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Shiyun Xiao, Wen Zhang, Nancy R Manley
BACKGROUND: Hematopoietic stem cells (HSCs) derived from birth through adult possess differing differentiation potential for T or B cell fate in the thymus; neonatal bone marrow (BM) cells also have a higher potential for B cell production in BM compared to adult HSCs. We hypothesized that this hematopoietic-intrinsic B potential might also regulate B cell development in the thymus during ontogeny. METHODS: Foxn1lacZ mutant mice are a model in which down regulation of a thymic epithelial cell (TEC) specific transcription factor beginning one week postnatal causes a dramatic reduction of thymocytes production...
2018: PloS One
Patrick Schöffski, Jean-Pierre Delord, Etienne Brain, Jacques Robert, Herlinde Dumez, Jamal Gasmi, André Trouet
PURPOSE: DTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental models in terms of both efficacy and safety compared with conventional Dox. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose (RD) for clinical phase II studies and to assess potential anticancer activity of the compound. EXPERIMENTAL DESIGN: DTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with advanced solid tumours according to common clinical phase I criteria...
November 2017: European Journal of Cancer
Fengyang Lei, Mohammad Haque, Praneet Sandhu, Swetha Ravi, Jianyong Song, Bing Ni, Songguo Zheng, Deyu Fang, Hongyan Jia, Jin-Ming Yang, Jianxun Song
Optimal approaches to differentiate tumor antigen-specific cytotoxic T lymphocytes (CTLs) from pluripotent stem cells (PSCs) remain elusive. In the current study, we showed that combination of in vitro priming through Notch ligands and in vivo development facilitated the generation of tumor Ag-specific CTLs that effectively inhibited tumor growth. We co-cultured the murine induced PSCs (iPSCs) genetically modified with tyrosinase-related protein 2 (TRP2)-specific T cell receptors with OP9 cell line expressing both Notch ligands Delta-like 1 and 4 (OP9-DL1/DL4) for a week before adoptively transferred into recipient C67BL/6 mice...
2017: Oncoimmunology
Sylvie Négrier, David Pérol, Rastislav Bahleda, Antoine Hollebecque, Etienne Chatelut, Helen Boyle, Philippe Cassier, Séverine Metzger, Ellen Blanc, Jean-Charles Soria, Bernard Escudier
BACKGROUND: Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors...
August 15, 2017: BMC Cancer
Austin G Duffy, Chi Ma, Susanna V Ulahannan, Osama E Rahma, Oxana Makarova-Rusher, Liang Cao, Yunkai Yu, David E Kleiner, Jane Trepel, Min-Jung Lee, Yusuke Tomita, Seth M Steinberg, Theo Heller, Baris Turkbey, Peter L Choyke, Cody J Peer, William D Figg, Brad J Wood, Tim F Greten
Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.Experimental Design: Patients with HCC (Child-Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily...
August 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sandrine Aspeslagh, Mark Stein, Rastilav Bahleda, Antoine Hollebecque, Gilles Salles, Emmanuel Gyan, Salvador Fudio, Sonia Extremera, Vicente Alfaro, Arturo Soto-Matos, Jean-Charles Soria
This phase I trial evaluated the combination of the marine-derived cyclodepsipeptide plitidepsin (trade name Aplidin) with sorafenib or gemcitabine in advanced cancer and lymphoma patients. The study included two treatment arms: a sorafenib/plitidepsin (S/P) and a gemcitabine/plitidepsin (G/P) arm. In the S/P arm, patients were treated orally with sorafenib continuous dosing at two dose levels (DL1: 200 mg twice daily and DL2: 400 mg twice daily) combined with plitidepsin (1.8 mg/m, day 1, day 8, day 15, and, q4wk, intravenously)...
March 2017: Anti-cancer Drugs
Mohammad Haque, Kristin Fino, Praneet Sandhu, Jianxun Song
Autoimmune diseases arise due to the loss of immunological self-tolerance. Regulatory T cells (Tregs) are important mediators of immunologic self-tolerance. Tregs represent about 5 - 10% of the mature CD4(+) T cell subpopulation in mice and humans, with about 1 - 2% of those Tregs circulating in the peripheral blood. Induced pluripotent stem cells (iPSCs) can be differentiated into functional Tregs, which have a potential to be used for cell-based therapies of autoimmune diseases. Here, we present a method to develop antigen (Ag)-specific Tregs from iPSCs (i...
November 8, 2016: Journal of Visualized Experiments: JoVE
Walid L Shaib, Natalyn Hawk, Richard J Cassidy, Zhengjia Chen, Chao Zhang, Edith Brutcher, David Kooby, Shishir K Maithel, Juan M Sarmiento, Jerome Landry, Bassel F El-Rayes
PURPOSE: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. METHODS AND MATERIALS: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM...
October 1, 2016: International Journal of Radiation Oncology, Biology, Physics
Laura D Reyes, Tessa Harland, Roger L Reep, Chet C Sherwood, Bob Jacobs
The current study investigates neuron morphology in presumptive primary somatosensory (S1) and primary visual (V1) cortices of the Florida manatee (Trichechus manatus latirostris) as revealed by Golgi impregnation. Sirenians, including manatees, have an aquatic lifestyle, a large body size, and a relatively large lissencephalic brain. The present study examines neuron morphology in 3 cortical areas: in S1, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2) and in V1, dorsolateral cortex area 4 (DL4)...
2016: Brain, Behavior and Evolution
Mignon L Loh, Sarah K Tasian, Karen R Rabin, Patrick Brown, Daniel Magoon, Joel M Reid, Xuejun Chen, Charlotte H Ahern, Brenda J Weigel, Susan M Blaney
BACKGROUND: Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. PROCEDURE: A phase 1 trial of ruxolitinib was performed to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m(2)/dose)...
October 2015: Pediatric Blood & Cancer
Nicolas Fasnacht, Hsin-Ying Huang, Ute Koch, Stéphanie Favre, Floriane Auderset, Qian Chai, Lucas Onder, Sandra Kallert, Daniel D Pinschewer, H Robson MacDonald, Fabienne Tacchini-Cottier, Burkhard Ludewig, Sanjiv A Luther, Freddy Radtke
Fibroblast-like cells of secondary lymphoid organs (SLO) are important for tissue architecture. In addition, they regulate lymphocyte compartmentalization through the secretion of chemokines, and participate in the orchestration of appropriate cell-cell interactions required for adaptive immunity. Here, we provide data demonstrating the functional importance of SLO fibroblasts during Notch-mediated lineage specification and immune response. Genetic ablation of the Notch ligand Delta-like (DL)1 identified splenic fibroblasts rather than hematopoietic or endothelial cells as niche cells, allowing Notch 2-driven differentiation of marginal zone B cells and of Esam(+) dendritic cells...
October 20, 2014: Journal of Experimental Medicine
Govindan Raghunathan, Ganapathiraman Munussami, Hyojin Moon, Hyun-jong Paik, Seong Soo A An, Yong-Sung Kim, Sebyung Kang, Sun-Gu Lee
BACKGROUND: Inclusion bodies (IBs) were generally considered to be inactive protein deposits and did not hold any attractive values in biotechnological applications. Recently, some IBs of recombinant proteins were confirmed to show their functional properties such as enzyme activities, fluorescence, etc. Such biologically active IBs are not commonly formed, but they have great potentials in the fields of biocatalysis, material science and nanotechnology. RESULTS: In this study, we characterized the IBs of DL4, a deletion variant of green fluorescent protein which forms active intracellular aggregates...
2014: Microbial Cell Factories
M G Fury, E J Sherman, S S Rao, S Wolden, S Smith-Marrone, B Mueller, K K Ng, P R Dutta, D Y Gelblum, J L Lee, R Shen, S Kurz, N Katabi, S Haque, N Y Lee, D G Pfister
BACKGROUND: There is a clinical need to improve the efficacy of standard cetuximab + concurrent intensity-modulated radiation therapy (IMRT) for patients with locally and/or regionally advanced HNSCC. Taxanes have radiosensitizing activity against HNSCC, and nab-paclitaxel may offer therapeutic advantage in comparison with other taxanes. PATIENTS AND METHODS: This was a single-institution phase I study with a modified 3 + 3 design. Four dose levels (DLs) of weekly nab-paclitaxel were explored (30, 45, 60, and 80 mg/m(2)), given with standard weekly cetuximab (450 mg/m(2) loading dose followed by 250 mg/m(2) weekly) and concurrent IMRT (total dose, 70 Gy)...
March 2014: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Mahmood Mohtashami, Divya K Shah, Korosh Kianizad, Geneve Awong, Juan Carlos Zúñiga-Pflücker
The thymus provides a unique environment for the induction of T-cell lineage commitment and differentiation, which is predicted by specific Notch ligand-receptor interactions on epithelial cells and lymphoid progenitors, respectively. Accordingly, a bone marrow-derived stromal cell line (OP9) ectopically expressing the Notch ligand Delta-like 1 (Dll1) or Dll4 (OP9-DL1 and OP9-DL4, respectively) gains the ability to recapitulate thymus-like function, supporting T-cell differentiation of both mouse and human progenitors...
October 2013: International Immunology
Isabel Ferrero, Ute Koch, Stephanie Claudinot, Stéphanie Favre, Freddy Radtke, Sanjiv A Luther, H R MacDonald
T-cell development depends upon interactions between thymocytes and thymic epithelial cells (TECs). The engagement of delta-like 4 (DL4) on TECs by Notch1 expressed by blood-borne BM-derived precursors is essential for T-cell commitment in the adult thymus. In contrast to the adult, the earliest T-cell progenitors in the embryo originate in the fetal liver and migrate to the nonvascularized fetal thymus via chemokine signals. Within the fetal thymus, some T-cell precursors undergo programmed TCRγ and TCRδ rearrangement and selection, giving rise to unique γδ T cells...
November 2013: European Journal of Immunology
Govindan Raghunathan, Nagasundarapandian Soundrarajan, Sriram Sokalingam, Hyungdon Yun, Sun-Gu Lee
Diversification of protein sequence-structure space is a major concern in protein engineering. Deletion mutagenesis can generate a protein sequence-structure space different from substitution mutagenesis mediated space, but it has not been widely used in protein engineering compared to substitution mutagenesis, because it causes a relatively huge range of structural perturbations of target proteins which often inactivates the proteins. In this study, we demonstrate that, using green fluorescent protein (GFP) as a model system, the drawback of the deletional protein engineering can be overcome by employing the protein structure with high stability...
2012: PloS One
E Francois, J Bennouna, E Chamorey, M C Etienne-Grimaldi, N Renée, H Senellart, C Michel, P Follana, V Mari, J Y Douillard, G Milano
BACKGROUND: The aim of this phase I trial was to define the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of erlotinib combined with capecitabine and gemcitabine in the treatment of advanced pancreatic cancer (APC). METHODS: Gemcitabine was administered intravenously at 1,000 mg/m(2)/week (days 1, 8 and 15) and oral capecitabine from day 1 to day 21 at 1,660 mg/m(2)/day. Oral erlotinib was administered daily continuously at escalating doses (28-day cycle)...
2012: Chemotherapy
E Brain, N Isambert, F Dalenc, V Diéras, J Bonneterre, K Rezai, M Jimenez, F Mefti-Lacheraf, E Cottura, P Tresca, L Vanlemmens, C Mahier-Aït Oukhatar, F Lokiec, P Fumoleau
BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD)...
February 14, 2012: British Journal of Cancer
Sara Suliman, Joanne Tan, Keli Xu, Philaretos C Kousis, Paul E Kowalski, Greg Chang, Sean E Egan, Cynthia Guidos
Notch1 (N1) signaling induced by intrathymic Delta-like (DL) ligands is required for T cell lineage commitment as well as self-renewal during "β-selection" of TCRβ⁺CD4⁻CD8⁻ double negative 3 (DN3) T cell progenitors. However, over-expression of the N1 intracellular domain (ICN1) renders N1 activation ligand-independent and drives leukemic transformation during β-selection. DN3 progenitors also express Notch3 (N3) mRNA, and over-expression of ligand-independent mutant N3 (ICN3) influences β-selection and drives T cell leukemogenesis...
2011: PloS One
N Starling, E A Hawkes, I Chau, D Watkins, J Thomas, J Webb, G Brown, K Thomas, Y Barbachano, J Oates, D Cunningham
BACKGROUND: Targeting platelet-derived growth factor receptor-β (PDGFR-β) is a potential strategy to reduce tumour-related interstitial fluid pressure, enhance cytotoxic drug uptake and reduce chemoresistance. This study aimed to define safe doses of gemcitabine plus oxaliplatin when combined with imatinib (potent PDGFR-β inhibitor) in patients with advanced gemcitabine-refractory pancreatic cancer (PC). PATIENTS AND METHODS: Using a 3 + 3 dose escalation design, patients of performance status zero or one were entered into five sequential dose levels (DLs) of gemcitabine [day 1, from 400 (DL1) to 1000 mg/m(2) (DL4)] and oxaliplatin [day 2, 85 (DL1-4) and 100 mg/m(2) (DL5)] two weekly...
April 2012: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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