tbuckley/cabot-search huggingface dataset:
Hepatitis B virus X protein accelerates hepatocarcinogenesis with partner survivin through modulating miR-520b and HBXIP
Authors: Weiying Zhang, Zhanping Lu, Guangyao Kong, Yuen Gao, Tao Wang, Qi Wang, Na Cai, Honghui Wang, Fabao Liu, Lihong Ye, Xiaodong Zhang
Journal: Molecular Cancer (2014)

Hepatitis B virus X protein (HBx) plays crucial roles in hepatocarcinogenesis. However, the underlying mechanism remains elusive. We have reported that HBx is able to up-regulate survivin in hepatocellular carcinoma tissues. The oncopreotein hepatitis B X-interacting protein (HBXIP), a target of miR-520b, is involved in the development of cancer. In this study, we focus on the investigation of hepatocarcinogenesis mediated by HBx. The expression of HBx and survivin was examined in the liver tissues of HBx-Tg mice. The effect of HBx/survivin on the growth of LO2-X-S cells was determined by colony formation and transplantation in nude mice. The effect of HBx/survivin on promoter of miR-520b was determined by Western blot analysis, luciferase reporter gene assay, co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP), respectively. The expression of HBx, survivin and HBXIP was detected by immunohistochemistry and real-time PCR in clinical HCC tissues, respectively. The DNA demethylation of HBXIP promoter was examined. The functional influence of miR-520b and HBXIP on proliferation of hepatoma cells was analyzed by MTT, colony formation, EdU and transplantation in nude mice in vitro and in vivo. In this study, we provided evidence that HBx up-regulated survivin in the liver cancer tissues of HBx-Tg mice aged 18 M. The engineered LO2 cell lines with survivin and/or HBx were successfully established, termed LO2-X-S. MiR-520b was down-regulated in LO2-X-S cells and clinical HCC tissues. Our data revealed that HBx survivin-dependently down-regulated miR-520b through interacting with Sp1 in the cells. HBXIP was highly expressed in LO2-X-S cells, liver cancer tissues of HBx-Tg mice aged 18 M and clinical HCC tissues (75.17%, 112/149). The expression level of HBXIP was positively associated with those of HBx or survivin in clinical HCC tissues. In addition, we showed that HBx survivin-dependently up-regulated HBXIP through inducing demethylation of HBXIP promoter in LO2-X-S cells and clinical HCC tissues. In function, low level miR-520b and high level HBXIP mediated by HBx with partner survivin contributed to the growth of LO2-X-S cells in vitro and in vivo. HBx accelerates hepatocarcinogenesis with partner survivin through modulating tumor suppressor miR-520b and oncoprotein HBXIP.
Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria
Authors: M. Yoshida
Journal: Journal of Clinical Investigation (2006)

The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. Selective expression of FcRn in the epithelium is shown here to be associated with secretion of IgG into the lumen that allows for defense against an epithelium-associated pathogen (Citrobacter rodentium). This pathway of host resistance to a bacterial pathogen as mediated by FcRn involves retrieval of bacterial antigens from the lumen and initiation of adaptive immune responses in regional lymphoid structures. Epithelial-associated FcRn, through its ability to secrete and absorb IgG, may thus integrate luminal antigen encounters with systemic immune compartments and as such provide essential host defense and immunoregulatory functions at the mucosal surfaces.
Renal Failure in Cirrhosis
Authors: Pere Ginès, Robert W. Schrier
Journal: New England Journal of Medicine (2009)

Renal failure, a challenging complication of cirrhosis, is one of the most important risk factors for liver transplantation. In recent years, substantial progress has been made toward understanding the pathogenesis and natural history of renal failure in cirrhosis. This review discusses recently identified information about renal failure in cirrhosis and clinical interventions that may assist in the prevention and management of this complication.
Proliferation and Migration of Label-Retaining Cells of the Kidney Papilla
Authors: Juan A. Oliver, Apostolos Klinakis, Faisal H. Cheema, Jonathan Friedlander, Rosemary V. Sampogna, Timothy P. Martens, Charles Liu, Argiris Efstratiadis, Qais Al-Awqati
Journal: Journal of the American Society of Nephrology (2009)

The kidney papilla contains a population of cells with several characteristics of adult stem cells, including the retention of proliferation markers during long chase periods (i.e., they are label-retaining cells [LRCs]). To determine whether the papillary LRCs generate new cells in the normal adult kidney, we examined cell proliferation throughout the kidney and found that the upper papilla is a site of enhanced cell cycling. Using genetically modified mice that conditionally expressed green fluorescence protein fused to histone 2B, we observed that the LRCs of the papilla proliferated only in its upper part, where they associate with "chains" of cycling cells. The papillary LRCs decreased in number with age, suggesting that the cells migrated to the upper papilla before entering the cell cycle. To test this directly, we marked papillary cells with vital dyes in vivo and found that some cells in the kidney papilla, including LRCs, migrated toward other parts of the kidney. Acute kidney injury enhanced both cell migration and proliferation. These results suggest that during normal homeostasis, LRCs of the kidney papilla (or their immediate progeny) migrate to the upper papilla and form a compartment of rapidly proliferating cells, which may play a role in repair after ischemic injury.
Pharmacokinetics and Toxicity of Weekly Docetaxel in Older Patients
Authors: Arti Hurria, Mark T. Fleming, Sharyn D. Baker, Wm. Kevin Kelly, Katie Cutchall, Katherine Panageas, James Caravelli, Henry Yeung, Mark G. Kris, Jorge Gomez, Vincent A. Miller, Gabriella D'Andrea, Howard I. Scher, Larry Norton, Clifford Hudis
Journal: Clinical Cancer Research (2006)

Abstract Purpose: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy. Experimental Design: Twenty patients ages ≥65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board–approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel. Results: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade ≥3 toxicity: 16% (3 of 19) grade ≥3 hematologic toxicity, and 53% (10 of 19) grade ≥3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade ≥3 toxicity. Conclusions: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade ≥3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.
Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study
Authors: J.-L. Faillie, L. Azoulay, V. Patenaude, D. Hillaire-Buys, S. Suissa
Journal: BMJ (2014)

To determine whether the use of incretin based drugs, compared with sulfonylureas, is associated with an increased risk of acute pancreatitis.Population based cohort study.680 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink.From 1 January 2007 to 31 March 2012, 20 748 new users of incretin based drugs were compared with 51 712 users of sulfonylureas and followed up until 31 March 2013.Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for acute pancreatitis in users of incretin based drugs compared with users of sulfonylureas. Models were adjusted for tenths of high dimensional propensity score (hdPS).The crude incidence rate for acute pancreatitis was 1.45 per 1000 patients per year (95% confidence interval 0.99 to 2.11) for incretin based drug users and 1.47 (1.23 to 1.76) for sulfonylurea users. The rate of acute pancreatitis associated with the use of incretin based drugs was not increased (hdPS adjusted hazard ratio: 1.00, 95% confidence interval 0.59 to 1.70) relative to sulfonylurea use.Compared with use of sulfonylureas, the use of incretin based drugs is not associated with an increased risk of acute pancreatitis. While this study is reassuring, it does not preclude a modest increased risk, and thus additional studies are needed to confirm these findings.
Peptidylarginine Deiminase Inhibition Reduces Vascular Damage and Modulates Innate Immune Responses in Murine Models of Atherosclerosis
Authors: Jason S. Knight, Wei Luo, Alexander A. O’Dell, Srilakshmi Yalavarthi, Wenpu Zhao, Venkataraman Subramanian, Chiao Guo, Robert C. Grenn, Paul R. Thompson, Daniel T. Eitzman, Mariana J. Kaplan
Journal: Circulation Research (2014)

Rationale: Neutrophil extracellular trap (NET) formation promotes vascular damage, thrombosis, and activation of interferon-α–producing plasmacytoid dendritic cells in diseased arteries. Peptidylarginine deiminase inhibition is a strategy that can decrease in vivo NET formation. Objective: To test whether peptidylarginine deiminase inhibition, a novel approach to targeting arterial disease, can reduce vascular damage and inhibit innate immune responses in murine models of atherosclerosis. Methods and Results: Apolipoprotein-E (Apoe ) −/− mice demonstrated enhanced NET formation, developed autoantibodies to NETs, and expressed high levels of interferon-α in diseased arteries. Apoe −/− mice were treated for 11 weeks with daily injections of Cl-amidine, a peptidylarginine deiminase inhibitor. Peptidylarginine deiminase inhibition blocked NET formation, reduced atherosclerotic lesion area, and delayed time to carotid artery thrombosis in a photochemical injury model. Decreases in atherosclerosis burden were accompanied by reduced recruitment of netting neutrophils and macrophages to arteries, as well as by reduced arterial interferon-α expression. Conclusions: Pharmacological interventions that block NET formation can reduce atherosclerosis burden and arterial thrombosis in murine systems. These results support a role for aberrant NET formation in the pathogenesis of atherosclerosis through modulation of innate immune responses.
Motive in Medical Demobilization
Authors: H. G. Estcourt
Journal: BMJ (1946)

We explored working and living with cancer at a large research-intensive National Health Service hospital breast cancer service and adjoining non-governmental organisation (NGO). The project had three elements that were largely autonomous in practice but conceptually integrated through a focus on personalised cancer medicine. Di Sherlock held conversations with staff and patients from which she produced a collection of poems, <i>Written Portraits</i>. At the same time, we conducted interviews and observation in the hospital, and hosted a public series of science cafés in the NGO. The trajectory of this project was not predetermined, but we found that the poetry residency provided a context for viewing participation in experimental cancer care and vice versa. Taking themes from the poetry practice, we show how they revealed categories of relevance to participants and illuminated others that circulated in the hospital and NGO. Reciprocally, turning to findings from long-term ethnographic research with patients, we show that their observations were not only representations but also tools for navigating life in waiting with cancer. The categories that we discovered and assembled about living and working with cancer do not readily combine into an encompassing picture, we argue, but instead provide alternating perspectives. Through analysis of different forms of research participation, we hope to contribute to an understanding of how categories are made, recognised and inhabited through situated comparisons. In personalised medicine, category-making is enabled if not dependent on increasingly intensive computation and so the practices seem far removed from mundane processes of interaction. Yet, we emphasise connections with everyday practices, in which people categorise themselves and others routinely according to what they like and resemble.
Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome
Authors: H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, R. S. Kass
Journal: Circulation (2000)

Multiple mutations of SCN5A, the gene that encodes the human Na(+) channel alpha-subunit, are linked to 1 form of the congenital long-QT syndrome (LQT-3). D1790G (DG), an LQT-3 mutation of the C-terminal region of the Na(+) channel alpha-subunit, alters steady-state inactivation of expressed channels but does not promote sustained Na(+) channel activity. Recently, flecainide, but not lidocaine, has been found to correct the disease phenotype, delayed ventricular repolarization, in DG carriers.To understand the molecular basis of this difference, we studied both drugs using wild-type (WT) and mutant Na(+) channels expressed in HEK 293 cells. The DG mutation conferred a higher sensitivity to lidocaine (EC(50), WT=894 and DG=205 micromol/L) but not flecainide tonic block in a concentration range that is not clinically relevant. In contrast, in a concentration range that is therapeutically relevant, DG channels are blocked selectively by flecainide (EC(50), WT=11.0 and DG=1.7 micromol/L), but not lidocaine (EC(50), WT=318.0 and DG=176 micromol/L) during repetitive stimulation.These results (1) demonstrate that the DG mutation confers a unique pharmacological response on expressed channels; (2) suggest that flecainide use-dependent block of DG channels underlies its therapeutic effects in carriers of this gene mutation; and (3) suggest a role of the Na(+) channel alpha-subunit C-terminus in the flecainide/channel interaction.
Distinctive Clinical Profile of Blacks Versus Whites Presenting With Sudden Cardiac Arrest
Authors: Kyndaron Reinier, Gregory A. Nichols, Adriana Huertas-Vazquez, Audrey Uy-Evanado, Carmen Teodorescu, Eric C. Stecker, Karen Gunson, Jonathan Jui, Sumeet S. Chugh
Journal: Circulation (2015)

Sudden cardiac arrest (SCA) is a major contributor to mortality, but data are limited among nonwhites. Identification of differences in clinical profile based on race may provide opportunities for improved SCA prevention.
SpliceGrapher: detecting patterns of alternative splicing from RNA-Seq data in the context of gene models and EST data
Authors: Mark F Rogers, Julie Thomas, Anireddy SN Reddy, Asa Ben-Hur
Journal: Genome biology (2012)

We propose a method for predicting splice graphs that enhances curated gene models using evidence from RNA-Seq and EST alignments. Results obtained using RNA-Seq experiments in Arabidopsis thaliana show that predictions made by our SpliceGrapher method are more consistent with current gene models than predictions made by TAU and Cufflinks. Furthermore, analysis of plant and human data indicates that the machine learning approach used by SpliceGrapher is useful for discriminating between real and spurious splice sites, and can improve the reliability of detection of alternative splicing. SpliceGrapher is available for download at http://SpliceGrapher.sf.net.
Relationship between area-level socio-economic deprivation and autoantibody status in patients with rheumatoid arthritis: multicentre cross-sectional study
Authors: Sarah L Mackie, John C Taylor, Sarah Twigg, Stephen G Martin, Sophia Steer, Jane Worthington, Anne Barton, Anthony G Wilson, Lynne Hocking, Adam Young, Paul Emery, Jennifer H Barrett, Ann W Morgan
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> The aims of this study were to assess the association between area-level socio-economic deprivation and the phenotype of rheumatoid arthritis (RA), defined by rheumatoid factor (RF) and anticitrullinated peptide antibody (AC PA) status, and to determine whether any observed association can be explained by smoking. <h3>Methods</h3> The authors performed logistic regression analysis of 6298 patients with RA, defined by American College of Rheumatology classification criteria modified for genetic studies. Analysis was stratified by cohort/recruitment centre. Socio-economic deprivation was measured using the Townsend Index. <h3>Results</h3> Deprivation predicted RF but not ACPA positivity, independent of smoking. The ORs for trend across tertiles, adjusted for smoking, gender, period of birth and cohort/recruitment centre, were 1.14 (95% CI 1.01 to 1.29) for RF and 1.01 (95% CI 0.87 to 1.16) for ACPA. Even after adjusting for deprivation, smoking was strongly associated with ACPA positivity (OR 1.38, 95% CI 1.22 to 1.55). There was no evidence of any effect modification by the RA risk alleles (<i>HLA-DRB1</i> shared epitope and <i>PTPN22</i> rs2476601) that have previously been shown to modify the effect of smoking on ACPA and RF positivity. <h3>Conclusions</h3> Among patients with RA, deprivation predicted RF positivity but not ACPA positivity. The effect of deprivation did not appear to be explained by smoking. Deprivation may be a marker for previously unrecognised, potentially modifiable environmental influences on the immunological phenotype of RA. Furthermore, given the known associations of RF positivity with prognosis and response to treatment in RA, these findings have potential implications for resource allocation and healthcare delivery.
FOLLOW-UP RESULTS IN PSYCHIATRIC ILLNESS
Authors: DONALD W. HASTINGS
Journal: American Journal of Psychiatry (1958)

1. The study considered 1,638 patients consecutively admitted to the psychiatric section of a university hospital. 2. The duration of illness prior to hospitalization, as determined by admission policy, was reasonably short, i.e., they tended to have "acute" illnesses. 3. No "modern" therapies were used. Outcomes are judged to represent spontaneous outcomes. 4. Follow-up was by personal interview within a range of 6-12 years subsequent to hospitalization; 77% of the group were followed up. 5. The criteria were those of social adjustment or lack of it. 6. Results are presented in the tables.
Regulation of constitutive and alternative mRNA splicing across the human transcriptome by PRPF8 is determined by 5′ splice site strength
Authors: Vihandha O. Wickramasinghe, Mar Gonzàlez-Porta, David Perera, Arthur R. Bartolozzi, Christopher R. Sibley, Martina Hallegger, Jernej Ule, John C. Marioni, Ashok R. Venkitaraman
Journal: Genome biology (2015)

Sequential assembly of the human spliceosome on RNA transcripts regulates splicing across the human transcriptome. The core spliceosome component PRPF8 is essential for spliceosome assembly through its participation in ribonucleoprotein (RNP) complexes for splice-site recognition, branch-point formation and catalysis. PRPF8 deficiency is linked to human diseases like retinitis pigmentosa or myeloid neoplasia, but its genome-wide effects on constitutive and alternative splicing remain unclear. Here, we show that alterations in RNA splicing patterns across the human transcriptome that occur in conditions of restricted cellular PRPF8 abundance are defined by the altered splicing of introns with weak 5′ splice sites. iCLIP of spliceosome components reveals that PRPF8 depletion decreases RNP complex formation at most splice sites in exon–intron junctions throughout the genome. However, impaired splicing affects only a subset of human transcripts, enriched for mitotic cell cycle factors, leading to mitotic arrest. Preferentially retained introns and differentially used exons in the affected genes contain weak 5′ splice sites, but are otherwise indistinguishable from adjacent spliced introns. Experimental enhancement of splice-site strength in mini-gene constructs overcomes the effects of PRPF8 depletion on the kinetics and fidelity of splicing during transcription. Competition for PRPF8 availability alters the transcription-coupled splicing of RNAs in which weak 5′ splice sites predominate, enabling diversification of human gene expression during biological processes like mitosis. Our findings exemplify the regulatory potential of changes in the core spliceosome machinery, which may be relevant to slow-onset human genetic diseases linked to PRPF8 deficiency.
The prognostic significance of left ventricular ejection fraction in patients with advanced cancer treated in phase I clinical trials
Authors: R. Said, J. Banchs, J. Wheler, K.R. Hess, G. Falchook, S. Fu, A. Naing, D. Hong, S. Piha-Paul, Y. Ye, E. Yeh, R.A. Wolff, A.M. Tsimberidou
Journal: Annals of Oncology (2013)
Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival.
Authors: J A McCaffrey, M Mazumdar, D F Bajorin, G J Bosl, V Vlamis, R J Motzer
Journal: Journal of Clinical Oncology (1997)

PURPOSE To evaluate the efficacy and toxicity of ifosfamide- and cisplatin-containing chemotherapy as first-line salvage treatment for patients with germ cell tumors (GCT). PATIENTS AND METHODS Fifty-six patients with advanced GCT resistant to one prior cisplatin-containing regimen were treated with a salvage chemotherapy regimen of ifosfamide, cisplatin, and either vinblastine or etoposide (VeIP/VIP). RESULTS Twenty of 56 (36%) assessable patients achieved a complete response (CR). Thirteen (23%) are alive and continuously free of disease at a median follow-up time of 52 months; the median survival duration was 18 months. Among patients with a testis primary tumor site and a prior CR to first-line therapy, 65% are alive and 41% continuously disease-free, and the median survival time has not been reached. In contrast, for patients with an extragonadal primary tumor or with a testis primary tumor site and an incomplete response (IR) to first-line therapy, 31% are alive and 15% continuously free of disease, with a median survival time of 12 months (P &lt; .03). CONCLUSION Ifosfamide- and cisplatin-containing therapy achieves a durable CR in a minority of patients with resistant GCT as first-line therapy. Patients with a primary testis site who relapsed from a CR to first-line cisplatin therapy have a better prognosis than patients with an extragonadal primary tumor site or an IR to first-line therapy. Risk-directed clinical trials to improve response and survival in both subsets are warranted.