tbuckley/cabot-search huggingface dataset:
Pathogenic factors in cirrhosis with and without hepatocellular carcinoma: A multicenter Italian study
Authors: Carlo De Bac, Tommaso Stroffolini, Giovanni B. Gaeta, Gloria Taliani, Giuseppe Giusti
Journal: Hepatology (1994)

We designed a multicenter cross-sectional study to evaluate the role of alcohol abuse, the hepatitis viruses and other pathogenic factors in cirrhosis and hepatocellular carcinoma. A total of 1,829 consecutive cirrhosis patients, with or without HCC, was enrolled over 6 mo in 21 centers throughout Italy. The etiological categories and diagnostic criteria were preestablished. The median age of the patients was 59 yr (range, 13 to 85 yr); 63.6% of the patients were graded as Child class A, 23.4% as Child class B and 13% as Child class C. Hepatitis C virus antibodies were found in 72.1% of cases (47.7% alone, 21.2% with alcohol abuse, 3.2% with hepatitis B virus); HBsAg was present in 13.8% (4.2% alone, 3.2% with hepatitis D virus, 3.2% with hepatitis C virus, 3% with alcohol abuse), alcohol abuse with no concomitant viral infection was recorded in 8.7%, primary biliary cirrhosis was found in 1.8%, other causes were found in 1.4% and cryptogenic cirrhosis was only present in 5.3%. Hepatocellular carcinoma was detected in 11.9% of patients (217 cases). The presence of hepatocellular carcinoma was more frequent in males than females (14.7% vs. 7.3%; p < 0.001) and increased with worsening Child class (8.3% in Child class A, 16.9% in Child class B, 19.9% in Child class C, p < 0.001). The highest prevalences of hepatocellular carcinoma were observed in hepatitis B virus infection, with or without alcohol abuse (20% and 16%, respectively) and in hepatitis C virus cirrhosis, with or without alcohol abuse (16% and 10.3%, p < 0.005). Our data indicate chronic viral infection to be responsible for most cirrhosis and hepatocellular carcinoma in Italy. This finding may aid development of guidelines for prevention programs. (Hepatology 1994;20:1225–1230).
Enhanced cardiac function in mice overexpressing protein phosphatase Inhibitor-2
Authors: U KIRCHHEFER, H BABA, P BOKNIK, K BREEDEN, N MAVILA, N BRUCHERT, I JUSTUS, M MATUS, W SCHMITZ, A DEPAOLIROACH
Journal: Cardiovascular Research (2005)

Protein phosphatase 1 (PP1) has been implicated in the control of cardiac function. Cardiac specific overexpression of the catalytic subunit, PP1c, results in hypertrophy and depressed contractility.To further address the role of PP1, transgenic mice (TG) were generated that overexpress in heart a functional COOH-terminally truncated form (amino acids 1-140) of the PP1 inhibitor-2 (I-2(140)).The TG hearts show increased levels of I-2(140) mRNA as well as protein and activity. No increase in absolute or relative heart weight was observed, nor any changes in gross pathology or increase in morbidity or mortality in the TG mice. Immunohistochemical and biochemical analyses revealed that expression of the I-2(140) protein is confined to cardiomyocytes where it is mainly localized in the cytosol. The total protein phosphatase (PP) activity was reduced by 80% in TG hearts as compared to wild-type littermates (WT). The PP1c mRNA level was the same in TG and WT, while the protein level was increased by approximately 7-fold in TG animals. The maximal rates of contraction (+dP/dt) and of relaxation (-dP/dt) were increased by 32% and 40%, respectively, in the intact catheterized TG mice compared to WT. However, the maximal contractile response to beta-adrenergic agonists was comparable in hearts from TG and WT mice. In isolated cardiomyocytes of TG mice, Ca2+transient amplitude was increased by 50% under basal conditions and by 60% upon rapid caffeine application. The phospholamban (PLB) protein level was unchanged whereas the basal phosphorylation of PLB at Ser(16) was significantly increased in TG hearts.These results indicate that I-2(140) overexpression results in decreased PP1 activity and enhanced contractility in the heart, underscoring the fundamental role of PP1 in cardiac function.
Molecular mechanisms that control expression of the B lymphocyte antigen receptor complex.
Authors: S A Grupp, R N Mitchell, K L Schreiber, D J McKean, A K Abbas
Journal: The Journal of Experimental Medicine (1995)

The B cell receptor for antigen (BCR) is a complex of membrane immunoglobulin (mIg) and at least two other proteins, Ig alpha (mb-1) and Ig beta (B29). This complex promotes surface expression of the BCR and acts to transduce an activation signal. We have used a system of mu heavy chain constructs transfected into murine B cell lines to probe structure-function relationships in the BCR complex. One mutant mu chain, in which two polar transmembrane residues (Tyr587, Ser588) are replaced with valine, fails to associate with Ig alpha and Ig beta and is incapable of transducing signals as a result of mIg cross-linking. This mutant is expressed on the surface at high levels when transfected into a plasmacytoma line that lacks Ig alpha, whereas wild-type mu is retained in this cell line in the endoplasmic reticulum. Pulse-chase and immunoprecipitation analyses indicate that the mutant is more rapidly released from calnexin than the wild-type mu. Further, transfection of Ig alpha into this Ig alpha-negative cell line allows release of the mu chain from calnexin and surface expression of the BCR. These results identify the transmembrane residues of mu heavy chain that control binding to calnexin and Ig alpha, and suggest that calnexin-dependent intracellular retention is an important control mechanism for expression of the BCR complex.
Health-Related Quality of Life as a Predictor of Mortality Following Coronary Artery Bypass Graft Surgery
Authors: John S. Rumsfeld
Journal: JAMA (1999)

Health-related quality of life has not been evaluated as a predictor of mortality following coronary artery bypass graft (CABG) surgery. Evaluation of health status as a mortality predictor may be useful for preoperative risk stratification.To determine whether the Physical and Mental Component Summary scores from the preoperative Short-Form 36 (SF-36) health status survey predict mortality following CABG surgery after adjustment for known clinical risk variables.Prospective cohort study conducted between September 1992 and December 1996.Fourteen Veterans Affairs hospitals.Of the 3956 patients undergoing CABG surgery only and who were enrolled in the Processes, Structures, and Outcomes of Care in Cardiac Surgery study, the 2480 who completed a preoperative SF-36.All-cause mortality within 180 days after surgery.A total of 117 deaths (4.7%) occurred within 180 days of CABG surgery. The Physical Component Summary of the preoperative SF-36 was a statistically significant risk factor for 6-month mortality after adjustment for known clinical risk factors for mortality following CABG surgery. In multivariate analysis, a 10-point lower SF-36 Physical Component Summary score had an odds ratio (OR) of 1.39 (95% confidence interval [CI], 1.11-1.77; P=.006) for predicting mortality. The SF-36 Mental Component Summary score was not associated with 6-month mortality in multivariate analyses (OR, 1.09; 95% CI, 0.92-1.29; P=.31).The Physical Component Summary score from the preoperative SF-36 is an independent risk factor for mortality following CABG surgery. The baseline Mental Component Summary score does not appear to be predictive of mortality. Preoperative patient self-report of the physical component of health status may be helpful for risk stratification and clinical decision making for patients undergoing CABG surgery.
NAMPT (visfatin), a direct target of hypoxia-inducible factor-2α, is an essential catabolic regulator of osteoarthritis
Authors: Siyoung Yang, Je-Hwang Ryu, Hwanhee Oh, Jimin Jeon, Ji-Sun Kwak, Jin-Hong Kim, Hyun Ah Kim, Churl-Hong Chun, Jang-Soo Chun
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> Hypoxia-inducible factor 2α (HIF-2α), encoded by <i>Epas1</i>, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction. <h3>Methods</h3> The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-<i>Epas1</i> or Ad-<i>Nampt</i> in wild-type, <i>Epas1</i><sup>+/−</sup>, <i>Epas1</i><sup>fl/fl</sup>;<i>Col2a1-Cre</i> and <i>Col2a1-Nampt</i> transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. <h3>Results</h3> We found that the <i>Nampt</i> gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-<i>Nampt; Col2a1-Nampt</i> TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery. <h3>Conclusions</h3> Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.
Stress Ulceration in the Acutely Ill
Authors: John J. Skillman, William Silen
Journal: Annual Review of Medicine (1976)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects
Authors: Laura L. Gathercole, Gareth G. Lavery, Stuart A. Morgan, Mark S. Cooper, Alexandra J. Sinclair, Jeremy W. Tomlinson, Paul M. Stewart
Journal: Endocrine Reviews (2013)

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.
Adolescent BMI Trajectory and Risk of Diabetes versus Coronary Disease
Authors: Amir Tirosh, Iris Shai, Arnon Afek, Gal Dubnov-Raz, Nir Ayalon, Barak Gordon, Estela Derazne, Dorit Tzur, Ari Shamis, Shlomo Vinker, Assaf Rudich
Journal: New England Journal of Medicine (2011)

The association of body-mass index (BMI) from adolescence to adulthood with obesity-related diseases in young adults has not been completely delineated.
Autoantibodies to human asialoglycoprotein receptor in autoimmune-type chronic hepatitis
Authors: Ulrich Treichel, Thomas Poralla, Georg Hess, Michael Manns, Karl-Hermann Meyer Zum Büschenfelde
Journal: Hepatology (1990)

Autoantibodies to the human asialoglycoprotein receptor (anti-h-ASGPR) were studied with a solid-phase ELISA in the sera of 421 patients with inflammatory liver diseases, 288 patients with various other disorders and 31 controls. Anti-h-ASGPR were found predominantly in autoimmune chronic active hepatitis (44 of 88, 50%) and were closely related to inflammatory activity. In a subpopulation of these patients with untreated, biopsy-proven active disease or relapse, 15 of 17 were positive (88%). In contrast, only 11 of 204 patients (5.3%) with viral hepatitis were anti-h-ASGPR receptors-positive (chi 2 analysis; p less than 0.001). We also compared the occurrence of anti-h-ASGPR with antibodies to rabbit and rat asialoglycoprotein receptors in 352 sera. In contrast to the anti-human asialoglycoprotein receptor antibodies (3 of 107), anti-rabbit- or anti-rat-asialoglycoprotein receptor antibodies were found in 21 and 28 of 107 cases of viral hepatitis, indicating that different epitopes were recognized by these sera. In various other diseases anti-human asialoglycoprotein receptor antibodies were rarely found. Some sera from patients with connective-tissue diseases (8 of 73) and primary or secondary liver malignancies (6 of 55) exhibited anti-h-ASGPR. In autoimmune chronic active hepatitis the presence of anti-human asialoglycoprotein receptors did not correlate to other established autoantibody systems. Thus we conclude that anti-human asialoglycoprotein receptor antibodies can serve as diagnostic markers for inflammatory active cases of autoimmune chronic active hepatitis. Immune reactions to the asialoglycoprotein receptor, which is expressed on the hepatocellular membrane as a liver-specific antigen, might contribute to the pathogenesis of autoimmune chronic active hepatitis.
Water-dispersible magnetic carbon nanotubes as T2-weighted MRI contrast agents
Authors: Yue Liu, Timothy C. Hughes, Benjamin W. Muir, Lynne J. Waddington, Thomas R. Gengenbach, Christopher D. Easton, Tracey M. Hinton, Bradford A. Moffat, Xiaojuan Hao, Jieshan Qiu
Journal: Biomaterials (2013)
Thrombotic Stroke and Myocardial Infarction with Hormonal Contraception
Authors: Øjvind Lidegaard, Ellen Løkkegaard, Aksel Jensen, Charlotte Wessel Skovlund, Niels Keiding
Journal: New England Journal of Medicine (2012)

Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting.In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries.A total of 1,626,158 women contributed 14,251,063 person-years of observation, during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 μg was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 μg, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5).Although the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception were low, the risk was increased by a factor of 0.9 to 1.7 with oral contraceptives that included ethinyl estradiol at a dose of 20 μg and by a factor of 1.3 to 2.3 with those that included ethinyl estradiol at a dose of 30 to 40 μg, with relatively small differences in risk according to progestin type. (Funded by the Danish Heart Association.).
Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy
Authors: Carlo Aschele, Domizia Debernardis, Sara Lonardi, Roberto Bandelloni, Stefania Casazza, Silvio Monfardini, Luigi Gallo
Journal: Journal of Clinical Oncology (2004)

To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors.DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin-modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases.Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P =.04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16.Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.
Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type
Authors: Steven Rust, Sandrine Guillard, Kris Sachsenmeier, Carl Hay, Max Davidson, Anders Karlsson, Roger Karlsson, Erin Brand, David Lowne, John Elvin, Matt Flynn, Gene Kurosawa, Robert Hollingsworth, Lutz Jermutus, Ralph Minter
Journal: Molecular Cancer (2013)

The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a 'triple negative' breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options.The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other 'triple negative' breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model.All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated using the anti-CD73 antibody, which bound other 'triple negative' breast cancer cell lines and produced significant tumour growth inhibitory activity in a MDA-MB-231 xenograft model.This study has demonstrated that multiple methods are required to successfully analyse the membranome of a desired cell type. It has also successfully demonstrated that phenotypic antibody screening provides a mechanism for rapidly discovering and evaluating antibody tractable targets, which can significantly accelerate the therapeutic discovery process.
Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib
Authors: Melissa A. Wilson, Fengmin Zhao, Richard Letrero, Kurt D'Andrea, David L. Rimm, John M. Kirkwood, Harriet M. Kluger, Sandra J. Lee, Lynn M. Schuchter, Keith T. Flaherty, Katherine L. Nathanson
Journal: Clinical Cancer Research (2014)

Sorafenib is an inhibitor of VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAF kinases, amongst others. We assessed the association of somatic mutations with clinicopathologic features and clinical outcomes in patients with metastatic melanoma treated on E2603, comparing treatment with carboplatin, paclitaxel ± sorafenib (CP vs.
Bone mineral density and biochemical parameters of bone metabolism in female patients with systemic lupus erythematosus
Authors: K. Redlich
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To evaluate bone mineral density and biochemical parameters of bone metabolism in ambulatory premenopausal female patients with systemic lupus erythematosus (SLE). <h3>METHODS</h3> 30 women who fulfilled the ARA criteria for the classification of SLE were studied. Lumbar and femoral bone mineral density was determined by dual energy<i>x</i> ray absorptiometry. Various laboratory parameters including serum calcium, serum phosphorus, alkaline phosphatase, bone specific isoform of alkaline phophatase, propeptide of type 1 procollagen, deoxypyridinoline excretion, telopeptide of type 1 collagen, serum creatinine, osteocalcin, parathyroid hormone, 25-OH vitamin D, testosterone, progesterone, estradiol, follicle stimulating hormone and luteinotropic hormone were measured. <h3>RESULTS</h3> According to the WHO criteria 39% of all patients with SLE studied had normal bone mineral density, 46% had osteopenia and 15% had osteoporosis at the lumbar spine; at the femoral neck 38.5% had normal bone mineral density, 38.5% had osteopenia and 23% suffered from osteoporosis. Significantly lower osteocalcin levels were found in SLE patients. All other bone resorption and formation markers measured were not statistically different, but higher serum albumin corrected calcium and lower phosphorus values were found in the SLE group. Of all sex hormones tested lower testosterone and higher follicle stimulating hormone concentrations were seen in patients with SLE. <h3>CONCLUSION</h3> A high incidence was found of osteopenia and osteoporosis in premenopausal patients with SLE. Bone diminution in SLE seems to be attributable, at least in part, to decreased bone formation in SLE patients.