tbuckley/cabot-search huggingface dataset:
Local administration of a novel Toll-like receptor 7 agonist in combination with doxorubicin induces durable tumouricidal effects in a murine model of T cell lymphoma
Authors: Jiang Zhu, Shiping He, Jie Du, Zhulin Wang, Wang Li, Xianxiong Chen, Wenqi Jiang, Duo Zheng, Guangyi Jin
Journal: Journal of Hematology & Oncology (2015)

Conventional chemotherapy and radiotherapy for the treatment of lymphoma have notable drawbacks, and passive immunotherapy using a monoclonal antibody is restricted to CD20-positive B cell lymphoma. Therefore, new treatment types are urgently required, especially for T cell lymphoma. One type of new antitumour therapy is the use of active immunotherapeutic agents, such as agonists of the Toll-like receptors (TLRs), which facilitate the induction of prolonged antitumour immune responses. We have synthesised a novel TLR7 agonist called SZU-101 and investigated the systemic antitumour effect on a murine model of T cell lymphoma in vivo. Here, we report that the intratumoural administration of SZU-101 enhanced the effectiveness of a conventionally used chemotherapeutic agent, doxorubicin (DOX). SZU-101 administration improved tumour clearance in a murine model of T cell lymphoma. The novel combination of intratumourally administered SZU-101 and DOX generated strong cytokine production and enhanced the cytotoxic T lymphocyte response, leading to the eradication of both local and distant tumours in tumour-bearing mice. These findings suggested that combined active immunotherapy can be developed as a promising treatment for T cell lymphoma, which may further improve the effectiveness of the current standard cyclophosphamide, DOX, vincristine and prednisone (CHOP) therapy.
Proteomic analysis reveals heat shock protein 70 has a key role in polycythemia Vera
Authors: Miguel Gallardo, Santiago Barrio, Marisol Fernandez, Alberto Paradela, Alicia Arenas, Oscar Toldos, Rosa Ayala, Enriqueta Albizua, Ana Jimenez, Santiago Redondo, Rosa Garcia-Martin, Florinda Gilsanz, Juan Albar, Joaquin Martinez-Lopez
Journal: Molecular Cancer (2013)

JAK-STAT signaling through the JAK2V617F mutation is central to the pathogenesis of myeloproliferative neoplasms (MPN). However, other events could precede the JAK2 mutation. The aim of this study is to analyze the phenotypic divergence between polycytemia vera (PV) and essential thrombocytemia (ET) to find novel therapeutics targets by a proteomic and functional approach to identify alternative routes to JAK2 activation. Through 2D-DIGE and mass spectrometry of granulocyte protein from 20 MPN samples, showed differential expression of HSP70 in PV and ET besides other 60 proteins. Immunohistochemistry of 46 MPN bone marrow samples confirmed HSP70 expression. The median of positive granulocytes was 80% in PV (SD 35%) vs. 23% in ET (SD 34.25%). In an ex vivo model KNK437 was used as an inhibition model assay of HSP70, showed dose-dependent inhibition of cell growth and burst formation unit erythroid (BFU-E) in PV and ET, increased apoptosis in the erythroid lineage, and decreased pJAK2 signaling, as well as a specific siRNA for HSP70. These data suggest a key role for HSP70 in proliferation and survival of the erythroid lineage in PV, and may represent a potential therapeutic target in MPN, especially in PV.
Stem Cell Differentiation and Lumen Formation in Colorectal Cancer Cell Lines and Primary Tumors
Authors: Neil Ashley, Trevor M. Yeung, Walter F. Bodmer
Journal: Cancer Research (2013)

Single cancer stem-like cells (CSC) from colorectal cancers can be functionally identified by their ability to form large lumen-containing colonies in three-dimensional Matrigel cultures. These colonies contain the three types of differentiated colorectal epithelial cells, and single cells obtained from them can reproduce themselves and form tumors efficiently in immunodeficient mice. In this study, we show how hypoxia affects these CSC-derived lumens to control differentiation of stem-like cells and enterocytes via the homeobox gene CDX1. Lumens were identified by F-actin staining and they expressed many characteristics associated with normal differentiated intestinal epithelium, including brush border enzymes, polarization, and tight junctions. RNA interference-mediated silencing of CDX1 reduced lumen formation. Inhibitory effects of hypoxia on lumen formation and stem cell differentiation, including suppression of CDX1 expression, could be mimicked by inhibiting prolyl-hydroxylases that activate HIF1, suggesting that HIF1 is a critical mediator of the effects of hypoxia in this setting. Cell line-derived lumens were phenotypically indistinguishable from colorectal tumor glandular structures used by pathologists to grade tumor differentiation. Parallel results to those obtained with established cell lines were seen with primary cultures from fresh tumors. This in vitro approach to functional characterization of CSCs and their differentiation offers a valid model to study colorectal tumor differentiation and differentiation of colorectal CSCs, with additional uses to enable high-throughput screening for novel anticancer compounds.
Biomedical Differences Between Human and Nonhuman Hominids: Potential Roles for Uniquely Human Aspects of Sialic Acid Biology
Authors: Nissi M. Varki, Elizabeth Strobert, Edward J. Dick, Kurt Benirschke, Ajit Varki
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Although humans are genetically very similar to the evolutionarily related nonhuman hominids (chimpanzees, bonobos, gorillas, and orangutans), comparative studies suggest a surprising number of uniquely human differences in the incidence and/or severity of biomedical conditions. Some differences are due to anatomical changes that occurred during human evolution. However, many cannot be explained either by these changes or by known environmental factors. Because chimpanzees were long considered models for human disease, it is important to be aware of these differences, which appear to have been deemphasized relative to similarities. We focus on the pathophysiology and pathobiology of biomedical conditions that appear unique to humans, including several speculative possibilities that require further study. We pay particular attention to the possible contributions of uniquely human changes in the biology of cell-surface sialic acids and the proteins that recognize them. We also discuss the metabolic incorporation of a diet-derived nonhuman sialic acid, which generates a novel xeno-autoantigen reaction, and chronic inflammation known as xenosialitis.
Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer
Authors: G. Chong, A. Bhatnagar, D. Cunningham, T.M. Cosgriff, P.G. Harper, W. Steward, J. Bridgewater, M. Moore, J. Cassidy, R. Coleman, F. Coxon, C.H. Redfern, J.J. Jones, R. Hawkins, D. Northfelt, S. Sreedharan, F. Valone, J. Carmichael
Journal: Annals of Oncology (2005)
T‐cell chronic lymphocytic leukemia with pure red cell aplasia: Laboratory demonstration of persistent leukemia in spite of apparent complete clinical remission
Authors: Richard M. Hansen, Neil Lerner, Ross A. Abrams, Catherine W. Patrick, Mohammad I. Malik, Robert Keller
Journal: American Journal of Hematology (1986)

Abstract A 40‐year‐old woman presented with splenomegaly, macrocytic anemia, and red cell aplasia. Although lymphocytosis was absent in the peripheral blood, large atypical lymphoid aggregates were present in the bone marrow. Splenectomy resulted in partial remission of red cell aplasia, but a gradual increase in the number of peripheral blood lymphocytes followed during the next 36 months. Flow cytometric analysis demonstrated that the majority of these peripheral blood lymphocytes had suppressor, natural killer T‐cell phenotye. No other treatment was given until red cell hypoplasia worsened 42 months after initial presentation. Repeat bone marrow evaluation again demonstrated severe erythroid hypoplasia and large abnormal lymphocytic infiltrates. Cyclophosphamide given for 8 months resulted in complete resolution of the red cell aplasia and complete clinical remission of CLL. However, flow cytometric analysis revealed persistent increase in bone marrow T‐cells, and bone marrow co–culture studies demonstrated residual ability of peripheral blood mononuclear cells to inhibit erythropoiesis in vitro, suggesting that residual, clinically undetectable leukemia persists in spite of complete clinical remission.
Comparison of a high sensitivity and standard C reactive protein measurement in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis
Authors: D. Poddubnyy, M. Rudwaleit, J. Listing, J. Braun, J. Sieper
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Objective</h3> This study was aimed at comparing high sensitivity C reactive protein (hsCRP) measurement with routine C reactive protein (CRP) evaluation as disease activity parameters in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nrSpA). <h3>Methods</h3> A total of 269 patients (153 with AS and 116 with nrSpA) were included. Level of hsCRP was measured using particle-enhanced immunoturbidimetric method with the lowest detected level of 0.1 mg/litre. The hsCRP values were compared to results of routine turbidimetric CRP test with the lowest detected level of 6 mg/litre. <h3>Results</h3> In the whole group of patients with AS, hsCRP showed a better than routine CRP correlation with clinical parameters. In the whole group of patients with nrSpA, hsCRP correlated with the level of enthesitis-related tenderness only. In the AS subgroup with a negative routine CRP (&lt;6 mg/litre) there was a clear trend for an increased level of pain, stiffness and functional impairment in patients with higher hsCRP concentration. Such a trend was less pronounced in patients with nrSpA. <h3>Conclusions</h3> hsCRP correlates better than routine CRP with clinical disease activity parameters in patients with axial SpA, especially in AS. Therefore, hsCRP could be superior to standard CRP in assessing disease activity in axial SpA.
Proteolysis by the Ubiquitin-Proteasome System and Kidney Disease
Authors: Stewart H. Lecker, William E. Mitch
Journal: Journal of the American Society of Nephrology (2011)

Proteins in all cells turnover continuously such that rigorous control of proteolysis is required to govern levels of proteins with vastly different half-lives and actions including those regulating transcription, metabolic pathways, or the breakdown of muscle proteins to amino acids used in gluconeogenesis or the synthesis of new proteins. Critical cellular functions would be disrupted without precise regulation of protein degradation. Thus, it is surprising that the bulk of protein in all cells is degraded by the ATP-dependent, ubiquitin-proteasome system. The system achieves remarkable specificity by selective conjugation of ubiquitin (Ub) to a doomed protein in a process catalyzed by >1000 ubiquitin ligases that recognize individual substrate proteins. Because the pathogenesis of certain kidney diseases and their complications are linked to the function of the ubiquitin-proteasome system, understanding its mechanisms could lead to novel therapies.
Response to Letters Regarding Article, “Bayesian Methods Affirm the Use of Percutaneous Coronary Intervention to Improve Survival in Patients With Unprotected Left Main Coronary Artery Disease”
Authors: John A. Bittl, Yulei He, Alice K. Jacobs, Clyde W. Yancy, Sharon-Lise T. Normand
Journal: Circulation (2014)
Is Glycemic Control Improving in U.S. Adults?
Authors: Thomas J. Hoerger, Joel E. Segel, Edward W. Gregg, Jinan B. Saaddine
Journal: Diabetes Care (2007)

OBJECTIVE—The purpose of this study was to examine whether glycemic control has improved in recent years among individuals with diagnosed diabetes. RESEARCH DESIGN AND METHODS—We examined trends in A1C levels for adults with diagnosed diabetes using three consecutive waves of the National Health and Nutrition Examination Survey (NHANES): 1999–2000, 2001–2002, and 2003–2004. We estimated mean A1C levels and the proportion with A1C &amp;lt;7.0, &amp;lt;8.0, and &amp;lt;9.0%. We used multivariate regression to test whether A1C levels differed by NHANES wave after controlling for other factors. Multivariate dichotomous logistic regression and predictive margins were used to test whether the percentages of individuals with diabetes in selected A1C intervals differed by NHANES wave. RESULTS—Mean A1C levels among individuals with diagnosed diabetes declined from 7.82% in 1999–2000 to 7.47 and 7.18% in 2001–2002 and 2003–2004, respectively. After controlling for demographics and diabetes duration, A1C levels were 0.308 (P = 0.20) and 0.511 (P = 0.03) percentage points lower in 2001–2002 and 2003–2004, respectively, than in 1999–2000. The logistic results indicated corresponding improvements over time: the predictive margin for having A1C &amp;lt;7.0% increased from 37.0% in 1999–2000 to 49.7% in 2001–2002 and to 55.7% in 2003–2004. CONCLUSIONS—Glycemic control improved between 1999 and 2004. This trend may represent an important improvement in diabetes care and is encouraging for future reduction of diabetes-related complications.
Decitabine Effect on Tumor Global DNA Methylation and Other Parameters in a Phase I Trial in Refractory Solid Tumors and Lymphomas
Authors: David J. Stewart, Jean-Pierre Issa, Razelle Kurzrock, Maria I. Nunez, Jaroslav Jelinek, David Hong, Yasuhiro Oki, Zhong Guo, Sanjay Gupta, Ignacio I. Wistuba
Journal: Clinical Cancer Research (2009)

By hypomethylating genes, decitabine may up-regulate factors required for chemotherapeutic cytotoxicity. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1.Thirty-one patients with refractory malignancies received decitabine 2.5 to 10 mg/m(2) on days 1 to 5, and 8 to 12 or 15 to 20 mg/m(2) on days 1 to 5. Tumor was assessed for DNA methylation (by LINE assays), apoptosis, necrosis, mitoses, Ki67, DNA methyltransferase (DNMT1), CTR1, and p16.Febrile neutropenia was dose limiting. One thymoma patient responded. Decitabine decreased tumor DNA methylation (from median 51.2% predecitabine to 43.7% postdecitabine; P = 0.01, with effects at all doses) and in peripheral blood mononuclear cells (from 65.3-56.0%). There was no correlation between tumor and peripheral blood mononuclear cells. Patients starting decitabine < or =3 versus >3 months after last prior cytotoxic or targeted therapy had lower predecitabine tumor CTR1 scores (P = 0.02), higher p16 (P = 0.04), and trends (P = 0.07) toward higher tumor methylation and apoptosis. Decitabine decreased tumor DNMT1 for scores initially >0 (P = 0.04). Decitabine increased tumor apoptosis (P < 0.05), mitoses (if initially low, P = 0.02), and CTR1 (if initially low, P = 0.025, or if < or =3 months from last prior therapy, P = 0.04). Tumor CTR1 scores correlated inversely with methylation (r = -0.41, P = 0.005), but CTR1 promoter was not hypermethylated. Only three patients had tumor p16 promoter hypermethylation. P16 scores did not increase. Higher blood pressure correlated with lower tumor necrosis (P = 0.03) and a trend toward greater DNA demethylation (P = 0.10).Exposure to various cytotoxic and targeted agents might generate broad pleiotropic resistance by reducing CTR1 and other transporters. Decitabine decreases DNA methylation and augments CTR1 expression through methylation-independent mechanisms.
Advances in Image-Guided Radiation Therapy
Authors: Laura A. Dawson, David A. Jaffray
Journal: Journal of Clinical Oncology (2007)

Imaging is central to radiation oncology practice, with advances in radiation oncology occurring in parallel to advances in imaging. Targets to be irradiated and normal tissues to be spared are delineated on computed tomography (CT) scans in the planning process. Computer-assisted design of the radiation dose distribution ensures that the objectives for target coverage and avoidance of healthy tissue are achieved. The radiation treatment units are now recognized as state-of-the-art robotics capable of three-dimensional soft tissue imaging immediately before, during, or after radiation delivery, improving the localization of the target at the time of radiation delivery, to ensure that radiation therapy is delivered as planned. Frequent imaging in the treatment room during a course of radiation therapy, with decisions made on the basis of imaging, is referred to as image-guided radiation therapy (IGRT). IGRT allows changes in tumor position, size, and shape to be measured during the course of therapy, with adjustments made to maximize the geometric accuracy and precision of radiation delivery, reducing the volume of healthy tissue irradiated and permitting dose escalation to the tumor. These geometric advantages increase the chance of tumor control, reduce the risk of toxicity after radiotherapy, and facilitate the development of shorter radiotherapy schedules. By reducing the variability in delivered doses across a population of patients, IGRT should also improve interpretation of future clinical trials.
Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100
Authors: Franziska Leonhardt, Sebastian Grundmann, Martin Behe, Franziska Bluhm, Rebecca A. Dumont, Friederike Braun, Melpomeni Fani, Katarina Riesner, Gabriele Prinz, Anne-Kathrin Hechinger, Ulrike V. Gerlach, Heide Dierbach, Olaf Penack, Annette Schmitt-Gräff, Jürgen Finke, Wolfgang A. Weber, Robert Zeiser
Journal: Blood (2013)
Comparative study of multidrug resistance evaluated by means of the quantitative immunohistochemical detection of p‐glycoprotein and the functional release of rhodamine 123
Authors: Jean‐Pierre Delville, Olivier Pradier, Olivier Pauwels, Anne Van Onderbergen, Robert Kiss, Walter Feremans, Paul Capel
Journal: American Journal of Hematology (1995)

The immunological detection of P-Glycoprotein (P-GP) and the functional release of Rhodamine 123 (R123) have been compared in a number of human and murine cancer cell lines, in chemo- and/or radiotherapy-resistant subclones, and in clinical specimens from patients. The chemoresistance level was established from the viability index (IC50) in the presence of doxorubicin. Cytocentrifuge preparations were immunostained with JSB-1 monoclonal antibody followed by the alkaline phosphatase anti-alkaline phosphatase technique. The strength of the reaction was quantified by a digital image analyser. The kinetic incorporation and release of Rhodamine 123 were evaluated by flow cytometry. The parent cell lines and radiotherapy resistant subclones showed a low IC50, were JSB-1 negative and retained R123 during the whole experiment, while the chemoresistant and radio-chemoresistant cell line mutants had a high IC50, were JSB-1 positive, and actively pumped the R123 out of the cells. Good correlations were obtained between the IC50, the digital image analysis, and flow cytometry. The kinetic profile of the R123 release allowed the distinction between typical and atypical multidrug resistance phenotypes. These findings were confirmed in clinical specimens from patients. We conclude that antigenic and functional studies are complementary and are useful in experimental and clinical approaches to multidrug resistance.
Endobronchial ultrasound: new insight for the diagnosis of sarcoidosis
Authors: M. Wong, K. Yasufuku, T. Nakajima, F. J. F. Herth, Y. Sekine, K. Shibuya, T. Iizasa, K. Hiroshima, W. K. Lam, T. Fujisawa
Journal: European Respiratory Journal (2007)

A diagnosis of sarcoidosis should be substantiated by pathological means in order to thoroughly exclude other diseases. The role of real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of sarcoidosis has not been reported. The purpose of the present study is to evaluate the diagnostic yield of EBUS-TBNA in demonstrating the pathological features of sarcoidosis. In total, 65 patients with suspected sarcoidosis, with enlarged hilar or mediastinal lymph nodes on computed tomography, were included in the study. Patients with a suspected or known malignancy or previously established diagnosis of sarcoidosis were excluded. Convex probe endobronchial ultrasonography integrated with a separate working channel was used for EBUS-TBNA. Surgical methods were performed in those in whom no granulomas were detected by EBUS-TBNA. Patients were followed up clinically. EBUS-TBNA was performed on a total of 77 lymph node stations in 65 patients. A final diagnosis of sarcoidosis was made for 61 (93.8%) of the patients. The remaining four patients were diagnosed as having Wegener9s granulomatosis (n = 1) or indefinite (n = 3). In patients with a final diagnosis of sarcoidosis, EBUS-TBNA demonstrated noncaseating epithelioid cell granulomas in 56 (91.8%) of the patients. No complications were reported. Endobronchial ultrasound-guided transbronchial needle aspiration proved to be a safe procedure with a high yield for the diagnoses of sarcoidosis.
FTY720, a New Immunosuppressant, Promotes Long-Term Graft Survival and Inhibits the Progression of Graft Coronary Artery Disease in a Murine Model of Cardiac Transplantation
Authors: Myung-Woo Hwang, Akira Matsumori, Yutaka Furukawa, Koh Ono, Masaharu Okada, Atsushi Iwasaki, Masatake Hara, Shigetake Sasayama
Journal: Circulation (1999)

Background —Effective immunosuppression is a critical determinant of organ and patient survival in cardiac transplantation. The present study was designed to determine the potency of FTY720, a new synthesized immunosuppressant, and examine its clinical potential as an immunosuppressant. Methods and Results —Hearts of DBA/2 mice were transplanted heterotopically in C57BL/6 mice. Recipients were treated with oral FTY720 in doses of 0.3, 1, 3, or 10 mg · kg −1 · d −1 or with 40 mg · kg −1 · d −1 of cyclosporin A (CsA) as a comparative treatment. The median graft survival time (MST) was significantly prolonged by treatment with FTY720 10 mg · kg −1 · d −1 . MST was not prolonged by FTY720 1 mg · kg −1 · d −1 or CsA. However, FTY720 1 mg · kg −1 · d −1 combined with CsA 40 mg · kg −1 · d −1 resulted in a significant prolongation of MST. Histopathological studies performed 5 days after transplantation demonstrated remarkable suppression of inflammatory response by treatment with FTY720 10 mg · kg −1 · d −1 . Interleukin (IL)-2 and interferon (IFN)-γ production was not suppressed; however, cytotoxic T lymphocyte activity was strongly suppressed in vitro. In addition, IL-2–stimulated T-cell proliferation and class I and class II MHC antigen expression on IFN-γ–stimulated macrophages were strongly inhibited by FTY720. Histopathological studies 60 days after transplantation (DBA/2-B10.D2) demonstrated a beneficial effect on graft atherosclerosis. Conclusions —FTY720 promoted long-term cardiac graft survival and strongly inhibited the progression of graft atherosclerosis. These observations suggest that FTY720 has a promising clinical potential in cardiac transplantation.
Effect of a change in rate on atrial repolarization
Authors: R. Goyal, Z.A. Syed, P.S. Mukhopadhyay, B.C. Tran, J. Souza, A. Zivin, F. Pelosi, M. Flomming, B.P. Knight, K.C. Man, S.A. Strickberger, F. Morady
Journal: Journal of the American College of Cardiology (1998)