tbuckley/cabot-search huggingface dataset:
Natural killer cell function is intact after direct exposure to infectious hepatitis C virions
Authors: Joo Chun Yoon, Masaaki Shiina, Golo Ahlenstiel, Barbara Rehermann
Journal: Hepatology (2008)

Although hepatitis C virus (HCV) has been shown to readily escape from virus-specific T and B cell responses, its effects on natural killer (NK) cells are less clear. Based on two previous reports that recombinant, truncated HCV E2 protein inhibits NK cell functions via crosslinking of CD81, it is now widely believed that HCV impairs NK cells as a means to establish persistence. However, the relevance of these findings has not been verified with HCV E2 expressed as part of intact virions. Here we employed a new cell culture system generating infectious HCV particles with genotype 1a and 2a structural proteins, and analyzed direct and indirect effects of HCV on human NK cells. Antibody-mediated crosslinking of CD16 stimulated and antibody-mediated crosslinking of CD81 inhibited NK cell activation and interferon gamma (IFN-γ) production. However, infectious HCV itself had no effect even at titers that far exceeded HCV RNA and protein concentrations in the blood of infected patients. Consistent with these results, anti-CD81 but not HCV inhibited NK cell cytotoxicity. These results were independent of the presence or absence of HCV-binding antibodies and independent of the presence or absence of other peripheral blood mononuclear cell populations. Conclusion: HCV 1a or 2a envelope proteins do not modulate NK cell function when expressed as a part of infectious HCV particles. Without direct inhibition by HCV, NK cells may become activated by cytokines in acute HCV infection and contribute to infection outcome and disease pathogenesis. (HEPATOLOGY 2009;49:12-21.)
Is the downregulation of EphB2 receptor expression during colorectal tumorigenesis due to hypoxia?
Authors: A. Kaidi, M. Moorghen, A. C. Williams, C. Paraskeva
Journal: Gut (2007)

Mutations in components of the Wnt pathway contribute to the aberrant activation of the β-catenin/T-cell factor-4 (TCF-4) complex and initiate most colorectal cancers.1 Upon its activation, the β-catenin/TCF-4 complex induces the expression of target genes such as c-MYC , cyclin-D1 and EPHB receptors.2 EphB receptors are receptor tyrosine kinases (RTKs) that play an important role in the coordination of cell proliferation, migration and compartmentalisation along intestinal crypts.3 4 The main effectors of these functions in the intestine are believed to be EphB2 and EphB3 receptors.5 Although EphB receptors are targets of β-catenin/TCF-4, Batlle et al. reported the unexpected downregulation of EphB2 receptor expression at the colorectal “adenoma–carcinoma” transition, despite the evident nuclear localisation of β-catenin.6 Intriguingly, EphB receptors were found to play a suppressive role in colorectal tumorigenesis as their loss promotes tumour progression in mice.6 The authors proposed the existence of a secondary, yet unknown, silencing mechanism that underlies the downregulation of EphB receptors, thus allowing colorectal tumour progression.6 Such a mechanism, we suggest, could be instigated by alterations in the tumour microenvironment. Hypoxia, the …
Heat Shock Protein 90 as a Drug Target: Some Like It Hot
Authors: Udai Banerji
Journal: Clinical Cancer Research (2008)

Abstract Heat shock protein 90 (HSP90) is a ubiquitously expressed chaperone that is involved in the posttranslational folding and stability of proteins. Inhibition at the NH2-terminal ATP-binding site leads to the degradation of client proteins by the ubiquitin proteasome pathway. Inhibition of HSP90 leads to the degradation of known oncogenes, such as ERB-B2, BRAF, and BCR-ABL, leading to the combinatorial blockade of multiple signal transduction pathways, such as the RAS-RAF-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. Multiple structurally diverse HSP90 inhibitors are undergoing early clinical evaluation. The clinical focus of these drugs should be solid tumors, such as breast, prostate, and lung cancers, along with malignant melanoma, in addition to hematologic malignancies, such as chronic myeloid leukemia and multiple myeloma. HSP90 inhibitors can be used as single agents or in combination with other targeted treatments or conventional forms of treatment such as chemotherapy and radiotherapy. Clinical trials evaluating efficacy of these agents should include innovative designs to capture cytostasis evidenced by clinical nonprogression and enrichment of patient populations by molecular characterization. The results of clinical trials evaluating the efficacy of drugs targeting this exciting target are awaited.
Regulation of reaginic antibody production in mice. I. Suppression by antigen of IgE antibody production in vitro.
Authors: P J Danneman, J G Michael
Journal: The Journal of Experimental Medicine (1977)

Regulation of IgE production by antigen in a primed murine splenic lymphocyte culture system was described. Maximum IgE antibody production was found to occur when cells were cultured in the absence of exogenously added antigen. A cells and T lymphocytes did not affect the production of anti-DNP IgE antibody. By using a hapten-carrier antigen system (DNP-EA) for priming mice in vivo, it was found that the production of anti-DNP IgE by spleen cells in vitro was inhibited by hapten when coupled to homologous (EA) or heterologous (BGG) carrier, and was not enhanced or inhibited by homologous carrier. Anti-DNP IgE antibody production by cultures depleted of macrophages or T lymphocytes was found to be as sensitive to the suppressive effects of hapten as was the IgE production by whole spleen cell cultures. Both IgM and IgG secondary anti-DNP PFC responses in vitro were enhanced by the presence of the homologous hapten-carrier or carrier alone. DNP-BGG had no effect on the anti-DNP IgM or IgG PFC responses of the cultures. These data suggest that endogenous production of antibody (IgM or IgG) was not responsible for the observed suppression of the IgE response in vitrol The experimental results presented indicate that the regulation of the IgE production by antigen in the primed mouse splenic lymphocyte cultures was a consequence of the direct interaction of hapten with IgE B cells.
Gene expression profile in human leukocytes
Authors: Shin-ichi Hashimoto, Shigenori Nagai, Jun Sese, Takuji Suzuki, Aya Obata, Taku Sato, Nobuaki Toyoda, Hong-Yan Dong, Makoto Kurachi, Tomoyuki Nagahata, Ken-ichi Shizuno, Shinichi Morishita, Kouji Matsushima
Journal: Blood (2003)
Increased cytokine levels and thrombin generation in stable angina are reduced by aspirin. A randomised, controlled, cross-over trial
Authors: I. Ikonomidia, F. Andreotti, C. Stefanadia, C. Pitaavos, E. Economou, P. Toulouzas, P. Nihoyannopoulos
Journal: Journal of the American College of Cardiology (1998)
The <i>NFATc2</i> Gene Is Involved in a Novel Cloned Translocation in a Ewing Sarcoma Variant That Couples Its Function in Immunology to Oncology
Authors: Károly Szuhai, Marije IJszenga, Danielle de Jong, Apollon Karseladze, Hans J. Tanke, Pancras C.W. Hogendoorn
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Ewing sarcoma is an aggressive sarcoma and is the second most common bone sarcoma in childhood. Disease-specific t(11;22) (∼85-90%), t(21;22) (∼5-10%), or rarer variant translocations with the involvement of chromosome 22 (∼5%) are present. At the gene level, the EWSR1 gene fuses with FLI1, ERG, or other ETS transcription factor family members. Thus far, no Ewing sarcoma has been identified with a fusion to transcription factors other than ETS. Experimental Design: Using molecular tools such as multicolor fluorescence in situ hybridization and array comparative genomic hybridization, a ring chromosome containing chromosomes 20 and 22 was identified in four Ewing sarcoma cases. The breakpoint was mapped with (fiber-) fluorescence in situ hybridization and reverse transcription-PCR followed by sequencing of the fusion partners. Results: Molecular karyotyping showed the translocation and amplification of regions of chromosomes 20q13 and 22q12. Cloning of the breakpoint showed an in-frame fusion between the EWSR1 and NFATc2 genes, resulting in loss of the NH2-terminal, calcineurin-dependent control region and an intact active domain of NFATc2 controlled by the transactivation domains of EWSR1. Conclusion: A new translocation involving EWSRI and NFATc2 was cloned. NFATc2 is a transcription factor that is not a member of the ETS family and functions in T-cell differentiation and immune response. Direct involvement of NFATc2 has not yet been observed in oncogenesis. We show that due to the shared sequence recognition of NFATc2 and the ETS family, shared transcriptional control is possible using activating protein complex 1.
Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes
Authors: Shoichi Ehara, Makiko Ueda, Takahiko Naruko, Kazuo Haze, Akira Itoh, Masato Otsuka, Ryushi Komatsu, Toshihiko Matsuo, Hiroyuki Itabe, Tatsuya Takano, Yoshiaki Tsukamoto, Minoru Yoshiyama, Kazuhide Takeuchi, Junichi Yoshikawa, Anton E. Becker
Journal: Circulation (2001)

Background —There is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances. Methods and Results —Ox-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n=45), unstable angina pectoris (UAP; n=45), and stable angina pectoris (SAP; n=45) and in 46 control subjects using a sandwich ELISA method. In addition, 33 atherectomy specimens obtained from a different cohort of patients with SAP (n=10) and UAP (n=23) were studied immunohistochemically for ox-LDL. In AMI patients, ox-LDL levels were significantly higher than in patients with UAP ( P &lt;0.0005) or SAP ( P &lt;0.0001) or in controls ( P &lt;0.0001) (AMI, 1.95±1.42 ng/5 μg LDL protein; UAP, 1.19±0.74 ng/5 μg LDL protein; SAP, 0.89±0.48 ng/5 μg LDL protein; control, 0.58±0.23 ng/5 μg LDL protein). Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In the atherectomy specimens, the surface area containing ox-LDL–positive macrophages was significantly higher in patients with UAP than in those with SAP ( P &lt;0.0001). Conclusions —This study demonstrates that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox-LDL–positive macrophages. These observations suggest that increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions.
Healing hearts and fighting fat
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Arresting intracellular hormone production helps keep arteries clear, according to a study on page 517. Hermanowski-Vosatka and colleagues describe a novel chemical inhibitor that blocks the intracellular build up of the hormone cortisol, thereby preventing the development of atherosclerotic plaques in mice. This compound also alleviated multiple symptoms of a common disorder known as metabolic syndrome.As the epidemics of obesity and type 2 diabetes grow, so does the incidence of metabolic syndrome—a disorder characterized by hypertension, insulin resistance, and visceral obesity. These symptoms add up to an elevated risk of atherosclerosis and coronary heart disease.






Figure 

Inhibition of the cortisol-producing enzyme 11β-HSD1 prevents the development of atherosclerosis and improves the symptoms of metabolic syndrome.




Although the etiology of metabolic syndrome remains obscure, increased intracellular levels of the glucocorticoid cortisol may be partly to blame. Cortisol is an adrenal hormone that regulates nutrient metabolism and inflammation. Recent studies in mice showed that overexpression of 11β-HSD1—the intracellular enzyme that converts inactive cortisone into active cortisol—leads to a disorder resembling metabolic syndrome, suggesting that an excess of intracellular cortisol may contribute to disease.

Although cardiovascular disease is the leading cause of mortality among patients with metabolic syndrome, a role for 11β-HSD1 in the development of cardiovascular symptoms had never been explored. Hermanowski-Vosatka et al. now describe a novel inhibitor of 11β-HSD1 that reduced the accumulation of plaque-forming cholesterol by nearly 90% in the aortas of mice. This inhibitor also protected mice from diet-induced obesity and type 2 diabetes, suggesting that deregulation of intracellular cortisol may be a unifying cause of the symptoms of metabolic syndrome.

The dramatic protection against plaque formation was associated with only modest reductions in serum lipids and glucose (known contributors to atherosclerotic plaque formation), suggesting that the inhibitor also affects other pathways. The authors suspect that the drug may suppress inflammation in vessels, which could help protect against atherosclerosis, as inflammation is associated with exacerbated cardiovascular disease in both mice and humans.
Quality-of-Life Assessment in Cancer Treatment Protocols: Research Issues in Protocol Development
Authors: C. C. Gotay, E. L. Korn, M. S. McCabe, T. D. Moore, B. D. Cheson
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Quality-of-Life Assessment in Cancer Treatment Protocols: Research Issues in Protocol Development Get access Carolyn Cook Gotay, Carolyn Cook Gotay * EMMES Corporation. Potomac, Md. *Correspondence to : Carolyn Cook Gotay, Ph.D., EMMES Corporation. 11325 Seven Locks Rd., Suite 214, Potomac, MD 20854. Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward L. Korn, Edward L. Korn Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer InstituteBethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary S. McCabe, Mary S. McCabe Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer InstituteBethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar Timothy D. Moore, Timothy D. Moore Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer InstituteBethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar Bruce D. Cheson Bruce D. Cheson Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer InstituteBethesda, Md. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 8, 15 April 1992, Pages 575–579, https://doi.org/10.1093/jnci/84.8.575 Published: 15 April 1992 Article history Received: 10 September 1991 Revision received: 15 November 1991 Accepted: 06 January 1992 Published: 15 April 1992
Effects of a Na+/Ca2+ exchanger inhibitor on pulmonary vein electrical activity and ouabain-induced arrhythmogenicity
Authors: W WONGCHAROEN, Y CHEN, Y CHEN, C CHANG, H YEH, C LIN, S CHEN
Journal: Cardiovascular Research (2006)

Pulmonary veins (PVs) are the most important focus for generation of atrial fibrillation. The Na(+)/Ca(2+) exchange (NCX) current is important in PV electrical activity and cardiac glycosides-induced arrhythmias. The purpose of this study was to investigate whether KB-R7943, a NCX current blocker with preferential inhibition of the Ca(2+) influx, may alter PV electrophysiological characteristics and reduce glycoside-induced arrhythmogenicity.Conventional microelectrodes were used to record the effects of KB-R7943 on action potentials and contractility in isolated rabbit PV tissue specimens with and without administration of ouabain. The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes before and after KB-R7943 by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.KB-R7943 (0, 3, 10, 30 microM) concentration-dependently prolonged APD(50) and APD(90) and decreased the PV firing rates (2.3 +/- 1.2 Hz, 2.1 +/- 1.2 Hz, 1.9 +/- 0.9 Hz, 1.7 +/- 1.1 Hz, n = 7, p < 0.05) and incidences of delayed afterdepolarizations (DADs). KB-R7943 (3, 30 microM) decreased transient inward currents, Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content. Ouabain (0, 0.1, 1 microM) concentration-dependently increased the PV firing rates and DADs in PVs with spontaneous activity (n = 7) and induced nonsustained spontaneous activity (1 microM) in the PVs without spontaneous activity (n = 14). However, in the presence of KB-R7943 (30 microM), ouabain (1 microM) did not increase the PV firing rates or induce spontaneous activity in the PVs without spontaneous activity (n = 7).KB-R7943 reduces the PV arrhythmogenic activity and prevents the ouabain-induced arrhythmogenicity. Our findings support the role of the NCX current in the PV electrical activity.
Ileal dysfunction in Crohn's disease assessed by the postprandial serum bile acid response.
Authors: F S Suchy, W F Balistreri
Journal: Gut (1981)

We assessed ileal functional integrity in 20 consecutive patients with Crohn's disease by sequential measurement of the postprandial serum bile acid concentration. In all 14 patients with active Crohn's disease involving the terminal ileum, the mean (+/- SEM) peak response in the cholylglycine (0.4 +/- 0.04 mumol/l, n = 14) as well as in the total serum bile acid concentration (2.0 +/- 0.4 mumol/l, n = 10) was similar to that seen in a group of children who had undergone ileal resection. A significantly greater increase in the cholylglycine (1.8 +/- 0.18 mumol/l, n = 16, P less than 0.01) and in the total serum bile acid concentration (9.8 +/- 2.4 mumol/l, n = 11, P less than 0.025) was noted in normal children. In five of the six remaining patients (three with Crohn's disease shown not to involve the ileum and two of three with asymptomatic, treated Crohn's ileitis) and in seven patients with ulcerative colitis, the meal stimulated responses were normal. These preliminary results suggest that measurement of the serum bile concentration after a meal stimulus may provide a valuable index of ileal inflammation in patients with Crohn's disease.
The discovery, positioning and verification of a set of transcription-associated motifs in vertebrates.
Authors: Laurence Ettwiller, Benedict Paten, Marcel Souren, Felix Loosli, Jochen Wittbrodt, Ewan Birney
Journal: Genome biology (2005)

Abstract We have developed several new methods to investigate transcriptional motifs in vertebrates. We developed a specific alignment tool appropriate for regions involved in transcription control, and exhaustively enumerated all possible 12-mers for involvement in transcription by virtue of their mammalian conservation. We then used deeper comparative analysis across vertebrates to identify the active instances of these motifs. We have shown experimentally in Medaka fish that a subset of these predictions is involved in transcription.
Human papillomavirus and squamous cell carcinoma
Authors: T.‐Y. Chuang
Journal: British Journal of Dermatology (2011)

Journal Article Human papillomavirus and squamous cell carcinoma Get access T.‐Y. Chuang T.‐Y. Chuang Department of Dermatology, University of Southern California, Los Angeles and Department of Dermatology, Desert Oasis Healthcare, Palm Springs, CA, U.S.A. E‐mail: chuang004@gmail.com Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 165, Issue 4, 1 October 2011, Pages 708–709, https://doi.org/10.1111/j.1365-2133.2011.10602.x Published: 01 October 2011
Effect of Policosanol on Lipid Levels Among Patients With Hypercholesterolemia or Combined Hyperlipidemia
Authors: Heiner K. Berthold, Susanne Unverdorben, Ralf Degenhardt, Michael Bulitta, Ioanna Gouni-Berthold
Journal: JAMA (2006)

Policosanol is a natural substance derived from sugar cane that is advertised for its lipid-lowering effects as a nonprescription drug. More than 80 placebo-controlled or comparative trials, performed mostly by a single research institute, suggest that policosanol at doses of 5 to 40 mg/d has lipoprotein-lowering effects comparable with statins.To determine the lipoprotein-lowering effects of Cuban sugar cane-derived policosanol and to establish, if effective, dose-dependency up to 80 mg/d in patients with hypercholesterolemia or combined hyperlipidemia.A multicenter (lipid outpatient clinics and general practitioners in Germany), randomized, double-blind, placebo-controlled, parallel-group trial conducted from September 29, 2000, to May 10, 2001, of patients with hypercholesterolemia or combined hyperlipidemia having baseline low-density lipoprotein cholesterol (LDL-C) levels of at least 150 mg/dL (> or =3.88 mmol/L) and either no or 1 cardiovascular risk factor other than known coronary heart disease, or baseline LDL-C levels of between 150 and 189 mg/dL (3.88-4.89 mmol/L) and 2 or more risk factors.Open-label 6-week placebo and diet run-in phase followed by a double-blind 12-week treatment phase after randomization to 5 groups: 10, 20, 40, or 80 mg/d of policosanol or placebo.The percentage change of LDL-C, with changes in other lipoproteins as secondary outcome measures.A total of 143 patients were randomized to 5 equal groups and were analyzed on an intention-to-treat basis. In none of the 5 treatment groups did LDL-C levels decrease more than 10% from baseline. No statistically significant difference between policosanol and placebo was observed. A nonparametric test analyzing dose-dependency yielded nonsignificant results. In none of the secondary outcome measures, namely total cholesterol, high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and ratio of total or LDL-C to HDL-C, were there any significant effects of policosanol. Policosanol was tolerated well without serious adverse events.In patients with hypercholesterolemia or combined hyperlipidemia, the sugar cane-derived policosanol in usual and high doses does not demonstrate a reduction in lipid levels beyond placebo.clinicaltrials.gov Identifier: NCT00288483.