Anke Werner

    2017-07-01

    Full Text Available In the tumor microenvironment, arginine is metabolized by arginase-expressing myeloid cells. This arginine depletion profoundly inhibits T cell functions and is crucially involved in tumor-induced immunosuppression. Reconstitution of adaptive immune functions in the context of arginase-mediated tumor immune escape is a promising therapeutic strategy to boost the immunological antitumor response. Arginine can be recycled in certain mammalian tissues from citrulline via argininosuccinate (ASA in a two-step enzymatic process involving the enzymes argininosuccinate synthase (ASS and argininosuccinate lyase (ASL. Here, we demonstrate that anti-CD3/anti-CD28-activated human primary CD4+ and CD8+ T cells upregulate ASS expression in response to low extracellular arginine concentrations, while ASL is expressed constitutively. ASS expression peaked under moderate arginine restriction (20 µM, but no relevant induction was detectable in the complete absence of extracellular arginine. The upregulated ASS correlated with a reconstitution of T cell proliferation upon supplementation of citrulline, while the suppressed production of IFN-γ was refractory to citrulline substitution. In contrast, ASA reconstituted proliferation and cytokine synthesis even in the complete absence of arginine. By direct quantification of intracellular metabolites we show that activated primary human T cells import citrulline but only metabolize it further to ASA and arginine when ASS is expressed in the context of low amounts of extracellular arginine. We then clarify that citrulline transport is largely mediated by the L-type amino acid transporter 1 (LAT1, induced upon human T cell activation. Upon siRNA-mediated knockdown of LAT1, activated T cells lost the ability to import citrulline. These data underline the potential of citrulline substitution as a promising pharmacological way to treat immunosuppression in settings of arginine deprivation.

  16. Contemporary adjuvant polymethyl methacrylate cementation optimally limits recurrence in primary giant cell tumor of bone patients compared to bone grafting: a systematic review and meta-analysis.

    Science.gov (United States)

    Zuo, Dongqing; Zheng, Longpo; Sun, Wei; Fu, Dong; Hua, Yingqi; Cai, Zhengdong

    2013-07-16

    Reports of recurrence following restructuring of primary giant cell tumor (GCT) defects using polymethyl methacrylate (PMMA) bone cementation or allogeneic bone graft with and without adjuvants for intralesional curettage vary widely. Systematic review and meta-analysis were conducted to investigate efficacy of PMMA bone cementation and allogeneic bone grafting following intralesional curettage for GCT. Medline, EMBASE, Google Scholar, and Cochrane databases were searched for studies reporting GCT of bone treatment with PMMA cementation and/or bone grafting with or without adjuvant therapy following intralesional curettage of primary GCTs. Pooled risk ratios and 95% confidence intervals (CIs) for local recurrence risks were calculated by fixed-effects methods. Of 1,690 relevant titles, 6 eligible studies (1,293 patients) spanning March 2008 to December 2011 were identified in published data. Treatment outcomes of PMMA-only (n = 374), bone graft-only (n = 436), PMMA with or without adjuvant (PMMA + adjuvant; n = 594), and bone graft filling with or without adjuvant (bone graft + adjuvant; n = 699) were compared. Bone graft-only patients exhibited higher recurrence rates than PMMA-treated patients (RR 2.09, 95% CI (1.64, 2.66), Overall effect: Z = 6.00; P <0.001), and bone graft + adjuvant patients exhibited higher recurrence rates than PMMA + adjuvant patients (RR 1.66, 95% CI (1.21, 2.28), Overall effect: Z = 3.15, P = 0.002). Local recurrence was minimal in PMMA cementation patients, suggesting that PMMA is preferable for routine clinical restructuring in eligible GCT patients. Relationships between tumor characteristics, other modern adjuvants, and recurrence require further exploration.

  17. Recombinant feline leukemia virus (FeLV) variants establish a limited infection with altered cell tropism in specific-pathogen-free cats in the absence of FeLV subgroup A helper virus.

    Science.gov (United States)

    Bechtel, M K; Hayes, K A; Mathes, L E; Pandey, R; Stromberg, P C; Roy-Burman, P

    1999-03-01

    Feline leukemia virus subgroup B (FeLV-B) is commonly associated with feline lymphosarcoma and arises through recombination between endogenous retroviral elements inherited in the cat genome and corresponding regions of the envelope (env) gene from FeLV subgroup A (FeLV-A). In vivo infectivity for FeLV-B is thought to be inefficient in the absence of FeLV-A. Proposed FeLV-A helper functions include enhanced replication efficiency, immune evasion, and replication rescue for defective FeLV-B virions. In vitro analysis of the recombinant FeLV-B-like viruses (rFeLVs) employed in this study confirmed these viruses were replication competent prior to their use in an in vivo study without FeLV-A helper virus. Eight specific-pathogen-free kittens were inoculated with the rFeLVs alone. Subsequent hematology and histology results were within normal limits, however, in the absence of detectable viremia, virus expression, or significant seroconversion, rFeLV proviral DNA was detected in bone marrow tissue of 4/4 (100%) cats at 45 weeks postinoculation (pi), indicating these rFeLVs established a limited but persistent infection in the absence of FeLV-A. Altered cell tropism was also noted. Focal infection was seen in T-cell areas of the splenic follicles in 3/4 (75%) rFeLV-infected cats analyzed, while an FeLV-A-infected cat showed focal infection in B-cell areas of the splenic follicles. Nucleotide sequence analysis of the surface glycoprotein portion of the rFeLV env gene amplified from bone marrow tissue collected at 45 weeks pi showed no sequence alterations from the original rFeLV inocula.

  18. HOME Income Limits

    Data.gov (United States)

    Department of Housing and Urban Development — HOME Income Limits are calculated using the same methodology that HUD uses for calculating the income limits for the Section 8 program. These limits are based on HUD...

  19. Adaptive limit margin detection and limit avoidance

    Science.gov (United States)

    Yavrucuk, Ilkay

    This thesis concerns the development of methods, algorithms, and control laws for the development of an adaptive flight envelope protection system to be used for both manned and unmanned aircraft. The proposed method lifts the requirement for detailed a priori information of aircraft dynamics by enabling adaptation to system uncertainty. The system can be used for limits that can be either measured or related to selected measurable quantities. Specifically, an adaptive technique for predicting limit margins and calculating the corresponding allowable control or controller command margins of an aircraft is described in an effort to enable true carefree maneuvering. This new approach utilizes adaptive neural network based loops for the approximation of required aircraft dynamics. For limits that reach their maximum value in steady state, a constructed estimator model is used to predict the maneuvering quasi-steady response behavior---the so called dynamic trim---of the limit parameters and the corresponding control or command margins. Linearly Parameterized Neural Networks as well as Single Hidden Layer Neural Networks are used for on-line adaptation. The approach does not require any off-line training of the neural networks, instead all learning is achieved during flight. Lyapunov based weight update laws are derived. The method is extended for multi-channelled control limiting for aircraft subject to multiple limits, and for automatic control and command limiting for UAV's. Simulation evaluations of the method using a linear helicopter model and a nonlinear Generalized Tiltrotor Simulation (GTRSIM) model are presented. Limit avoidance methods are integrated and tested through the implementation of an artificial pilot model and an active-stick controller model for tactile cueing in the tiltrotor simulation, GTRSIM. Load factor, angle-of-attack, and torque limits are considered as examples. Similarly, the method is applied to the Georgia Tech's Yamaha R-Max (GTMax

  20. A Phase I/II Study of Chemotherapy Concurrent with Twice-daily Radiotherapy 
Schedules by Intensity Modulated Radiation Therapy Using Simultaneous Integrated Boost for Limited-stage Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jing YOU

    2017-01-01

    Full Text Available Background and objective Twice-daily radiation concurrent with chemotherapy is one of the standard methods for limited-stage small cell lung cancer. The study was to evaluate the feasibility of chemotherapy concurrent with dose-escalating twice-daily radiotherapy by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT approach in patients with limited-stage small cell lung cancer. Methods Patients with limited-stage small cell lung cancer were included, treated with twice-daily radiotherapy by SIB-IMRT concurrent with chemotherapy of etoposide plus cisplatin. Dose escalation was conducted by “classical” 3+3 methods with three patients enrolled in each dose level. The therapeutic gross tumor volume (GTV was treated according to three consecutive dose levels i.e., 45 Gy at 1.5 Gy twice daily, 50 Gy at 1.67 Gy twice daily and 54 Gy at 1.8 Gy twice daily. The planning target volume (PTV received a dose of 45 Gy delivered in 30 fractions of 1.5 Gy. The primary endpoints were acute toxicities. The secondary endpoints included overall survival (OS, progression-free survival (PFS and loco-regional failure-free survival (LRFFS at 1-year of follow-up. Results Twenty men and six women were included. The median age was 52 (30-68 months. 12 patients experienced grade 2 acute esophagitis, and 1 patient developed grade 3 acute esophagitis. Only 3 patients developed Grade 2 pneumonitis. Grade 3 or higher radiation-related pneumonia was not observed. None died of treatment-related causes. With median follow-up of 11.2 months (3.2-36.2 months, 1-year OS, PFS and LRFFS were 89.0%, 51.0% and 85.0%, respectively. Conclusion Dose escalation for twice-daily radiation concurrent with chemotherapy in LS-SCLC has been safely achieved up to 54 Gy for GTV using SIB-IMRT technique.

  1. Limited taste discrimination in Drosophila.

    Science.gov (United States)

    Masek, Pavel; Scott, Kristin

    2010-08-17

    In the gustatory systems of mammals and flies, different populations of sensory cells recognize different taste modalities, such that there are cells that respond selectively to sugars and others to bitter compounds. This organization readily allows animals to distinguish compounds of different modalities but may limit the ability to distinguish compounds within one taste modality. Here, we developed a behavioral paradigm in Drosophila melanogaster to evaluate directly the tastes that a fly distinguishes. These studies reveal that flies do not discriminate among different sugars, or among different bitter compounds, based on chemical identity. Instead, flies show a limited ability to distinguish compounds within a modality based on intensity or palatability. Taste associative learning, similar to olfactory learning, requires the mushroom bodies, suggesting fundamental similarities in brain mechanisms underlying behavioral plasticity. Overall, these studies provide insight into the discriminative capacity of the Drosophila gustatory system and the modulation of taste behavior.

  2. The utility and limitations of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography in patients with primary mediastinal B-cell lymphoma: single institution experience and literature review.

    Science.gov (United States)

    Cheah, Chan Y; Hofman, Michael S; Seymour, John F; Ritchie, David S; Dickinson, Michael; Wirth, Andrew; Prince, H Miles; Wolf, Max; Januszcewicz, Elchanan H; Carney, Dennis A; Herbert, Kirsten E; Harrison, Simon J; Burbury, Kate L; Tam, Constantine S

    2015-01-01

    There are limited data regarding the role of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET-CT) scanning in primary mediastinal B-cell lymphoma (PMBL). We analyzed 28 patients with PMBL treated with chemotherapy, of whom 25 (89%) also received rituximab and 17 (61%) radiotherapy. PET-CT scans were interpreted using visual analysis and a 5-point scale. After a median follow-up of 2.6 years, four patients relapsed and two died. The 2-year progression-free survival and overall survival were 86% and 94%. PET-CT has excellent negative predictive value (interim, 86-87%; end of treatment, 95%) but limited positive predictive value due to the high frequency of positive scans. Several patients with persistent metabolically active masses underwent biopsies, which showed necrosis but no lymphoma. Thus a negative PET-CT is an excellent predictor of subsequent outcome. However, residual metabolically active masses after treatment should be biopsied to confirm viable lymphoma prior to salvage therapy.

  3. VT Limited Access Highways

    Data.gov (United States)

    Vermont Center for Geographic Information — A limited-access road, known by various terms worldwide, including limited-access highway, dual carriageway, expressway, and partial controlled access highway, is a...

  4. LANSCE beam current limiter

    International Nuclear Information System (INIS)

    Gallegos, F.R.

    1996-01-01

    The Radiation Security System (RSS) at the Los Alamos Neutron Science Center (LANSCE) provides personnel protection from prompt radiation due to accelerated beam. Active instrumentation, such as the Beam Current Limiter, is a component of the RSS. The current limiter is designed to limit the average current in a beam line below a specific level, thus minimizing the maximum current available for a beam spill accident. The beam current limiter is a self-contained, electrically isolated toroidal beam transformer which continuously monitors beam current. It is designed as fail-safe instrumentation. The design philosophy, hardware design, operation, and limitations of the device are described

  5. Phase I North Central Cancer Treatment Group Trial-N9923 of escalating doses of twice-daily thoracic radiation therapy with amifostine and with alternating chemotherapy in limited stage small-cell lung cancer

    International Nuclear Information System (INIS)

    Garces, Yolanda I.; Okuno, Scott H.; Schild, Steven E.; Mandrekar, Sumithra J.; Bot, Brian M.; Martens, John M.; Wender, Donald B.; Soori, Gamini S.; Moore, Dennis F.; Kozelsky, Timothy F.; Jett, James R.

    2007-01-01

    Purpose: The primary goal was to identify the maximum tolerable dose (MTD) of thoracic radiation therapy (TRT) that can be given with chemotherapy and amifostine for patients with limited-stage small-cell lung cancer (LSCLC). Methods and Materials: Treatment began with two cycles of topotecan (1 mg/m 2 ) Days 1 to 5 and paclitaxel (175 mg/m 2 ) Day 5 (every 3 weeks) given before and after TRT. The TRT began at 6 weeks. The TRT was given in 120 cGy fractions b.i.d. and the dose escalation (from 4,800 cGy, dose level 1, to 6,600 cGy, dose level 4) followed the standard 'cohorts of 3' design. The etoposide (E) (50 mg/day) and cisplatin (C) (3 mg/m 2 ) were given i.v. before the morning TRT and amifostine (500 mg/day) was given before the afternoon RT. This was followed by prophylactic cranial irradiation (PCI). The dose-limiting toxicities (DLTs) were defined as Grade ≥4 hematologic, febrile neutropenia, esophagitis, or other nonhematologic toxicity, Grade ≥3 dyspnea, or Grade ≥2 pneumonitis. Results: Fifteen patients were evaluable for the Phase I portion of the trial. No DLTs were seen at dose levels 1 and 2. Two patients on dose level 4 experienced DLTs: 1 patient had a Grade 4 pneumonitis, dyspnea, fatigue, hypokalemia, and anorexia, and 1 patient had a Grade 5 hypoxia attributable to TRT. One of 6 patients on dose level 3 had a DLT, Grade 3 esophagitis. The Grade ≥3 toxicities seen in at least 10% of patients during TRT were esophagitis (53%), leukopenia (33%), dehydration (20%), neutropenia (13%), and fatigue (13%). The median survival was 14.5 months. Conclusion: The MTD of b.i.d. TRT was 6000 cGy (120 cGy b.i.d.) with EP and amifostine

  6. JET pump limiter

    International Nuclear Information System (INIS)

    Sonnenberg, K.; Deksnis, E.; Shaw, R.; Reiter, D.

    1988-01-01

    JET plans to install two pump limiter modules which can be used for belt-limiter, inner-wall and X-point discharges and, also, for 1-2s as the main limiter. A design is presented which is compatible with two diagnostic systems, and which allows partial removal of the pump limiter to provide access for remote-handling operations. The high heat-flux components are initially cooled during a pulse. Heat is removed between discharges by radiation and pressure contacts to a water-cooled support structure. The pumping edge will be made of annealed pyrolytic graphite. Exhaust efficiency has been estimated, for a 1-d edge model, using a Monte-Carlo calculation of neutral gas transport. When the pump limiter is operated together with other wall components we expect an efficiency of ≅ 5% (2.5 x 10 21 part/s). As a main limiter the efficiency increases to about 10%. (author)

  7. Limit analysis via creep

    International Nuclear Information System (INIS)

    Taroco, E.; Feijoo, R.A.

    1981-07-01

    In this paper it is presented a variational method for the limit analysis of an ideal plastic solid. This method has been denominated as Modified Secundary Creep and enables to find the collapse loads through a minimization of a functional and a limit process. Given an ideal plastic material it is shown how to determinate the associated secundary creep constitutive equation. Finally, as an application, it is found the limit load in an pressurized von Mises rigid plastic sphere. (Author) [pt

  8. Detector limitations, STAR

    Energy Technology Data Exchange (ETDEWEB)

    Underwood, D. G.

    1998-07-13

    Every detector has limitations in terms of solid angle, particular technologies chosen, cracks due to mechanical structure, etc. If all of the presently planned parts of STAR [Solenoidal Tracker At RHIC] were in place, these factors would not seriously limit our ability to exploit the spin physics possible in RHIC. What is of greater concern at the moment is the construction schedule for components such as the Electromagnetic Calorimeters, and the limited funding for various levels of triggers.

  9. Limit loads in nozzles

    International Nuclear Information System (INIS)

    Zouain, N.

    1983-01-01

    The static method for the evaluation of the limit loads of a perfectly elasto-plastic structure is presented. Using the static theorem of Limit Analysis and the Finite Element Method, a lower bound for the colapso load can be obtained through a linear programming problem. This formulation if then applied to symmetrically loaded shells of revolution and some numerical results of limit loads in nozzles are also presented. (Author) [pt

  10. IONIC LIQUIDS: PREPARATIONS AND LIMITATIONS

    Directory of Open Access Journals (Sweden)

    Dzulkefly Kuang Abdullah

    2010-11-01

    Full Text Available Ionic liquids are considered as an ideal alternative to volatile organic solvents and chemical industries in the future,because they are non-volatile. Ionic liquids are also considered as new novel chemical agents and widely regarded as agreener alternative to many commonly used solvents. Ionic liquids have been studied for a wide range of syntheticapplications and have attracted considerable interest for use as electrolytes in the areas of organic synthesis, catalysis,solar cell, fuel cells, electrodeposition and supercapacitors. However, some ionic liquids suffer from more or less somedrawbacks such as toxicity, preparation and high cost in the process for use. Most recently, three types of ionic liquidsare attracted much attentions specifically traditional ionic liquid, protic ionic liquid and deep eutectic solvent, wheretheir preparation, mechanism and limitation were differentiated. However, those liquids are having their ownadvantages and limitations based on applications. Traditional ionic liquid and protic ionic liquid are highly cost andtoxic for applied engineering research, but they consist of micro-biphasic systems composed of ionic compounds whichhave more varieties in the applications. The deep eutectic solvent is very economic for large-scale possessing but thereare only limited ionic mixtures to certain application such as electrochemistry.

  11. The limiting current in a one-dimensional situation: Transition from a space charge limited to magnetically limited flow

    International Nuclear Information System (INIS)

    Kumar, Raghwendra; Biswas, Debabrata

    2008-01-01

    For a nonrelativistic electron beam propagating in a cylindrical drift tube, it is shown that the limiting current density does not saturate to the electrostatic one-dimensional (1D) estimate with increasing beam radius. Fully electromagnetic particle-in-cell (PIC) simulation studies show that beyond a critical aspect ratio, the limiting current density is lower than the 1D electrostatic prediction. The lowering in the limiting current density is found to be due to the transition from the space charge limited to magnetically limited flow. An adaptation of Alfven's single particle trajectory method is used to estimate the magnetically limited current as well as the critical radius beyond which the flow is magnetically limited in a drift tube. The predictions are found to be in close agreement with PIC simulations

  12. Limits to Inclusion

    Science.gov (United States)

    Hansen, Janne Hedegaard

    2012-01-01

    In this article, I will argue that a theoretical identification of the limit to inclusion is needed in the conceptual identification of inclusion. On the one hand, inclusion is formulated as a vision that is, in principle, limitless. On the other hand, there seems to be an agreement that inclusion has a limit in the pedagogical practice. However,…

  13. Numerical Limit Analysis:

    DEFF Research Database (Denmark)

    Damkilde, Lars

    2007-01-01

    Limit State analysis has a long history and many prominent researchers have contributed. The theoretical foundation is based on the upper- and lower-bound theorems which give a very comprehensive and elegant formulation on complicated physical problems. In the pre-computer age Limit State analysis...... also enabled engineers to solve practical problems within reinforced concrete, steel structures and geotechnics....

  14. Limited data speaker identification

    Indian Academy of Sciences (India)

    The evidences from all these integrated systems can be combined to obtain a speaker identification system that provides improved performance under limited data. Hence the motivation for this work. A few attempts have been made earlier to study and provide solution to the problem of limited data in the speaker recognition ...

  15. Advanced limiters for ISX

    International Nuclear Information System (INIS)

    Mioduszewski, P.K.; Edmonds, P.H.; Sheffield, J.

    1982-01-01

    Continuous removal of heat and particles becomes a vital necessity in future steady-state fusion devices. The pump limiter seems to be an attractive concept to combine these two tasks. On ISX, various schemes of pump limiters are being explored with the final goal to furnish the ISX--C device with a pump limiter to handle heat removal and particle control in steady state. The emphasis of the present paper is on pump limiters based on ballistic particle collection. If this concept turns out to be successful in supplying sufficient pumping efficiency, it may be possible to design pump limiters without a leading edge. Analytical calculations of the particle collection efficiency are given for various limiter configurations. Pumping efficiencies of approximately 4--10%, depending on the specific configuration, seem to be feasible and should be sufficient for steady-state operation. Initial experimental results on pump limiter studies in ISX--B confirm the calculated collection efficiencies. By measuring the ion saturation current to the limiter blade and the pressure buildup simultaneously, we found a correlation between the incident particle flux and the pressure rise that agrees well with a simple model

  16. Universal Limits on Computation

    CERN Document Server

    Krauss, L M

    2004-01-01

    The physical limits to computation have been under active scrutiny over the past decade or two, as theoretical investigations of the possible impact of quantum mechanical processes on computing have begun to make contact with realizable experimental configurations. We demonstrate here that the observed acceleration of the Universe can produce a universal limit on the total amount of information that can be stored and processed in the future, putting an ultimate limit on future technology for any civilization, including a time-limit on Moore's Law. The limits we derive are stringent, and include the possibilities that the computing performed is either distributed or local. A careful consideration of the effect of horizons on information processing is necessary for this analysis, which suggests that the total amount of information that can be processed by any observer is significantly less than the Hawking-Beckenstein entropy associated with the existence of an event horizon in an accelerating universe.

  17. Modeling Complex Time Limits

    Directory of Open Access Journals (Sweden)

    Oleg Svatos

    2013-01-01

    Full Text Available In this paper we analyze complexity of time limits we can find especially in regulated processes of public administration. First we review the most popular process modeling languages. There is defined an example scenario based on the current Czech legislature which is then captured in discussed process modeling languages. Analysis shows that the contemporary process modeling languages support capturing of the time limit only partially. This causes troubles to analysts and unnecessary complexity of the models. Upon unsatisfying results of the contemporary process modeling languages we analyze the complexity of the time limits in greater detail and outline lifecycles of a time limit using the multiple dynamic generalizations pattern. As an alternative to the popular process modeling languages there is presented PSD process modeling language, which supports the defined lifecycles of a time limit natively and therefore allows keeping the models simple and easy to understand.

  18. Mitigating greenhouse: Limited time, limited options

    International Nuclear Information System (INIS)

    Moriarty, Patrick; Honnery, Damon

    2008-01-01

    Most human-caused climate change comes from fossil fuel combustion emissions. To avoid the risk of serious climate change, very recent research suggests that emission reductions will need to be both large and rapidly implemented. We argue that technical solutions-improving energy efficiency, use of renewable and nuclear energy, and carbon capture and sequestration-can only be of minor importance, mainly given the limited time available to take effective climate action. Only curbing energy use, perhaps through 'social efficiency' gains, particularly in the high-energy consumption countries, can provide the rapid emissions reductions needed. The social efficiency approach requires a basic rethinking in how we can satisfy our human needs with low environmental impacts. Large cuts in emissions could then occur rapidly, but only if resistance to such changes can be overcome. Particularly in transport, there are also serious potential conflicts between the technical and the social efficiency approaches, requiring a choice to be made

  19. The limits on trypanosomatid morphological diversity.

    Directory of Open Access Journals (Sweden)

    Richard John Wheeler

    Full Text Available Cell shape is one, often overlooked, way in which protozoan parasites have adapted to a variety of host and vector environments and directional transmissions between these environments. Consequently, different parasite life cycle stages have characteristic morphologies. Trypanosomatid parasites are an excellent example of this in which large morphological variations between species and life cycle stage occur, despite sharing well-conserved cytoskeletal and membranous structures. Here, using previously published reports in the literature of the morphology of 248 isolates of trypanosomatid species from different hosts, we perform a meta-analysis of the occurrence and limits on morphological diversity of different classes of trypanosomatid morphology (trypomastigote, promastigote, etc. in the vertebrate bloodstream and invertebrate gut environments. We identified several limits on cell body length, cell body width and flagellum length diversity which can be interpreted as biomechanical limits on the capacity of the cell to attain particular dimensions. These limits differed for morphologies with and without a laterally attached flagellum which we suggest represent two morphological superclasses, the 'juxtaform' and 'liberform' superclasses. Further limits were identified consistent with a selective pressure from the mechanical properties of the vertebrate bloodstream environment; trypanosomatid size showed limits relative to host erythrocyte dimensions. This is the first comprehensive analysis of the limits of morphological diversity in any protozoan parasite, revealing the morphogenetic constraints and extrinsic selection pressures associated with the full diversity of trypanosomatid morphology.

  20. 7 CFR 1400.204 - Limited partnerships, limited liability partnerships, limited liability companies, corporations...

    Science.gov (United States)

    2010-01-01

    ..., limited liability companies, corporations, and other similar legal entities. 1400.204 Section 1400.204..., limited liability partnerships, limited liability companies, corporations, and other similar legal entities. (a) A limited partnership, limited liability partnership, limited liability company, corporation...

  1. Mammalian cloning: advances and limitations.

    Science.gov (United States)

    Solter, D

    2000-12-01

    For many years, researchers cloning mammals experienced little success, but recent advances have led to the successful cloning of several mammalian species. However, cloning by the transfer of nuclei from adult cells is still a hit-and-miss procedure, and it is not clear what technical and biological factors underlie this. Our understanding of the molecular basis of reprogramming remains extremely limited and affects experimental approaches towards increasing the success rate of cloning. Given the future practical benefits that cloning can offer, the time has come to address what should be done to resolve this problem.

  2. Novel limiter pump topologies

    International Nuclear Information System (INIS)

    Schultz, J.H.

    1981-01-01

    The use of limiter pumps as the principle plasma exhaust system of a magnetic confinement fusion device promises significant simplification, when compared to previously investigating divertor based systems. Further simplifications, such as the integration of the exhaust system with a radio frequency heating system and with the main reactor shield and structure are investigated below. The integrity of limiters in a reactor environment is threatened by many mechanisms, the most severe of which may be erosion by sputtering. Two novel topolgies are suggested which allow high erosion without limiter failure

  3. HOME Rent Limits

    Data.gov (United States)

    Department of Housing and Urban Development — In accordance with 24 CFR Part 92.252, HUD provides maximum HOME rent limits. The maximum HOME rents are the lesser of: The fair market rent for existing housing for...

  4. ACA Federal Upper Limits

    Data.gov (United States)

    U.S. Department of Health & Human Services — Affordable Care Act Federal Upper Limits (FUL) based on the weighted average of the most recently reported monthly average manufacturer price (AMP) for...

  5. HUD Program Income Limits

    Data.gov (United States)

    Department of Housing and Urban Development — Income limits used to determine the income eligibility of applicants for assistance under three programs authorized by the National Housing Act. These programs are...

  6. Limited Denial of Participation

    Data.gov (United States)

    Department of Housing and Urban Development — A Limited Denial of Participation (LDP) is an action taken by a HUD Field Office or the Deputy Assistant Secretary for Single Family (DASSF) or Multifamily (DASMF)...

  7. Limited Income and Resources

    Data.gov (United States)

    U.S. Department of Health & Human Services — Information for those with limited income and resources (those who may qualify for or already have the Low Income Subsidy to lower their prescription drug coverage...

  8. Towards Improved Optical Limiters

    National Research Council Canada - National Science Library

    Huffman, Peter

    2002-01-01

    .... The first approach was to synthesize and study soluble thallium phthalocyanines. Thallium, due to its proximity to lead and indium on the periodic table, should exhibit favorable optical limiting properties...

  9. SIS - Annual Catch Limit

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Annual Catch Limit (ACL) dataset within the Species Information System (SIS) contains information and data related to management reference points and catch data.

  10. Limited Scleroderma (CREST Syndrome)

    Science.gov (United States)

    ... limited scleroderma is believed to be an autoimmune disorder, in which your immune system turns against your body. The immune system appears to stimulate the production of too much collagen, a key component of connective tissue. This overproduction ...

  11. Political campaign spending limits

    OpenAIRE

    Pastine, Ivan; Pastine, Tuvana

    2010-01-01

    Political campaign spending ceilings are purported to limit the incumbent’s ability to exploit his fundraising advantage. If the challenger does not have superior campaign effectiveness, in contrast to conventional wisdom, we show that the incumbent always benefits from a limit as long as he has an initial voter disposition advantage, however small and regardless of the candidates’ relative fundraising ability. If the challenger has higher campaign spending effectiveness, th...

  12. Safety and design limits

    International Nuclear Information System (INIS)

    Shishkov, L. K.; Gorbaev, V. A.; Tsyganov, S. V.

    2007-01-01

    The paper touches upon the issues of NPP safety ensuring at the stage of fuel load design and operation by applying special limitations for a series of parameters, that is, design limits. Two following approaches are compared: the one used by west specialists for the PWR reactor and the Russian approach employed for the WWER reactor. The closeness of approaches is established, differences that are mainly peculiarities of terms are noted (Authors)

  13. Altruism and Reproductive Limitations

    Directory of Open Access Journals (Sweden)

    Carey J. Fitzgerald

    2009-04-01

    Full Text Available We examined how different types of reproductive limitations — functional (schizoid personality disorder and schizophrenia, physical (malnutrition, and sexual (bisexuality and homosexuality — influenced altruistic intentions toward hypothetical target individuals of differing degrees of relatedness (r = 0, .25, and .50. Participants were 312 undergraduate students who completed a questionnaire on altruism toward hypothetical friends, half-siblings, and siblings with these different types of reproductive limitations. Genetic relatedness and reproductive limitations did not influence altruistic decision-making when the cost of altruism was low but did as the cost of altruism increased, with participants being more likely to help a sibling over a half-sibling and a half-sibling over a friend. Participants also indicated they were more likely to help a healthy (control person over people with a reproductive limitation. Of the three types of reproductive limitations, functional limitations had the strongest effect on altruistic decision-making, indicating that people were less likely to help those who exhibit abnormal social behavior.

  14. Treatment of limited stage small-cell lung cancer: results from a single center; Tratamento do cancer de pequenas celulas de pulmao - doenca limitada: resultados de uma unica instituicao

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Michael Jenwei; Faria, Sergio Luis; Souhami, Luis; Niazi, Tamil Mohammed; Duclos, Marie; Guerra, Julio [McGill University Health Centre, Montreal, Quebec (Canada). Montreal General Hospital. Dept. de Radio-Oncologia]. E-mail: sergio.faria@muhc.mcgill.ca

    2006-01-15

    Objective: To report the results of the treatment of patients with small-cell lung cancer with limited disease (SCLC-LD) in a single institution during a 10-year period, for quality assurance and comparison with data from the literature. Materials and methods: Between January 1992 and December 2002, 101 patients with SCLC-LD completed treatment at our institution. The outcomes were reviewed and included chemotherapy, radiotherapy, the sequence of the two treatments, and the use of prophylactic cranial irradiation. Radiation was delivered with a median dose of 45 Gy in 1.8 to 2 Gy per fraction. The median dose of the prophylactic cranial irradiation was 25 Gy in 10 fractions. Results: Average follow-up was of 50.6 months and the average age of the patients was 63 years. There were 85 confirmed deaths, 5 patients were lost to follow up and 11 patients were alive. The median survival time was 11 months, the overall survival at 2 and 5 years was 25.5% and 10% respectively. There were no significant difference in overall survival at 2 or 5 years according to the age and sex of the patients. In addition, there were no statistical difference in overall survival among patients who had prophylactic cranial irradiation or not, or who were treated in two different periods (1997-2002 vs. 1992-1996). Conclusion: The results of the treatment of SCLC-LD patients in our institution reflect the constant changes in the management of SCLC. The 2-year's 25.5% overall survival seen in our institution is similar to reports published from other single institution, but lower than the 47% to 54% recently published results from cooperative groups. (author)

  15. Correlation Between En Face Optical Coherence Tomography Defects of the Inner Retinal Layers and Ganglion Cell Inner Plexiform Layer Analysis After Internal Limiting Membrane Peeling for Idiopathic Full-Thickness Macular Hole.

    Science.gov (United States)

    Sabry, Dalia; El-Kannishy, Amr; Kamel, Rania; Abou Samra, Waleed

    2016-07-01

    The purpose of this study was to report en face optical coherence tomography (OCT) inner retinal changes after internal limiting membrane (ILM) peeling for idiopathic full-thickness macular hole (IFTMH) and to correlate these findings with macular ganglion cell inner plexiform layer (GC-IPL) analysis. This prospective study included 20 patients with IFTMH treated using pars plana vitrectomy with ILM peeling. All patients were analyzed using en face OCT at 6 months after surgery to determinate the effect of ILM peeling on the inner retinal layers. Correlation between the GC-IPL en face OCT findings and that obtained by three-dimensional volumetric OCT scanning also was performed. Seven patients (35%) showed defects in the retinal nerve fiber layer (RNFL) that appeared as multiple dark dots with no visible defects at the GC-IPL, either with en face OCT or 3D volumetric OCT scanning. Thirteen patients (65%) showed a similar combination of RNFL defects and well-circumscribed defects in the underlying GC-IPL. These defects could be visualized on en face OCT display, and they correlated with areas of GC-IPL thinning detected in the 3D volumetric OCT scanning. With ILM peeling, en face OCT scanning showed two forms of inner retinal layers changes. The first form was the concentric macular dark spots (CMDS) with intact GC-IPL. The second form appeared in the CMDS with evident localized defects in the underlying GC-IPL. These defects correlate with the areas of GC-IPL thinning detected using 3D volumetric OCT scanning.

  16. Quantum-limit spectroscopy

    CERN Document Server

    Ficek, Zbigniew

    2017-01-01

    This book covers the main ideas, methods, and recent developments of quantum-limit optical spectroscopy and applications to quantum information, resolution spectroscopy, measurements beyond quantum limits, measurement of decoherence, and entanglement. Quantum-limit spectroscopy lies at the frontier of current experimental and theoretical techniques, and is one of the areas of atomic spectroscopy where the quantization of the field is essential to predict and interpret the existing experimental results. Currently, there is an increasing interest in quantum and precision spectroscopy both theoretically and experimentally, due to significant progress in trapping and cooling of single atoms and ions. This progress allows one to explore in the most intimate detail the ways in which light interacts with atoms and to measure spectral properties and quantum effects with high precision. Moreover, it allows one to perform subtle tests of quantum mechanics on the single atom and single photon scale which were hardly eve...

  17. Evaluating total lymphocyte count as a surrogate marker for CD4 cell count in the management of HIV-infected patients in resource-limited settings: a study from China.

    Directory of Open Access Journals (Sweden)

    Jieqing Chen

    Full Text Available OBJECTIVE: To evaluate the correlation of total lymphocyte count (TLC and CD4 cell count and the suitability of TLC as a surrogate marker for CD4 cell count of HIV-infected patients in China. METHODS: Usefulness of TLC as a surrogate marker for a CD4 cell count <350 cells/mm(3 for HIV-positive patients in China was evaluated by 977 pairs of TLC and CD4 cell count from 977 outpatients. The result was then validated by a literature review which was conducted on 9 relevant articles. Further investigation using the 977 pairs of TLC and CD4 cell count data was done to determine a TLC threshold for predicting a CD4 cell count <500 cells/mm(3. Correlation and receiver operating characteristic (ROC analysis were performed for both CD4 cell counts, and the sensitivity and specificity were computed. RESULTS: Good correlation was noted between TLC and CD4 count (r = 0.60, 95% CI, 0.56-0.64. TLC obtained a relatively high diagnostic performance (area under ROC curve, 0.80 for predicting a CD4 cell count <350 cells/mm(3, with a sensitivity of 0.65 (95% CI, 0.61-0.68 and a specificity of 0.80 (95% CI, 0.75-0.85 at the TLC threshold of 1570 cells/mm(3. The literature review suggested that for a CD4 cell count <350 cells/mm(3, the optimal TLC threshold was 1500 cells/mm(3, which was similar to the figure presented in this observational study. As for predicting a CD4 cell count <500 cells/mm(3, TLC obtained a high diagnostic performance (area under ROC curve, 0.82 as well with a sensitivity of 0.70 (95% CI, 0.67-0.73 and a specificity of 0.80 (95% CI, 0.73-0.87. CONCLUSIONS: When considering the antiretroviral therapy for HIV-infected Chinese individuals, total lymphocyte count can be considered as an inexpensive and easily available surrogate marker for predicting two clinically important thresholds of CD4 count of 350 cells/mm(3 and 500 cells/mm(3.

  18. Hadron collider luminosity limitations

    CERN Document Server

    Evans, Lyndon R

    1992-01-01

    The three colliders operated to date have taught us a great deal about the behaviour of both bunched and debunched beams in storage rings. The main luminosity limitations are now well enough understood that most of them can be stronglu attenuated or eliminated by approriate design precautions. Experience with the beam-beam interaction in both the SPS and the Tevatron allow us to predict the performance of the new generation of colliders with some degree of confidence. One of the main challenges that the accelerator physicist faces is the problem of the dynamic aperture limitations due to the lower field quality expected, imposed by economic and other constraints.

  19. SLC kicker magnet limitations

    International Nuclear Information System (INIS)

    Cassel, R.; Donaldson, A.; Mattison, T.; Bowden, G.; Weaver, J.; Bulos, F.; Fiander, D.

    1991-01-01

    The SLC Damping Ring kicker magnets requires a fast magnetic field rise time of 58 nsec, a peak field of 800 gauss, a pulse amplitude stability of 0.01%, and a reasonable operational lifetime. The original kicker magnets designed by SLAC and at Fermi were not able to fulfill the SLC kicker requirements. Extensive studies were conducted to determine the limitation in the magnets, response of the ferrite in kicker magnet, and the modifications needed to improve the kicker magnet performance. The paper details the SLAC and Fermi kicker magnets limitation of performance

  20. The crystal structure of human dipeptidyl peptidase I (cathepsin C) in complex with the inhibitor Gly-Phe-CHN2

    DEFF Research Database (Denmark)

    Mølgaard, Anne; Arnau, Jose; Lauritzen, C.

    2007-01-01

    hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase. In the ......hDDPI (human dipeptidyl peptidase I) is a lysosomal cysteine protease involved in zymogen activation of granule-associated proteases, including granzymes A and B from cytotoxic T-lymphocytes and natural killer cells, cathepsin G and neutrophil elastase, and mast cell tryptase and chymase...

  1. Evaluating total lymphocyte count as a surrogate marker for CD4 cell count in the management of HIV-infected patients in resource-limited settings: a study from China.

    Science.gov (United States)

    Chen, Jieqing; Li, Wei; Huang, Xiaojie; Guo, Caiping; Zou, Ran; Yang, Qiuying; Zhang, Hongwei; Zhang, Tong; Chen, Hui; Wu, Hao

    2013-01-01

    To evaluate the correlation of total lymphocyte count (TLC) and CD4 cell count and the suitability of TLC as a surrogate marker for CD4 cell count of HIV-infected patients in China. Usefulness of TLC as a surrogate marker for a CD4 cell count China was evaluated by 977 pairs of TLC and CD4 cell count from 977 outpatients. The result was then validated by a literature review which was conducted on 9 relevant articles. Further investigation using the 977 pairs of TLC and CD4 cell count data was done to determine a TLC threshold for predicting a CD4 cell count TLC and CD4 count (r = 0.60, 95% CI, 0.56-0.64). TLC obtained a relatively high diagnostic performance (area under ROC curve, 0.80) for predicting a CD4 cell count TLC threshold of 1570 cells/mm(3). The literature review suggested that for a CD4 cell count TLC threshold was 1500 cells/mm(3), which was similar to the figure presented in this observational study. As for predicting a CD4 cell count TLC obtained a high diagnostic performance (area under ROC curve, 0.82) as well with a sensitivity of 0.70 (95% CI, 0.67-0.73) and a specificity of 0.80 (95% CI, 0.73-0.87). When considering the antiretroviral therapy for HIV-infected Chinese individuals, total lymphocyte count can be considered as an inexpensive and easily available surrogate marker for predicting two clinically important thresholds of CD4 count of 350 cells/mm(3) and 500 cells/mm(3).

  2. Activation analysis. Detection limits

    International Nuclear Information System (INIS)

    Revel, G.

    1999-01-01

    Numerical data and limits of detection related to the four irradiation modes, often used in activation analysis (reactor neutrons, 14 MeV neutrons, photon gamma and charged particles) are presented here. The technical presentation of the activation analysis is detailed in the paper P 2565 of Techniques de l'Ingenieur. (A.L.B.)

  3. Limited data speaker identification

    Indian Academy of Sciences (India)

    Speaker identification; limited training and testing data; MFSR; LPR; LPRP; LVQ; GMM–UBM and combining. ... Department of Information Science and Engineering, Siddaganga Institute of Technology, Tumkur 572 103; Department of Electronics and Communication Engineering, Indian Institute of Technology Guwahati, ...

  4. Occupational dose equivalent limits

    International Nuclear Information System (INIS)

    Goldfinch, E.P.

    1980-01-01

    This paper considers methods of limiting individual radiation risks by recognizing the variation of risk with age at exposure, taking into account both somatic and genetic risks and proposes a simple formula for controlling individual cumulative exposure and hence risk. (Author)

  5. Limited data speaker identification

    Indian Academy of Sciences (India)

    dependent or text-independent type. Speech for the same text is used for ... are practical situations like forensic investigations where the availability of speech data is limited and technology is ...... Murthy K S R, Yegnanarayana B 2006 Combining evidence from residual phase and MFCC features for speaker recognition.

  6. Limits of Software Reuse

    NARCIS (Netherlands)

    Holenderski, L.

    2006-01-01

    Software reuse is considered one of the main techniques to increasesoftware productivity. We present two simple mathematical argumentsthat show some theoretical limits of reuse. It turns out that the increase of productivity due to internal reuse is at most linear, farfrom the needed exponential

  7. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01)

    NARCIS (Netherlands)

    Pechoux, C. Le; Laplanche, A.; Faivre-Finn, C.; Ciuleanu, T.; Wanders, R.; Lerouge, D.; Keus, R.; Hatton, M.; Videtic, G.M.; Senan, S.; Wolfson, A.; Jones, R.; Arriagada, R.; Quoix, E.; Dunant, A.; Bussink, J.

    2011-01-01

    BACKGROUND: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a

  8. The inducible caspase-9 suicide gene system as a ‘safety switch’ to limit on-target, off-tumor toxicities of chimeric antigen receptor T-cells.

    Directory of Open Access Journals (Sweden)

    Tessa eGargett

    2014-10-01

    Full Text Available Immune modulation has become a central element in many cancer treatments, and T cells genetically engineered to express chimeric antigen receptors (CAR may provide a new approach to cancer immunotherapy. Autologous CAR T cells that have been re-directed towards tumor-associated antigens (TAA have shown promising results in phase 1 clinical trials, with some patients undergoing complete tumor regression. However this T-cell therapy must carefully balance effective T-cell activation, to ensure antitumor activity, with the potential for uncontrolled activation that may produce immunopathology. An inducible Caspase 9 (iCasp9 ‘safety switch’ offers a solution that allows for the removal of inappropriately activated CAR T cells. The induction of iCasp9 depends on the administration of the small molecule dimerizer drug AP1903 and dimerization results in rapid induction of apoptosis in transduced cells, preferentially killing activated cells expressing high levels of transgene. The iCasp9 gene has been incorporated into vectors for use in preclinical studies and demonstrates effective and reliable suicide gene activity in phase 1 clinical trials. A third-generation CAR incorporating iCasp9 re-directs T cells towards the GD2 TAA. GD2 is over-expressed in melanoma and other malignancies of neural crest origin and the safety and activity of these GD2-iCAR T cells will be investigated in CARPETS and other actively recruiting phase 1 trials.

  9. Current limiter circuit system

    Energy Technology Data Exchange (ETDEWEB)

    Witcher, Joseph Brandon; Bredemann, Michael V.

    2017-09-05

    An apparatus comprising a steady state sensing circuit, a switching circuit, and a detection circuit. The steady state sensing circuit is connected to a first, a second and a third node. The first node is connected to a first device, the second node is connected to a second device, and the steady state sensing circuit causes a scaled current to flow at the third node. The scaled current is proportional to a voltage difference between the first and second node. The switching circuit limits an amount of current that flows between the first and second device. The detection circuit is connected to the third node and the switching circuit. The detection circuit monitors the scaled current at the third node and controls the switching circuit to limit the amount of the current that flows between the first and second device when the scaled current is greater than a desired level.

  10. FTU pump limiter

    International Nuclear Information System (INIS)

    Alessandrini, C.; Ciotti, M.; Mattei, A. De; Maddaluno, G.; Mazzitelli, G.

    1989-01-01

    The control of the refuelling and recycling of the plasma is crucial in providing enhanced performances in tokamaks and steady-state operation in future reactors. In this paper, we report details of the design and analysis for the pump limiter to be incorporated into the FTU tokamak. The FTU, presently under commissioning, is a compact high field (B=8T), medium high density, circular cross section machine with small accesses. The dimensions of the equatorial port (width 8 cm) would reduce the length of the entrance throat to a few centimeters, which is unacceptable for efficient particle trapping. We have, therefore, designed a rotating blade of the pump limiter head that, in the working position, extends in the toroidal direction inside the vacuum chamber. (author) 8 refs., 4 figs

  11. Age Limit of Pediatrics.

    Science.gov (United States)

    Hardin, Amy Peykoff; Hackell, Jesse M

    2017-09-01

    Pediatrics is a multifaceted specialty that encompasses children's physical, psychosocial, developmental, and mental health. Pediatric care may begin periconceptionally and continues through gestation, infancy, childhood, adolescence, and young adulthood. Although adolescence and young adulthood are recognizable phases of life, an upper age limit is not easily demarcated and varies depending on the individual patient. The establishment of arbitrary age limits on pediatric care by health care providers should be discouraged. The decision to continue care with a pediatrician or pediatric medical or surgical subspecialist should be made solely by the patient (and family, when appropriate) and the physician and must take into account the physical and psychosocial needs of the patient and the abilities of the pediatric provider to meet these needs. Copyright © 2017 by the American Academy of Pediatrics.

  12. Are Limit Orders Rational?

    Czech Academy of Sciences Publication Activity Database

    Šmíd, Martin

    2007-01-01

    Roč. 14, č. 4 (2007), s. 32-38 ISSN 0572-3043 R&D Projects: GA ČR(CZ) GA402/06/1417; GA ČR GA402/04/1294; GA ČR GD402/03/H057 Institutional research plan: CEZ:AV0Z10750506 Keywords : market microstructure * limit order market * portfolio selection Subject RIV: AH - Economics

  13. Density limits in Tokamaks

    International Nuclear Information System (INIS)

    Tendler, M.

    1984-06-01

    The energy loss from a tokamak plasma due to neutral hydrogen radiation and recycling is of great importance for the energy balance at the periphery. It is shown that the requirement for thermal equilibrium implies a constraint on the maximum attainable edge density. The relation to other density limits is discussed. The average plasma density is shown to be a strong function of the refuelling deposition profile. (author)

  14. Photovoltaic energy cost limit

    International Nuclear Information System (INIS)

    Coiante, D.

    1992-01-01

    Referring to a photovoltaic system for grid connected applications, a parametric expression of kWh cost is derived. The limit of kWh cost is carried out extrapolating the values of cost components to their lowest figure. The reliability of the forecast is checked by disaggregating kWh cost in direct and indirect costs and by discussing the possible cost reduction of each component

  15. Limits of Nuclear Stability

    CERN Document Server

    Nerlo-Pomorska, B; Kleban, M

    2003-01-01

    The modern version of the liquid-drop model (LSD) is compared with the macroscopic part of the binding energy evaluated within the Hartree-Fock- Bogoliubov procedure with the Gogny force and the relativistic mean field theory. The parameters of a liquid-drop like mass formula which approximate on the average the self-consistent results are compared with other models. The limits of nuclear stability predicted by these models are discussed.

  16. Pressure limitation method

    International Nuclear Information System (INIS)

    Brady, M.

    1989-01-01

    The pressure in a glovebox is maintained, for safety, between predetermined negative and positive limits relative to atmospheric pressure by means of a lute comprising a closed vessel having a tube sealed through its upper region and extending downwards towards its lower region and having an open end thereat. The other end of the tube is connected to the glovebox and the upper region of the vessel is vented to atmosphere via an extract system. The vessel and tube are filled with liquid to such a level, sealing the open end of the tube, that (a) at the said negative limit the liquid level in the vessel falls to unseal the tube and allow atmospheric air to enter the glovebox, and (b) at the said positive limit the liquid level in the tube falls to unseal the tube and allow gas from the glovebox to vent to atmosphere. A catch-pot is provided between tube and the glovebox to prevent any entrained liquid entering the glovebox, and similar means may also be provided to prevent any entrained liquid entering the extract system. (author)

  17. [Bionics: limits and perspectives].

    Science.gov (United States)

    Grassmann, P

    1990-07-01

    Bionics, based on analogies between living beings and technical systems, neglect fundamental differences, e.g., on the one hand, technology uses high temperatures, a mean closed to all living beings and, on the other hand, the cells of all organisms keep high autonomy. The first fact makes it possible, e.g., to construct airplanes three or four powers of ten heavier than the heaviest birds, whereas the second fact enables each cell to reproduce itself, to restore lost limbs or even the whole organism, far beyond the reach of technology. The symbiosis of organisms and technical installations (biotechnology) or, on a higher level, of mankind and environment, may be a guiding star for future development.

  18. Neurotoxic injury pathways in differentiated mouse motor neuron–neuroblastoma hybrid (NSC-34D) cells in vitro—Limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Hemendinger, Richelle A., E-mail: richelle.hemendinger@carolinashealthcare.org [ALS Translational Neuroscience Laboratory, Carolinas Medical Center, Charlotte, NC 28203 (United States); Carolinas Neuromuscular/ALS-MDA Center, Department of Neurology, Carolinas Medical Center, Charlotte, NC 28203 (United States); Armstrong, Edward J. [ALS Translational Neuroscience Laboratory, Carolinas Medical Center, Charlotte, NC 28203 (United States); Carolinas Neuromuscular/ALS-MDA Center, Department of Neurology, Carolinas Medical Center, Charlotte, NC 28203 (United States); Radio, Nick [ThermoScientific, Pittsburgh, PA (United States); Brooks, Benjamin Rix [ALS Translational Neuroscience Laboratory, Carolinas Medical Center, Charlotte, NC 28203 (United States); Carolinas Neuromuscular/ALS-MDA Center, Department of Neurology, Carolinas Medical Center, Charlotte, NC 28203 (United States); University of North Carolina School of Medicine-Charlotte Campus (United States)

    2012-01-15

    The neuroblastoma–spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H{sub 2}O{sub 2}) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC{sub 50} = 0.01 μM), followed by Thaps (TC{sub 50} = 0.9 μM) and H{sub 2}O{sub 2} (TC{sub 50} = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC{sub 50} = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H{sub 2}O{sub 2}- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. -- Highlights: ► Calcium-dependent neurotoxins are potent cell death inducers in NSC-34D cells. ► Riluzole provides neurorescue against Thaps-induced NSC-34D cell death. ► Riluzole had no effect on neurotoxicity by STS, H{sub 2}O{sub 2} and Hcy. ► Riluzole reduces NSC-34D cell death independent of

  19. Neurotoxic injury pathways in differentiated mouse motor neuron–neuroblastoma hybrid (NSC-34D) cells in vitro—Limited effect of riluzole on thapsigargin, but not staurosporine, hydrogen peroxide and homocysteine neurotoxicity

    International Nuclear Information System (INIS)

    Hemendinger, Richelle A.; Armstrong, Edward J.; Radio, Nick; Brooks, Benjamin Rix

    2012-01-01

    The neuroblastoma–spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H 2 O 2 ) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC 50 = 0.01 μM), followed by Thaps (TC 50 = 0.9 μM) and H 2 O 2 (TC 50 = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC 50 = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H 2 O 2 - and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. -- Highlights: ► Calcium-dependent neurotoxins are potent cell death inducers in NSC-34D cells. ► Riluzole provides neurorescue against Thaps-induced NSC-34D cell death. ► Riluzole had no effect on neurotoxicity by STS, H 2 O 2 and Hcy. ► Riluzole reduces NSC-34D cell death independent of caspase-3/7 activation.

  20. Tracing the Origins of IgE, Mast Cells, and Allergies by Studies of Wild Animals.

    Science.gov (United States)

    Hellman, Lars Torkel; Akula, Srinivas; Thorpe, Michael; Fu, Zhirong

    2017-01-01

    In most industrialized countries, allergies have increased in frequency quite dramatically during the past 50 years. Estimates show that 20-30% of the populations are affected. Allergies have thereby become one of the major medical challenges of the twenty-first century. Despite several theories including the hygiene hypothesis, there are still very few solid clues concerning the causes of this increase. To trace the origins of allergies, we have studied cells and molecules of importance for the development of IgE-mediated allergies, including the repertoire of immunoglobulin genes. These studies have shown that IgE and IgG most likely appeared by a gene duplication of IgY in an early mammal, possibly 220-300 million years ago. Receptors specific for IgE and IgG subsequently appeared in parallel with the increase in Ig isotypes from a subfamily of the recently identified Fc receptor-like molecules. Circulating IgE levels are generally very low in humans and laboratory rodents. However, when dogs and Scandinavian wolfs were analyzed, IgE levels were found to be 100-200 times higher compared to humans, indicating a generally much more active IgE synthesis in free-living animals, most likely connected to intestinal parasite infections. One of the major effector molecules released upon IgE-mediated activation by mast cells are serine proteases. These proteases, which belong to the large family of hematopoietic serine proteases, are extremely abundant and can account for up to 35% of the total cellular protein. Recent studies show that several of these enzymes, including the chymases and tryptases, are old. Ancestors for these enzymes were most likely present in an early mammal more than 200 million years ago before the separation of the three extant mammalian lineages; monotremes, marsupials, and placental mammals. The aim is now to continue these studies of mast cell biology and IgE to obtain additional clues to their evolutionary conserved functions. A focus

  1. Peptidomics for Studying Limited Proteolysis.

    Science.gov (United States)

    Tsuchiya, Takashi; Osaki, Tsukasa; Minamino, Naoto; Sasaki, Kazuki

    2015-11-06

    Limited proteolysis is a pivotal mechanism regulating protein functions. Identifying physiologically or pathophysiologically relevant cleavage sites helps to develop molecular tools that can be used for diagnostics or therapeutics. During proteolysis of secretory and membrane proteins, part of the cleaved protein is liberated and destined to undergo degradation but should retain original cleavage sites created by proteolytic enzymes. We profiled endogenous peptides accumulated for 4 h in media conditioned by primary cultured rat cardiac fibroblasts. A total of 3916 redundant peptide sequences from 94 secretory proteins and membrane proteins served to identify limited cleavage sites, both annotated and unannotated, for signal peptide or propeptide removal, peptide hormone processing, ectodomain shedding, and regulated intramembrane proteolysis. Incorrectly predicted signal cleavage sites are found in typical proteins such as extracellular matrix proteins and the peptide hormone precursor adrenomedullin ADM. The revealed signal peptide cleavage site for ADM was experimentally verified by identifying the major molecular form of flanking proadrenomedullin N-terminal peptide. We suggest that profiling of endogenous peptides, like transcriptome sequence reads, makes sense in regular cells such as fibroblasts and that peptidomics provides insight into proteolysis-regulated protein functions.

  2. Strategic arms limitation

    Science.gov (United States)

    Allen Greb, G.; Johnson, Gerald W.

    1983-10-01

    Following World War II, American scientists and politicians proposed in the Baruch plan a radical solution to the problem of nuclear weapons: to eliminate them forever under the auspices of an international nuclear development authority. The Soviets, who as yet did not possess the bomb, rejected this plan. Another approach suggested by Secretary of War Henry Stimson to negotiate directly with the Soviet Union was not accepted by the American leadership. These initial arms limitation failures both reflected and exacerbated the hostile political relationship of the superpowers in the 1950s and 1960s. Since 1969, the more modest focus of the Soviet-American arms control process has been on limiting the numbers and sizes of both defensive and offensive strategic systems. The format for this effort has been the Strategic Arms Limitatins Talks (Salt) and more recently the Strategic Arms Reduction Talks (START). Both sides came to these negotiations convinced that nuclear arsenals had grown so large that some for of mutual restraint was needed. Although the SALT/START process has been slow and ponderous, it has produced several concrete the agreements and collateral benefits. The 1972 ABM Treaty restricts the deployment of ballistic missile defense systems, the 1972 Interim Agreement places a quantitative freeze on each side's land based and sea based strategic launchers, and the as yet unratified 1979 SALT II Treaty sets numerical limits on all offensive strategic systems and sublimits on MIRVed systems. Collateral benefits include improved verification procedures, working definitions and counting rules, and permanent bureaucratic apparatus which enhance stability and increase the chances for achieving additional agreements.

  3. Limits to Cloud Susceptibility

    Science.gov (United States)

    Coakley, James A., Jr.

    2002-01-01

    1-kilometer AVHRR observations of ship tracks in low-level clouds off the west coast of the U S. were used to determine limits for the degree to which clouds might be altered by increases in anthropogenic aerosols. Hundreds of tracks were analyzed to determine whether the changes in droplet radii, visible optical depths, and cloud top altitudes that result from the influx of particles from underlying ships were consistent with expectations based on simple models for the indirect effect of aerosols. The models predict substantial increases in sunlight reflected by polluted clouds due to the increases in droplet numbers and cloud liquid water that result from the elevated particle concentrations. Contrary to the model predictions, the analysis of ship tracks revealed a 15-20% reduction in liquid water for the polluted clouds. Studies performed with a large-eddy cloud simulation model suggested that the shortfall in cloud liquid water found in the satellite observations might be attributed to the restriction that the 1-kilometer pixels be completely covered by either polluted or unpolluted cloud. The simulation model revealed that a substantial fraction of the indirect effect is caused by a horizontal redistribution of cloud water in the polluted clouds. Cloud-free gaps in polluted clouds fill in with cloud water while the cloud-free gaps in the surrounding unpolluted clouds remain cloud-free. By limiting the analysis to only overcast pixels, the current study failed to account for the gap-filling predicted by the simulation model. This finding and an analysis of the spatial variability of marine stratus suggest new ways to analyze ship tracks to determine the limit to which particle pollution will alter the amount of sunlight reflected by clouds.

  4. Dose. Detriment. Limit assessment

    International Nuclear Information System (INIS)

    Breckow, J.

    2015-01-01

    One goal of radiation protection is the limitation of stochastic effects due to radiation exposure. The probability of occurrence of a radiation induced stochastic effect, however, is only one of several other parameters which determine the radiation detriment. Though the ICRP-concept of detriment is a quantitative definition, the kind of detriment weighting includes somewhat subjective elements. In this sense, the detriment-concept of ICRP represents already at the stage of effective dose a kind of assessment. Thus, by comparing radiation protection standards and concepts interconvertible or with those of environment or occupational protection one should be aware of the possibly different principles of detriment assessment.

  5. Marketing with limited budget

    OpenAIRE

    Smirnova, Daria

    2017-01-01

    The purpose of this research-based thesis was to get an idea how managers of two small resembling hotels of a specific region deal with marketing process with a limited budget. In addition, the aim of the thesis was to examine if hotel managers who were interviewed perceive marketing only in the way of ‘promotion’ rather than marketing research, marketing mix and marketing environment theories. It was also found out if hotel managers of those hotels consider marketing as a key to successful h...

  6. Limitation of Auditors' Liability

    DEFF Research Database (Denmark)

    Werlauff, Erik; Foged-Ladefoged, Lise Kolding

    2014-01-01

    The article examines the question of whether rules on the limitation of auditors’ liability within the perspective of EU law are needed, and if so, which rules can provide an appropriate balance between the potential injured party’s interests and those of the auditing sector, including with respect...... to the fact that the insurance premiums associated with an unlimited liability must of course make the auditor’s tasks more expensive. Relevant EU recommendations and a comparative glance at other EU countries’ proposed solutions to the problem are included....

  7. Search with Limited Resources.

    Science.gov (United States)

    1983-02-01

    D-R1-76 122 SERCH WITH ’LIMITED RESOURCES(U) DUKE UNIV DURHM NC i/i DEPTOF COMPUTER SCIENCE D C MUTCHLER FEB 83 CS11983-1 USI FE AFOSR-TR-83-i154...over all possible S" g ame trees. How to weight this average has not yet been specified. It is reasonable. glven the lack of additional information, to...complete binary 0-1 tree can be described by two parameters: P a number of goal nodes with value ŕ". and vt = number of goal nodes. This Justifies

  8. Limitations of Boltzmann's principle

    International Nuclear Information System (INIS)

    Lavenda, B.H.

    1995-01-01

    The usual form of Boltzmann's principle assures that maximum entropy, or entropy reduction, occurs with maximum probability, implying a unimodal distribution. Boltzmann's principle cannot be applied to nonunimodal distributions, like the arcsine law, because the entropy may be concave only over a limited portion of the interval. The method of subordination shows that the arcsine distribution corresponds to a process with a single degree of freedom, thereby confirming the invalidation of Boltzmann's principle. The fractalization of time leads to a new distribution in which arcsine and Cauchy distributions can coexist simultaneously for nonintegral degrees of freedom between √2 and 2

  9. Limitations of Expert Evidence

    OpenAIRE

    Serpil Salaçin

    1997-01-01

    Limitations of Expert Evidence Edited by Stephen Leadbeatter MB ChB MCRPath ISBN 1 86016 029 8 Printed in Great Britain by Cathedral Print Services Ltd, Salisbury, 1996 Kitap 25 Ekim 1994 te The Royal College of Physicians ve The Royal College of Pathologists tarafından düzenlenen konferanstan sonra hekimlere ve avukatlara konuyu tartışmaya açmak için basılmış. Bilirkişi görüşünün temel filozofisinin, bu görevi yapanlar ve bu hizmeti alanların yapabileceklerin...

  10. Fault current limiter

    Science.gov (United States)

    Darmann, Francis Anthony

    2013-10-08

    A fault current limiter (FCL) includes a series of high permeability posts for collectively define a core for the FCL. A DC coil, for the purposes of saturating a portion of the high permeability posts, surrounds the complete structure outside of an enclosure in the form of a vessel. The vessel contains a dielectric insulation medium. AC coils, for transporting AC current, are wound on insulating formers and electrically interconnected to each other in a manner such that the senses of the magnetic field produced by each AC coil in the corresponding high permeability core are opposing. There are insulation barriers between phases to improve dielectric withstand properties of the dielectric medium.

  11. Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: A phase II study of the Southwest Oncology Group (SWOG-9229)

    International Nuclear Information System (INIS)

    Thomas, Charles R.; Giroux, Dori J.; Stelzer, Keith J.; Craig, Johnny B.; Laufman, Leslie R.; Taylor, Sarah A.; Goodwin, John W.; Crowley, John J.; Livingston, Robert B.

    1998-01-01

    Purpose: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. Methods and Materials: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m 2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m 2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m 2 i.v., doxorubicin 50 mg/m 2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. Results: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the

  12. Limitations of inclusive fitness.

    Science.gov (United States)

    Allen, Benjamin; Nowak, Martin A; Wilson, Edward O

    2013-12-10

    Until recently, inclusive fitness has been widely accepted as a general method to explain the evolution of social behavior. Affirming and expanding earlier criticism, we demonstrate that inclusive fitness is instead a limited concept, which exists only for a small subset of evolutionary processes. Inclusive fitness assumes that personal fitness is the sum of additive components caused by individual actions. This assumption does not hold for the majority of evolutionary processes or scenarios. To sidestep this limitation, inclusive fitness theorists have proposed a method using linear regression. On the basis of this method, it is claimed that inclusive fitness theory (i) predicts the direction of allele frequency changes, (ii) reveals the reasons for these changes, (iii) is as general as natural selection, and (iv) provides a universal design principle for evolution. In this paper we evaluate these claims, and show that all of them are unfounded. If the objective is to analyze whether mutations that modify social behavior are favored or opposed by natural selection, then no aspect of inclusive fitness theory is needed.

  13. (Limiting the greenhouse effect)

    Energy Technology Data Exchange (ETDEWEB)

    Rayner, S.

    1991-01-07

    Traveler attended the Dahlem Research Conference organized by the Freien Universitat, Berlin. The subject of the conference was Limiting the Greenhouse Effect: Options for Controlling Atmospheric CO{sub 2} Accumulation. Like all Dahlem workshops, this was a meeting of scientific experts, although the disciplines represented were broader than usual, ranging across anthropology, economics, international relations, forestry, engineering, and atmospheric chemistry. Participation by scientists from developing countries was limited. The conference was divided into four multidisciplinary working groups. Traveler acted as moderator for Group 3 which examined the question What knowledge is required to tackle the principal social and institutional barriers to reducing CO{sub 2} emissions'' The working rapporteur was Jesse Ausubel of Rockefeller University. Other working groups examined the economic costs, benefits, and technical feasibility of options to reduce emissions per unit of energy service; the options for reducing energy use per unit of GNP; and the significant of linkage between strategies to reduce CO{sub 2} emissions and other goals. Draft reports of the working groups are appended. Overall, the conference identified a number of important research needs in all four areas. It may prove particularly important in bringing the social and institutional research needs relevant to climate change closer to the forefront of the scientific and policy communities than hitherto.

  14. Limits to biofuels

    Directory of Open Access Journals (Sweden)

    Johansson S.

    2013-06-01

    Full Text Available Biofuel production is dependent upon agriculture and forestry systems, and the expectations of future biofuel potential are high. A study of the global food production and biofuel production from edible crops implies that biofuel produced from edible parts of crops lead to a global deficit of food. This is rather well known, which is why there is a strong urge to develop biofuel systems that make use of residues or products from forest to eliminate competition with food production. However, biofuel from agro-residues still depend upon the crop production system, and there are many parameters to deal with in order to investigate the sustainability of biofuel production. There is a theoretical limit to how much biofuel can be achieved globally from agro-residues and this amounts to approximately one third of todays’ use of fossil fuels in the transport sector. In reality this theoretical potential may be eliminated by the energy use in the biomass-conversion technologies and production systems, depending on what type of assessment method is used. By surveying existing studies on biofuel conversion the theoretical limit of biofuels from 2010 years’ agricultural production was found to be either non-existent due to energy consumption in the conversion process, or up to 2–6000TWh (biogas from residues and waste and ethanol from woody biomass in the more optimistic cases.

  15. The limitation and modification of flux-limited diffusion theory

    International Nuclear Information System (INIS)

    Liu Chengan; Huang Wenkai

    1986-01-01

    The limitation of various typical flux-limited diffusion theory and advantages of asymptotic diffusion theory with time absorption constant are analyzed and compared. The conclusions are as following: Though the flux-limited problem in neutron diffusion theory are theoretically solved by derived flux-limited diffusion equation, it's going too far to limit flux due to the inappropriate assumption in deriving flux-limited diffusion equation. The asymptotic diffusion theory with time absorption constant has eliminated the above-mentioned limitation, and it is more accurate than flux-limited diffusion theory in describing neutron transport problem

  16. [Does medicine limit enlightenment?].

    Science.gov (United States)

    Schipperges, H

    1977-01-01

    In the first, historical part the most important programs of "Medical Enlightenment", are pointed out, beginning with Leibniz, followed by the public health movement of the 18th century, up to the time of Immanuel Kant. Based on this historical background several concepts of a "Medical Culture" are analysed in detail, for instance the "Theorie einer Medizinal-Ordnung" by Johann Benjamin Ehrhard (1800), the "Medicinische Reform" by Rudolf Virchow (1848) and the programs of the "Gesellschaft Deutscher Naturforscher und Arzte" (about 1850-1890), the latter bearing both scientific and political character. Following the historical part, the question is raised whether "Enlightenment" is limited by medicine and whether medicine is able to provide a program for individual health education resulting in a more cultivated style of private life, and lastly how this might be realized.

  17. Personal Freedom beyond Limits

    Directory of Open Access Journals (Sweden)

    Juan Fernando Sellés

    2013-07-01

    Full Text Available In this work we distinguish between freedom in the human manifestations (intelligence, will,actions and personal freedom in the personal intimacy. This second is beyond the freedom reached bythe classic and modern thought, since it takes root in the personnel act of being. Because of it, it is not possible to characterize this freedom like the classic description as ‘domain over the own acts’, becauseit is a description of ‘categorial’ order; neither like present day ‘autonomy’ or ‘independence’, becausethe existence of one person alone is impossible, since ‘person’ means relation, personal free openingto other persons, description of the ‘transcendental’ order and, therefore, to the margin of limits.

  18. Drinking to the Limit

    DEFF Research Database (Denmark)

    Järvinen, Margaretha; Ellersgaard, Christoph Houman; Larsen, Anton Grau

    2014-01-01

    : economic, cultural, inherited and organisational. A range of variables measuring alcohol norms, drinking practices and alcohol-related problems are then inserted into the space. This article identifies status differences in the employees’ drinking patterns indicating that respondents with large amounts...... of economic, cultural and inherited capital are more responsive to alcohol-related health messages than respondents (and especially males) occupying positions low in the social space. This, however, does not mean that respondents from dominant groups have ‘safe’ drinking habits, as these are defined...... by the Danish National Health Board. Rather, this article identifies a relatively large group of high-positioned respondents balancing at the limits of risky drinking – or transgressing them, if measured by international standards....

  19. Limits to oil pricing

    International Nuclear Information System (INIS)

    Austvik, O.G.

    1992-01-01

    The bad record of oil price forecasting indicates that conventional oil market models should be critically reassessed. Scenario planning may be one alternative approach. This approach does not contradict other theories of the market. But it claims that no single discipline is able to tell the whole truth about the market. The SP approach stresses and clarifies the role of uncertainty. It argues that without a cross-disciplinary approach, with an adequate choice of parameters, at the right level of in depth discussion, the analysis may either lose essential input or drown in detail. As an example of the methodology, an analysis of the oil market in the 1990s is presented. This shows how upper and lower limits for the price can be constructed, and which actual price development can be expected, in a combination of economic and political reasoning. (author)

  20. Limit, breakthrough and prosperity

    International Nuclear Information System (INIS)

    Takahashi, Minoru

    1973-01-01

    It is pointed out that the flow toward serious crises is in progress with regard to energy and industrial problems. Technical and industrial preparation and countermeasure to the flow are proposed, and the existence of a certain new world attainable on the assumption that the countermeasure is successful is described. The relation between oil output and the increasing demand for energy is pointed out as a subject matter of the crisis. The contribution of oil energy to total energy, after the output turns to decreasing process, decreases by 177.87x10 6 tons (converted to coal at the rate 6848 kcal/kg) per year at maximum. Converted to the GNP of the world, this becomes (425 dollar/ton x 177.87 x 10 6 ton=75.6 x 10 9 dollar). This fluctuation width in a year must be compensated by the change of industrial structure and energy supplying means. The countermeasure and preparation are proposed from the viewpoints of the energy and the industrial structure in which nuclear power generation plays important role. The largest production on the earth limited by energy consumption and the temperature balance on the earth is investigated, and the perspective in the future is given. (Yamamoto, Y.)

  1. Topotecan and cisplatin in combination with concurrent twice-daily chemoradiation in limited disease small cell lung cancer-a Danish Oncological Lung Cancer Group (DOLG) phase II trial

    DEFF Research Database (Denmark)

    Sorensen, M.; Lassen, U.; Palshof, T.

    2008-01-01

    with no prior treatment for SCLC, adequate organ functions, and WHO performance status (PS) PS=2 and LDH>two times the upper limit were excluded. RESULT: Fourty-five pts were included in four centres. Five patients did not meet the inclusion criteria. The median age...

  2. Identification of the limiting factors for high-temperature GaAs, GaInP, and AlGaInP solar cells from device and carrier lifetime analysis

    Science.gov (United States)

    Perl, E. E.; Kuciauskas, D.; Simon, J.; Friedman, D. J.; Steiner, M. A.

    2017-12-01

    We analyze the temperature-dependent dark saturation current density and open-circuit voltage (VOC) for GaAs, GaInP, and AlGaInP solar cells from 25 to 400 °C. As expected, the intrinsic carrier concentration, ni, dominates the temperature dependence of the dark currents. However, at 400 °C, we measure VOC that is ˜50 mV higher for the GaAs solar cell and ˜60-110 mV lower for the GaInP and AlGaInP solar cells compared to what would be expected from commonly used solar cell models that consider only the ni2 temperature dependence. To better understand these deviations, we measure the carrier lifetimes of p-type GaAs, GaInP, and AlGaInP double heterostructures (DHs) from 25 to 400 °C using time-resolved photoluminescence. Temperature-dependent minority carrier lifetimes are analyzed to determine the relative contributions of the radiative recombination, interface recombination, Shockley-Read-Hall recombination, and thermionic emission processes. We find that radiative recombination dominates for the GaAs DHs with the effective lifetime approximately doubling as the temperature is increased from 25 °C to 400 °C. In contrast, we find that thermionic emission dominates for the GaInP and AlGaInP DHs at elevated temperatures, leading to a 3-4× reduction in the effective lifetime and ˜40× increase in the surface recombination velocity as the temperature is increased from 25 °C to 400 °C. These observations suggest that optimization of the minority carrier confinement layers for the GaInP and AlGaInP solar cells could help to improve VOC and solar cell efficiency at elevated temperatures. We demonstrate VOC improvement at 200-400 °C in GaInP solar cells fabricated with modified AlGaInP window and back surface field layers.

  3. Identification of the Limiting Factors for High-Temperature GaAs, GaInP, and AlGaInP Solar Cells from Device and Carrier Lifetime Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kuciauskas, Darius [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Perl, Emmett [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Simon, John D [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Friedman, Daniel J [National Renewable Energy Laboratory (NREL), Golden, CO (United States); Steiner, Myles A [National Renewable Energy Laboratory (NREL), Golden, CO (United States)

    2017-12-19

    We analyze the temperature-dependent dark saturation current density and open-circuit voltage (VOC) for GaAs, GaInP, and AlGaInP solar cells from 25 to 400 degrees C. As expected, the intrinsic carrier concentration, ni, dominates the temperature dependence of the dark currents. However, at 400 degrees C, we measure VOC that is ~50 mV higher for the GaAs solar cell and ~60-110 mV lower for the GaInP and AlGaInP solar cells compared to what would be expected from commonly used solar cell models that consider only the ni2 temperature dependence. To better understand these deviations, we measure the carrier lifetimes of p-type GaAs, GaInP, and AlGaInP double heterostructures (DHs) from 25 to 400 degrees C using time-resolved photoluminescence. Temperature-dependent minority carrier lifetimes are analyzed to determine the relative contributions of the radiative recombination, interface recombination, Shockley-Read-Hall recombination, and thermionic emission processes. We find that radiative recombination dominates for the GaAs DHs with the effective lifetime approximately doubling as the temperature is increased from 25 degrees C to 400 degrees C. In contrast, we find that thermionic emission dominates for the GaInP and AlGaInP DHs at elevated temperatures, leading to a 3-4x reduction in the effective lifetime and ~40x increase in the surface recombination velocity as the temperature is increased from 25 degrees C to 400 degrees C. These observations suggest that optimization of the minority carrier confinement layers for the GaInP and AlGaInP solar cells could help to improve VOC and solar cell efficiency at elevated temperatures. We demonstrate VOC improvement at 200-400 degrees C in GaInP solar cells fabricated with modified AlGaInP window and back surface field layers.

  4. The limits of deterrence

    International Nuclear Information System (INIS)

    Tertrais, Bruno

    2009-01-01

    The objective of this contribution is to propose a better insight of the validity of the theory of deterrence, and of related doctrines in more complex and more various situations than in the past: emergence of powers like China and India, of new nuclear States like North Korea and Pakistan, of countries planning to acquire nuclear weapons like Iran, and possibility of a new wave of nuclear proliferation in Middle-East and north-eastern Asia. It also aims at providing arguments in the debates on the struggle against nuclear proliferation and on the future of deterrence. The author first presents and comments the principles of deterrence, and illustrates them by more or less recent historical situations (Iran during the war with Iraq, USA after Pearl Harbour, Arab-Israeli wars, Iraq, and so on). He notably outlines that the notion of deterrence is present in Islamic culture, and that Iran has well integrated it in its defence strategy. Examples of statements and behaviours of other Arab leaders are discussed. The author also briefly indicates how the deterrence strategy is present in the official doctrines of Russia, India, Pakistan, and North Korea. In a second part, based on various examples, the author analyses the practical limitations of deterrence by distinguishing the psychological dimension (bounded rationality, political leaders suffering from various psychological problems, importance of the ideological and spiritual dimension, values prevailing on interests, the case of Iran), and the strategic dimension (good understanding of the enemy, sensitivity of the threat of massive damages, existence of a single decision centre and of an efficient communication). The author finally proposes seven recommendations for better deterrence efficiency

  5. Over the limit.

    Science.gov (United States)

    Qu, G

    1989-01-01

    With over 1 billion population, China is adding some 15 million to that total each year. And in the 18 years from 1982 to 2000, the net increase of Chinese population is expected to exceed 200 million. Because of the gigantic pressure from population and some mistakes in policies, the levels of ecological destruction and environment pollution are both serious. This includes deforestation, grassland degradation, desert encroachment, water resources shortage, and waste of mineral resources. Natural disasters including floods and droughts caused by those problems happen more and more frequently. If development damages the resource base, it can only result in a false prosperity, the so-called hollow economy. A large number of environmental problems result directly or indirectly from the pressure of population growth. Studies show that the appropriate number of people that can be supported by China's 9.6 million sq. km is about 700 million. However, this limit is now exceeded by over 300 million people, and will be exceeded by 500 million by the end of this century. Therefore, the task is to implement a birth control policy. At present, in urban areas, the goal of family planning has been reached, but in rural areas hard work is needed. Population control in urban areas, especially in big and medium-sized cities, includes dealing with the inflow of migrants from the countryside. There are 13 cities with a population above 2 million, 37 cities above 1-2 million, and 75 cities above 0.5-1 million. A lot of cities are very crowded, exerting great pressure on the environment. The booming of rural enterprises could provide a good solution to control the flow of rural people into big and medium-sized cities. The relationship between population, resources, environment, and development should be managed properly.

  6. Subcloning Dt40 by limiting dilution.

    Science.gov (United States)

    Buerstedde, Jean-Marie

    2006-01-01

    Subcloning by limited dilution can be used to derive clonally related cell populations from a heterogeneous DT40 cell culture. For example, if one suspects that a drug resistant population may represent the progeny of more than one transfectant, the protocol can be used to isolate genetically homogeneous mutant clones. Other uses are the excision of floxed DNA sequences after Cre recombinase expression or fluctuation analysis to determine mutation rates (see Protocols 'Excision of floxed-DNA sequences by transient induction of Mer-Cre-Mer' and 'Analysis of sIgM expression by FACS').

  7. Os limites da competitividade

    Directory of Open Access Journals (Sweden)

    Henrique Rattner

    2009-08-01

    Full Text Available

    Costuma-se destacar os aspectos aparentemente positivos e as vantagens hipotéticas da concorrência e da competitividade entre empresas e também entre nações. Não se pode negar que a concorrência nos mercados tenha exercido uma função central e fundamental na gênese e na expansão do sistema de produção capitalista. Ela contribuiu para a geração e acumulação de riquezas materiais. Também estimulou e fortaleceu as aspirações de seus principais atores sociais, os empreendedores, de exigir uma organização política mais democrática em oposição ao regime feudal ou absolutista, em determinado período da história do mundo ocidental.

  8. Prophylactic Sublingual Immunization with Mycobacterium tuberculosis Subunit Vaccine Incorporating the Natural Killer T Cell Agonist Alpha-Galactosylceramide Enhances Protective Immunity to Limit Pulmonary and Extra-Pulmonary Bacterial Burden in Mice

    Directory of Open Access Journals (Sweden)

    Arshad Khan

    2017-12-01

    Full Text Available Infection by Mycobacterium tuberculosis (Mtb remains a major global concern and the available Bacillus Calmette-Guerin (BCG vaccine is poorly efficacious in adults. Therefore, alternative vaccines and delivery strategies focusing on Mtb antigens and appropriate immune stimulating adjuvants are needed to induce protective immunity targeted to the lungs, the primary sites of infections and pathology. We present here evidence in support of mucosal vaccination by the sublingual route in mice using the subunit Mtb antigens Ag85B and ESAT-6 adjuvanted with the glycolipid alpha-galactosylceramide (α-GalCer, a potent natural killer T (NKT cell agonist. Vaccinated animals exhibited strong antigen-specific CD4 and CD8 T cells responses in the spleen, cervical lymph nodes and lungs. In general, inclusion of the α-GalCer adjuvant significantly enhanced these responses that persisted over 50 days. Furthermore, aerosolized Mtb infection of vaccinated mice resulted in a significant reduction of bacterial load of the lungs and spleens as compared to levels seen in naïve controls or those vaccinated with subunit proteins, adjuvant , or BCG alone. The protection induced by the Mtb antigens and-GalCer vaccine through sublingual route correlated with a TH1-type immunity mediated by antigen-specific IFN-γ and IL-2 producing T cells.

  9. Intercell Interference Coordination through Limited Feedback

    Directory of Open Access Journals (Sweden)

    Lingjia Liu

    2010-01-01

    Full Text Available We consider the applications of multicell transmission schemes to the downlink of future wireless communication networks. A multicell multiple-input multiple output-(MIMOs based scheme with limited coordination among neighboring base stations (BSs is proposed to effectively combat the intercell interference by taking advantage of the degreesoffreedom in the spatial domain. In this scheme, mobile users are required to feedback channel-related information to both serving base station and interfering base station. Furthermore, a chordal distance-based compression scheme is introduced to reduce the feedback overhead. The performance of the proposed scheme is investigated through theoretical analysis as well as system level simulations. Both results suggest that the so-called “intercell interference coordination through limited feedback” scheme is a very good candidate for improving the cell-edge user throughput as well as the average cell throughput of the future wireless communication networks.

  10. Limitations of Expert Evidence

    Directory of Open Access Journals (Sweden)

    Serpil Salaçin

    1997-10-01

    Full Text Available Limitations of Expert Evidence Edited by Stephen Leadbeatter MB ChB MCRPath ISBN 1 86016 029 8 Printed in Great Britain by Cathedral Print Services Ltd, Salisbury, 1996 Kitap 25 Ekim 1994 te The Royal College of Physicians ve The Royal College of Pathologists tarafından düzenlenen konferanstan sonra hekimlere ve avukatlara konuyu tartışmaya açmak için basılmış. Bilirkişi görüşünün temel filozofisinin, bu görevi yapanlar ve bu hizmeti alanların yapabileceklerinin sınırlarının tartışılması amaçlanmış.Seksen altı sayfadan oluşan kitabın fiatı on iki İngiliz Sterlini. Kitap üç bölüm ve bunların altında toplanan on ana başlıktan oluşmakta. Elinize aldığınızda küçük boyutu ve anlaşılır dili ile hemen okunup bitirelecek kitaplardan sanılıyor. En azından ben böyle düşünmüştüm. Ancak daha L A Tuınberg ve A J Bellinham’ın ön yazısında ben çarpıldım. Değerli yazarların kaleme aldığı başlıklar ve gündeme getirdiği tartışmaların tüm Adli Bilimlerle uğraşanların dikkatle okuması gereken cinsten olduğu kanısındayım. Birinci bölüm The Legal Perspective iki anabaşlıktan oluşuyor, The Criminal legal perspective Honour Judje Martin Stephens tarafından yazılmış,bilirkişi olarak görev yapabilmek için belgelenmiş bir eğitim olması gerektiği, mahkemelerde ya da yazılı raporlarda verilebilecek görüşlerin incelikleri tartışılmış. Bu bölümün ikinci anabaşlığı The civil legal perspective avukat Jennifer Cummin tarafından yazılmış. Toplum gözünde bilirkişinin anlamı ve mahkemenin bilirkişi görüşünü değişmez bilimsel doğru gibi algılayarak düştüğü bilimsel yanılgı ve raporlardaki kavram farkı dile getirilmiş. İkinci Bölüm The Medical And Scientific Perspective başlığı altında Roger C Evans MD Clinical evidence başlığında toplumun hasta tedavisi ve bilirkişilik hizmetinden beklentilerinin unrealistik olduğu ve

  11. Outer Limits of Biotechnologies: A Jewish Perspective

    Directory of Open Access Journals (Sweden)

    John D. Loike

    2018-01-01

    Full Text Available A great deal of biomedical research focuses on new biotechnologies such as gene editing, stem cell biology, and reproductive medicine, which have created a scientific revolution. While the potential medical benefits of this research may be far-reaching, ethical issues related to non-medical applications of these technologies are demanding. We analyze, from a Jewish legal perspective, some of the ethical conundrums that society faces in pushing the outer limits in researching these new biotechnologies.

  12. FED pumped limiter configuration issues

    International Nuclear Information System (INIS)

    Haines, J.R.; Fuller, G.M.

    1983-01-01

    Impurity control in the Fusion Engineering Device (FED) is provided by a toroidal belt pumped limiter. Limiter design issues addressed in this paper are (1) poloidal location of the limiter belt, (2) shape of the limiter surface facing the plasma, and (3) whether the belt is pumped from one or both sides. The criteria used for evaluation of limiter configuration features were sensitivity to plasma edge conditions and ease of maintenance and fabrication. The evaluation resulted in the selection of a baseline FED limiter that is located at the bottom of the device and has a flat surface with a single leading edge

  13. Microenvironmental Regulation of Mammary Carcinogenesis

    Science.gov (United States)

    2009-06-01

    involvement of chymase-angiotensin-dependent pathway in the hamster sponge angiogenesis model. J Biol Chem 275, 5545-5552 (2000). 17. Lundequist, A...infiltrates has been obscure for many years. Historically, activated macrophages were merely thought of as effector cells that phagocyte microorganisms ... microorganisms and release chemokines and proteases that in turn recruit additional immune effector cells. Moreover, neutrophils are involved in

  14. Charter Halibut Limited Access Program

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This limited access system limits the number of charter vessels that may participate in the guided sport fishery for halibut in area 2C and 3A. NMFS issues a charter...

  15. The Delta fbpA mutant derived from Mycobacterium tuberculosis H37Rv has an enhanced susceptibility to intracellular antimicrobial oxidative mechanisms, undergoes limited phagosome maturation and activates macrophages and dendritic cells.

    Science.gov (United States)

    Katti, Muralidhar K; Dai, Guixiang; Armitige, Lisa Y; Rivera Marrero, Carlos; Daniel, Sundarsingh; Singh, Christopher R; Lindsey, Devin R; Dhandayuthapani, Subramanian; Hunter, Robert L; Jagannath, Chinnaswamy

    2008-06-01

    Mycobacterium tuberculosis H37Rv (Mtb) excludes phagocyte oxidase (phox) and inducible nitric oxide synthase (iNOS) while preventing lysosomal fusion in macrophages (MPhis). The antigen 85A deficient (Delta fbpA) mutant of Mtb was vaccinogenic in mice and the mechanisms of attenuation were compared with MPhis infected with H37Rv and BCG. Delta fbpA contained reduced amounts of trehalose 6, 6, dimycolate and induced minimal levels of SOCS-1 in MPhis. Blockade of oxidants enhanced the growth of Delta fbpA in MPhis that correlated with increased colocalization with phox and iNOS. Green fluorescent protein-expressing strains within MPhis or purified phagosomes were analysed for endosomal traffick with immunofluorescence and Western blot. Delta fbpA phagosomes were enriched for rab5, rab11, LAMP-1 and Hck suggesting enhanced fusion with early, recycling and late endosomes in MPhis compared with BCG or H37Rv. Delta fbpA phagosomes were thus more mature than H37Rv or BCG although, they failed to acquire rab7 and CD63 preventing lysosomal fusion. Finally, Delta fbpA infected MPhis and dendritic cells (DCs) showed an enhanced MHC-II and CD1d expression and primed immune T cells to release more IFN-gamma compared with those infected with BCG and H37Rv. Delta fbpA was thus more immunogenic in MPhis and DCs because of an enhanced susceptibility to oxidants and increased maturation.

  16. Mass transport limitation in implantable defibrillator batteries

    Science.gov (United States)

    Schmidt, C.; Tam, G.; Scott, E.; Norton, J.; Chen, K.

    Using cells with lithium reference electrodes, the power-limiting behavior in the lithium-SVO cell was shown to be due to a rapid voltage transition at the anode. A novel test cell was developed to explore the influence of current density, bulk LiAsF 6 concentration, separator type and separator proximity to the anode on the time to onset ( τ) of the anode polarization. The results were found to follow a relationship, iτ1/2∝ Cbulk, consistent with the Sand equation. This relationship also predicts that the critical concentration of LiAsF 6, at which onset of the anode polarization occurs, is near the solubility limit of LiAsF 6 in our system (around 3.5-4.0 M). This general phenomenon was found to be quantitatively similar for two dissimilar separator types, and the anode polarization could also be induced in the absence of separator at high concentration and current density. However, it appears that τ decreases with closer proximity of the separator to the anode surface (i.e. cell stack pressure), suggesting that the effect of separator is to inhibit convective transport to and from the Li surface.

  17. Guidelines for setting speed limits

    CSIR Research Space (South Africa)

    Wium, DJW

    1986-02-01

    Full Text Available A method is described for setting the speed limit for a particular road section. Several speed limits based on different criteria are described for each of nine traffic and road factors. The most appropriate speed limit for each relevant factor...

  18. Theoretical efficiency limits for thermoradiative energy conversion

    Science.gov (United States)

    Strandberg, Rune

    2015-02-01

    A new method to produce electricity from heat called thermoradiative energy conversion is analyzed. The method is based on sustaining a difference in the chemical potential for electron populations above and below an energy gap and let this difference drive a current through an electric circuit. The difference in chemical potential originates from an imbalance in the excitation and de-excitation of electrons across the energy gap. The method has similarities to thermophotovoltaics and conventional photovoltaics. While photovoltaic cells absorb thermal radiation from a body with higher temperature than the cell itself, thermoradiative cells are hot during operation and emit a net outflow of photons to colder surroundings. A thermoradiative cell with an energy gap of 0.25 eV at a temperature of 500 K in surroundings at 300 K is found to have a theoretical efficiency limit of 33.2%. For a high-temperature thermoradiative cell with an energy gap of 0.4 eV, a theoretical efficiency close to 50% is found while the cell produces 1000 W/m2 has a temperature of 1000 K and is placed in surroundings with a temperature of 300 K. Some aspects related to the practical implementation of the concept are discussed and some challenges are addressed. It is, for example, obvious that there is an upper boundary for the temperature under which solid state devices can work properly over time. No conclusions are drawn with regard to such practical boundaries, because the work is aimed at establishing upper limits for ideal thermoradiative devices.

  19. Regulation of glycolytic rate in Streptococcus sanguis grown under glucose-limited and glucose-excess conditions in a chemostat.

    OpenAIRE

    Iwami, Y; Yamada, T

    1985-01-01

    The biochemical mechanisms of the acidogenic potential of Streptococcus sanguis ATCC 10556 grown in glucose-excess and glucose-limited continuous culture were studied. The rate of acid production during the glucose metabolism by the cells grown under glucose limitation (glucose-limited cells) was 2.1 to 2.6 times that by the cells grown in an excess of glucose (glucose-excess cells). When the glucose-limited cells were metabolizing glucose, intracellular concentrations of glucose 6-phosphate,...

  20. Material limitations on the detection limit in refractometry.

    Science.gov (United States)

    Skafte-Pedersen, Peder; Nunes, Pedro S; Xiao, Sanshui; Mortensen, Niels Asger

    2009-01-01

    We discuss the detection limit for refractometric sensors relying on high-Q optical cavities and show that the ultimate classical detection limit is given by min {Δn} ≳ η, with n + iη being the complex refractive index of the material under refractometric investigation. Taking finite Q factors and filling fractions into account, the detection limit declines. As an example we discuss the fundamental limits of silicon-based high-Q resonators, such as photonic crystal resonators, for sensing in a bio-liquid environment, such as a water buffer. In the transparency window (λ ≳ 1100 nm) of silicon the detection limit becomes almost independent on the filling fraction, while in the visible, the detection limit depends strongly on the filling fraction because the silicon absorbs strongly.

  1. Material Limitations on the Detection Limit in Refractometry

    Directory of Open Access Journals (Sweden)

    Niels Asger Mortensen

    2009-10-01

    Full Text Available We discuss the detection limit for refractometric sensors relying on high-Q optical cavities and show that the ultimate classical detection limit is given by min {Δn} ≳ η with n + iη being the complex refractive index of the material under refractometric investigation. Taking finite Q factors and filling fractions into account, the detection limit declines. As an example we discuss the fundamental limits of silicon-based high-Q resonators, such as photonic crystal resonators, for sensing in a bio-liquid environment, such as a water buffer. In the transparency window (λ ≳ 1100 nm of silicon the detection limit becomes almost independent on the filling fraction, while in the visible, the detection limit depends strongly on the filling fraction because the silicon absorbs strongly.

  2. Modelling the influence of silicon and phosphorus limitation on the ...

    African Journals Online (AJOL)

    Pseudo-nitzschia seriata (Cleve) H. Peragallo isolated from Scottish west coast waters was studied in laboratory batch culture. The neurotoxin domoic acid was produced in both P- and Si-limited stationary phase, but in greater quantities when Si was the limiting nutrient. A mathematical model based on cell quota kinetics ...

  3. Material limitations on the detection limit in refractometry

    DEFF Research Database (Denmark)

    Skafte-Pedersen, Peder; Nunes, Pedro; Xiao, Sanshui

    2009-01-01

    We discuss the detection limit for refractometric sensors relying on high-Q optical cavities and show that the ultimate classical detection limit is given by min {Δn} ≳ η with n + iη being the complex refractive index of the material under refractometric investigation. Taking finite Q factors and...

  4. Optimum shapes for pump limiters

    International Nuclear Information System (INIS)

    Ulrickson, M.

    1982-05-01

    The design of a pump limiter depends strongly on the details of the plasma scrapeoff zone. A model has been developed which allows the transport coefficients in the scrapeoff to be functions of n and t. This model has been used to predict scrapeoff profiles for FED/INTOR. The profiles are used to find and analyze limiter profiles. The results suggest the use of limiter shapes which curve toward the plasma

  5. ICRF power limitation relation to density limit in ASDEX

    International Nuclear Information System (INIS)

    Ryter, F.

    1992-01-01

    Launching high ICRF power into ASDEX plasmas required good antenna-plasma coupling. This could be achieved by sufficient electron density in front of the antennas i.e. small antenna-plasma distance (1-2 cm) and moderate to high line-averaged electron density compared to the density window in ASDEX. These are conditions eventually close to the density limit. ICRF heated discharges terminated by plasma disruptions caused by the RF pulse limited the maximum RF power which can be injected into the plasma. The disruptions occurring in these cases have clear phenomenological similarities with those observed in density limit discharges. We show in this paper that the ICRF-power limitation by plasma disruptions in ASDEX was due to reaching the density limit. (author) 3 refs., 3 figs

  6. Limit cycles in quantum systems

    Energy Technology Data Exchange (ETDEWEB)

    Niemann, Patrick

    2015-04-27

    In this thesis we investigate Limit Cycles in Quantum Systems. Limit cycles are a renormalization group (RG) topology. When degrees of freedom are integrated out, the coupling constants flow periodically in a closed curve. The presence of limit cycles is restricted by the necessary condition of discrete scale invariance. A signature of discrete scale invariance and limit cycles is log-periodic behavior. The first part of this thesis is concerned with the study of limit cycles with the similarity renormalization group (SRG). Limit cycles are mainly investigated within conventional renormalization group frameworks, where degrees of freedom, which are larger than a given cutoff, are integrated out. In contrast, in the SRG potentials are unitarily transformed and thereby obtain a band-diagonal structure. The width of the band structure can be regarded as an effective cutoff. We investigate the appearance of limit cycles in the SRG evolution. Our aim is to extract signatures as well as the scaling factor of the limit cycle. We consider the 1/R{sup 2}-potential in a two-body system and a three-body system with large scattering lengths. Both systems display a limit cycle. Besides the frequently used kinetic energy generator we apply the exponential and the inverse generator. In the second part of this thesis, Limit Cycles at Finite Density, we examine the pole structure of the scattering amplitude for distinguishable fermions at zero temperature in the medium. Unequal masses and a filled Fermi sphere for each fermion species are considered. We focus on negative scattering lengths and the unitary limit. The properties of the three-body spectrum in the medium and implications for the phase structure of ultracold Fermi gases are discussed.

  7. Magnetic shielding of a limiter

    International Nuclear Information System (INIS)

    Brevnov, N.N.; Stepanov, S.B.; Khimchenko, L.N.; Matthews, G.F.; Goodal, D.H.J.

    1991-01-01

    Localization of plasma interaction with material surfaces in a separate chamber, from where the escape of impurities is hardly realized, i.e. application of magnetic divertors or pump limiters, is the main technique for reduction of the impurity content in a plasma. In this case, the production of a divertor configuration requires a considerable power consumption and results in a less effective utilization of the magnetic field volume. Utilization of a pump limiter, for example the ICL-type, under tokamak-reactor conditions would result in the extremely high and forbidden local heat loadings onto the limiter surface. Moreover, the magnetically-shielded pump limiter (MSL) was proposed to combine positive properties of the divertor and the pump limiter. The idea of magnetic shielding is to locate the winding with current inside the limiter head so that the field lines of the resultant magnetic field do not intercept the limiter surface. In this case the plasma flows around the limiter leading edges and penetrates into the space under the limiter. The shielding magnetic field can be directed either counter the toroidal field or counter the poloidal one of a tokamak, dependent on the concrete diagram of the device. Such a limiter has a number of advantages: -opportunity to control over the particle and impurity recycling without practical influence upon the plasma column geometry, - perturbation of a plasma column magnetic configuration from the side of such a limiter is less than that from the side of the divertor coils. The main deficiency is the necessity to locate active windings inside the discharge chamber. (author) 5 refs., 3 figs

  8. Therapeutic cloning: The ethical limits

    International Nuclear Information System (INIS)

    Whittaker, Peter A.

    2005-01-01

    A brief outline of stem cells, stem cell therapy and therapeutic cloning is given. The position of therapeutic cloning with regard to other embryonic manipulations - IVF-based reproduction, embryonic stem formation from IVF embryos and reproductive cloning - is indicated. The main ethically challenging stages in therapeutic cloning are considered to be the nuclear transfer process including the source of eggs for this and the destruction of an embryo to provide stem cells for therapeutic use. The extremely polarised nature of the debate regarding the status of an early human embryo is noted, and some potential alternative strategies for preparing immunocompatible pluripotent stem cells are indicated

  9. Solubility limits on radionuclide dissolution

    Energy Technology Data Exchange (ETDEWEB)

    Kerrisk, J.F.

    1984-12-31

    This paper examines the effects of solubility in limiting dissolution rates of a number of important radionuclides from spent fuel and high-level waste. Two simple dissolution models were used for calculations that would be characteristics of a Yucca Mountain repository. A saturation-limited dissolution model, in which the water flowing through the repository is assumed to be saturated with each waste element, is very conservative in that it overestimates dissolution rates. A diffusion-limited dissolution model, in which element-dissolution rates are limited by diffusion of waste elements into water flowing past the waste, is more realistic, but it is subject to some uncertainty at this time. Dissolution rates of some elements (Pu, Am, Sn, Th, Zr, Sm) are always limited by solubility. Dissolution rates of other elements (Cs, Tc, Np, Sr, C, I) are never solubility limited; their release would be limited by dissolution of the bulk waste form. Still other elements (U, Cm, Ni, Ra) show solubility-limited dissolution under some conditions. 9 references, 3 tables.

  10. FUEL CASK IMPACT LIMITER VULNERABILITIES

    International Nuclear Information System (INIS)

    Leduc, D.; England, J.; Rothermel, R.

    2009-01-01

    Cylindrical fuel casks often have impact limiters surrounding just the ends of the cask shaft in a typical 'dumbbell' arrangement. The primary purpose of these impact limiters is to absorb energy to reduce loads on the cask structure during impacts associated with a severe accident. Impact limiters are also credited in many packages with protecting closure seals and maintaining lower peak temperatures during fire events. For this credit to be taken in safety analyses, the impact limiter attachment system must be shown to retain the impact limiter following Normal Conditions of Transport (NCT) and Hypothetical Accident Conditions (HAC) impacts. Large casks are often certified by analysis only because of the costs associated with testing. Therefore, some cask impact limiter attachment systems have not been tested in real impacts. A recent structural analysis of the T-3 Spent Fuel Containment Cask found problems with the design of the impact limiter attachment system. Assumptions in the original Safety Analysis for Packaging (SARP) concerning the loading in the attachment bolts were found to be inaccurate in certain drop orientations. This paper documents the lessons learned and their applicability to impact limiter attachment system designs

  11. Test limits using correlated measurements

    NARCIS (Netherlands)

    Albers, Willem/Wim; Arts, G.R.J.; Kallenberg, W.C.M.

    1998-01-01

    In the standard model for inspection of manufactured parts measurements of the characteristic of interest are subject to, typically small, measurement errors. This leads to test limits which are slightly more strict than the corresponding specification limits. Quite often, however, such direct

  12. New power limits for extremes

    NARCIS (Netherlands)

    Balkema, G.

    2013-01-01

    For order statistics there is a deceptively simple link between affine and power norming, using exponential transforms. This link does not tell the whole story about limit distributions. The exponential transforms W=eV and W=−e−V yield limit variables which are either positive or negative. Under

  13. Dose limits for ionising radiation

    International Nuclear Information System (INIS)

    Gifford, D.

    1989-01-01

    Dose limits for exposure to ionising radiation are assessed to see if they give sufficient protection both for the occupationally exposed and for the general public. It is concluded that current limits give a level of safety that satisfies the necessary criteria in the light of present knowledge and further reductions would be unlikely to improve standards of safety. (author)

  14. Beam-limiting and radiation-limiting interlocks

    International Nuclear Information System (INIS)

    Macek, R.J.

    1996-01-01

    This paper reviews several aspects of beam-limiting and radiation- limiting interlocks used for personnel protection at high-intensity accelerators. It is based heavily on the experience at the Los Alamos Neutron Science Center (LANSCE) where instrumentation-based protection is used extensively. Topics include the need for ''active'' protection systems, system requirements, design criteria, and means of achieving and assessing acceptable reliability. The experience with several specific devices (ion chamber-based beam loss interlock, beam current limiter interlock, and neutron radiation interlock) designed and/or deployed to these requirements and criteria is evaluated

  15. Beam-limiting and radiation-limiting interlocks

    Energy Technology Data Exchange (ETDEWEB)

    Macek, R.J.

    1996-04-01

    This paper reviews several aspects of beam-limiting and radiation- limiting interlocks used for personnel protection at high-intensity accelerators. It is based heavily on the experience at the Los Alamos Neutron Science Center (LANSCE) where instrumentation-based protection is used extensively. Topics include the need for ``active`` protection systems, system requirements, design criteria, and means of achieving and assessing acceptable reliability. The experience with several specific devices (ion chamber-based beam loss interlock, beam current limiter interlock, and neutron radiation interlock) designed and/or deployed to these requirements and criteria is evaluated.

  16. The Limits of Exercise Physiology

    DEFF Research Database (Denmark)

    Gabriel, Brendan M; Zierath, Juleen R

    2017-01-01

    Many of the established positive health benefits of exercise have been documented by historical discoveries in the field of exercise physiology. These investigations often assess limits: the limits of performance, or the limits of exercise-induced health benefits. Indeed, several key findings have...... been informed by studying highly trained athletes, in addition to healthy or unhealthy people. Recent progress has been made in regard to skeletal muscle metabolism and personalized exercise regimes. In this perspective, we review some of the historical milestones of exercise physiology, discuss how...

  17. Nuclear Structure at the Limits

    International Nuclear Information System (INIS)

    Nazarewicz, W.

    1998-01-01

    One of the frontiers of todays nuclear science is the journey to the limits of atomic charge and nuclear mass, of neutron-to-proton ratio, and of angular momentum. The tour to the limits is not only a quest for new, exciting phenomena, but the new data are expected, as well, to bring qualitatively new information about the fundamental properties of the nucleonic many-body system, the nature of the nuclear interaction, and nucleonic correlations at various energy-distance scales. In this series of lectures, current developments in nuclear structure at the limits are discussed from a theoretical perspective, mainly concentrating on medium-mass and heavy nuclei

  18. Nuclear Structure at the Limits

    Energy Technology Data Exchange (ETDEWEB)

    Nazarewicz, Witold

    1997-12-31

    One of the frontiers of today`s nuclear science is the ``journey to the limits``: of atomic charge and nuclear mass, of neutron-to-proton ratio, and of angular momentum. The tour to the limits is not only a quest for new, exciting phenomena but the new data are expected, as well, to bring qualitatively new information about the fundamental properties of the nucleonic many-body system, the nature of the nuclear interaction, and nucleonic correlations at various energy-distance scales. In this talk, current developments in nuclear structure at the limits are discussed from a theoretical perspective.

  19. Limited Releases of Krsko NPP

    International Nuclear Information System (INIS)

    Breznik, B.; Kovac, A.

    2001-01-01

    Full text: Krsko Nuclear Power Plant is about 700 MW Pressurised Water Reactor plant located in Slovenia close to the border with Croatia. The authorised limit for the radioactive releases is basically set to 50 μSv effective dose per year to the members of the public. There is also additional limitation of total activities released in a year and concentration. The poster presents the effluents of the year 2000 and evaluated dose referring to the limits and to the natural and other sources of radiation around the plant. (author)

  20. Biased limiter experiments on text

    International Nuclear Information System (INIS)

    Phillips, P.E.; Wootton, A.J.; Rowan, W.L.; Ritz, C.P.; Rhodes, T.L.; Bengtson, R.D.; Hodge, W.L.; Durst, R.D.; McCool, S.C.; Richards, B.; Gentle, K.W.; Schoch, P.; Forster, J.C.; Hickok, R.L.; Evans, T.E.

    1987-01-01

    Experiments using an electrically biased limiter have been performed on the Texas Experimental Tokamak (TEXT). A small movable limiter is inserted past the main poloidal ring limiter (which is electrically connected to the vacuum vessel) and biased at V Lim with respect to it. The floating potential, plasma potential and shear layer position can be controlled. With vertical strokeV Lim vertical stroke ≥ 50 V the plasma density increases. For V Lim Lim > 0 the results obtained are inconclusive. Variation of V Lim changes the electrostatic turbulence which may explain the observed total flux changes. (orig.)