tbuckley/cabot-search huggingface dataset:
TLR4 as receptor for HMGB1 induced muscle dysfunction in myositis
Authors: Mei Zong, Joseph D Bruton, Cecilia Grundtman, Huan Yang, Jian Hua Li, Helene Alexanderson, Karin Palmblad, Ulf Andersson, Helena E Harris, Ingrid E Lundberg, Håkan Westerblad
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Polymyositis and dermatomyositis are characterised by muscle weakness and fatigue even in patients with normal muscle histology via unresolved pathogenic mechanisms. In this study, we investigated the mechanisms by which high mobility group box protein 1 (HMGB1) acts to accelerate muscle fatigue development. <h3>Methods</h3> Intact single fibres were dissociated from flexor digitorum brevis (FDB) of wild type, receptor for advanced glycation endproduct (RAGE) knockout and toll like receptor 4 (TLR4) knockout mice and cultured in the absence or presence of recombinant HMGB1. A decrease in sarcoplasmic reticulum Ca<sup>2+</sup> release during a series of 300 tetanic contractions, which reflects the development of muscle fatigue, was determined by measuring myoplasmic free tetanic Ca<sup>2+</sup>. TLR4 and major histocompatibility complex (MHC)-class I expression in mouse FDB fibres were investigated by immunofluorescence and confocal microscopy. Immunohistochemistry was used to investigate TLR4, MHC-class I and myosin heavy chain expression in muscle fibres of patients. <h3>Results</h3> Our results demonstrate that TLR4 is expressed in human and mouse skeletal muscle fibres, and coexpressed with MHC-class I in muscle fibres of patients with myositis. Furthermore, we show that HMGB1 acts via TLR4 but not RAGE to accelerate muscle fatigue and to induce MHC-class I expression in vitro. In order to bind and signal via TLR4, HMGB1 must have a reduced cysteine 106 and a disulphide linkage between cysteine 23 and 45. <h3>Conclusions</h3> The HMGB1-TLR4 pathway may play an important role in causing muscle fatigue in patients with polymyositis or dermatomyositis and thus is a potential novel target for future therapy.
Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with<i>MEFV</i>genotype
Authors: Alessia Omenetti, Sonia Carta, Laura Delfino, Alberto Martini, Marco Gattorno, Anna Rubartelli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To define in patients affected by familial Mediterranean fever (FMF) whether or not interleukin (IL)-1β secretion (1) is enhanced, (2) correlates with the type of <i>MEFV</i> mutation and (3) is mediated by NLRP3. <h3>Methods</h3> Freshly isolated monocytes from 21 patients with FMF (12 homozygous and 9 heterozygous), 14 <i>MEFV</i> healthy carriers and 30 healthy donors (HDs), unstimulated or after lipopolysaccharide (LPS)-induced activation, were analysed for redox state (production of reactive oxygen species (ROS) and antioxidant responses) and IL-1β and IL-1 receptor antagonist (IL-1Ra) secretion. <i>NLRP3</i> down-modulation was induced by in vitro silencing of the <i>NLRP3</i> gene. <h3>Results</h3> LPS-stimulated monocytes from patients with FMF displayed enhanced IL-1β secretion, which correlated with number and penetrance of <i>MEFV</i> mutations. Silencing of <i>NLRP3</i> consistently inhibited IL-1β secretion. As in other autoinflammatory diseases, FMF monocytes produced more ROS than genetically negative cells from HDs. Unlike in cryopyrin-associated periodic fever syndromes (CAPS), however, they were characterised by a conserved and sustained antioxidant response. Consistent with this finding, activated <i>MEFV</i>-mutated monocytes did not exhibit the functional indicators of oxidative stress observed in CAPS, including accelerated IL-1β secretion and deficient production of IL-1Ra. <h3>Conclusions</h3> <i>MEFV</i>-mutated monocytes display enhanced IL-1β secretion, which correlates with number of high-penetrance mutations and level of endogenous ROS. Unlike <i>NLRP3</i>-mutated cells, monocytes carrying <i>MEFV</i> mutations withstand oxidative stress and preserve IL-1Ra production, thereby limiting inflammation. Finally, in contrast with that found in the animal model, the increased secretion of IL-1β by LPS-stimulated FMF monocytes is NLRP3-dependent.
Symptoms and medical conditions in 204 912 patients visiting primary health-care practitioners in India: a 1-day point prevalence study (the POSEIDON study)
Authors: Sundeep Salvi, Komalkirti Apte, Sapna Madas, Monica Barne, Sushmeeta Chhowala, Tavpritesh Sethi, Kunal Aggarwal, Anurag Agrawal, Jaideep Gogtay
Journal: The Lancet Global Health (2015)

India has one of the highest disease burdens in the world. A better understanding of what ails India will help policy makers plan appropriate health-care services and infrastructure development, design medical education curricula, and identify health research priorities that are relevant to the needs of the country. The POSEIDON study aimed to record the prevalence of symptoms and medical conditions for which patients visit a primary health-care practitioner in India.We randomly selected 12 000 general practitioners, general physicians, and paediatricians from 880 cities and towns and invited them to record demographic details, symptoms, and medical conditions for every patient they saw on Feb 1, 2011. A further 1225 practitioners volunteered to participate and their responses were included. We did simple descriptive analyses of prevalence rates and used χ(2) tests to study comorbid associations. Through application of systems biology methods, we visualised inter-relations between organ involvement of diseases and symptoms and deciphered how these associations change with age and gender.We included responses from 7400 health-care practitioners, which represented data for 204 912 patients, who presented with 554 146 reasons for visit. Fever (35·5%) was the most common presenting symptom. More than half of all patients presented with respiratory symptoms across all age groups and regions of India. Other common presentations were digestive system symptoms (25%), circulatory symptoms (12·5%), skin complaints (9%), and endocrine disorders (6·6%). Hypertension (14·52%), obstructive airways diseases (14·51%), and upper respiratory tract infections (12·9%) were the most common diagnoses reported. Of note was that 21·4% of all patients with hypertension reported by the primary health-care practitioners were younger than 40 years. Anaemia was the fourth most common disease reported by these health-care practitioners and was most common in women of menstrual age living outside metro cities.The POSEIDON study provides insight into the reasons that patients visit primary health-care practitioners in India; our results highlight important social and medical challenges in the developing world.Chest Research Foundation, Council of Scientific and Industrial Research-Institute of Genomics and Integrated Biology (CSIR-IGIB), and Cipla Ltd.
Severity of atopic disease inversely correlates with intestinal microbiota diversity and butyrate-producing bacteria
Authors: L. Nylund, M. Nermes, E. Isolauri, S. Salminen, W. M. de Vos, R. Satokari
Journal: Allergy (2014)

The reports on atopic diseases and microbiota in early childhood remain contradictory, and both decreased and increased microbiota diversity have been associated with atopic eczema. In this study, the intestinal microbiota signatures associated with the severity of eczema in 6-month-old infants were characterized. Further, the changes in intestinal microbiota composition related to the improvement of this disease 3 months later were assessed. The severity of eczema correlated inversely with microbiota diversity (r = −0.54, P = 0.002) and with the abundance of butyrate-producing bacteria (r = −0.52, P = 0.005). During the 3-month follow-up, microbiota diversity increased (P < 0.001) and scoring atopic dermatitis values decreased (P < 0.001) in all infants. This decrease coincided with the increase in bacteria related to butyrate-producing Coprococcus eutactus (r = −0.59, P = 0.02). In conclusion, the high diversity of microbiota and high abundance of butyrate-producing bacteria were associated with milder eczema, thus suggesting they have a role in alleviating symptoms of atopic eczema.
Cellular distribution of the C-type II lectin dendritic cell immunoreceptor (DCIR) and its expression in the rheumatic joint: identification of a subpopulation of DCIR+ T cells
Authors: C Eklow, D Makrygiannakis, L Backdahl, L Padyukov, A-K Ulfgren, J C Lorentzen, V Malmstrom
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> An association to variations in the dendritic cell immunoreceptor (DCIR) gene with rheumatoid arthritis (RA) was recently shown. However, protein expression of DCIR has so far not been assessed in a disease setting. In the present work, we aimed to determine the cellular and tissue distribution of this receptor in healthy controls and in patients with RA before and after local glucocorticoid administration. <h3>Methods:</h3> DCIR mRNA expression was evaluated by quantitative PCR (n = 3) and protein expression by flow cytometry (n = 18), immunohistochemistry (n = 14) and double immunofluorescence (n = 5). <h3>Results:</h3> DCIR protein was not detected in healthy synovia. By contrast, expression was abundant on cells from rheumatic joints in synovial fluid and in tissue. Following corticosteroid treatment this expression was downregulated. Interestingly, DCIR could be detected on natural killer (NK) cells and T cells, and CD4+ and CD8+, as well as on monocytes, B cells, dendritic cells and granulocytes. The frequency of DCIR+ T cells and the level of surface expression were increased in the rheumatic joint compared to blood. In synovial fluid the typical DCIR+ T cells were large activated cells, whereas blasted DCIR+ T cells were not detected in blood. <h3>Conclusions:</h3> We demonstrate increased protein and mRNA expression of DCIR in RA, especially in the rheumatic joint. Expression was widespread and included a subpopulation of T cells. This suggests that the inflammatory synovial environment induces DCIR expression, and this may be related to synovial T cell function. Ligation of DCIR, or lack thereof, could contribute to the chronic inflammation characterising autoimmune diseases such as RA.
Elevated Fibroblast Growth Factor 23 is a Risk Factor for Kidney Transplant Loss and Mortality
Authors: Myles Wolf, Miklos Z. Molnar, Ansel P. Amaral, Maria E. Czira, Anna Rudas, Akos Ujszaszi, Istvan Kiss, Laszlo Rosivall, Janos Kosa, Peter Lakatos, Csaba P. Kovesdy, Istvan Mucsi
Journal: Journal of the American Society of Nephrology (2011)

An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P<0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.
Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer
Authors: David D. Bowtell, Steffen Böhm, Ahmed A. Ahmed, Paul-Joseph Aspuria, Robert C. Bast, Valerie Beral, Jonathan S. Berek, Michael J. Birrer, Sarah Blagden, Michael A. Bookman, James D. Brenton, Katherine B. Chiappinelli, Filipe Correia Martins, George Coukos, Ronny Drapkin, Richard Edmondson, Christina Fotopoulou, Hani Gabra, Jérôme Galon, Charlie Gourley, Valerie Heong, David G. Huntsman, Marcin Iwanicki, Beth Y. Karlan, Allyson Kaye, Ernst Lengyel, Douglas A. Levine, Karen H. Lu, Iain A. McNeish, Usha Menon, Steven A. Narod, Brad H. Nelson, Kenneth P. Nephew, Paul Pharoah, Daniel J. Powell, Pilar Ramos, Iris L. Romero, Clare L. Scott, Anil K. Sood, Euan A. Stronach, Frances R. Balkwill
Journal: Nature reviews. Cancer (2015)
Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
Authors: Ning Liang, Chi Zhang, Patricia Dill, Ganna Panasyuk, Delphine Pion, Vonda Koka, Morgan Gallazzini, Eric N. Olson, Hilaire Lam, Elizabeth P. Henske, Zheng Dong, Udayan Apte, Nicolas Pallet, Randy L. Johnson, Fabiola Terzi, David J. Kwiatkowski, Jean-Yves Scoazec, Guido Martignoni, Mario Pende
Journal: The Journal of Experimental Medicine (2014)

Genetic studies have shown that the tuberous sclerosis complex (TSC) 1–TSC2–mammalian target of Rapamycin (mTOR) and the Hippo–Yes-associated protein 1 (YAP) pathways are master regulators of organ size, which are often involved in tumorigenesis. The crosstalk between these signal transduction pathways in coordinating environmental cues, such as nutritional status and mechanical constraints, is crucial for tissue growth. Whether and how mTOR regulates YAP remains elusive. Here we describe a novel mouse model of TSC which develops renal mesenchymal lesions recapitulating human perivascular epithelioid cell tumors (PEComas) from patients with TSC. We identify that YAP is up-regulated by mTOR in mouse and human PEComas. YAP inhibition blunts abnormal proliferation and induces apoptosis of TSC1–TSC2-deficient cells, both in culture and in mosaic Tsc1 mutant mice. We further delineate that YAP accumulation in TSC1/TSC2-deficient cells is due to impaired degradation of the protein by the autophagosome/lysosome system. Thus, the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth-permissive conditions. YAP may serve as a potential therapeutic target for TSC and other diseases with dysregulated mTOR activity.
Plasticity of Renal Erythropoietin-Producing Cells Governs Fibrosis
Authors: Tomokazu Souma, Shun Yamazaki, Takashi Moriguchi, Norio Suzuki, Ikuo Hirano, Xiaoqing Pan, Naoko Minegishi, Michiaki Abe, Hideyasu Kiyomoto, Sadayoshi Ito, Masayuki Yamamoto
Journal: Journal of the American Society of Nephrology (2013)

CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction–induced inflammatory milieu activated NFκB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFκB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFκB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction–induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.
DNA Topoisomerase I Gene Copy Number and mRNA Expression Assessed as Predictive Biomarkers for Adjuvant Irinotecan in Stage II/III Colon Cancer
Authors: Sune Boris Nygård, Ben Vainer, Signe Lykke Nielsen, Fred Bosman, Sabine Tejpar, Arnaud Roth, Mauro Delorenzi, Nils Brünner, Eva Budinska
Journal: Clinical Cancer Research (2015)

Prospective-retrospective assessment of the TOP1 gene copy number and TOP1 mRNA expression as predictive biomarkers for adjuvant irinotecan in stage II/III colon cancer.Formalin-fixed, paraffin-embedded tissue microarrays were obtained from an adjuvant colon cancer trial (PETACC3) where patients were randomized to 5-fluorouracil/folinic acid with or without additional irinotecan. TOP1 copy number status was analyzed by fluorescence in situ hybridization (FISH) using a TOP1/CEN20 dual-probe combination. TOP1 mRNA data were available from previous analyses.TOP1 FISH and follow-up data were obtained from 534 patients. TOP1 gain was identified in 27% using a single-probe enumeration strategy (≥4 TOP1 signals per cell) and in 31% when defined by a TOP1/CEN20 ratio ≥ 1.5. The effect of additional irinotecan was not dependent on TOP1 FISH status.TOP1 mRNA data were available from 580 patients with stage III disease. Benefit of irinotecan was restricted to patients characterized by TOP1 mRNA expression ≥ third quartile (RFS: HRadjusted, 0.59;P= 0.09; OS: HRadjusted, 0.44;P= 0.03). The treatment by TOP1 mRNA interaction was not statistically significant, but in exploratory multivariable fractional polynomial interaction analysis, increasing TOP1 mRNA values appeared to be associated with increasing benefit of irinotecan.In contrast to the TOP1 copy number, a trend was demonstrated for a predictive property of TOP1 mRNA expression. On the basis of TOP1 mRNA, it might be possible to identify a subgroup of patients where an irinotecan doublet is a clinically relevant option in the adjuvant setting of colon cancer.
Effect of lifestyle on levels of specific IgE antibodies
Authors: T. Shirakawa, K. Morimoto
Journal: Allergy (1993)

Specific IgE antibodies against cobalt‐conjugated human serum albumin (Co‐HSA) were determined in serum samples from 706 hard metal workers who responded to a questionnaire on 17 physical and mental health practices. Hard metal (an alloy of cobalt) exposure resulted in significant ( P &lt;0.05) increases in Co‐HSA RAST indices in male subjects. In contrast, no factor concerning health practices made an independent contribution to elevation or suppression of specific IgE levels against cobalt. Although total IgE level was found to be significantly ( P &lt;0.01) modulated by the cumulative health practice index (HPIA: Health Practice Index in Allergic reaction), which was extracted by MANOVA analysis while controlling for sex, age, and environmental factors, no significant association was found between HPIA and specific IgE level against cobalt. Multiple logistic analysis also revealed that health practices and hard metal exposure had a significant relative risk (&gt;2.3; P &lt;0.05) of elevating Co‐HSA RAST index when the total IgE level was more than 400 IU/ml. Thus, a healthy lifestyle as well as discouragement of occupational exposure may be of benefit in reducing allergic disorders for persons with high IgE levels.
Aurora-A and hBora Join the Game of Polo
Authors: Libor Macurek, Arne Lindqvist, René H. Medema
Journal: Cancer Research (2009)

Abstract Overactivation of both Polo-like kinase-1 (Plk1) and Aurora-A is linked to cancer development, and small-molecule inhibitors that target these kinases are currently tested as anticancer drugs. Here, we discuss recent advances in the understanding of the functional crosstalk between Plk1 and Aurora-A before and during mitosis. Several recent findings have led to a better appreciation of how the activities of these distinct mitotic kinases are intertwined. Such insight is important for the expected utility of small-molecule inhibitors targeting Plk1 or Aurora-A, and it might help us to improve their application. [Cancer Res 2009;69(11):4555–8]
ANTIGENICITY OF POLYPEPTIDES (POLY ALPHA AMINO ACIDS)
Authors: Paul Pinchuck, Paul H. Maurer
Journal: The Journal of Experimental Medicine (1965)

The ability of mice to form antibodies against the random terpolymer glu57lys38ala5 is controlled by a codominant Mendelian factor. Three of 7 inbred strains were 100 per cent responders; the others were completely negative. All of these strains could make antibody to related polymers with higher alanine content (10 and 40 mole per cent). Breeding studies using the progeny of Swiss mice indicated that a similar genetic factor was involved.
Non-equilibrium behavior of HCN channels: Insights into the role of HCN channels in native and engineered pacemakers
Authors: E AZENE, T XUE, E MARBAN, G TOMASELLI, R LI
Journal: Cardiovascular Research (2005)

I(f), encoded by the hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channel gene family, modulates cardiac pacing. During cardiac pacing, changes in membrane potential are rapid, preventing the very slow HCN channels from reaching equilibrium. Here, we examined the properties of HCN channels under non-equilibrium conditions to shed insight into how different HCN isoforms contribute to cardiac pacing.HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp. We found that HCN1 channel activation (V1/2) depended strongly on the holding potential (V(H)) for short (100 ms; V1/2=-118 mV, -78 mV and -19 mV for V(H)= +70, -75 and -140 mV, respectively, in Xenopus oocytes) but not long (300-ms) test-pulses, hinting that shifts of V1/2 under non-equilibrium conditions may alter the impact of I(f) in different phases of the cardiac circle. Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis. Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing. By contrast, HCN4 did not exhibit IV-hysteresis. This difference can be attributed to the relatively large activation time constant and markedly delayed onsets of time-dependent HCN4 currents. Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype.We conclude that non-equilibrium properties of HCN channels contribute to cardiac pacing. These results provide insight for tuning the firing rate of endogenous and induced pacemakers using engineered HCN constructs with distinct gating phenotypes.