tbuckley/cabot-search huggingface dataset:
Natural history of hepatitis C
Authors: Rachel H. Westbrook, Geoffrey Dusheiko
Journal: Journal of Hepatology (2014)

There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1∗0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10–20% of patients over 20–30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1–5% annual risk of HCC and a 3–6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated.
The Binding Site of Acetylcholine Receptor as Visualized in the X-Ray Structure of a Complex between α-Bungarotoxin and a Mimotope Peptide
Authors: Michal Harel, Roni Kasher, Anne Nicolas, J.Mitchell Guss, Moshe Balass, Mati Fridkin, August B. Smit, Katjuša Brejc, Titia K. Sixma, Ephraim Katchalski-Katzir, Joel L. Sussman, Sara Fuchs
Journal: Neuron (2001)
Screening for latent tuberculosis before tumour necrosis factor antagonist therapy
Authors: Richard J. Hewitt, Aran Singanayagam, Saranya Sridhar, Melissa Wickremasinghe, Onn Min Kon
Journal: European Respiratory Journal (2015)

We read with great interest the recent letter by Woodfield et al. [1]. The authors report a retrospective study evaluating the use of either an interferon-γ release assay (IGRA) result or a chest radiograph, alone, as a screening approach for identifying patients with latent tuberculosis (TB) infection (LTBI) before initiating tumour necrosis factor (TNF)-α antagonist therapy. In this study, 353 IGRA-negative patients were commenced on TNF-α antagonists for a variety of inflammatory conditions without further LTBI assessment; one patient subsequently developed active TB. Reliance on interferon-γ release assays alone for screening before anti-TNF therapy may miss patients with latent TB <http://ow.ly/JXx74>
510 THE FORKHEAD BOX A2 TRANSCRIPTION FACTOR REGULATES THE HEPATOTROPHIC PROTEIN ALR (AUGMENTER OF LIVER REGENERATION)
Authors: R. Dayoub, T. Dobner, P. Groitl, W.E. Thasler, C. Hellerbrand, A.K. Bosserhoff, H.J. Schlitt, T.S. Weiss
Journal: Journal of Hepatology (2008)
Reconstructing the Origins and Dispersal of the Polynesian Bottle Gourd (Lagenaria siceraria)
Authors: Andrew C. Clarke, Michael K. Burtenshaw, Patricia A. McLenachan, David L. Erickson, David Penny
Journal: Molecular Biology and Evolution (2006)

The origin of the Polynesian bottle gourd (Lagenaria siceraria), an important crop species in prehistoric Polynesia, has remained elusive. Most recently, a South American origin has been favored as the bottle gourd could have been introduced from this continent with the sweet potato by Polynesian voyagers around A.D. 1,000. To test the hypothesis of an American origin for the Polynesian bottle gourd, we developed seven markers specific to bottle gourd (two chloroplast and five nuclear). The nuclear markers were developed using a new technique where polymorphic inter simple sequence repeat (ISSR) markers are converted into single-locus polymerase chain reaction and sequencing markers—an approach that will be useful for developing markers in other taxa. All seven markers were sequenced in 36 cultivars of bottle gourd from Asia, the Americas, and Polynesia. The results support a dual origin for the Polynesian bottle gourd: the chloroplast markers are exclusively of Asian origin, but the nuclear markers show alleles originating in both the Americas and Asia. Because hybridization of Polynesian bottle gourds with post-European introductions cannot be excluded, ancient DNA from archaeological material will be useful for further elucidating the prehistoric movements of this species in Polynesia. This work has implications not only for the dispersal of the Polynesian bottle gourd but also for the domestication and dispersal of the species as a whole.
EWS/FLI1 Oncogene Activates Caspase 3 Transcription and Triggers Apoptosis <i>In vivo</i>
Authors: Eun Jung Sohn, Hongjie Li, Karen Reidy, Lisa F. Beers, Barbara L. Christensen, Sean Bong Lee
Journal: Cancer Research (2010)

EWS/FLI1 is a fusion gene product generated by a chromosomal translocation t(11;22)(q24;q12) found in Ewing sarcoma. EWS/FLI1 encodes an aberrant transcription factor with oncogenic properties in vitro. Paradoxically, expression of EWS/FLI1 in nontransformed primary cells results in apoptosis, but the exact mechanism remains unclear. In primary mouse embryonic fibroblasts derived from conditional EWS/FLI1 knock-in embryos, expression of EWS/FLI1 resulted in apoptosis with concomitant increase in the endogenous Caspase 3 (Casp3) mRNA. EWS/FLI1 directly bound and activated the CASP3 promoter, whereas small interfering RNA-mediated knockdown of EWS/FLI1 led to a marked decrease in CASP3 transcripts in Ewing sarcoma cell lines. Ectopic expression of EWS/FLI1 resulted in an increased expression of CASP3 protein in heterologous cell lines. Importantly, expression of EWS/FLI1 in the mouse triggered an early onset of apoptosis in kidneys and acute lethality. These findings suggest that EWS/FLI1 induces apoptosis, at least partially, through the activation of CASP3 and show the cell context-dependent roles of EWS/FLI1 in apoptosis and tumorigenesis.
Endothelin B receptor-mediated vasoconstriction induced by endothelin A receptor antagonist
Authors: Yi Zhang, John R. Oliver, John D. Horowitz
Journal: Cardiovascular Research (1998)

Objective: The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evaluate and compare the effects of BQ-123, an ETA receptor antagonist, and bosentan, an ETA and ETB receptor antagonist, on coronary vasomotor tone, left ventricular systolic function and ET-1 efflux in the presence or absence of myocardial ischaemia/reperfusion. Methods: Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 68±2% (±standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate was measured by radioimmunoassay. Results: In non-ischaemic hearts (n=7), BQ-123 (10−6 M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan (10−5 M, n=7) induced no change in perfusion rate. In the absence of ET antagonists (n=16), there was a 22±6% post-ischaemic increase in perfusion flow-rate. BQ-123 (n=5) but not bosentan (n=12) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P<0.05) accentuated and BQ-123 tended to accentuate (P=0.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P<0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 730±188% and 315±81% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan. Conclusions: In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ETA receptors; (2) ETA receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ETB stimulation. Furthermore, the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.
Changes in Red Meat Consumption and Subsequent Risk of Type 2 Diabetes Mellitus
Authors: An Pan, Qi Sun, Adam M. Bernstein, JoAnn E. Manson, Walter C. Willett, Frank B. Hu
Journal: JAMA Internal Medicine (2013)

Red meat consumption has been consistently associated with an increased risk of type 2 diabetes mellitus (T2DM). However, whether changes in red meat intake are related to subsequent T2DM risk remains unknown.To evaluate the association between changes in red meat consumption during a 4-year period and subsequent 4-year risk of T2DM in US adults.Three prospective cohort studies in US men and women.We followed up 26,357 men in the Health Professionals Follow-up Study (1986-2006), 48,709 women in the Nurses' Health Study (1986-2006), and 74,077 women in the Nurses' Health Study II (1991-2007). Diet was assessed by validated food frequency questionnaires and updated every 4 years. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios with adjustment for age, family history, race, marital status, initial red meat consumption, smoking status, and initial and changes in other lifestyle factors (physical activity, alcohol intake, total energy intake, and diet quality). Results across cohorts were pooled by an inverse variance-weighted, fixed-effect meta-analysis.Incident T2DM cases validated by supplementary questionnaires.During 1,965,824 person-years of follow-up, we documented 7540 incident T2DM cases. In the multivariate-adjusted models, increasing red meat intake during a 4-year interval was associated with an elevated risk of T2DM during the subsequent 4 years in each cohort (all P < .001 for trend). Compared with the reference group of no change in red meat intake, increasing red meat intake of more than 0.50 servings per day was associated with a 48% (pooled hazard ratio, 1.48; 95% CI, 1.37-1.59) elevated risk in the subsequent 4-year period, and the association was modestly attenuated after further adjustment for initial body mass index and concurrent weight gain (1.30; 95% CI, 1.21-1.41). Reducing red meat consumption by more than 0.50 servings per day from baseline to the first 4 years of follow-up was associated with a 14% (pooled hazard ratio, 0.86; 95% CI, 0.80-0.93) lower risk during the subsequent entire follow-up through 2006 or 2007.Increasing red meat consumption over time is associated with an elevated subsequent risk of T2DM, and the association is partly mediated by body weight. Our results add further evidence that limiting red meat consumption over time confers benefits for T2DM prevention.
Fifty Additional Cases of Complete Ovariotomy, with Brief Notes of Six Other Cases of Abdominal Section
Authors: J. K. Thornton
Journal: BMJ (1878)

IN MayI877, I brought before the Society a table of twenty-five cases Council did me the honour to publish that which accompanied it, in the Transactions I now place before the profession, contains complete ovariotomies, and the two together May 1878.With the presenit table, also some particulars of six other cases, which, of hysterotomy already published (Medical Times
Current status of bronchoscopic lung volume reduction with endobronchial valves
Authors: Pallav L Shah, Felix J F Herth
Journal: Thorax (2013)

<h3>Introduction</h3> Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Emphysema is a component of COPD characterised by hyperinflation resulting in reduced gas exchange and interference with breathing mechanics. Endoscopic lung volume reduction using one-way valves to induce atelectasis of the hyperinflated lobe has been developed and studied in clinical trials over the last decade. <h3>Methods</h3> Searches for appropriate studies were undertaken on PubMed and Clinical Trials Databases using the search terms COPD, emphysema, lung volume reduction and endobronchial valves. <h3>Results</h3> The evidence from the randomised clinical trials suggests that complete lobar occlusion in the absence of collateral ventilation or where there is an intact lobar fissure are the key predictors for clinical success. Other indicators are greater heterogeneity in disease distribution between upper and lower lobes. The proportion of patients that respond to treatment improves from 20% in the unselected population to 75% with appropriate patient selection. The safety profile for endobronchial valves in this severely affected group of patients with emphysema was acceptable and the main adverse events observed were an excess of pneumothoraces. <h3>Conclusion</h3> Selected patients have the potential of significant benefit in terms of lung function, exercise capacity and possibly even survival. These considerations are essential in-order to maximise patient benefit in a resource-limited environment and also to ensure that beneficial treatments are available for the appropriate patient.
Cardioembolic Source of ST-Segment Elevation Myocardial Infarction
Authors: Owen Mooney, Kapil M. Bhagirath, Nasir Shaikh, Kelly MacDonald, Farrukh Hussain, Iain D.C. Kirkpatrick, Edward Pascoe, Davinder S. Jassal
Journal: Journal of the American College of Cardiology (2009)
A Role for Mac-1 (CDIIb/CD18) in Immune Complex–stimulated Neutrophil Function In Vivo: Mac-1 Deficiency Abrogates Sustained Fcγ Receptor–dependent Neutrophil Adhesion and Complement-dependent Proteinuria in Acute Glomerulonephritis
Authors: Tao Tang, Alexander Rosenkranz, Karel J.M. Assmann, Michael J. Goodman, Jose-Carlos Gutierrez-Ramos, Michael C. Carroll, Ramzi S. Cotran, Tanya N. Mayadas
Journal: The Journal of Experimental Medicine (1997)

Mac-1 (αmβ2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcγ receptors to facilitate immune complex (IC)–stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1–FcγR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti–glomerular basement membrane (GBM) nephritis in wild-type and Mac-1–deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1– deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1–null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5–12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1–FcγR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1–FcγR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3–deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1–null mice.
Biological aspects of radiation and drug-eluting stents for the prevention of restenosis
Authors: J SINDERMANN, V VERIN, J HOPEWELL, H RODEMANN, J HENDRY
Journal: Cardiovascular Research (2004)

Based on recent advances, this article aims to review the biological basis for the use of either radiation or drug-eluting stents for the prevention of restenosis, and to elucidate the complementary role that they may play in the future. Vascular restenosis is a multifactorial process primarily driven by the remodeling of the arterial wall, as well as by the hyperproliferation of smooth muscle cells (SMC). These pathophysiological features are the target of therapeutic strategies aimed at inhibiting constrictive remodeling as well as inhibiting SMC proliferation. The success of radiation as well as anti-proliferative drugs such as paclitaxel and sirolimus lies in the primary and/or multifactorial inhibition of cell proliferation. Radiation has the additional feature of preventing constrictive remodeling while sirolimus has the potential property of being anti-inflammatory, which may be a desirable feature. The effects of radiation are not reliant on any uptake and "metabolism" by the target cells, as in the case with drugs, and thus radiation potentially may be more effective as a result of its more-direct action. However, radiation does have some significant drawbacks compared to drug-eluting stents, including a much delayed re-endothelialization resulting in the need for prolonged anti-platelet therapy. Based on recent clinical data, drug-eluting stents have been shown to markedly reduce the likelihood of restenosis, which actually favors this approach for the prevention of restenosis. From a biological perspective, drug-eluting stents and radiation have certain differences, which are reviewed in this article.
PREPARATION OF THE TYPE-SPECIFIC POLYSACCHARIDE OF THE TYPE I MENINGOCOCCUS AND A STUDY OF ITS EFFECTIVENESS AS AN ANTIGEN IN HUMAN BEINGS
Authors: Elvin A. Kabat, Hilda Kaiser, Helen Sikorski
Journal: The Journal of Experimental Medicine (1944)

1. Methods for preparing small amounts of Type I meningococcal polysaccharide which are electrophoretically homogeneous and contain only traces of other immunologically reactive material are given. 2. These polysaccharides are very poor antigens in man but in a small number of instances definite amounts of precipitin and protective antibody were formed. 3. The significance of these findings is discussed.
Identification of early molecular markers for breast cancer
Authors: Céline Kretschmer, Anja Sterner-Kock, Friederike Siedentopf, Winfried Schoenegg, Peter M Schlag, Wolfgang Kemmner
Journal: Molecular Cancer (2011)

The ductal carcinoma in situ (DCIS) of the mammary gland represents an early, pre-invasive stage in the development of invasive breast carcinoma. Since DCIS is a curable disease, it would be highly desirable to identify molecular markers that allow early detection. Mice transgenic for the WAP-SV40 early genome region were used as a model for DCIS development. Gene expression profiling was carried out on DCIS-bearing mice and control animals. Additionally, a set of human DCIS and invasive mammary tumors were analyzed in a similar fashion. Enhanced expression of these marker genes in human and murine samples was validated by quantitative RT-PCR. Besides, marker gene expression was also validated by immunohistochemistry of human samples. Furthermore in silico analyses using an online microarray database were performed.In DCIS-mice seven genes were identified that were significantly up-regulated in DCIS: DEPDC1, NUSAP1, EXO1, RRM2, FOXM1, MUC1 and SPP1. A similar up-regulation of homologues of the murine genes was observed in human DCIS samples. Enhanced expression of these genes in DCIS and IDC (invasive ductal carcinoma) was validated by quantitative RT-PCR and immunohistochemistry.By comparing murine markers for the ductal carcinoma in situ (DCIS) of the mammary gland with genes up-regulated in human DCIS-samples we were able to identify a set of genes which might allow early detection of DCIS and invasive carcinomas in the future. The similarities between gene expression in DCIS and invasive carcinomas in our data suggest that the early detection and treatment of DCIS is of utmost relevance for the survival of patients who are at high risk of developing breast carcinomas.
Proteolytic Release of Soluble UL16-Binding Protein 2 from Tumor Cells
Authors: Inja Waldhauer, Alexander Steinle
Journal: Cancer Research (2006)

The MHC class I-related ligands of the immunoreceptor NKG2D are frequently expressed by tumor cells and stimulate tumor immunity mediated by CD8 T cells and natural killer (NK) cells. In humans, NKG2D ligands (NKG2DL) are encoded by the MHC-encoded MIC and non-MHC-encoded UL16-binding protein (ULBP) families of proteins. Recently, we and others showed that tumor cells release soluble MICA (sMICA), thereby counteracting NKG2D-mediated tumor immunosurveillance. Here, we now report that ULBP2 molecules are likewise released from tumor cells in a processed soluble form, and that soluble ULBP2 (sULBP2) can be detected in sera of some patients with hematopoietic malignancies. Tumor cell-derived sULBP2 as opposed to cell-bound ULBP2 does not down-regulate NKG2D on NK cells. Unexpectedly, the glycosylphosphatidylinositol-anchored ULBP2 molecules are not released by phospholipases but by the action of metalloproteases. Proteolytic shedding of both NKG2D ligands MICA and ULBP2 by tumor cells was strongly enhanced after phorbol 12-myristate 13-acetate treatment and paralleled by a markedly reduced susceptibility to NKG2D-mediated cytotoxicity. Shedding of MICA and ULBP2 can be blocked by the same inhibitors, suggesting the involvement of related metalloproteases. Thus, our data suggest that reducing NKG2DL surface densities is due to a common cleavage process executed by metalloproteases that promotes escape of tumors from NKG2D-mediated immunosurveillance.