tbuckley/cabot-search huggingface dataset:
Continuous Activation of Autoreactive CD4+ CD25+ Regulatory T Cells in the Steady State
Authors: Sylvain Fisson, Guillaume Darrasse-Jèze, Elena Litvinova, Franck Septier, David Klatzmann, Roland Liblau, Benoît L. Salomon
Journal: The Journal of Experimental Medicine (2003)

Despite a growing interest in CD4+ CD25+ regulatory T cells (Treg) that play a major role in self-tolerance and immunoregulation, fundamental parameters of the biology and homeostasis of these cells are poorly known. Here, we show that this population is composed of two Treg subsets that have distinct phenotypes and homeostasis in normal unmanipulated mice. In the steady state, some Treg remain quiescent and have a long lifespan, in the order of months, whereas the other Treg are dividing extensively and express multiple activation markers. After adoptive transfer, tissue-specific Treg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens. These results reveal the existence of a cycling Treg subset composed of autoreactive Treg that are continuously activated by tissue self-antigens.
Myocardial Necrosis in Rats: Serum Enzymes, Adrenal Steroid and Histopathological Alterations
Authors: Bernard C. Wexler, George W. Kittinger, Myra E. Springs, DHman Conatser
Journal: Circulation Research (1963)

Acute infarctoid myocardial necrosis has been produced in virgin rats by injection of isoproterenol. The lesions are essentially identical, both grossly and microscopically, with naturally occurring acute infarcts which we have observed in arteriosclerotic breeder rats. During the establishment of drug-induced necrosis the animals displayed signs of shock and congestive heart failure. Serum transaminases and lactic dehydrogenase levels underwent changes which coincided with the establishment and repair of the myocardial damage. The male rats had a higher mortality rate than the females. The male rats also developed more massive myocardial necrosis and showed a decreased capacity to repair myocardial damage. The adrenal glands became greatly hypertrophied and the thymus became severely involuted coincident with the acute establishment of the myocardial lesion. In vitro studies indicated that changes in adrenal function also accompanied the acute onset of myocardial destruction. The adrenal hypertrophy decreased during recovery from shock and during repair of the lesion.
Diagnosis of Down's syndrome at birth.
Authors: M K Strelling
Journal: BMJ (1976)

In the chick chorioallantoic membrane system heparin plus cortisone caused a marked depression in the rate of collagenous protein biosynthesis in vivo during inhibition of angiogenesis. This suggests that monitoring the rate of collagenous protein biosynthesis in the chick chorioallantoic membrane system can be used as a quantitative method for evaluating angiogenesis inhibitors.
Association of mitral annulus calcification, aortic valve sclerosis and aortic root calcification with abnormal myocardial perfusion single photon emission tomography in subjects age ≤65 years old
Authors: Doo-Soo Jeon, Shaul Atar, Andrea V Brasch, Huai Luo, James Mirocha, Tasneem Z Naqvi, Robert Kraus, Daniel S Berman, Robert J Siegel
Journal: Journal of the American College of Cardiology (2001)
Sleep Disturbance in Bipolar Disorder: Therapeutic Implications
Authors: David T. Plante, John W. Winkelman
Journal: American Journal of Psychiatry (2008)

In this review, the authors detail our current understanding of the crucial role that sleep and its disturbances play in bipolar disorder. Multiple lines of evidence suggest that impaired sleep can induce and predict manic episodes. Similarly, treatment of sleep disturbance may serve as both a target of treatment and a measure of response in mania. The depressive phase of bipolar illness is marked by sleep disturbance that may be amenable to somatic therapies that target sleep and circadian rhythms. Residual insomnia in the euthymic period may represent a vulnerability to affective relapse in susceptible patients. Given the importance of sleep in all phases of bipolar disorder, appropriate evaluation and management of sleep disturbance in patients with bipolar illness is further detailed.
Neuropathic Pain Features in Patients With Bone Metastases Referred for Palliative Radiotherapy
Authors: Marc Kerba, Jackson S.Y. Wu, Qiuli Duan, Neil A. Hagen, Michael I. Bennett
Journal: Journal of Clinical Oncology (2010)

To estimate the prevalence of pain with neuropathic features among patients with metastatic bone pain and to assess differences between patients with and without neuropathic features by pain severity, functional interference, and quality-of-life (QOL) measures.A prospective cross-sectional survey of consecutive patients with symptomatic bone metastases was conducted between December 2006 and March 2008 at a comprehensive cancer center. Patients completed the Brief Pain Inventory (BPI), the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS), and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30). Statistical associations between pain with neuropathic features and other measures were explored.Ninety-eight patients were enrolled. Seventeen percent of patients (95% CI, 10% to 24%) had positive S-LANSS scores suggesting pain with neuropathic features. Mean worst pain and mean interference scores were 7.2 (standard deviation [SD], 2.0) and 5.8 (SD, 2.5), respectively. EORTC QLQ-C30 global QOL, function, and symptom scores were 42 (SD, 24), 52 (SD, 20), and 46 (SD, 17), respectively. Patients with neuropathic features had a higher BPI worst pain score than patients without neuropathic features (8.3 v 7.0, respectively; P = .016). Corticosteroid use, oral morphine equivalent dosing, and site of bone pain were not associated with neuropathic features.Some patients with bone metastases manifest bone pain with distinguishable neuropathic features, and these patients reported greater pain intensity. Additional work is required to validate the S-LANSS against clinical criteria for neuropathic pain in this context and to explore the unmet pain management needs in this population.
Is the mucosal route of administration essential for probiotic function? Subcutaneous administration is associated with attenuation of murine colitis and arthritis
Authors: B Sheil
Journal: Gut (2004)

<b>Background:</b> We and others have reported the prophylactic efficacy of oral consumption of probiotic lactobacilli in the interleukin 10 knockout (IL-10 KO) model of colitis. It has not been demonstrated that the oral route is essential for probiotic efficacy. <b>Aims:</b> (i) To determine the effect of parenteral administration (subcutaneous) of <i>Lactobacillus salivarius</i> 118 on colitis of IL-10 KO mice; and (ii) to determine if observed responses are disease specific. <b>Methods:</b> (i) IL-10 KO mice were injected subcutaneously with <i>L salivarius</i> 118 or saline over 19 weeks. At sacrifice, the bowels were histologically scored. Isolated splenocytes were cultured in vitro and cytokine levels measured. (ii) In the collagen induced arthritis model, DBA/1 mice were injected subcutaneously with the probiotic or saline. At sacrifice, paw thickness was measured and joints were histologically scored. <b>Results:</b> (i) Colonic inflammatory scores were significantly decreased in IL-10 KO mice injected with <i>L salivarius</i> 118 compared with controls (p&lt;0.05). Proinflammatory cytokine production from stimulated splenocytes was significantly lower for the probiotic group whereas stimulated transforming growth factor β (TGF-β) levels were significantly increased (p&lt;0.05). (ii) Scoring of arthritis and paw thickness were significantly improved in the group of mice injected with <i>L salivarius</i> 118 compared with controls. <b>Conclusions:</b> (1) Subcutaneous administration of <i>L salivarius</i> 118 significantly attenuated colitis in the IL-10 KO model and suppressed collagen induced arthritis, suggesting that the oral route may not be essential for probiotic anti-inflammatory effects and that responses are not disease specific. (2) The probiotic effect was associated with reduced production of proinflammatory (T helper 1) cytokines and maintained production of anti-TGF-β.
Massive cavitary pulmonary rheumatoid nodules in a patient with HIV
Authors: N. Khazeni, R. J. Homer, A. N. Rubinowitz, G. L. Chupp
Journal: European Respiratory Journal (2006)

The case of a 52-yr-old female with rheumatoid arthritis and HIV who developed massive, progressive, cavitary pulmonary nodules is described. Multiple diagnostic bronchoscopies and lung biopsies failed to demonstrate the presence of any microorganisms. Pathological analysis showed palisading histiocytes with necrobiosis consistent with rheumatoid nodules. The effect of co-existing HIV infection on the course and prognosis of rheumatoid arthritis is discussed, and it is concluded that the complex relationship between these two disease processes warrants further investigation.
Pentoxifylline Improves Hemoglobin Levels in Patients with Erythropoietin-resistant Anemia in Renal Failure
Authors: Angela Cooper, Ashraf Mikhail, Mark W. Lethbridge, D. Michael Kemeny, Iain C. Macdougall
Journal: Journal of the American Society of Nephrology (2004)

It was hypothesized that pentoxifylline might improve the response to recombinant human erythropoietin (rh-Epo) in anemic renal failure patients. Sixteen patients with ESRD and rh-Epo-resistant anemia, defined by a hemoglobin of <10.7 g/dl for 6 mo before treatment and a rh-Epo dose of > or =12,000 IU/wk, were recruited. They were treated with oral pentoxifylline 400 mg o.d. for 4 mo. Ex vivo T cell generation of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) from the patients was assessed before treatment and 6 to 8 wk after therapy. A total of 12 of 16 patients completed the study. Before therapy, the 12 patients' mean hemoglobin concentration was 9.5 +/- 0.9 g/dl. After 4 mo of pentoxifylline treatment, the mean hemoglobin concentration increased to 11.7 +/- 1.0 g/dl (P = 0.0001). Baseline ex vivo T cell expression of TNF-alpha decreased from 58% +/- 11% to 31% +/- 23% (P = 0.0007) after therapy. Likewise, IFN-gamma expression decreased from 31% +/- 10% to 13% +/- 10% (P = 0.0002). Pentoxifylline therapy may significantly improve the hemoglobin response in patients with previously rh-Epo-resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production, which could interfere with the effectiveness of rh-Epo.
Identification of an immunodominant and highly immunopathogenic determinant in the retinal interphotoreceptor retinoid-binding protein (IRBP).
Authors: H Sanui, T M Redmond, S Kotake, B Wiggert, L H Hu, H Margalit, J A Berzofsky, G J Chader, I Gery
Journal: The Journal of Experimental Medicine (1989)

Interphotoreceptor retinoid-binding protein (IRBP), a glycoprotein specific for the retina and pineal gland, induces inflammatory changes in these two organs in immunized animals. We report here on the identification of an immunodominant determinant of bovine IRBP that is highly immunogenic and immunopathogenic in the Lewis rat. The peptide, which comprises the sequence 1169-1191 of bovine IRBP, was shown to be immunodominant by its capacity to stimulate lymphocytes sensitized against whole IRBP. A comparison was made between peptide 1169-1191 and another peptide, 1158-1180, which is nondominant but is immunogenic and immunopathogenic in the Lewis rat. Peptide 1169-1191 was found to be superior in its immunological capacities; the minimal dose of 1169-1191 needed to induce cellular immune response or disease in Lewis rats (0.02-0.1 nmol/rat) is congruent to 1,000 times smaller than that of 1158-1180. In addition, unlike the ocular disease induced by 1158-1180, the disease produced by 1169-1191 resembled that induced by whole IRBP in its kinetics and histopathological features. The immunological activity of 1169-1191 in the Lewis rat was localized to the 10 residues at the COOH terminus; no such activity was exhibited by the truncated peptide 1169-1188, which comprises the 20 residues at the NH2 terminus of the full peptide. The usefulness of this unique experimental system in analyzing the role of immunodominance in peptide immunogenicity and immunopathogenicity is underscored.
Identification and Characterization of Small Molecules That Inhibit Nonsense-Mediated RNA Decay and Suppress Nonsense p53 Mutations
Authors: Leenus Martin, Arsen Grigoryan, Ding Wang, Jinhua Wang, Laura Breda, Stefano Rivella, Timothy Cardozo, Lawrence B. Gardner
Journal: Cancer Research (2014)

Abstract Many of the gene mutations found in genetic disorders, including cancer, result in premature termination codons (PTC) and the rapid degradation of their mRNAs by nonsense-mediated RNA decay (NMD). We used virtual library screening, targeting a pocket in the SMG7 protein, a key component of the NMD mechanism, to identify compounds that disrupt the SMG7–UPF1 complex and inhibit NMD. Several of these compounds upregulated NMD-targeted mRNAs at nanomolar concentrations, with minimal toxicity in cell-based assays. As expected, pharmacologic NMD inhibition disrupted SMG7–UPF1 interactions. When used in cells with PTC-mutated p53, pharmacologic NMD inhibition combined with a PTC “read-through” drug led to restoration of full-length p53 protein, upregulation of p53 downstream transcripts, and cell death. These studies serve as proof-of-concept that pharmacologic NMD inhibitors can restore mRNA integrity in the presence of PTC and can be used as part of a strategy to restore full-length protein in a variety of genetic diseases. Cancer Res; 74(11); 3104–13. ©2014 AACR.
PACE BOM chemotherapy: A 12-week regimen for advanced Hodgkin’s disease
Authors: P.D. Simmonds, G.M. Mead, J.W. Sweetenham, A. O’Callaghan, P. Smartt, J. Kerr, C.R. Hamilton, P.F. Golding, A.E. Milne, J.M.A. Whithouse
Journal: Annals of Oncology (1997)
Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer
Authors: Chenzhang Shi, Yongzhi Yang, Yang Xia, Yoshinaga Okugawa, Jun Yang, Yong Liang, Hongqi Chen, Peng Zhang, Feng Wang, Huazhong Han, Wen Wu, Renyuan Gao, Christoph Gasche, Huanlong Qin, Yanlei Ma, Ajay Goel
Journal: Gut (2015)

<h3>Objective</h3> miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). <h3>Design</h3> miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. <h3>Results</h3> miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. <h3>Conclusions</h3> These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
E47 is required for V(D)J recombinase activity in common lymphoid progenitors
Authors: Lisa Borghesi, Jennifer Aites, Shakira Nelson, Preslav Lefterov, Pamela James, Rachel Gerstein
Journal: The Journal of Experimental Medicine (2005)

Common lymphoid progenitors (CLPs) are the first bone marrow precursors in which V(D)J recombinase activity is up-regulated. Here, we show that loss of the transcription factor E47 produces a reduced CLP population that lacks V(D)J recombinase activity and D-JH rearrangements in vivo. Apart from a profound arrest before the pro–B cell stage, other downstream lymphoid progeny of CLPs are still intact in these mice albeit at reduced numbers. In contrast to the inhibition of recombinase activity in early B lineage precursors in E47-deficient animals, loss of either E47 or its cis-acting target Erag (enhancer of rag transcription) has little effect on recombinase activity in thymic T lineage precursors. Taken together, this work defines a role for E47 in regulating lineage progression at the CLP stage in vivo and describes the first transcription factor required for lineage-specific recombinase activity.
Pirfenidone should be prescribed for patients with idiopathic pulmonary fibrosis: Table 1
Authors: Gisli Jenkins
Journal: Thorax (2013)

Pirfenidone works. There have been four randomised placebo-control trials of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF); a phase II and phase III study in Japan, and two international multicentre phase III studies.1–3 In all four studies, patients treated with pirfenidone had slower rates of decline in lung volume (vital capacity (VC) in the Japanese studies and forced vital capacity (FVC) in the international studies) than placebo, and in three studies, the results were statistically significant. National Institute of Clinical Excellence (NICE) agrees that pirfenidone has a ‘modest but measurable effect on slowing the decline in lung function’.4 Therefore, whether patients receive pirfenidone depends on whether pirfenidone works enough to justify its cost.

IPF is a chronic progressive disease of unknown aetiology, it is fatal with a median survival of approximately 3 years,5 or less than one electoral cycle. No therapy has been proven to improve survival. Despite the absence of good evidence, various combinations of N-acetylcysteine (NAC), prednisolone and azathioprine have been used for many years to treat patients with IPF. In the early 1990s, a small study suggested that prednisolone and azathioprine might be beneficial,6 and the initial British Thoracic Society (BTS) guidelines for the treatment of cryptogenic fibrosing alveolitis (as IPF was then known) recommended this therapy.7 In 2005, the Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual (IFIGENIA) study demonstrated that NAC might be beneficial in IPF.8 However, this study was criticised at the time for including azathioprine and prednisolone in both the placebo and treatment arms. The inclusion of this faux placebo lead some, possibly correctly, to suggest that NAC was inhibiting the adverse effects of prednisolone and azathioprine, rather than possessing any direct antifibrotic effect. The 2008 BTS IPF guidelines9 implicitly recommended treatment with triple …
Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer
Authors: Malou van den Boogaard, L.Y. Elaine Wong, Federico Tessadori, Martijn L. Bakker, Lisa K. Dreizehnter, Vincent Wakker, Connie R. Bezzina, Peter A.C. ‘t Hoen, Jeroen Bakkers, Phil Barnett, Vincent M. Christoffels
Journal: Journal of Clinical Investigation (2012)

The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system–regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias.
Thrombopoietin Stimulates Endothelial Cell Motility and Neoangiogenesis by a Platelet-Activating Factor–Dependent Mechanism
Authors: Maria Felice Brizzi, Edda Battaglia, Giuseppe Montrucchio, Patrizia Dentelli, Lorenzo Del Sorbo, Giovanni Garbarino, Luigi Pegoraro, Giovanni Camussi
Journal: Circulation Research (1999)

Abstract —In this study, we demonstrate that human umbilical cord vein–derived endothelial cells (HUVECs) expressed c-Mpl, the thrombopoietin (TPO) receptor, and that TPO activates HUVECs in vitro, as indicated by directional migration, synthesis of 1-alkyl-/1-acyl-platelet-activating factor (PAF) and interleukin-8 (IL-8), and phosphorylation of the signal transducers and activators of transcription (STAT) STAT1 and STAT5B. The observation that WEB 2170 and CV3988, 2 structurally unrelated PAF receptor antagonists, prevented the motility of HUVECs induced by TPO suggests a role of PAF as secondary mediator. Moreover, kinetic analysis of TPO-induced tyrosine phosphorylation of STAT demonstrated that STAT5B activation temporally correlated with the synthesis of PAF. PAF, in turn, induced a rapid tyrosine phosphorylation of STAT5B and PAF receptor blockade, by WEB 2170, preventing both TPO- and PAF-mediated STAT5B activation. The in vivo angiogenic effect of TPO, studied in a mouse model of Matrigel implantation, demonstrated that TPO induced a dose-dependent angiogenic response that required the presence of heparin. Moreover, the in vivo angiogenic effect of TPO was inhibited by the PAF receptor antagonist WEB 2170 but not by the anti–basic fibroblast growth factor neutralizing antibody. These results indicate that the effects of TPO are not restricted to cells of hematopoietic lineages, because TPO is able to activate endothelial cells and to induce an angiogenic response in which the recruitment of endothelial cells is mediated by the synthesis of PAF. Moreover, biochemical analysis supports the hypothesis that STAT5B may be involved in the signaling pathway leading to PAF-dependent angiogenesis.