tbuckley/cabot-search huggingface dataset:
T Lymphocytes Redirected against the Chondroitin Sulfate Proteoglycan-4 Control the Growth of Multiple Solid Tumors both <i>In Vitro</i> and <i>In Vivo</i>
Authors: Claudia Geldres, Barbara Savoldo, Valentina Hoyos, Ignazio Caruana, Ming Zhang, Eric Yvon, Michele Del Vecchio, Chad J. Creighton, Michael Ittmann, Soldano Ferrone, Gianpietro Dotti
Journal: Clinical Cancer Research (2013)

Because of its high expression on various types of tumors and its restricted distribution in normal tissues, chondroitin sulfate proteoglycan-4 (CSPG4) represents an attractive target for the antibody-based therapy of several solid tumors. We tested whether T cells transduced with a CSPG4-specific chimeric antigen receptor (CAR) inhibited the growth of CSPG4-expressing tumor cells both in vitro and in vivo.We first independently validated by immunohistochemistry (IHC) the expression of CSPG4 in an extensive panel of tumor arrays and normal tissues as well as queried public gene expression profiling datasets of human tumors. We constructed a second-generation CSPG4-specific CAR also encoding the CD28 costimulatory endodomain (CAR.CSPG4). We then evaluated human T lymphocytes expressing this CAR for their ex vivo and in vivo antitumor activity against a broad panel of solid tumors.IHC showed that CSPG4 is highly expressed in melanoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), and mesothelioma. In addition, in silico analysis of microarray expression data identified other important potential tumors expressing this target, including glioblastoma, clear cell renal carcinoma, and sarcomas. T lymphocytes genetically modified with a CSPG4-CAR controlled tumor growth in vitro and in vivo in NSG mice engrafted with human melanoma, HNSCC, and breast carcinoma cell lines.CAR.CSPG4-redirected T cells should provide an effective treatment modality for a variety of solid tumors.
Cytomegalovirus containing TRP2 antigen provides protective immunity against the poorly immunogenic B16BL6-D5 melanoma
Authors: Michael Neuberger, Shawn M Jensen, Guangwu Xu, Tameka Smith, Hong-Ming Hu, Ann B Hill, Carlo B Bifulco, Bernard A Fox
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Cytomegalovirus is known to induce long-lived humoral and cellular immune responses that persist and increase over time. In humans on average more than 5% of T cells are CMV-reactive. We have previously reported that mouse cytomegalovirus (MCMV) encoding the unmodified TRP2
A2.33 <b>Haplotype TTTT in the BAFF gene is associated with idiopathic inflammatory myopathies in HLA-DRB1*03 negative patients</b>
Authors: O Kryštůfková, T Svitálková, M Remáková, L Pleštilová, H Mann, P Novota, J Vencovský
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> B-cell activating factor of the TNF family (BAFF) plays a role in (auto)antibody production. Patients with idiopathic inflammatory myopathies (IIMs or myositis) have elevated levels of BAFF in the serum which associate with disease activity. We have previously found an association between TTTT haplotype from the four single nucleotide polymorphisms (SNPs) in the promoter region of BAFF gene (rs9514827, rs3759467, rs1041569 and rs9514828) with presence of myositis in our cohort of IIM patients. The HLA-DRB1*03 allele is a well-known genetic risk factor for myositis in Caucasians. In this study we have analysed the possible interference of HLA-DRB1*03 allele with the presence of the particular SNPs of BAFF gene in patients with myositis. <h3>Materials and methods</h3> The SNPs (rs9514827, rs3759467, rs1041569 and rs9514828) were analysed by direct DNA sequencing in a cohort of 311 patients with myositis (age 5–80 years, females 74%) and in 113 healthy controls (age 18–79 years, females 69%). The HLA-DRB1 genotyping with PCR using sequence-specific oligonucleotide and sequence based typing technique was available in the subgroups of 297 patients and 103 controls. The χ<sup>2</sup> or Fisher tests for analysis of allelic, haplotype and genotype associations with Bonferroni's correction were used. <h3>Results</h3> The four BAFF SNPs were in strong linkage disequilibrium and formed four common haplotypes (TTAC, CTAT, TCAC, TTTT) in both IIM patients and controls, compatible with already reported results. A significantly higher frequency of the TTTT haplotype was present in myositis patients compared to healthy controls (16% vs. 10%; OR = 1.65, 95% CI = 1.03–2.65; p &lt; 0.05). There were no significant differences between patients and controls in the frequencies of alleles and genotypes. 162 IIM patients (55%) and 87 healthy controls (84%) were HLA-DRB1*03 negative and a significant association of the TTTT haplotype in IIM patients was confirmed by a higher frequency (19%) compared to controls (11.5%; OR = 1.79, 95% CI = 1.04–3.07; p &lt; 0.05) within the DRB1*03 negative cohorts. The trend for lower frequency of -2701A allele and AA genotype (rs1041569) in myositis was also found within the HLA-DRB1*03 negative cohort, with IIM patients having a significantly lower proportion of AA genotype compared to controls (62% vs. 77%; OR = 0.48, CI = 0.27–0.87; p &lt; 0.05). <h3>Conclusions</h3> An association of the TTTT haplotype with myositis and a lower frequency of -2701 A allele and AA genotype in patients with IIM are independent from the presence of HLA-DRB1*03 risk allele. <h3>Acknowledgements</h3> IGA-MZ CR NT/12438–4, IMI-funded project BeTheCure, 115142-2
Scavenger Receptor-A Negatively Regulates Antitumor Immunity
Authors: Xiang-Yang Wang, John Facciponte, Xing Chen, John R. Subjeck, Elizabeth A. Repasky
Journal: Cancer Research (2007)

The scavenger receptor-A (SR-A), originally recognized by its ability to internalize modified lipoproteins, has largely been studied in relation to atherosclerosis as well as innate immunity against pathogen infection. SR-A was recently shown to be a receptor on antigen-presenting cell for heat shock protein (HSP) and was implicated in the cross-presentation of HSP-chaperoned antigens. Here, we show that SR-A is not required for antitumor immunity generated by HSP-based (e.g., grp170) vaccine approaches in vivo. The lack of SR-A significantly enhances HSP- or lipopolysaccharide-mediated vaccine activities against poorly immunogenic tumors, indicating that SR-A is able to attenuate immunostimulatory effects of adjuvants or "danger" molecules. The improved antitumor response in SR-A knockout mice is correlated with an increased antigen-specific T-cell response. Moreover, SR-A-deficient dendritic cells are more responsive to inflammatory stimuli and display a more effective antigen-presenting capability compared with wild-type cells. This is the first report illustrating that SR-A negatively regulates antigen-specific antitumor immunity, which has important clinical implications in vaccine design for cancer immunotherapy.
B Effector Cells Activated by a Chimeric Protein Consisting of IL-2 and the Ectodomain of TGF-β Receptor II Induce Potent Antitumor Immunity
Authors: Claudia Penafuerte, Spencer Ng, Norma Bautista-Lopez, Elena Birman, Kathy Forner, Jacques Galipeau
Journal: Cancer Research (2012)

We have previously shown that interleukin (IL)-2 receptor-expressing lymphoid cells stimulated with a chimeric protein linking IL-2 to the ectodomain of TGF-β receptor II (also known as FIST) become resistant to TGF-β-mediated suppression and produce significant amounts of proinflammatory cytokines. In this study, we have characterized the antigen presentation properties of FIST-stimulated B cells (hereafter inducible B effector cells, iBEC). FIST converts naïve splenic B cells to B effector cells characterized by potent antigen presentation properties and production of TNFα and IFNγ. iBECs display hyperphosphorylation of STAT3 and STAT5 downstream of the IL-2 receptor and upregulation of T-bet expression. iBECs maintain B-cell identity based on the expression of PAX5 and CD19 and overexpress Smad7, which confers resistance to TGF-β-mediated suppression of B-cell activation. iBEC antitumor immunity was determined by a mouse model of lymphoma-expressing ovalbumin (E.G7-OVA) as a specific tumor antigen. OVA-pulsed iBECs function as antigen-presenting cells (APC) in vitro by inducing the activation of OVA-specific CD4(+) and CD8(+) T cells, respectively, and in vivo by conferring complete protective immunity against E.G7-OVA tumor challenge. In addition, OVA-pulsed iBECs promote tumor regression in immunocompetent C57Bl/6 mice bearing E.G7-OVA tumors. In conclusion, iBECs represent an entirely novel B cell-derived APC for immune therapy of cancer.
The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis
Authors: Robert J Burns, Raymond J Gibbons, Qilong Yi, Robin S Roberts, Todd D Miller, Gary L Schaer, Jeffrey L Anderson, Salim Yusuf
Journal: Journal of the American College of Cardiology (2002)
High-resolution magnification endoscopy can reliably identify normal gastric mucosa, <i>Helicobacter pylori</i>-associated gastritis, and gastric atrophy
Authors: G. Anagnostopoulos, K. Yao, P. Kaye, E. Fogden, P. Fortun, A. Shonde, S. Foley, S. Sunil, J. Atherton, C. Hawkey, K. Ragunath
Journal: Endoscopy (2007)

The aims of the study were to describe the magnified endoscopic findings in the gastric body, correlate these with histology, and evaluate their reproducibility in the assessment of the magnified endoscopic patterns seen.A total of 95 consecutive dyspeptic patients underwent upper gastrointestinal endoscopy with a magnifying endoscope. The endoscopists classified the magnified endoscopic patterns and correlated them with the histological findings. In the second part of the study, 200 images were shown to five endoscopists in order to examine inter- and intraobserver variability in image assessment.The magnified endoscopic findings in the gastric body were categorized into four types: type 1, honeycomb-type subepithelial capillary network (SECN) with regular arrangement of collecting venules and regular, round pits; type 2, honeycomb-type SECN with regular, round pits, but loss of collecting venules; type 3, loss of normal SECN and collecting venules, with enlarged white pits surrounded by erythema; and type 4, loss of normal SECN and round pits, with irregular arrangement of collecting venules. The sensitivity, specificity, and positive and negative predictive values of the type 1 pattern for predicting normal gastric mucosa were 92.7% (95% confidence interval [CI] 93.2-97.3%), 100% (95% CI 83.9-100%), 100% (95% CI 92.9-100%), and 83.8% (95% CI 65.5-93.9%). The sensitivity, specificity, and positive and negative predictive values of types 2 and 3 patterns for predicting a Helicobacter pylori-infected stomach were 100% (95% CI 83.9-100%), 92.7% (95% CI 93.2-97.3%), 83.8% (95% CI 65.5-93.9%), and 100% (95% CI 92.9-100%). The sensitivity, specificity, and positive and negative predictive values of a type 4 pattern for predicting gastric atrophy were 90% (95% CI 66.8-98.2%), 96% (95% CI 87.9-98.9%), 85.7% (95% CI 62.6-96.2%), and 97.3% (95% CI 89.6-99.5%. The kappa values for inter- and intraobserver agreement in predicting normal gastric mucosa, H. pylori gastritis, and gastric atrophy were 0.864 and 0.913 respectively.High-resolution magnification endoscopy can reliably identify the normal gastric mucosa, H. pylori-associated gastritis, and gastric atrophy in a Western population.
Biochemistry, Physiology, and Pathophysiology of NADPH Oxidases in the Cardiovascular System
Authors: Bernard Lassègue, Alejandra San Martín, Kathy K. Griendling
Journal: Circulation Research (2012)

The NADPH oxidase (Nox) enzymes are critical mediators of cardiovascular physiology and pathophysiology. These proteins are expressed in virtually all cardiovascular cells, and regulate such diverse functions as differentiation, proliferation, apoptosis, senescence, inflammatory responses and oxygen sensing. They target a number of important signaling molecules, including kinases, phosphatases, transcription factors, ion channels, and proteins that regulate the cytoskeleton. Nox enzymes have been implicated in many different cardiovascular pathologies: atherosclerosis, hypertension, cardiac hypertrophy and remodeling, angiogenesis and collateral formation, stroke, and heart failure. In this review, we discuss in detail the biochemistry of Nox enzymes expressed in the cardiovascular system (Nox1, 2, 4, and 5), their roles in cardiovascular cell biology, and their contributions to disease development.
Phosphorylation of the 6-Phosphofructo-2-Kinase/Fructose 2,6-Bisphosphatase/PFKFB3 Family of Glycolytic Regulators in Human Cancer
Authors: Hidenori Bando, Toshiya Atsumi, Taro Nishio, Hirokatsu Niwa, Shinya Mishima, Chikara Shimizu, Narihito Yoshioka, Richard Bucala, Takao Koike
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Fructose 2,6-bisphosphate (F2,6BP) is a potent activator of phosphofructokinase, which is a rate-limiting enzyme of glycolysis. The concentration of F2,6BP depends on the activity of the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase). Four genes encoding PFK-2/FBPase have been identified and termed PFKFB1 to PFKFB4. PFKFB3 protein is expressed in high levels in human tumors in situ. The purpose of this study was to determine the role of functional interactions between the phosphorylation of PFKFB3 and activated glycolysis in human cancer cells. Experimental Design: cDNA from several human tumor cell lines and human colon carcinoma were analyzed by reverse transcription-PCR to identify different splicing variants of PFKFB3. The effect of phosphorylation of Ser461 was studied by recombinantly replacing this residue with glutamate (PFKFB3S461E). The phosphorylation of PFKFB3 protein in human cancer was determined by immunostaining using an anti-phospho-PFK-2(PFKFB3) antibody. Results: Two splicing variants of PFKFB3 are expressed in human cancer cell lines: PFKFB3-ACG and PFKFB3-AG. Quantitative, real-time PCR analysis confirmed the overexpression of PFKFB3 mRNA in colon carcinoma, with the dominant variant being the PFKFB3-ACG isoform that contains a phosphorylation site at Ser461. Forced expression of PFKFB3-ACG in COS-7 cells resulted in enhanced glycolysis. Introduction of PFKFB3-ACGS461E into COS-7 cells led to increased the lactate production and cell proliferation. Highly phosphorylated PFKFB3 protein was found in human tumor cells, vascular endothelial cells, and smooth muscle cells, as determined by immunostaining with an anti-phospho-PFK-2(PFKFB3) antibody. Conclusions: These findings support a potential role for the phosphorylation of PFKFB3 protein in the progression of cancer and angiogenesis.
AN INTENSIVE NEUROPSYCHIATRIC TREATMENT PROGRAM IN A VETERANS HOSPITAL
Authors: WILFRED BLOOMBERG, SAMUEL SILVERMAN, ANNE G. LEVINGSTON, WILLIAM F. MURPHY
Journal: American Journal of Psychiatry (1948)

Cushing is a new hospital, and our service is feeling its way by trial and error into its permanent pattern. The material above represents a fair cross section of our present activity. We hope in the future to be able to say more specifically what has been found useful, and what has been abandoned. Not only our psychiatric orientation but our total situation is dynamic. We believe that our organization has a contribution to make to the care and treatment of neuropsychiatric patients. We shall continue to evaluate ourselves and to welcome criticism.
Mutation in the <i>KCNQ1</i> Gene Leading to the Short QT-Interval Syndrome
Authors: Chloé Bellocq, Antoni C.G. van Ginneken, Connie R. Bezzina, Mariel Alders, Denis Escande, Marcel M.A.M. Mannens, Isabelle Baró, Arthur A.M. Wilde
Journal: Circulation (2004)

The electrocardiographic short QT-interval syndrome forms a distinct clinical entity presenting with a high rate of sudden death and exceptionally short QT intervals. The disorder has recently been linked to gain-of-function mutation in KCNH2. The present study demonstrates that this disorder is genetically heterogeneous and can also be caused by mutation in the KCNQ1 gene.A 70-year man presented with idiopathic ventricular fibrillation. Both immediately after the episode and much later, his QT interval was abnormally short without any other physical or electrophysiological anomalies. Analysis of candidate genes identified a g919c substitution in KCNQ1 encoding the K+ channel KvLQT1. Functional studies of the KvLQT1 V307L mutant (alone or coexpressed with the wild-type channel, in the presence of IsK) revealed a pronounced shift of the half-activation potential and an acceleration of the activation kinetics leading to a gain of function in I(Ks). When introduced in a human action potential computer model, the modified biophysical parameters predicted repolarization shortening.We present an alternative molecular mechanism for the short QT-interval syndrome. Functional and computational studies of the KCNQ1 V307L mutation identified in a patient with this disorder favor the association of short QT with mutation in KCNQ1.
Old but Not (So) Degenerated—Slow Evolution of Largely Homomorphic Sex Chromosomes in Ratites
Authors: Homa Papoli Yazdi, Hans Ellegren
Journal: Molecular Biology and Evolution (2014)

Degeneration of the nonrecombining chromosome is a common feature of sex chromosome evolution, readily evident by the presence of a pair of largely heteromorphic chromosomes, like in eutherian mammals and birds. However, in ratites (order Palaeognathae, including, e.g., ostrich), the Z and W chromosomes are similar in size and largely undifferentiated, despite avian sex chromosome evolution was initiated > 130 Ma. To better understand what may limit sex chromosome evolution, we performed ostrich transcriptome sequencing and studied genes from the nonrecombining region of the W chromosome. Fourteen gametologous gene pairs present on the W chromosome and Z chromosome were identified, with synonymous sequence divergence of 0.027–0.177. The location of these genes on the Z chromosome was consistent with a sequential increase in divergence, starting 110–157 and ending 24–30 Ma. On the basis of the occurrence of Z-linked genes hemizygous in females, we estimate that about one-third of the Z chromosome does not recombine with the W chromosome in female meiosis. Pairwise dN/dS between gametologs decreased with age, suggesting strong evolutionary constraint in old gametologs. Lineage-specific dN/dS was consistently higher in W-linked genes, in accordance with the lower efficacy of selection expected in nonrecombining chromosomes. A higher ratio of GC > AT:AT > GC substitutions in W-linked genes supports a role for GC-biased gene conversion in differentially driving base composition on the two sex chromosomes. A male-to-female (M:F) expression ratio of close to one for recombining genes and close to two for Z-linked genes lacking a W copy show that dosage compensation is essentially absent. Some gametologous genes have retained active expression of the W copy in females (giving a M:F ratio of 1 for the gametologous gene pair), whereas for others W expression has become severely reduced resulting in a M:F ratio of close to 2. These observations resemble the patterns of sex chromosome evolution seen in other avian and mammalian lineages, suggesting similar underlying evolutionary processes, although the rate of sex chromosome differentiation has been atypically low. Lack of dosage compensation may be a factor hindering sex chromosome evolution in this lineage.
Depletion of cardiac norepinephrine during two forms of hemolytic anemia in the rat.
Authors: J W Swann, J F Contrera
Journal: Circulation Research (1976)

Knowledge of the status of cardiac norepinephrine (NE) during anemia could lead to a better understanding of the role the sympathetic nervous system plays in cardiac function during anemia. Rats were made anemic by treatment with phenylhydrazine (PHZ). After the rapid onset of anemia, 60% of the stored NE in the heart was lost within 48 hours after treatment. Associated with the loss of cardiac NE was an increase in the wet weight of the heart, which reached a value 40% above control 48 hours after treatment. PHZ itself probably does not directly mediate this depletion of NE, since the vas deferens, brain and spleen had a normal store of NE at 48 hours. This contention was supported when rats, treated with PHZ, were transfused with normal rat red blood cells. This transfusion resulted in PHZ-treated rats which were not anemic. The hearts of these rats were not depleted of NE, but the hearts of the nontransfused, PHZ-treated controls were. Anemia also was induced by treating rats with anti-rat red blood cell serum. The hearts of these rats also were depleted of NE. These experiments show that during two forms of anemia there is a loss of NE from the sympathetic neurons innervating the heart. The effect of this on regulation of cardiac function remains to be determined.
Mycosis fungoides: HLA class II associations among Ashkenazi and non-Ashkenazi Jewish patients
Authors: E. Hodak, M. Lapidoth, Y. Kohn, M. David, C. Brautbar, B. Kfir, R. Narinski, C. Safirman, L. Maron, T. Klein
Journal: British Journal of Dermatology (2001)

An immunogenetic mechanism has been suggested to play a role in the pathogenesis of mycosis fungoides (MF). While results of studies on HLA class I associations haveproved inconsistent, two previous studies showed that certain HLA class II alleles were significantly increased among North American caucasian patients with MF: HLA-DRB1*11 and DQB1*03.To investigate the possible HLA class I and class II associations with MF among Jewish patients.The patient group comprised 68 Jewish patients with MF: 38 Ashkenazi and 30 non-Ashkenazi. The control group comprised 252 healthy Jewish volunteers: 132 Ashkenazi and 120 non-Ashkenazi. Tissue typing for HLA class I (A and B) was performed using the National Institutes of Health microlymphocytotoxicity technique. DNA-based low-medium resolution analysis for DRB1* and DQB1* alleles was performed using polymerase chain reaction (PCR) amplification with sequence-specific primers. For those alleles found to have significantly increased frequency, high-resolution analysis was done by means of PCR sequence-specific oligotyping.The allele frequency of HLA-DRB1*11 was found to be significantly increased but only among Ashkenazi patients with MF (30% vs. 19% in the controls; P = 0.034). High-resolution analysis for DRB1*11, not previously performed, suggested that its greater frequency is due to the increased number of Ashkenazi MF patients with the DRB1*1104 allele (P corrected = 0.036). Analysed together, DQB1*03 alleles (DQB1*0301-0304) had a significantly greater frequency in MF as a group as compared with controls (47% vs. 33%, P = 0.003). DQB1*0301 was demonstrated to be the specific allele associated with MF in Jewish patients (allele frequency of 36% vs. 23% in controls; P corrected = 0.0068), which was not the case for North American caucasian patients with MF. No greater frequencies of any of the HLA class I A or B antigens were found.Our findings further demonstrate the 'universality' of MF HLA class II susceptibility alleles, i.e. HLA-DRB1*11 and HLA-DQB1*03, suggesting that HLA polymorphism is likely to be important in the pathogenesis of MF in Jewish patients, as it is in North American caucasian patients. Not previously reported is our finding that HLA-DRB1*1104 is the specific allele more prevalent among patients with MF. Our study also underscores some differences in HLA profiles between non-Jewish and Jewish patients with MF and between Ashkenazi and non-Ashkenazi Jewish patients, indicating the possibility of diverse HLA disease associations in populations with different genetic backgrounds. Our study provides further evidence for the lack of association between HLA class I and MF.