tbuckley/cabot-search huggingface dataset:
Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease
Authors: Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2016)

Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1β and of the alarmin IL-1α Dying cells release IL-1α also, independently of the inflammasome. Both IL-1α and IL-1β ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1α/IL-β-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1α/β regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1α/IL-β-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1α/IL-β-IL-1R system in kidney disease should be further explored.
Relieving Inhibition of Prothrombinase By TFPIα: a Procoagulant Activity of Unfractionated, Low Molecular Weight, and Nonanticoagulant Heparins
Authors: Jeremy P Wood, Lisa M Baumann Kreuziger, Rodney M. Camire, Umesh R Desai, Alan E. Mast
Journal: Blood (2014)
P0104 : The liver sinusoid within a microfluidic chamber: A new tool for vascular biology research
Authors: R. Maeso-Díaz, X. Illa, S. Vila, J. Yeste, G. Marrone, M. Navarro-Zornoza, C. Peralta, R. Villa, J. Gracia-Sancho
Journal: Journal of Hepatology (2015)
Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study
Authors: Joachim Sieper, Atul Deodhar, Helena Marzo-Ortega, Jacob A Aelion, Ricardo Blanco, Tseng Jui-Cheng, Mats Andersson, Brian Porter, Hanno B Richards
Journal: Annals of the Rheumatic Diseases (2016)

There is significant unmet need in patients with ankylosing spondylitis (AS) who have inadequate response or intolerance to anti-tumour necrosis factor (TNF) treatment. Secukinumab, an anti-interleukin-17A monoclonal antibody, significantly improved signs and symptoms of AS in the MEASURE 2 study (NCT01649375).Subjects with active AS (N=219) received secukinumab (150 or 75 mg) or placebo at baseline, weeks 1, 2, 3 and 4, and every 4 weeks thereafter. Randomisation was stratified by prior anti-TNF use: anti-TNF-naive or inadequate response/intolerance to one anti-TNF (anti-TNF-IR). The primary endpoint was Assessment of SpondyloArthritis International Society criteria (ASAS) 20 at week 16.At week 16, 68.2% of anti-TNF-naive subjects treated with secukinumab 150 mg achieved ASAS20 compared with 31.1% treated with placebo (p<0.001). In the anti-TNF-IR group, 50.0% of subjects treated with secukinumab 150 mg achieved an ASAS20 response compared with 24.1% treated with placebo (p<0.05). Numerically greater improvements were observed with secukinumab than with placebo for most secondary endpoints. Clinical responses were sustained through week 52.Secukinumab 150 mg provided sustained improvements in signs and symptoms of AS in anti-TNF-naive and anti-TNF-IR subjects through 52 weeks of therapy.NCT01649375.
Risk Factors for Degree and Type of Sequelae After Involution of Untreated Hemangiomas of Infancy
Authors: Eulalia Baselga, Esther Roe, Julien Coulie, Fania Z. Muñoz, Laurence M. Boon, Catherine McCuaig, Angela Hernandez-Martín, Ignasi Gich, Luis Puig
Journal: JAMA Dermatology (2016)

<h3>Importance</h3> Infantile hemangiomas involute to some extent, but they often leave sequelae that may cause disfigurement. Factors determining the risk of permanent sequelae after regression are of crucial importance in treatment decision making. <h3>Objectives</h3> To describe the sequelae left by infantile hemangiomas after natural involution and to identify clinical characteristics that could predict the most severe or a particular type of sequelae. <h3>Design, Setting, and Participants</h3> Multicentric retrospective cohort study of images from 187 infantile hemangiomas that had not received systemic treatment and had follow-up pictures until regression that were selected from photographic files taken between 2003 and 2013 at 4 university hospitals with large vascular clinics in 3 different countries. <h3>Main Outcomes and Measures</h3> Outcome measures were the type of sequelae classified as residual telangiectasia, anetodermal skin, redundant skin, persistent superficial component, and the degree of sequelae ranging from 1 to 4. <h3>Results</h3> A total of 184 hemangiomas were included. The overall incidence of significant sequelae was 101 of 184 (54.9%). The most common sequelae after involution were telangiectasias (145, 84.3%), fibrofatty tissue (81, 47.1%), and anetodermic skin (56, 32.6%). The average age at which hemangioma completed involution was 3.5 years. Superficial and deep hemangiomas left significantly fewer sequelae than combined hemangiomas (Mann-Whitney; superficial vs deep, OR, 1.6; 95% CI, 0.6-3.8;<i>P</i> = .81; superficial vs combined, OR, 3.3; 95% CI, 1.7-6.3;<i>P</i> &lt; .001; deep vs combined, OR, 2.1; 95% CI, 0.9-5.1;<i>P</i> &lt; .001). Hemangiomas with a step or abrupt border of the superficial component left more severe sequelae than those with a smooth border (χ<sup>2</sup><i>,</i>OR, 3.4; 95% CI, 1.8-6.6;<i> P</i> &lt; .001). Superficial hemangiomas with a cobblestone appearance or rough surface left more severe sequelae than those with a smooth surface (Kruskal-Wallis; α, 0.05;<i> P</i> &lt; .001). Using multivariate analysis, combined hemangiomas with a superficial component and a step border were associated with more sequelae. <h3>Conclusions and Relevance</h3> In this retrospective study of sequelae in a large cohort of untreated infants, we quantified the prevalence of permanent scarring and identified clinical features predictive of permanent sequelae. Our observations provide useful information at a time when the treatment paradigm for hemangiomas has changed. Such knowledge may help primary care physicians predict the risk of sequelae and identify high-risk lesions to implement early treatment.
Comparison of two regimes of neoadjuvant chemoradiation in the treatment of rectal tumors: Bolus versus infusional fluorouracil.
Authors: C. A. de Azevedo, T. F. de Paiva, L. A. Costa, C. L. Benevides, R. C. Fogaroli, W. T. Nakagawa, F. N. Santos, L. T. Chinen, M. F. Fanelli, C. L. Mello
Journal: Journal of Clinical Oncology (2010)

e14130 Background: In metastatic rectal cancer, continuous infusion of fluorouracil (cFU) is more effective and less toxic than the bolus regimen. However, the ideal regimen of FU administration concomitant with radiotherapy (RDT) is not well established. There are few direct comparisons of cFU versus bolus FU in the neoadjuvant setting. Methods: We conducted a retrospective analysis of 78 patients with rectal cancer, treated from August/2002 to November/2008, with external beam pelvic radiation (50.4 Gy) concomitant with the following chemotherapeutic regimens: weekly bolus FU 350-425 mg/m2 or 350-380 mg/m2 D1-D5 in the 1º and 5° weeks (group I); or cFU 1 g/m2 D1-D5 during 1º and 5° week (group II). Relapse-free survival (RFS) was the primary endpoint. Pathological response rate was secondary endpoint. Results: Data from 78 patients were analyzed (I/II:55/23). Pretreatment characteristics were: 52% female; median age 55y/52y (I/II); clinical staging approach was: CT scan in 66/56% (I/II), and magnetic resonance in 34/52% (I/II). Clinical T3-T4 69/69% and cN+ 36/43% (I/II). Groups were well balanced. The median interval from RDT to surgery was 1.84 month. Sphincter-sparing surgery was performed in 75/86% (I/II).The proposed RDT was delivered in 94/100% (I/II) of patients and median total delivered FU dose was 2.1 g/10 g (I/II). Patients in group I also received leucovorin 20 mg/m2 in 90.4%. Pathologic T3-T4 was 36/31% (I/II) and pN+ 36/26% (I/II). Pathological complete response (pCR) was achieved in 28.3/9.1% (I/II). There was no significant association between pCR and regimen of treatment (p = 0.13). The median follow-up was 27.4 m, median RFS was not reached. In 2y, RFS was 73% in both groups (p = 0.59). Twenty-six patients relapsed, 1/15 (6%) (two patients were lost for follow up) among those with pCR and 25/56 (44%) (4 patients were lost for follow-up) among those with non-pCR. Conclusions: Pathologic complete response was associated with lower relapses rates in our series. There was no difference in pCR and RFS between bolus and infusional FU. Bolus FU remains a treatment option, associated with radiotherapy, in patients with locally advanced rectal carcinoma. No significant financial relationships to disclose.
Phase II part of EORTC study 26101: The sequence of bevacizumab and lomustine in patients with first recurrence of a glioblastoma.
Authors: Wolfgang Wick, Roger Stupp, Thierry Gorlia, Martin Bendszus, Felix Sahm, Jacoline E Bromberg, Alba Ariela Brandes, Maaike J Vos, Julien Domont, Ahmed Idbaih, Jean-Sebastien Frenel, Paul M. Clement, Michel Fabbro, Emilie Le Rhun, François Dubois, Davide Musmeci, Michael Platten, Vassilis Golfinopoulos, Martin J. Van Den Bent
Journal: Journal of Clinical Oncology (2016)

2019 Background: Both lomustine (LOM) and bevacizumab (BEV) are approved agents for recurrent or progressive glioblastoma. We aimed at evaluating the optimal treatment sequence (single agent vs sequential vscombination) of these agents in a randomized phase II design. Methods: Progressive patients after initial radiotherapy and temozolomide were randomized 2:2:2:1 between Arm 1: LOM 90 mg/m2 (max. 160 mg) every 6 weeks plus BEV (10 mg/kg) every 2 weeks until progression, subsequent salvage treatment at the investigators best choice (MD choice); Arm 2: LOM 110 mg/m2 (max. 200 mg) every 6 weeks, at progression switch to BEV every two weeks; Arm 3: BEV every 2 weeks, at progression add LOM 90 mg/m2 (max. 160 mg) every 6 weeks and continue BEV; and Arm 4: LOM single agent 110 mg/m2 (max. 200 mg) every 6 weeks, at progression MD choice (arm 4). Eligibility criteria included performance status 0-2, adequate hematological, liver and renal function, and an interval since the end of radiotherapy of ≥ 3 months to rule out pseudoprogression. The primary endpoint was overall survival at 12 months (OS12), progression free survival (PFS) was measured from the start of study treatment until 1st PD. Response was locally assessed using RANO criteria. Results: Between Oct 2011 and July 2013 274 patients were randomized. Baseline characteristics were well balanced, and all treatment generally well tolerated. In arm 4, 43% received subsequent salvage BEV. Time to first progression was longer in initially BEV treated patients, but survival was similar in all arms. Conclusions: Initially BEV treated patients had longer PFS, but OS 12 or median OS were similar in the various schedules of BEV and LOM. Following the emergence of the data of the BELOB study, prior to any analysis arms 1 and 4 of this phase II trial were continued as a phase III trial. Clinical trial information: NCT01290939.Study treatment (per protocol population) n OS 12 (95% CI) Med OS Med PFS Arm 1: LOM+BEV à MD choice 70 32.9% (25.4, 41.1) 9.1 mo 4.2 mo Arm 2: LOM, à BEV 73 27.4% (20.6, 35.2) 7.8 mo 1.5 mo Arm 3: BEV, à LOM+BEV 70 32.9% (25.4, 41.1) 7.9 mo 2.8 mo Arm 4: LOM, à MD choice 36 41.7% (30.4, 53.7) 9.3 mo 1.6 mo
Effect of fulvestrant on PSA doubling time in patients with castration-resistant prostate cancer (CRPC).
Authors: S. Srinivas, L. C. Harshman, D. Feldman
Journal: Journal of Clinical Oncology (2010)

e15112 Background: While independent of androgens, the growth and proliferation of CRPC cells remain dependent on the presence of androgen receptors (ARs). Estrogens are known to down regulate ARs in prostate cancer cell lines. Fulvestrant, a 7α-alkylsulphinyl analog of 17β-estradiol inhibits AR activity in LNCaP prostate cancer cells, an AR dependent cell line. Treatment of LNCaP cells with fulvestrant reduces AR levels by over 50% compared to vehicle-treated controls. In growth assays, fulvestrant inhibited LNCaP cell growth by 80% compared to controls. These data support the hypotheses that decreasing AR levels with fulvestrant results in reduced growth and PSA expression in AR containing cells. Objectives: To determine the effectiveness of fulvestrant in delaying progression of CRPC as measured by serum PSA, PSA doubling time (PSADT), bone scans and CT scans. Methods: Metastatic or non-metastatic CRPC patients who had progressed after initial combined androgen blockade and ≤1 chemotherapy treatment were eligible. Disease progression was defined as 3 consecutive rises in serum PSA or objective progression by RECIST. Intramuscularfulvestrant (250mg) was given on day 1 and day 14 of the first month followed by monthly injections. After 3 months, patients were evaluated for response. Patients received fulvestrant until disease progression for up to 12 months. Due to no PSA responses (decreases ≥50%), the study was terminated after 10 patients. Results: Ten patients with CRPC were treated from March 2007 to February 2009. Median age was 75 (58-99). Six had radical prostatectomy as primary therapy, 2 had radiation, and 2 had hormonal monotherapy. The majority had ≥2 hormonal therapies. Four patients had prior chemotherapy. There were no serum PSA responses, but 3 patients had PSADT prolongation. One patient had a 2.5 fold prolongation and remained on the drug for 1 year without progression. Therapy was well tolerated with no adverse events. Conclusions: In this heavily pretreated CRPC population, fulvestrant did not result in objective PSA responses or change in measurable disease, but 30% had a PSADT prolongation and one patient had stable disease for at least one year. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Infographic. Physical activity for children and young people
Authors: Hamish Reid, Charlie Foster
Journal: British Journal of Sports Medicine (2016)

Physical activity (PA) levels amongst children and young people in the UK fall short of the Chief Medical Officers' (CMOs) guidelines and continue to decline.1 ,2 This trend is exaggerated in specific groups such as those of low socio-economic status and teenage girls.2 Childhood inactivity has huge implications for physical and psychological development …
Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice
Authors: Hirohisa Okabe, Jing Yang, Kyle Sylakowski, Mladen Yovchev, Yoshitaka Miyagawa, Shanmugam Nagarajan, Maria Chikina, Michael Thompson, Michael Oertel, Hideo Baba, Satdarshan P Monga, Kari Nichole Nejak‐Bowen
Journal: Hepatology (2016)

Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate‐tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling. First we identify up‐regulation of specific Wnt proteins in the cholangiocytes. Next, using conditional knockouts of Wntless and Wnt coreceptors low‐density lipoprotein‐related protein 5/6, transgenic mice expressing stable β‐catenin, and in vitro studies, we show a role of Wnt signaling through β‐catenin in hepatocyte to biliary transdifferentiation. Last, we show that specific Wnts regulate cholangiocyte proliferation, but in a β‐catenin‐independent manner. Conclusion: Wnt signaling regulates hepatobiliary repair after cholestatic injury in both β‐catenin‐dependent and ‐independent manners. (H epatology 2016;64:1652‐1666)
Identification of thymosin beta 15 A (TMSB15A) mRNA expression as a predictor for response to neoadjuvant chemotherapy in patients with operable breast cancer.
Authors: S. Darb-Esfahani, R. Kronenwett, G. Von Minckwitz, S. Kuemmel, J. Budczies, A. Rody, M. Gehrmann, C. Denkert, A. Du Bois, S. Loibl
Journal: Journal of Clinical Oncology (2010)

10514 Background: Novel biomarkers for prediction of a pathological complete response (pCR) in neoadjuvant chemotherapy for breast cancer are needed. Thymosin beta 15 is a small peptide with essential functions in the regulation of actin polymerization and immune response, as shown in various cancer cell lines. Methods: TMSB15A isoform mRNA expression in fresh-frozen preoperative biopsies of patients from the neoadjuvant GeparTrio trial (TAC; n = 55) as well as in cultured tumor cells was determined by Affymetrix array analysis. Kinetic RT-PCR was used to investigate mRNA expression in formalin-fixed, paraffin-embedded (FFPE) biopsies from the GeparTrio (n = 257) and the GeparQuattro trial (neoadjuvant EC-Doc or EC-DocX; n = 392). Results: TMSB15A mRNA expression was identified as a positive predictor for pCR in frozen tumor tissue from GeparTrio by a ROC analysis (p = 0.0042, auc = 0.824). In FFPE tissue from GeparTrio, TMSB15A mRNA expression again showed significant predictive impact: OR = 7.583, 95% CI = 3.798-15.139, p < 0.0001, pCR rate 41.3% vs. 8.5%. This finding was validated in the GeparQuattro cohort: OR = 3.829, 95% CI = 2.138-6.854, p < 0.0001, pCR rate 26.2% vs. 8.5%. In multivariate analysis, TMSB15A expression was predictive independently from cT, cN, histology, grading, hormone receptor expression, and age in both FFPE cohorts. A relationship between TMSB15A mRNA expression and response was further detected in cultured triple-negative Cal51 cells that revealed a strong down-regulation of TMSB15A after induction of secondary paclitaxel resistance (p = 0.004), an effect which was not seen in luminal MCF7 and HER2-positive HCC1954 cells, which primarily showed a low-level expression of TMSB15A. Conclusions: Using a training-test approach in two well-characterized cohorts of patients with operable breast cancer as well as cell culture, we identified TMSB15A mRNA expression as a promising candidate biomarker for response to neoadjuvant chemotherapy with anthracycline/taxane. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Siemens Healthcare Diagnostics AstraZeneca Siemens Healthcare Diagnostics AstraZeneca
Hypertension: Mechanisms, Diagnosis, and Treatment.
Journal: Annals of Internal Medicine (1979)

hypertension mechanisms diagnosis and treatment is available in our book collection an online access to it is set as public so you can download it instantly. Our book servers saves in multiple locations, allowing you to get the most less latency time to download any of our books like this one. Merely said, the hypertension mechanisms diagnosis and treatment is universally compatible with any devices to read.
Gene name errors are widespread in the scientific literature
Authors: Mark Ziemann, Yotam Eren, Assam El-Osta
Journal: Genome biology (2016)

The spreadsheet software Microsoft Excel, when used with default settings, is known to convert gene names to dates and floating-point numbers. A programmatic scan of leading genomics journals reveals that approximately one-fifth of papers with supplementary Excel gene lists contain erroneous gene name conversions.
Sixty seconds on . . . the £20 000 golden hello
Authors: Anne Gulland
Journal: BMJ (2016)

You need to contact NHS Scotland, which is offering a £20 000 (€23 000; $26 000) incentive to doctors who sign up to one of 37 places in unpopular locations in its GP training scheme.1 Hurry, though: you have only until 25 August to apply.

There doesn’t seem to be one. The payment will be made in a lump sum after trainees have …
Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure
Authors: Jose L. Sanchez-Alonso, Anamika Bhargava, Thomas O’Hara, Alexey V. Glukhov, Sophie Schobesberger, Navneet Bhogal, Markus B. Sikkel, Catherine Mansfield, Yuri E. Korchev, Alexander R. Lyon, Prakash P. Punjabi, Viacheslav O. Nikolaev, Natalia A. Trayanova, Julia Gorelik
Journal: Circulation Research (2016)

Disruption in subcellular targeting of Ca(2+) signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias.To explore microdomain-targeted remodeling of ventricular L-type Ca(2+) channels (LTCCs) in HF.Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034±0.011 versus 0.154±0.027, P<0.001). High open probability was linked to enhance calcium-calmodulin kinase II-mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias.Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electric remodeling in HF and adds a new dimension to cardiovascular disease.
No Evidence That Azathioprine Increases Risk of Cholangiocarcinoma in Patients With Primary Sclerosing Cholangitis
Authors: Roman Zenouzi, Tobias J. Weismüller, Kristin K. Jørgensen, Michael Bubenheim, Henrike Lenzen, Peter Hübener, Kornelius Schulze, Christina Weiler-Normann, Marcial Sebode, Hanno Ehlken, Nadine Pannicke, Johannes Hartl, Moritz Peiseler, Sina Hübener, Tom H. Karlsen, Kirsten M. Boberg, Michael P. Manns, Ansgar W. Lohse, Christoph Schramm
Journal: Clinical Gastroenterology and Hepatology (2016)
Immunoglobulin Heavy Chain (IGH) Gene Rearrangement In Waldenström Macroglobulinemia and Other Monoclonal IgM Disorders
Authors: Marzia Varettoni, Silvia Zibellini, Luca Arcaini, Ester Orlandi, Cristiana Pascutto, Emanuela Boveri, Alessandro Corso, Francesco Passamonti, Silvia Mangiacavalli, Silvia Rizzi, Lara Pochintesta, Marco Paulli, Enrica Morra, Mario Lazzarino
Journal: Blood (2010)
Hypothermic Oxygenated Dual Machine Perfusion after Cold Preservation Improves Viability and Hepatobiliary Function of Human Donor Livers by Restoring ATP content
Authors: Alix Matton, Negin Karimian, Andrie Westerkamp, Rianne van Rijn, Paria Mahboub, Janneke Wiersema-Buist, Sanna op den Dries, Ton Lisman, Robert J. Porte
Journal: Hepatology (2014)