tbuckley/cabot-search huggingface dataset:
Cytotoxic T Lymphocytes to An Unmutated Tumor Rejection Antigen P1A: Normal Development but Restrained Effector Function In Vivo
Authors: Supria Sarma, Yong Guo, Yannik Guilloux, Cheng Lee, Xue-Feng Bai, Yang Liu
Journal: The Journal of Experimental Medicine (1999)

Unmutated tumor antigens are chosen as primary candidates for tumor vaccine because of their expression on multiple lineages of tumors. A critical issue is whether unmutated tumor antigens are expressed in normal cells, and if so, whether such expression imposes special restrictions on cytotoxic T lymphocyte (CTL) responses. In this study, we use a transgenic approach to study the development and effector function of T cells specific for P1A, a prototypical unmutated tumor antigen. We report here that although P1A is expressed at low levels in normal tissues, including lymphoid tissues, the P1A-specific transgenic T cells develop normally and remain highly responsive to the P1A antigen. The fact that transgenic expression of P1A antigen in the thymus induces T cell clonal deletion demonstrates that normal hematopoietic cells can process and present the P1A antigen and that P1A-specific T cells are susceptible to clonal deletion. By inference, P1A-specific T cells must have escaped clonal deletion due to low expression of P1A in the thymus. Interestingly, despite the fact that an overwhelming majority of T cells in the T cell receptor for antigen (TCR)–transgenic mice are specific for P1A, these mice are no more resistant to a P1A-expressing plasmocytoma than nontransgenic littermates. Moreover, when the same TCR-transgenic mice were challenged simultaneously with B7-1+ and B7-1− tumors, only B7-1+ tumors were rejected. Therefore, even though P1A can be a tumor rejection antigen, the effector function of P1A-specific CTL is restrained in vivo. These results have important implications for the strategy of tumor immunotherapy.
Calmodulin Kinases II and IV and Calcineurin Are Involved in Leukemia Inhibitory Factor–Induced Cardiac Hypertrophy in Rats
Authors: Takahiro Kato, Motoaki Sano, Shunichiro Miyoshi, Toshihiko Sato, Daihiko Hakuno, Hideyuki Ishida, Hiroe Kinoshita-Nakazawa, Keiichi Fukuda, Satoshi Ogawa
Journal: Circulation Research (2000)

Abstract —We recently reported that leukemia inhibitory factor (LIF) enhances Ca 2+ ] i through an increase in L-type Ca 2+ current ( I Ca,L ) in adult cardiomyocytes. The aim of this study was to investigate whether LIF activates Ca 2+ -dependent signaling molecules, such as calcineurin and calmodulin kinases II and IV (CaMKII and CaMKIV), and, if so, whether these Ca 2+ -mediated signaling events contribute to LIF-mediated cardiac hypertrophy. We first confirmed that LIF increased I Ca,L and [Ca 2+ ] i in primary cultured rat neonatal cardiomyocytes. Calcineurin, CaMKII, and CaMKIV activities increased at 2 minutes and peaked by 1.6-, 2.2-, and 2.2-fold, respectively, at 15 minutes. Nicardipine or verapamil fully inhibited these activities. Autophosphorylation of CaMKII was also observed to parallel the timing of CaMKII activity, and this phosphorylation was blocked by nicardipine, verapamil, or EGTA. LIF treatment led to a 3-fold increase in nuclear factor of activated T cell–luciferase activity. To confirm that inositol triphosphate (IP 3 )-induced Ca 2+ release from sarcoplasmic reticulum was not involved in this process, IP 3 content and phosphorylation of phospholipase Cγ were investigated. LIF did not increase IP 3 content or phosphorylate phospholipase Cγ. KN62 (an inhibitor of CaMKII and CaMKIV) attenuated c-fos, brain natriuretic peptide, α-skeletal actin, and atrial natriuretic peptide expression. KN62 suppressed the LIF-induced increase in [ 3 H]phenylalanine uptake and cell size. Cyclosporin A and FK506 slightly attenuated brain natriuretic peptide but did not affect c-fos or atrial natriuretic peptide expression. Cyclosporin A significantly reduced the LIF-induced increase in [ 3 H]phenylalanine uptake. These findings indicated that LIF activated CaMKII, CaMKIV, and calcineurin through an increase in I Ca,L and [Ca 2+ ] i and that CaMKII, CaMKIV, and calcineurin are critically involved in LIF-induced cardiac hypertrophy.
Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia
Authors: Dale A. Moulding, Michael P. Blundell, David G. Spiller, Michael R.H. White, Giles O. Cory, Yolanda Calle, Helena Kempski, Jo Sinclair, Phil J. Ancliff, Christine Kinnon, Gareth E. Jones, Adrian J. Thrasher
Journal: The Journal of Experimental Medicine (2007)

Specific mutations in the human gene encoding the Wiskott-Aldrich syndrome protein (WASp) that compromise normal auto-inhibition of WASp result in unregulated activation of the actin-related protein 2/3 complex and increased actin polymerizing activity. These activating mutations are associated with an X-linked form of neutropenia with an intrinsic failure of myelopoiesis and an increase in the incidence of cytogenetic abnormalities. To study the underlying mechanisms, active mutant WASpI294T was expressed by gene transfer. This caused enhanced and delocalized actin polymerization throughout the cell, decreased proliferation, and increased apoptosis. Cells became binucleated, suggesting a failure of cytokinesis, and micronuclei were formed, indicative of genomic instability. Live cell imaging demonstrated a delay in mitosis from prometaphase to anaphase and confirmed that multinucleation was a result of aborted cytokinesis. During mitosis, filamentous actin was abnormally localized around the spindle and chromosomes throughout their alignment and separation, and it accumulated within the cleavage furrow around the spindle midzone. These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization.
Genetic and Expression Analysis of MET, MACC1, and HGF in Metastatic Colorectal Cancer: Response to Met Inhibition in Patient Xenografts and Pathologic Correlations
Authors: Francesco Galimi, Davide Torti, Francesco Sassi, Claudio Isella, Davide Corà, Stefania Gastaldi, Dario Ribero, Andrea Muratore, Paolo Massucco, Dimitrios Siatis, Gianluca Paraluppi, Federica Gonella, Francesca Maione, Alberto Pisacane, Ezio David, Bruno Torchio, Mauro Risio, Mauro Salizzoni, Lorenzo Capussotti, Timothy Perera, Enzo Medico, Maria Flavia Di Renzo, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti
Journal: Clinical Cancer Research (2011)

Abstract Purpose: We determined the gene copy numbers for MET, for its transcriptional activator MACC1 and for its ligand hepatocyte growth factor (HGF) in liver metastases from colorectal carcinoma (mCRC). We correlated copy numbers with mRNA levels and explored whether gain and/or overexpression of MET and MACC1 predict response to anti-Met therapies. Finally, we assessed whether their genomic or transcriptional deregulation correlates with pathologic and molecular parameters of aggressive disease. Experimental Design: One hundred three mCRCs were analyzed. Copy numbers and mRNA were determined by quantitative PCR (qPCR). Thirty nine samples were implanted and expanded in NOD (nonobese diabetic)/SCID (severe combined immunodeficient) mice to generate cohorts that were treated with the Met inhibitor JNJ-38877605. In silico analysis of MACC1 targets relied on genome-wide mapping of promoter regions and on expression data from two CRC datasets. Results: No focal, high-grade amplifications of MET, MACC1, or HGF were detected. Chromosome 7 polysomy and gain of the p-arm were observed in 21% and 8% of cases, respectively, and significantly correlated with higher expression of both Met and MACC1. Met inhibition in patient-derived xenografts did not modify tumor growth. Copy number gain and overexpression of MACC1 correlated with unfavorable pathologic features better than overexpression of Met. Bioinformatic analysis of putative MACC1 targets identified elements besides Met, whose overexpression cosegregated with aggressive forms of colorectal cancer. Conclusions: Experiments in patient-derived xenografts suggest that mCRCs do not rely on Met genomic gain and/or overexpression for growth. On the basis of pathologic correlations and bioinformatic analysis, MACC1 could contribute to CRC progression through mechanisms other than or additional to Met transcriptional upregulation. Clin Cancer Res; 17(10); 3146–56. ©2011 AACR.
Narcolepsy risk after A/H1N1 2009 influenza vaccination
Authors: Simon B Drysdale
Journal: Thorax (2013)

Narcolepsy risk after A/H1N1 2009 influenza vaccinationVaccines are a critical tool used to prevent the of spread infectious diseases, particularly in the setting of a pandemic.While they are generally safe, rare but potentially serious adverse effects following vaccination have been reported, after licensure, for several vaccines.This retrospective study used case coverage analysis to investigate the risk of developing narcolepsy in children receiving the AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix) in England.In this study 75 children between 4-19 years of age were diagnosed with narcolepsy during the follow-up period; 11 had received the vaccine.The OR was 14.4 (95% CI 4.3 to 48.5) for vaccination after adjusting for the fact that children receiving the vaccine were more likely to be in high-risk groups.The relative incidence estimate for onset of narcolepsy after vaccination using self-controlled case series analysis was 9.9 (95% CI 2.1 to 47.9).The estimated attributable risk was between 1 in 57 500 and 1 in 52 000 vaccine doses.The authors, however, point out that potential cases of narcolepsy may have been referred more quickly during the follow-up period due to a previous Finnish study reporting on the association between narcolepsy and the vaccine, thus potentially overestimating the risk in this study.Longer follow-up of the cohort exposed to the vaccine would be required to attempt to reduce this potential bias.This study shows the need for ongoing postlicensure surveillance of vaccines and also poses the question if the association is real, how might the vaccine cause narcolepsy?
Awareness about MDR-TB in private medical practitioners of Pune City
Authors: Tushar Sahasrabudhe, Tinku Joseph, Shailesh Meshram, Ankur Pathak
Journal: European Respiratory Journal (2012)

Revised National TB Control Programme (RNTCP) is being implemented in Pune city since 1998 and is providing treatment under DOTS strategy. In view of increasing prevalence of MDR-TB, DOTS plus has also been recently introduced. However the fact remains that a large number of sensitive as well as MDR-TB patients are being treated by private medical practitioners. We conducted a questionnaire based KABP (Knowledge, Attitude, Beliefs and Practices) survey for private practitioners managing MDR-TB cases. The questionnaire was self filled by the participants. The answers were scored as good, average and poor considering WHO guidelines and RNTCP norms as a standard. A total of 425 private practitioners were assessed. 54.95% of practitioners were rated as average, 13.35% as poor and 31.7% as good in KABP. 405 allopath practitioners had better scores compared to 20 alternate medicine practitioners (P < 0.0001). Those who had received RNTCP modular training had better scores (P < 0.0001) but attending the seminars on TB had less impact (P < 0.005). Those with post graduation had better scores but super specialists had scores even lesser than the general practitioners. 83.53% felt that TB Sanatoria should open again. While 72.71% felt that MDR-TB is difficult to treat, only 32% were willing to notify their cases to RNTCP for further management. The survey throws light on the private practice scenario which may be an important hurdle in successful control of MDR-TB. The private practitioners need to be aggressively educated and involved in the RNTCP.
Tumor Suppressor Activity of CCAAT/Enhancer Binding Protein α Is Epigenetically Down-regulated in Head and Neck Squamous Cell Carcinoma
Authors: Kristi L. Bennett, Björn Hackanson, Laura T. Smith, Carl D. Morrison, James C. Lang, David E. Schuller, Frank Weber, Charis Eng, Christoph Plass
Journal: Cancer Research (2007)

Abstract Tumor suppressor CCAAT enhancer binding protein α (C/EBPα) is a transcription factor involved in cell cycle control and cellular differentiation. In a recent study, microarray expression profiling on head and neck squamous cell carcinoma (HNSCC) samples identified significant C/EBPα down-regulation, correlating with poor prognosis. However, the mechanisms of C/EBPα down-regulation remained elusive. C/EBPα has been previously found to provide an antiproliferative role in lung cancer, and our laboratory showed that its down-regulation involves epigenetic mechanisms. This prompted us to investigate the involvement of epigenetics in down-regulating C/EBPα in HNSCC. Here, we show that C/EBPα is down-regulated in HNSCC by loss of heterozygosity and DNA methylation, but not by gene mutation. We found a consistently methylated upstream regulatory region (−1,399 bp to −1,253 bp in relation to the transcription start site) in 68% of the HNSCC tumor samples, and DNA demethylation using 5-aza-2′-deoxycytidine treatment was able to significantly restore C/EBPα mRNA expression in the HNSCC cell lines we tested. In addition, C/EBPα overexpression in a HNSCC cell line (SCC22B) revealed its ability to provide tumor suppressor activity in HNSCC in vitro and in vivo. In conclusion, we showed for the first time not only that C/EBPα has tumor suppressor activity in HNSCC, but also that it is down-regulated by DNA promoter methylation. [Cancer Res 2007;67(10):4657–64]
Some Therapeutic Approaches to Chronic Renal Insufficiency
Authors: B H Scribner, E B Fergus, S T Boen, E D Thomas
Journal: Annual Review of Medicine (1965)

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is ...Read More
Wild-Type <i>BRAF</i> Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer
Authors: Federica Di Nicolantonio, Miriam Martini, Francesca Molinari, Andrea Sartore-Bianchi, Sabrina Arena, Piercarlo Saletti, Sara De Dosso, Luca Mazzucchelli, Milo Frattini, Salvatore Siena, Alberto Bardelli
Journal: Journal of Clinical Oncology (2008)

PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
Complementation studies of isovaleric acidemia and glutaric aciduria type II using cultured skin fibroblasts.
Authors: B Dubiel, C Dabrowski, R Wetts, K Tanaka
Journal: Journal of Clinical Investigation (1983)

Using cultured skin fibroblasts, we studied the heterogeneity of inborn errors of leucine metabolism such as isovaleric acidemia (IVA), glutaric aciduria type II (GA II), and multiple carboxylase deficiency (MC). We first developed a simple macromolecular-labeling test to measure the ability of cells to oxidize [1-14C]isovaleric acid in situ in culture. Cells from two different lines were fused using polyethylene glycol, and the ability of the heterokaryons to oxidize [1-14C]isovaleric acid was tested by the macromolecular-labeling test. The MC line complemented with all 10 IVA lines tested; heterokaryons showed 99 +/- 68% more activity than the unfused mixture of component cells. GA II/IVA heterokaryons exhibited poor growth, but when the culture remained confluent, the GA II cells complemented with all six IVA lines tested, showing a 71 +/- 41% increase in activity. The relatively large standard deviations are due to a few experiments in which significant enhancement of macromolecular-labeling test activity was not observed upon fusion, but significant complementation was clearly observed in repeats of the same combinations. These results are consistent with our previous findings, which indicated that the decreased ability of GA II cells to oxidize isovaleryl-CoA involves a defective electron-transporting system rather than a defective isovaleryl-CoA dehydrogenase. IVA/IVA heterokaryons showed no complementation in any combination tested, indicating no detectable heterogeneity in isovaleric acidemia. This finding indicates that the same gene is mutated in all IVA lines. Previous results indicated that this gene codes for isovaleryl-CoA dehydrogenase.
Urokinase-Type Plasminogen Activator Inhibits Efferocytosis of Neutrophils
Authors: Yanping Yang, Arnaud Friggeri, Sami Banerjee, Khalil Bdeir, Douglas B. Cines, Gang Liu, Edward Abraham
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Phagocytosis of apoptotic cells, also called efferocytosis, plays an essential role in the resolution of inflammation. Urokinase-type plasminogen activator (uPA) is a multifunctional protein that has been implicated in inflammatory conditions, including pneumonia and severe infection, which are often accompanied by the development of acute lung injury. However, the role of uPA in modulating efferocytosis of apoptotic neutrophils has not been defined.To characterize the role of uPA in regulation of efferocytosis and to delineate the underlying mechanisms involved in this process.In vitro and in vivo phagocytosis, immunoprecipitation, and Western blotting assays.The phagocytosis of apoptotic neutrophils by macrophages was significantly inhibited by uPA. Mutant uPA lacking the growth factor domain and catalytically inactive uPA had similar inhibitory effects on efferocytosis, as did wild-type uPA. In contrast, absence of the kringle domain abrogated the ability of uPA to diminish efferocytosis. Both the α(V)β₃ integrin and vitronectin seemed to be involved in the inhibition of efferocytosis by uPA. Incubation of macrophages with uPA also diminished activation of the small GTPase Rac-1, which normally occurs during ingestion of apoptotic neutrophils. Under in vivo conditions in the lungs, uPA decreased the uptake of apoptotic neutrophils by alveolar macrophages.Our data demonstrate a novel role for uPA in which it is able to diminish the uptake of apoptotic neutrophils by macrophages under both in vitro and in vivo conditions.
Effect of corticotropin-like intermediate lobe peptide on pancreatic exocrine function in isolated rat pancreatic lobules.
Authors: J B Marshall, L P Kapcala, L D Manning, A J McCullough
Journal: Journal of Clinical Investigation (1984)

Naturally occurring derivatives of pro-opiomelanocortin (POMC) have been identified in various extra-pituitary sites, including the endocrine and exocrine pancreas. Corticotropin-like intermediate lobe peptide (CLIP = ACTH18-39), a naturally occurring derivative of POMC, has been suggested to be an insulin secretagogue. To determine whether CLIP might also affect the exocrine pancreas, we measured its effect on amylase secretion and protein synthesis and secretion in isolated rat pancreatic lobules. Lobules were dual-pulsed with trace amounts of 14C- and 3H-leucine, both in the presence and absence of CLIP (10(-9)-10(-6) M), using a technique that permitted the labeling of both the synthetic and secretory compartments. The effect of CLIP on protein synthesis was determined by comparing 3H-leucine incorporation into lobules with and without CLIP. The secretory effect of CLIP was determined by measuring (a) secreted 14C-labeled protein as a percent of total incorporated radiolabeled protein, and (b) amylase release into incubation medium. The effect of CLIP on amylase release was compared with that of secretin, cholecystokinin-octapeptide, and carbamylcholine. To localize the biologically active region of CLIP, we similarly studied synthetic ACTH25-39. We demonstrated that CLIP stimulates amylase and protein secretion in a dose-dependent manner and is of similar potency to secretin and carbamylcholine. This effect appears to require the ACTH18-24 region of CLIP and results from stimulus-secretion coupling rather than augmented protein synthesis. We also confirmed the presence of immunoreactive-adrenocorticotropic hormone (IR-ACTH) in rat pancreatic extract using a COOH-terminally directed antibody to ACTH1-39 and demonstrated that this IR-ACTH co-eluted with synthetic CLIP. These findings suggest that CLIP might be an endogenous modulator of pancreatic exocrine function.
A Placebo-Controlled Trial of Omega-3 Fatty Acid (Ethyl Eicosapentaenoic Acid) Supplementation for Residual Symptoms and Cognitive Impairment in Schizophrenia
Authors: Wayne S. Fenton, Faith Dickerson, John Boronow, Joseph R. Hibbeln, Michael Knable
Journal: American Journal of Psychiatry (2001)

This study determined if augmentation of neuroleptics with 3 g/day of ethyl eicosapentaenoic acid (EPA) improves symptoms and cognition in patients with schizophrenia or schizoaffective disorder.Eighty-seven patients meeting criteria for schizophrenia or schizoaffective disorder who had residual symptoms despite neuroleptic treatment were randomly assigned to receive either 3 g/day of ethyl EPA (N=43) or placebo (N=44) in a 16-week, double-blind supplementation trial. Assessments were performed at baseline and at weeks 1, 2, 4, 8, 12, and 16; a cognitive battery was administered at baseline and at week 16.No differences were found between groups in positive or negative symptoms, mood, cognition, or global impression ratings. Results were similar for the intention-to-treat (N=87) and completer (N=75) groups.For schizophrenia patients treated with 3 g/day of ethyl EPA, improvement in residual symptoms and cognitive impairment was no greater than for schizophrenia patients treated with placebo.
Medical fraudster Trudeau sentenced to 10 years in prison
Authors: O. Dyer
Journal: BMJ (2014)

The television commercial pitchman and bestselling author Kevin Trudeau has been sentenced to 10 years in prison by a US federal judge after he broke an agreement to stop making medical claims.

Trudeau, author of Natural Cures “They” Don’t Want You to Know About and The Weight Loss Cure “They” Don’t Want You to Know About , built a commercial empire on popular mistrust of mainstream medicine. He promoted Japanese coral calcium as a cure for cancer and lupus and a product called Biotape as a panacea for chronic pain. He …