tbuckley/cabot-search huggingface dataset:
A7.11 IGA autoantigens – a link between the gut and the anti-TNF therapy response in rheumatoid arthritis patients analysed in two independent clinical trials
Authors: Z Konthur, U Nonhoff, MM Wiemkes, J Detert, T Braun, JM Hollidt, GR Burmester, K Skriner
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> So far no mechanism for non response to biologicals targeting TNFα has been described, despite one third of rheumatoid arthritis patients treated are Non-Responder. A link to the gut microbiota and its ability to drive an autoimmune disease (Immunity. 2010, 32(6):815–27) can be made via segmented filamentous bacteria (SFB) that cooperate to generate potent IgA and Th17 cell responses (Immunity. 2014, 40(4):608–20). We investigated the differences in seroreactivity of patients responding and not responding to anti-TNF therapies prior therapy and identified a diagnostically applicable set of IgA autoantigens to identify non response. <h3>Methods</h3> Baseline sera form PREDICT trial treated with Enbrel and patients treated with Humira in the HIT HARD trial (Ann Rheum Dis. 2013, 72(6):844–509) as well as 66 baseline sera from Charité in addition treated with Cimzia and Remicade were investigated on different autoantigens, which were previously identified by protein array screening. The five identified autoantigens (RAB11B, PPP2R1A, KPNB1, COG4, FTFT1) were developed into the pre.mark-TNF ELISA kit by DRDx GmbH. <h3>Results</h3> Biologicals-naïve sera from patients diagnosed with RA according to ACR classification criteria, which were initiated on therapy with TNFalpha inhibitors, were analysed with the pre.mark-TNF ELISA kit. In total, analyses of 203 patients were carried out, of which 162 were clearly defined as Responder and 41 clearly defined as Non-Responder after 6 month treatment. 81% of Non-Responder could be clearly identified with the pre.mark-TNF Test. Currently the assay shows a specificity of 94% within this group of 162 Responder. In detail, 80 baseline serum samples from the PREDICT trial (Enbrel) and 57 samples of the HIT HARD (Humira) trial were analysed. In HIT HARD – an early intervention study – all 3 Non-Responder were identified and the specificity of the assay was 98%. In the PREDICT study, Non-Responder were identified with a sensitivity of 69% and a specificity of 93%. Further analysis revealed that the amount of IgA producing B-cells in the synovia differs significantly between patients, while no difference is seen in IgG producing B-cells. Moreover of local TNF-alpha is produced from IgA B-cells in RA synovial tissue and TNFalpha producing macrophages via IgA stimulation. <h3>Conclusions</h3> These data suggest that non-response to anti-TNFalpha biologicals might be predicted based on frequency and magnitude of autoantibodies to specific IgA autoantigens. SFB can stimulate IgA production and Th17-cell responses and specific local IgA-producing B-cells might be decisive for disease persistence in TNFalpha inhibitor Non-Responder.
Lifetime exposure to cigarette smoking and the development of adult-onset atopic dermatitis
Authors: C.H. Lee, H.Y. Chuang, C.H. Hong, S.K. Huang, Y.C. Chang, Y.C. Ko, H.S. Yu
Journal: British Journal of Dermatology (2010)

Adult-onset atopic dermatitis (AD) has recently been recognized as a distinct disease entity, but its risk factors have not yet been clearly defined. Although gestational and perinatal exposure to tobacco smoking may be associated with the development of classic AD, the association between active/passive smoking and adult-onset AD remains controversial.To determine if exposure to smoking, including environmental tobacco smoke (ETS), is associated with the risk of adult-onset AD.Tobacco smoking and exposure to ETS were measured in a case-control association analysis in 83 patients with physician-diagnosed adult-onset AD and 142 age- and sex-matched controls.Multiple logistic regression analyses showed that, among the potential environmental risk factors, both current and ever smoking were significant risk factors for adult-onset AD [odds ratio (OR) 4·994 and 3·619, respectively], compared with never smoking. Also, packs per year was significantly associated with adult-onset AD (OR 1·058, 95% confidence interval 1·028-1·089), suggesting a lifelong cumulative risk in current smokers. Moreover, nonsmokers with adult-onset AD reported significantly more exposure to ETS.Early and/or current exposure to cigarette smoking may contribute cumulatively to the development of adult-onset AD. Exposure to ETS in childhood is associated with the development of adult-onset AD. Adults should be discouraged from smoking to prevent adult-onset AD in themselves and their family members.
<i>miR-375</i> Is Activated by ASH1 and Inhibits YAP1 in a Lineage-Dependent Manner in Lung Cancer
Authors: Eri Nishikawa, Hirotaka Osada, Yasumasa Okazaki, Chinatsu Arima, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Yasushi Yatabe, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi
Journal: Cancer Research (2011)

Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.
?-Arginine and ?-NAME have no effects on the reendothelialization process after arterial balloon injury
Authors: I Six
Journal: Cardiovascular Research (1999)

Objective: Growth regulatory properties of nitric oxide (NO) in cultured endothelial cells is controversial. The aim of our study was to investigate the effect of l-arginine, the endogenous NO precursor, and l-NAME, an inhibitor of NO synthase on the reendothelialization process after angioplasty. Methods: Fifty-five New Zealand White rabbits underwent denudation of the left iliac artery. After injury the rabbits were randomized in three groups: l-arginine 2.25% (l-arginine, n=19); NG-nitro-l-arginine methyl ester 15 mg/kg/day (l-NAME, n=19); and placebo (controls, n=17). Treatment was solubilized in drinking water. Reendothelialization was evaluated at 4 weeks by macroscopic evaluation of Evans blue staining and endothelial-specific immunostaining (CD-31) on cross sections. Intimal hyperplasia was evaluated by morphometric analysis. Results: Despite a significant increase in plasma arginine (P=0.001) and a reduction in intimal hyperplasia (P=0.003) with l-arginine, neither agent had a significant effect on reendothelialization at 4 weeks (controls=36±4%, l-arginine=43±3%, l-NAME=33±4%; NS). Conclusion: These results suggest that, in spite of previously demonstrated effects on neointimal hyperplasia, the NO pathway does not influence the regrowth of macrovascular endothelial cells in vivo.
Acute and modified rejection of heterotopic canine cardiac allotransplants studied by serial needle biopsy
Authors: P. W Leedham, M. Baum, P. A. Cullum
Journal: Thorax (1971)

Serial histological changes in heterotopic canine cardiac allografts are reported using a percutaneous needle biopsy technique. This procedure can be performed without general anaesthesia or major complications and gives a high success rate (over 98%) with representative sampling of the organ. A pattern of acute rejection is described and compares well with the findings in other orthotopic and heterotopic studies. Histological differences between a group of untreated dogs and a group receiving azathioprine and hydrocortisone, in amounts that would permit subacute rejection in treated human transplants, suggest that immunotherapy causes greater reduction in local cellular immunological activity than in graft necrosis. It is concluded that although major graft damage in acute and subacute rejection appears to be cell mediated other factors may also be concerned in the pathogenesis of graft necrosis.
Cytokine Stimulation of Epithelial Cancer Cells: The Similar and Divergent Functions of IL-4 and IL-13
Authors: Miranda A. Hallett, Katherine T. Venmar, Barbara Fingleton
Journal: Cancer Research (2012)

The Th2 cytokines interleukin (IL)-4 and -13 are acknowledged regulators of lymphocyte proliferation and activation. They have also been well studied in the regulation of various myeloid-derived populations in tumor biology. It has become clear, however, that both cytokines can have direct effects on epithelial tumor cells expressing appropriate receptors. Changes in tumor proliferation, survival, and metastatic capability have all been ascribed to IL-4 and/or IL-13 action. Here, we evaluate the evidence to support direct tumor-promoting roles of these cytokines. We also identify the questions that should be addressed before proceeding with therapeutic approaches based on neutralization of IL-4 or IL-13 pathways.
Intraprocedural Stent Thrombosis During Implantation of Sirolimus-Eluting Stents
Authors: Alaide Chieffo, Erminio Bonizzoni, Dejan Orlic, Goran Stankovic, Renata Rogacka, Flavio Airoldi, Ghada W. Mikhail, Matteo Montorfano, Iassen Michev, Mauro Carlino, Antonio Colombo
Journal: Circulation (2004)

Intraprocedural stent thrombosis (IPST) is a rare event (<0.01% in our experience with bare metal stents), with the exception of specific settings such as acute myocardial infarction, thrombus-containing lesions, and dissections. We report the occurrence of this event during elective implantation of sirolimus-eluting stents.Between April 2002 and August 2003, 670 patients with 1362 lesions were treated with Cypher (Cordis, Johnson and Johnson Co) sirolimus-eluting stent implantation in San Raffaele Hospital and EMO Centro Cuore Columbus. Diabetes mellitus was present in 142 patients (21%), and 164 (24.5%) had unstable angina. Pretreatment with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors was carried out in 235 patients (35%). Total stent length per vessel was 42.9+/-28.3 mm. IPST occurred in 5 patients (0.7%). None of the patients with IPST were pretreated with GP IIb/IIIa inhibitors. Using univariate exact logistic regression, only total stent length per vessel, in millimeters (exact OR, 1.03; 95% CI, 1.011 to 1.046; P=0.0028), was associated with the occurrence of IPST.Stent length was associated with the occurrence of IPST. Particular attention will need to be directed to this potential complication when long sirolimus-eluting stents are being used.
Kidneys from Donors after Cardiac Death Provide Survival Benefit
Authors: Maarten G. Snoeijs, Douglas E. Schaubel, Ronald Hené, Andries J. Hoitsma, Mirza M. Idu, Jan N. Ijzermans, Rutger J. Ploeg, Jan Ringers, Maarten H. Christiaans, Wim A. Buurman, L.W. Ernest van Heurn
Journal: Journal of the American Society of Nephrology (2010)

The continuing shortage of kidneys for transplantation requires major efforts to expand the donor pool. Donation after cardiac death (DCD) increases the number of available kidneys, but it is unknown whether patients who receive a DCD kidney live longer than patients who remain on dialysis and wait for a conventional kidney from a brain-dead donor (DBD). This observational cohort study included all 2575 patients who were registered on the Dutch waiting list for a first kidney transplant between January 1, 1999, and December 31, 2004. From listing until the earliest of death, living-donor kidney transplantation, or December 31, 2005, 459 patients received a DCD transplant and 680 patients received a DBD transplant. Graft failure during the first 3 months after transplantation was twice as likely for DCD kidneys than DBD kidneys (12 versus 6.3%; P=0.001). Standard-criteria DCD transplantation associated with a 56% reduced risk for mortality (hazard ratio 0.44; 95% confidence interval 0.24 to 0.80) compared with continuing on dialysis and awaiting a standard-criteria DBD kidney. This reduction in mortality translates into 2.4-month additional expected lifetime during the first 4 years after transplantation for recipients of DCD kidneys compared with patients who await a DBD kidney. In summary, standard-criteria DCD kidney transplantation associates with increased survival of patients who have ESRD and are on the transplant waiting list.
ON INDIVIDUAL DIFFERENCES IN HUMAN BLOOD
Authors: K. Landsteiner, Philip Levine
Journal: The Journal of Experimental Medicine (1928)

A clear-cut differentiation of human blood, aside from the blood groups, could be made by means of special agglutinating immune sera. The observations point to the existence of several agglutinable factors for which no agglutinins are demonstrable in normal human sera. In view of the latter circumstance the results reported do not imply any change in the scheme of the four blood groups. The body of serological evidence leads to the inference of a high degree of biochemical differentiation among individuals.
Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells
Authors: Melli Mahmoudi, Isabelle Gorenne, John Mercer, Nicola Figg, Trevor Littlewood, Martin Bennett
Journal: Circulation Research (2008)

Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used in atherosclerosis to reduce serum cholesterol, statins have multiple other effects, including direct effects on cells of the vessel wall. Recently, DNA damage, including telomere shortening, has been identified in vascular smooth muscle cells (VSMCs) in human atherosclerosis. Although statins reduce DNA damage in vitro, the mechanisms by which they might protect DNA integrity in VSMCs are unknown. We show that human atherosclerotic plaque VSMCs exhibit increased levels of double-stranded DNA breaks and basal activation of DNA repair pathways involving ataxia telangiectasia-mutated (ATM) and the histone H2AX in vivo and in vitro. Oxidant stress induced DNA damage and activated DNA repair pathways in VSMCs. Statin treatment did not reduce oxidant stress or DNA damage but markedly accelerated DNA repair. Accelerated DNA repair required both the Nijmegen breakage syndrome (NBS)-1 protein and the human double minute protein Hdm2, accompanied by phosphorylation of Hdm2, dissociation of NBS-1 and Hdm2, inhibition of NBS-1 degradation, and accelerated phosphorylation of ATM. Statin treatment reduced VSMC senescence and telomere attrition in culture, accelerated DNA repair and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR (ATM and Rad3-related) activity in atherosclerosis. We conclude that statins activate a novel mechanism of accelerating DNA repair, dependent on NBS-1 stabilization and Hdm2. Statin treatment may delay cell senescence and promote DNA repair in atherosclerosis.
Statins and Prostate Cancer Diagnosis and Grade in a Veterans Population
Authors: W. R. Farwell, L. W. D'Avolio, R. E. Scranton, E. V. Lawler, J. M. Gaziano
Journal: JNCI Journal of the National Cancer Institute (2011)

BackgroundAlthough prostate cancer is commonly diagnosed, few risk factors for high-grade prostate cancer are known and few prevention strategies exist. Statins have been proposed as a possible treatment to prevent prostate cancer.
Preoperative Circulating Tumor Cell Detection Using the Isolation by Size of Epithelial Tumor Cell Method for Patients with Lung Cancer Is a New Prognostic Biomarker
Authors: Véronique Hofman, Christelle Bonnetaud, Marius I. Ilie, Philippe Vielh, Jean Michel Vignaud, Jean François Fléjou, Sylvie Lantuejoul, Eric Piaton, Nadine Mourad, Catherine Butori, Eric Selva, Michel Poudenx, Stéphanie Sibon, Sabrina Kelhef, Nicolas Vénissac, Jean-Philippe Jais, Jérôme Mouroux, Thierry Jo Molina, Paul Hofman
Journal: Clinical Cancer Research (2010)

Pathologic TNM staging is currently the best prognostic factor for non-small cell lung carcinoma (NSCLC). However, even in early-stage NSCLC, the recurrence rates after surgery range from 25% to 50%. The preoperative detection of circulating tumor cells (CTC) could be useful to tailor new therapeutic strategies in NSCLC. We assessed the presence of CTC in NSCLC patients undergoing surgery, using cytologic analyses, after their isolation by size of epithelial tumor cells (ISET method). The presence and the number of CTCs were considered and correlated with clinicopathologic parameters including patient follow-up.Of the 247 blood samples tested, 208 samples were from patients with resectable NSCLC and 39 from healthy subjects. The mean follow-up was 24 months. An image of detected cells with presumably nonhematologic features [initially defined as "circulating nonhematologic cells" (CNHC)] was recorded. The presence of CNHC was assessed blindly and independently by 10 cytopathologists, using cytologic criteria of malignancy on stained filters. The count of detected CNHCs was made for each filter.One hundred two of 208 (49%) patients showed CNHCs corresponding to CNHC with malignant cytopathologic features in 76 of 208 (36%) cases. CNHCs were not detected in the control group. A level of 50 or more CNHCs corresponding to the third quartile was associated with shorter overall and disease-free-survival, independently of disease staging, and with a high risk of recurrence and death in early-stage I + II-resectable NSCLC.A high percentage of NSCLC patients show preoperative detection of CNHC by the ISET method. The presence and level of 50 or more CNHCs are associated with worse survival of patients with resectable NSCLC.
Schoenheimer effect explained - feedback regulation of cholesterol synthesis in mice mediated by Insig proteins
Authors: L. J. Engelking
Journal: Journal of Clinical Investigation (2005)

End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element-binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.
Hepatic macrophage activation predicts clinical decompensation in chronic liver disease
Authors: Anthony Rode, Amanda Nicoll, Holger Jon Møller, Lucy Lim, Peter W Angus, Ian Kronborg, Niranjan Arachchi, Alexandra Gorelik, Danny Liew, Konstantin Kazankov, Hendrik Vilstrup, Henning Grønbæk
Journal: Gut (2013)

Hepatic macrophages (Kupffer cells) play important roles in inflammation and portal hypertension in patients with chronic liver disease (CLD).1 We recently showed that plasma soluble CD163 (sCD163), a specific marker for macrophage activation, is produced within and released from the liver with a direct relationship to the portal venous pressure gradient.2 ,3 We hypothesised that: (1) sCD163 is elevated in patients with CLD with previous clinical decompensation; and (2) sCD163 is a marker for CLD progression and clinical deterioration.

We measured sCD163 in 52 controls and 116 consecutive patients with CLD (89% cirrhosis) caused by chronic hepatitis C (36%), alcohol (30%), non-alcoholic fatty liver disease (11%), chronic hepatitis B (10%); other liver diseases (12%) accounted for the remainder of the cases. Cirrhosis was diagnosed by consistent examination and radiological findings, or by liver biopsy. All controls had no history or clinical examination signs of CLD, and normal liver function tests. They were followed for a median of …
Sports massage.: J Ylinen, M Cash. Foreword by H Jones. (Pp 166; soft cover; pound13.99.) Colchester: The Book Service Ltd, 1998. ISBN 0-09-173746-X.
Authors: Tim Atter
Journal: British Journal of Sports Medicine (2000)

Use of imaging data for predicting clinical outcomeEDITOR,-We would like to air three points that arise from the paper Sonographic incidence of tendon microtears in athletes with chronic Achilles tendinosis. 1 Firstly, unfortunately the word "partial" has been omitted from the conclusion (abstract).The conclusion currently reads "There appears to be an association between microtear formation and Achilles tendon rupture".The distinction needs to be made, as the paper's Take home message concludes with the words "There may be a role for ultrasound in identifying athletes at high risk of tendon rupture", and in this case it appears that the authors mean complete tendon rupture.It is important that this ambiguity is clarified.Secondly, although it is well accepted that in many cases tendinosis precedes "spontaneous" tendon rupture, 2 it does not necessarily follow that sonographic abnormality will lead to (complete) tendon rupture.The tissue based pathologies found by Kannus and Jozsa may be more subtle than can be detected by sonography.We feel that, without longitudinal data in a large cohort with an appropriate control group, Gibbon and colleagues are not in a position to draw a conclusion on sonographic screenings of athletes.Thirdly, given the cross sectional study design, the authors should provide caveats emphasising that their theory of tendon remodelling paralleling that of bone is purely speculative.Cross sectional athlete-control comparisons (such as those provided to sustain the argument on tendon remodelling) do not provide evidence of causality-such diVerences can result merely from selection bias.If athlete-control diVerence were causally related, then one could take up basketball in order to grow tall.We emphasise the need for prospectively collected data to predict future outcome.Researchers and clinicians should desist from speculating as to the longitudinal clinical significance of imaging data collected at one point in time only.To our knowledge, there is only one published prospective ultrasonography and clinical correlation study in the tendon literature at present, 3 and it shows rather poor predictive value of ultrasonography in terms of development of symptoms and clinical findings of patellar tendinopathy in female basketball players.Until researchers and reviewers acknowledge the importance of longitudinally collected data for predicting clinical outcome, our imaging field will continue to be mired in a debate based on speculation rather than science.