tbuckley/cabot-search huggingface dataset:
Neutrophil-derived leukotriene B4 is required for inflammatory arthritis
Authors: Mei Chen, Bing K. Lam, Yoshihide Kanaoka, Peter A. Nigrovic, Laurent P. Audoly, K. Frank Austen, David M. Lee
Journal: The Journal of Experimental Medicine (2006)

Neutrophils serve as a vanguard of the acute innate immune response to invading pathogens. Neutrophils are also abundant at sites of autoimmune inflammation, such as the rheumatoid joint, although their pathophysiologic role is incompletely defined and relevant effector functions remain obscure. Using genetic and pharmacologic approaches in the K/BxN serum transfer model of arthritis, we find that autoantibody-driven erosive synovitis is critically reliant on the generation of leukotrienes, and more specifically on leukotriene B4 (LTB4), for disease induction as well as perpetuation. Pursuing the cellular source for this mediator, we find via reconstitution experiments that mast cells are a dispensable source of leukotrienes, whereas arthritis susceptibility can be restored to leukotriene-deficient mice by intravenous administration of wild-type neutrophils. These experiments demonstrate a nonredundant role for LTB4 in inflammatory arthritis and define a neutrophil mediator involved in orchestrating the synovial eruption.
Rapid DNA Double-Strand Breaks Resulting from Processing of Cr-DNA Cross-Links by Both MutS Dimers
Authors: Mindy F. Reynolds, Elizabeth C. Peterson-Roth, Ivan A. Bespalov, Tatiana Johnston, Volkan M. Gurel, Haley L. Menard, Anatoly Zhitkovich
Journal: Cancer Research (2009)

Abstract Mismatch repair (MMR) strongly enhances cyto- and genotoxicity of several chemotherapeutic agents and environmental carcinogens. DNA double-strand breaks (DSB) formed after two replication cycles play a major role in MMR-dependent cell death by DNA alkylating drugs. Here, we examined DNA damage detection and the mechanisms of the unusually rapid induction of DSB by MMR proteins in response to carcinogenic chromium(VI). We found that MSH2-MSH6 (MutSα) dimer effectively bound DNA probes containing ascorbate-Cr-DNA and cysteine-Cr-DNA cross-links. Binary Cr-DNA adducts, the most abundant form of Cr-DNA damage, were poor substrates for MSH2-MSH6, and their toxicity in cells was weak and MMR independent. Although not involved in the initial recognition of Cr-DNA damage, MSH2-MSH3 (MutSβ) complex was essential for the induction of DSB, micronuclei, and apoptosis in human cells by chromate. In situ fractionation of Cr-treated cells revealed MSH6 and MSH3 chromatin foci that originated in late S phase and did not require replication of damaged DNA. Formation of MSH3 foci was MSH6 and MLH1 dependent, whereas MSH6 foci were unaffected by MSH3 status. DSB production was associated with progression of cells from S into G2 phase and was completely blocked by the DNA synthesis inhibitor aphidicolin. Interestingly, chromosome 3 transfer into MSH3-null HCT116 cells activated an alternative, MSH3-like activity that restored dinucleotide repeat stability and sensitivity to chromate. Thus, sequential recruitment and unprecedented cooperation of MutSα and MutSβ branches of MMR in processing of Cr-DNA cross-links is the main cause of DSB and chromosomal breakage at low and moderate Cr(VI) doses. [Cancer Res 2009;69(3):1071–9]
Patient participation groups
Authors: S. Nagraj, S. Gillam
Journal: BMJ (2011)

NHS reforms offer new and wide ranging opportunities

Involvement of patients and the public is meant to be at the heart of the coalition government’s health policy. Liberating the NHS claims to “strengthen the collective voice of patients and public.”1 Patient participation groups are one way in which the views of patients might be heard more clearly in future. Such groups emerged more than 30 years ago but have been slow to gain hold. In 2007, 41% of practices were reported to have a patient participation group,2 but the true proportion of active groups is probably lower. Their role has always lacked clarity, but the current NHS reforms in England offer new opportunities for these groups.

Patient participation groups are voluntary and usually based around a general practice.2 Activities undertaken by these groups come under three broad categories.3 The first concerns health education—for example, running educational meetings for patients. The second role is that of “critical friend”—giving advice and feedback on services provided by the practice. Thirdly, some groups generate material support for practice …
Progression of Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT)
Authors: Aramesh Saremi, Gideon Bahn, Peter D. Reaven
Journal: Diabetes Care (2012)

To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM.After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm(3) vs. 4.2 ± 1.1 mm(3); P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users.More frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.
Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis
Authors: E. P. Navarese, K. Tandjung, B. Claessen, F. Andreotti, M. Kowalewski, D. E. Kandzari, D. J. Kereiakes, R. Waksman, L. Mauri, I. T. Meredith, A. V. Finn, H.-S. Kim, J. Kubica, H. Suryapranata, T. M. Aprami, G. Di Pasquale, C. von Birgelen, E. Kedhi
Journal: BMJ (2013)

<b>Objectives</b> To investigate the safety and efficacy of durable polymer drug eluting stents (DES) and biodegradable polymer biolimus eluting stents (biolimus-ES). <b>Design</b> Network meta-analysis of randomised controlled trials. <b>Data sources and study selection</b> Medline, Google Scholar, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) database search for randomised controlled trials comparing at least two of durable polymer sirolimus eluting stents (sirolimus-ES) and paclitaxel eluting stents (paclitaxel-ES), newer durable polymer everolimus eluting stents (everolimus-ES), Endeavor and Resolute zotarolimus eluting stents (zotarolimus-ES), and biodegradable polymer biolimus-ES. <b>Primary outcomes</b> Safety (death, myocardial infarction, definite or probable stent thrombosis) and efficacy (target lesion and target vessel revascularisation) assessed at up to one year and beyond. <b>Results</b> 60 randomised controlled trials were compared involving 63 242 patients with stable coronary artery disease or acute coronary syndrome treated with a DES. At one year, there were no differences in mortality among devices. Resolute and Endeavor zotarolimus-ES, everolimus-ES, and sirolimus-ES, but not biodegradable polymer biolimus-ES, were associated with significantly reduced odds of myocardial infarction (by 29-34%) compared with paclitaxel-ES. Compared with everolimus-ES, biodegradable polymer biolimus-ES were associated with significantly increased odds of myocardial infarction (by 29%), while Endeavor zotarolimus-ES and paclitaxel-ES were associated with significantly increased odds of stent thrombosis. All investigated DES were similar with regards to efficacy endpoints, except for Endeavor zotarolimus-ES and paclitaxel-ES, which were associated with significantly increased the odds of target lesion and target vessel revascularisations compared with other devices. Direction of results beyond one year did not diverge from the findings for up to one year follow-up. Bayesian probability curves showed a gradient in the magnitude of effect, with everolimus-ES and Resolute zotarolimus-ES offering the highest safety profiles. <b>Conclusions</b> The newer durable polymer everolimus-ES and Resolute zotarolimus-ES and the biodegradable polymer biolimus-ES maintain the efficacy of sirolimus-ES; however, for safety endpoints, differences become apparent, with everolimus-ES and Resolute zotarolimus-ES emerging as the safest stents to date.
Dysfunctions of neuronal and glial intermediate filaments in disease
Authors: Ronald K.H. Liem, Albee Messing
Journal: Journal of Clinical Investigation (2009)

Intermediate filaments (IFs) are abundant structures found in most eukaryotic cells, including those in the nervous system. In the CNS, the primary components of neuronal IFs are α-internexin and the neurofilament triplet proteins. In the peripheral nervous system, a fifth neuronal IF protein known as peripherin is also present. IFs in astrocytes are primarily composed of glial fibrillary acidic protein (GFAP), although vimentin is also expressed in immature astrocytes and some mature astrocytes. In this Review, we focus on the IFs of glial cells (primarily GFAP) and neurons as well as their relationship to different neurodegenerative diseases.
S –Adenosylmethionine Treatment Prevents Carbon Tetrachloride—Induced S –Adenosylmethionine Synthetase Inactivation and Attenuates Liver Injury
Authors: Fernando Corrales, América Giménez, Luis Alvarez, Joan Caballería, María A. Pajares, Hernán Andreu, Albert Parés, José M. Mato, Joan Rodés
Journal: Hepatology (1992)

Administration of carbon tetrachloride to rats resulted in induction of hepatic fibrosis and a 60% reduction of hepatic S-adenosylmethionine synthetase activity without producing any significant modification of hepatic levels of S-adenosylmethionine synthetase messenger RNA. The reduction of S-adenosylmethionine synthetase activity was corrected by treatment with S-adenosylmethionine (3 mg/kg/day, intramuscularly). Administration of carbon tetrachloride also produced a 45% depletion of liver glutathione (reduced form) that was corrected by S-adenosylmethionine treatment. After the rats received carbon tetrachloride, a 2.3-fold increase in liver collagen was observed; prolyl hydroxylase activity was 2.5 times greater than that seen in controls. These increases were attenuated in animals treated with carbon tetrachloride and S-adenosylmethionine. The attenuation by S-adenosylmethionine treatment of the fibrogenic effect of carbon tetrachloride was associated with a decrease in the number of rats in which cirrhosis developed.
Digital Three-Dimensional Reconstruction and Ultrastructure of the Mouse Proximal Tubule
Authors: Xiao Yue Zhai, Henrik Birn, Knud B. Jensen, Jesper S. Thomsen, Arne Andreasen, Erik I. Christensen
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Mice are prime targets of experimental gene modification and have become object of an increasing number of biologic studies in renal physiology, development, and molecular biology. Phenotypic changes in response to gene modification require detailed information on normal structure. However, detailed analyses of normal mouse kidney structure and organization are lacking. This study describes the 3D organization and ultrastructural, segmental variation of the mouse kidney proximal tubule. A total of 160 proximal tubules in three C57/BL/6J mouse kidneys were analyzed on 800 serial sections from each kidney from the surface to the inner stripe of the outer zone of medulla. All tubules were reconstructed in 3D and visualized by interactive computer graphics. A quantitative ultrastructural analysis of the mouse proximal tubule at every 300 to 400 μm was performed. The 3D representation revealed a distinct organization of the mouse proximal tubule, each occupying a separate domain within the cortex. Superficial proximal tubules have long straight parts converging into clusters within the medullary rays. Tubules originating deeper within the cortex become longer and increasingly tortuous. In the medullary rays, these are arranged in layers outside the clusters of more superficial tubules. In contrast to rat and human kidney, no major segmental variation in the ultrastructure of the proximal tubule was identified, and no parameters enabled definition of distinct segments in this strain of mice. In conclusion, significant new information on the 3D organization of the murine proximal tubule has been obtained. Quantitative, ultrastructural analyses of mouse proximal tubules reveal substantial differences compared with other species. E-mail: [email protected]
Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension
Authors: NF Voelkel, RM Tuder
Journal: European Respiratory Journal (1995)

Chronic pulmonary hypertension leads to structural alterations of the lung vessels. The pathophysiology of this remodelling process is still poorly understood. Furthermore, the structural damage of the lung vessels limits the clinical success of vasodilator treatment. Given a genetic susceptibility, shear stress and inflammation are the principal pathogenetic factors involved in lung vessel remodelling. In this overview, we compared the lung vascular histology of patients with unexplained pulmonary hypertension, scleroderma, or acquired immune deficiency syndrome (AIDS)-associated pulmonary hypertension. We demonstrate the presence of inflammatory cells (T- and B-lymphocytes and macrophages) in plexiform lesions and discuss the potential role of growth factors (platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF) in pulmonary hypertensive remodelling. Ultimately, we need to develop an in-depth understanding of the key mechanisms of gene expression and signalling pathways, which transduce signals generated from increased chronic shear stress (or from chronic hypoxia) and lead to vascular injury and repair.
Effects of Melatonin on Appetite and Other Symptoms in Patients With Advanced Cancer and Cachexia: A Double-Blind Placebo-Controlled Trial
Authors: Egidio Del Fabbro, Rony Dev, David Hui, Lynn Palmer, Eduardo Bruera
Journal: Journal of Clinical Oncology (2013)

Prior studies have suggested that melatonin, a frequently used integrative medicine, can attenuate weight loss, anorexia, and fatigue in patients with cancer. These studies were limited by a lack of blinding and absence of placebo controls. The primary purpose of this study was to compare melatonin with placebo for appetite improvement in patients with cancer cachexia.We performed a randomized, double-blind, 28-day trial of melatonin 20 mg versus placebo in patients with advanced lung or GI cancer, appetite scores ≥ 4 on a 0 to 10 scale (10 = worst appetite), and history of weight loss ≥ 5%. Assessments included weight, symptoms by the Edmonton Symptom Assessment Scale, and quality of life by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire. Differences between groups from baseline to day 28 were analyzed using one-sided, two-sample t tests or Wilcoxon two-sample tests. Interim analysis halfway through the trial had a Lan-DeMets monitoring boundary with an O'Brien-Fleming stopping rule. Decision boundaries were to accept the null hypothesis of futility if the test statistic z < 0.39 (P ≥ .348) and reject the null hypothesis if z > 2.54 (P ≤ .0056).After interim analysis of 48 patients, the study was closed for futility. There were no significant differences between groups for appetite (P = .78) or other symptoms, weight (P = .17), FAACT score (P = .95), toxicity, or survival from baseline to day 28.In cachectic patients with advanced cancer, oral melatonin 20 mg at night did not improve appetite, weight, or quality of life compared with placebo.
Phase III Study of <i>N,N</i>-Diethyl-2-[4-(Phenylmethyl) Phenoxy]Ethanamine (BMS-217380-01) Combined With Doxorubicin Versus Doxorubicin Alone in Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19
Authors: Leonard Reyno, Lesley Seymour, Dongsheng Tu, Susan Dent, Karen Gelmon, Barbara Walley, Anna Pluzanska, Vera Gorbunova, Avgust Garin, Jacek Jassem, Tadeusz Pienkowski, Janet Dancey, Laura Pearce, Mary MacNeil, Susan Marlin, David Lebwohl, Maurizio Voi, Kathleen Pritchard
Journal: Journal of Clinical Oncology (2004)

N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE; tesmilifene) is a novel agent that augments chemotherapy cytotoxicity in vitro and in vivo. A phase II trial combining DPPE and doxorubicin (DOX) in metastatic breast carcinoma showed increased response over that expected with DOX. We report a phase III trial comparing DOX with DPPE plus DOX in metastatic or recurrent breast cancer.Anthracycline-naive women with measurable metastatic disease were randomly assigned to receive, every 21 days, either DOX 60 mg/m(2) intravenously or DOX during the last 20 minutes of an 80-minute infusion of DPPE (5.3 mg/kg), in both cases to cumulative DOX doses of 450 mg/m(2). Patients receiving DPPE were aggressively premedicated to ameliorate toxicity. End points included progression-free survival (PFS), response rate (RR), and response duration (RD), quality of life (QOL), toxicity, and overall survival (OS).A planned interim analysis failed to detect an RR difference more than 5%. The study was closed to additional accrual and all DPPE was discontinued. The final analysis was conducted as planned after 256 progression events (median follow-up, 20.5 months). There was no significant difference in RR, RD, or PFS between arms. DPPE plus DOX was statistically superior to DOX in OS (hazard ratio, 0.66; 95% CI, 0.48 to 0.91; P =.021). DPPE plus DOX was associated with more gastrointestinal and CNS toxicity. No consistent influence on QOL was detected.This study demonstrated no advantage in RR, RD, or PFS but significantly superior OS for DPPE plus DOX. Additional studies of DPPE are warranted.
Tuberculosis in the Foreign-Born Population of Tarrant County, Texas by Immigration Status
Authors: STEPHEN E. WEIS, PATRICK K. MOONAN, JANICE M. POGODA, LE TURK, BARBARA KING, SHERRY FREEMAN-THOMPSON, GERRY BURGESS
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The epidemiology of tuberculosis is changing in the United States as a result of immigration, yet the extent to which different classes of immigrants contribute to overall morbidity is unknown. Tuberculosis in nonimmigrant visitors is of particular interest as they are currently exempt from screening requirements. We conducted a prospective survey of all culture-positive tuberculosis patients in Tarrant County, Texas from 1/98 to 12/00. Immigration status of foreign-born patients was classified as permanent residents, undocumented, or nonimmigrant visitors. Of 274 eligible participants, 114 (42%) were foreign-born; of these, 67 (59%) were permanent residents, 28 (25%) were undocumented, and 19 (17%) were nonimmigrant visitors. Among the foreign-born, we observed significant differences by immigration status in multidrug resistance (p = 0.02), human immunodeficiency virus (HIV) infection (p = 0.0007), and hospitalization (p = 0.03 for ever/never, 0.01 for duration). Compared with other immigrants, more nonimmigrant visitors were multi-drug-resistant (16 % versus 11% of undocumented residents and 1% of permanent residents), were HIV-positive (32% versus 0% of undocumented and 5% of permanent residents), were hospitalized (47% versus 36% of undocumented and 19% of permanent residents), and had lengthy hospitalizations (median [midspread] days = 87 [25 to 153] versus 8.5 [4 to 28] for undocumented and 10 [7 to 24 d] for permanent residents). We found nonimmigrant visitors to be an important source of tuberculosis morbidity in Tarrant County. Further studies in other regions of the U.S. are needed to determine if screening and treatment recommendations of persons who spend extended periods in the U.S. should be raised to the standards set for permanent residents.
Targeted Signal-Amplifying Enzymes Enhance MRI of EGFR Expression in an Orthotopic Model of Human Glioma
Authors: Mohammed S. Shazeeb, Christopher H. Sotak, Michael DeLeo, Alexei Bogdanov
Journal: Cancer Research (2011)

Epidermal growth factor receptor (EGFR) imaging in brain tumors is essential to visualize overexpression of EGFRvIII variants as a signature of highly aggressive gliomas and to identify patients that would benefit from anti-EGFR therapy. Seeking imaging improvements, we tested a novel pretargeting approach that relies on initial administration of enzyme-linked anti-EGFR monoclonal antibodies (mAb; EMD72000) followed by administration of a low-molecular-weight paramagnetic molecule (diTyr-GdDTPA) retained at the site of EGFR mAb accumulation. We hypothesized that diTyr-GdDTPA would become enzyme activated and retained on cells due to binding to tissue proteins. In support of this hypothesis, mAb-enzyme conjugates reacted with both membrane-isolated wild-type (wt) EGFR and EGFRvIII, but they bound primarily to EGFRvIII-expressing cells and not to EGFRwt-expressing cells. In vivo analysis of magnetic resonance (MR) tumor signal revealed differences in MR signal decay following diTyr-GdDTPA substrate administration. These differences were significant in that they suggested differences in substrate elimination from the tissue which relied on the specificity of the initial mAb binding: a biexponential signal decay was observed in tumors only upon preinjection with EGFR-targeted conjugates. Endpoint MRI in this setting revealed detailed images of tumors which correlated with immunohistochemical detection of EGFR expression. Together, our findings suggest an improved method to identify EGFRvIII-expressing gliomas in vivo that are best suited for treatment with therapeutic EGFR antibodies.
Retraction: Suppression of HMGA2 Protein Synthesis Could Be a Tool for the Therapy of Well Differentiated Liposarcomas Overexpressing <i>HMGA2</i>
Authors: Francesca Pentimalli, Monica Dentice, Monica Fedele, Giovanna Maria Pierantoni, Letizia Cito, Pierlorenzo Pallante, Massimo Santoro, Giuseppe Viglietto, Paola Dal Cin, Alfredo Fusco
Journal: Cancer Research (2018)

This article (1) has been retracted at the request of the editors. The editors were made aware of concerns regarding potential manipulation of data in the article. An internal review by the editors determined that multiple Gapdh bands appear to be duplicated in Fig. 3A. In addition, the same γ-tubulin Western blot band appears to be duplicated multiple times in Fig. 3B. The authors were not able to provide the original data to dispel these concerns.A copy of this Retraction Notice was sent to the last known e-mail addresses for all 10 authors. One author (P. Dal Cin) agreed to the retraction; two authors (M. Fedele and A. Fusco) did not agree to the retraction; two authors (M. Dentice and G.M. Pierantoni) take no position; the five remaining authors (F. Pentimalli, L. Cito, P. Pallante, M. Santoro, and G. Viglietto) did not respond.