tbuckley/cabot-search huggingface dataset:
04.21 Oncostatin m induces inflammation, angiogenesis and notch signalling in the ra joints, and displays pleiotropic effects on tnfα-induced pro-inflammatory effects
Authors: Megan Hanlon, Doug Veale, Tatsiana Rakovich, Siobhan Wade, Monika Biniecka, Ursula Fearon, Trudy McGarry
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Oncostatin M (OSM) is a pleiotropic cytokine that has both agonistic and antagonistic effects depending on the inflammatory microenvironment. This study examines the effect of OSM on TNFα-induced pro-inflammatory mechanisms and on Notch-1 signalling in Rheumatoid Arthritis. <h3>Methods</h3> Primary RA synovial fibroblasts (RASFC) isolated from RA synovial biopsies obtained at time of knee arthroscopy and human dermal microvascular endothelial cells (HMVEC) were grown to confluence. RASFC and HMVEC were cultured with OSM (10ngml) alone or in combination with increasing concentrations of TNFα (0.01–1 ng/ml). IL-6, IL-8, RANTES, GROα and MCP-1 cytokines/chemokines were quantified in culture supernatants by ELISA. Functionally, angiogenesis and invasion were assessed by matrigel tube formation and Transwell invasions assays, VEGF and β1-integrin in cell lysates by Real-time PCR. Finally, Notch-1, its ligands Delta-like-ligand 4 (DLL4) and Jagged-1 (Jag-1) and downstream transcriptional repressors-Hey-1 and Hey-2 were quantified by Real-time PCR. <h3>Results</h3> OSM alone significantly induced IL-6 and MCP-1 while inhibiting IL-8 and GROα in RASFC and HMVEC culture supernatants. OSM alone induced RANTES expression in HMVEC with no effect observed for RASFC. OSM potentiated the effect of TNFα on IL-6 and MCP-1 secretion from RASFC and HMVEC. Conversely OSM inhibited TNFα-induced-IL-8 and GROα secretion from RASFC and HMVEC. Interestingly, OSM significantly inhibited TNFα-induced RANTES expression in HMVEC and conversely potentiated this effect in RASFC. At a functional level, OSM induced both RASFC and HMVEC invasion and network formation and induced VEGF expression compared to basal control. Finally OSM significantly induced Notch-1 and Hey-2 in RASFC and HMVEC in a time dependent manner, but interestingly differentially regulated the Notch-1 ligands, with induction of Jag-1 only observed in RASFC, and induction of DLL-4 only observed in HMVEC. <h3>Conclusion</h3> OSM is a pleiotropic cytokine that differentially regulates pro-inflammatory mechanisms within the inflamed joint, effects that appear to be dependent on cell type and the inflammatory microenvironment. Targeting OSM or downstream signalling pathways may have therapeutic potential.
RISK FACTORS FOR OVERUSE SHOULDER INJURIES AMONG 329 ELITE HANDBALL PLAYERS: A PROSPECTIVE COHORT STUDY
Authors: Stig H. Andersson, Roald Bahr, Ben Clarsen, Grethe Myklebust
Journal: British Journal of Sports Medicine (2017)

Background Shoulder injuries are common among handball players and are dominated by overuse characteristics. Objective Assess the effect of three previously identified risk factors for shoulder problems (reduced glenohumeral rotation, external rotation weakness and scapula dyskinesis). Design Prospective cohort. Setting Twenty-three handball teams (12 male; 11 female) from the two upper divisions in Norway followed for one competitive season (7 months). Participants Of 333 players with a team contract, 329 (age 17–47) entered the study (168 male; 161 female); 39 of these dropped out (21 male; 18 female). Assessment of Risk Factors Prior to the 2014–2015 season we assessed glenohumeral internal and external rotation range of motion, isometric internal and external rotation, as well as scapular dyskinesis. Main Outcome Measurements Prevalence and severity of shoulder problems registered monthly using the Oslo Sports Trauma Research Center Overuse Injury Questionnaire. We used the average severity score for each player as the outcome measure in a multivariable logistic regression model to investigate associations between candidate risk factors and shoulder injury. Results The average season prevalence of shoulder problems was 20% (95% CI 15% to 26%) among men and 26% (95% CI 26% to 27%) among women; the average prevalence of substantial problems was 7% (95% CI 6% to 7%) and 9% (95% CI 8% to 11%) among men and women, respectively. Significant associations were found between internal rotation motion (OR 1.16 per 5° change, 95% CI 1.00 to 1.34) and isometric external:internal rotation strength ratio &lt;80% (OR 3.17, 95% CI 1.01 to 9) and shoulder injury. Scapula dyskinesis was not associated with shoulder injury (OR 1.36, 95% CI 0.41 to 4.50). Conclusions This study confirms that external rotation weakness is associated with shoulder injury and should be incorporated in injury prevention programmes, while exercises targeting internal rotation motion and scapula dyskinesis should be excluded.
Effect of continuous positive airway pressure on blood pressure and metabolic profile in women with sleep apnoea
Authors: Francisco Campos-Rodriguez, Monica Gonzalez-Martinez, Angeles Sanchez-Armengol, Bernabe Jurado-Gamez, Jose Cordero-Guevara, Nuria Reyes-Nuñez, Maria F. Troncoso, Araceli Abad-Fernandez, Joaquin Teran-Santos, Julian Caballero-Rodriguez, Mercedes Martin-Romero, Ana Encabo-Motiño, Lirios Sacristan-Bou, Javier Navarro-Esteva, Maria Somoza-Gonzalez, Juan F. Masa, Maria A. Sanchez-Quiroga, Beatriz Jara-Chinarro, Belen Orosa-Bertol, Miguel A. Martinez-Garcia
Journal: European Respiratory Journal (2017)

Continuous positive airway pressure (CPAP) reduces blood pressure levels in hypertensive patients with obstructive sleep apnoea (OSA). However, the role of CPAP in blood pressure and the metabolic profile in women has not yet been assessed. In this study we investigated the effect of CPAP on blood pressure levels and the glucose and lipid profile in women with moderate-to-severe OSA. A multicentre, open-label, randomised controlled trial was conducted in 307 women diagnosed with moderate-to-severe OSA (apnoea–hypopnoea index ≥15 events·h –1 ) in 19 Spanish Sleep Units. Women were randomised to CPAP (n=151) or conservative treatment (n=156) for 12 weeks. Changes in office blood pressure measures as well as in the glucose and lipid profile were assessed in both groups. Compared with the control group, the CPAP group achieved a significantly greater decrease in diastolic blood pressure (−2.04 mmHg, 95% CI −4.02– −0.05; p=0.045), and a nonsignificantly greater decrease in systolic blood pressure (−1.54 mmHg, 95% CI −4.58–1.51; p=0.32) and mean blood pressure (−1.90 mmHg, 95% CI −4.0–0.31; p=0.084). CPAP therapy did not change any of the metabolic variables assessed. In women with moderate-to-severe OSA, 12 weeks of CPAP therapy improved blood pressure, especially diastolic blood pressure, but did not change the metabolic profile, compared with conservative treatment.
FRI0049 Fc gamma receptor iv enhances bone erosion in experimental arthritis by promoting influx of pmns
Authors: I Di Ceglie, G Ascone, M van den Bosch, JS Verbeek, P van der Kraan, P van Lent
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> FcγRs are involved in regulation of synovial activation and bone destruction during immune complex (IC)-mediated arthritis. The balance between activating FcγRs (FcγRI,III and IV) and inhibiting FcγRII determines synovial activation. Here we investigated the particular role of activating FcγRIV in bone erosion in IC-mediated antigen induced arthritis (AIA) by comparing FcγRI,II,III,IV<sup>-/-</sup> mice, FcγRI,II,III<sup>-/-</sup> mice and wild type controls (WT). <h3>Objectives</h3> To investigate the role of FcγRIV in bone erosion during experimental arthritis. <h3>Methods</h3> AIA was induced by injection of mBSA into knee joints of mice previously immunized with mBSA/CFA. Joint inflammation, bone destruction, number of TRAP<sup>+</sup> osteoclasts and S100A8/A9 positive cells was determined using histology and immunohistochemistry. <i>In vitro</i> osteoclastogenesis was assessed using TRAP staining. <h3>Results</h3> Seven days after induction of AIA, we observed decreased inflammation and bone erosion in the knee joints of FcγRI,II,III,IV<sup>-/-</sup> mice compared to WT. The ability of bone marrow cells of FcγRI,II,III,IV<sup>-/-</sup> mice to differentiate into osteoclasts <i>in vitro</i> was comparable to the one of WT controls. Moreover, we observed comparable numbers of TRAP<sup>+</sup> osteoclasts on the bone surface of FcγRI/II/III/IV<sup>-/-</sup> and WT arthritic mice, suggesting that the observed decrease in bone erosion is mainly caused by a reduced osteoclast activity, rather than decreased osteoclast number. However, in contrast to FcγRI/II/III/IV<sup>-/-</sup>, AIA induction in knee joints of FcγRI/II/III <sup>-/-</sup> resulted in increased bone erosion and inflammation compared to WT, highlighting the possible crucial role of FcγRIV in the pathology. Interestingly, the number of PMNs infiltrated in the knee joint of FcγRI/II/III<sup>-/-</sup> resulted increased, whereas it was decreased in the knee joints of FcγRI/II/III/IV<sup>-/-</sup> compared to their WT controls. This observation suggests that particularly FcγRIV is involved in regulating influx of PMNs. PMNs are potent producers of alarmins S100A8/A9 which are described to promote osteoclast activity. In line the number of S100A8/A9 positive cells in synovium was increased in FcγRI/II/III<sup>-/-</sup> while decreased in FcγRI/II/III/IV<sup>-/-</sup>, compared to their WT control. <h3>Conclusions</h3> FcγRIV promotes bone erosion in AIA by enhancing influx of PMNs within the synovium. PMNs are potent producers of S100A8/A9 which has been described to induce osteoclast activity. <h3>Disclosure of Interest</h3> None declared
Setting the Record Straight on FDA Approvals in Oncology—Reply
Authors: Diana Zuckerman
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Abstract P273: Enhancement of Proteasomal Function Protects Against Proteinopathy and Myocardial Ischemia-Reperfusion Injury in Mice
Authors: Jie Li, Kathleen M Horak, Huabo Su, Atsushi Sanbe, Jeffrey Robbins, Xuejun (XJ) Wang
Journal: Circulation Research (2011)

The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) was observed in experimental proteinopathies and implicated in many human common diseases but its pathogenic role has not been established because a measure to enhance proteasome function in the cell has not been reported until very recently. We have recently discovered that overexpression of proteasome activator 28α (PA28α) enhances proteasome-mediated removal of abnormal proteins in the cell and protects against oxidative stress in cultured cardiomyocytes ( FASEB J 2011; 25(3):883-93 ). Here we have extended the in vitro discoveries to intact animals. First, we created inducible transgenic mice with cardiomyocyte-restricted PA28α overexpression (CR-PA28αOE). CR-PA28αOE does not alter the homeostasis of normal proteins and cardiac function but increases the degradation of a surrogate misfolded protein in the heart. This marks the establishment of the first animal model of benign enhancement of proteasomal function. Second, by breeding CR-PA28αOE mice with a well-established mouse model of mutant αB-crystallin (CryAB R120G ) based desmin-related cardiomyopathy, a bona fide cardiac proteinopathy, we demonstrate that CR-PA28αOE markedly reduced aberrant protein aggregation and cardiac hypertrophy and the lifespan of the animals significantly increased. Furthermore, PA28α knockdown promoted, while PA28αOE attenuated, CryAB R120G protein accumulation in cultured cardiomyocytes. Finally, we tested the effect of proteasome functional enhancement on myocardial ischemia/reperfusion (I/R) injury induced by ligation and subsequent release of the left anterior descending artery. We found that the infarct size was significantly reduced and cardiac function recovery during reperfusion was markedly facilitated in the CR-PA28αOE mice, compared with their littermate control mice. We conclude that (1) benign enhancement of cardiac proteasome function can be achieved by CR-PA28αOE; (2) PFI plays a major pathogenic role in proteinopathy and myocardial I/R injury; and (3) upregulating PA28α is potentially a novel therapeutic strategy for proteinopathies and disease alike.
Abstract P202: Role of Lipid Peroxidation--Derived Carbonyls in Left Ventricular Hypertrophy
Authors: Shahid P Baba, Mahavir Singh, Aruni Bhatnagar
Journal: Circulation Research (2011)

Pathological left ventricular hypertrophy (LVH) is a key factor in the development of heart failure and cardiomyopathy. It is characterized by increased oxidative stress however the mechanisms by which it affects pathological LVH remain unclear. Because the effects of reactive oxygen species are mediated by products of lipid peroxidation, we hypothesize that myocardial injury induced by LVH is mediated by lipid carbonyls, which form covalent adducts with proteins that induces autophagy. To test this hypothesis, we examined the role of aldose reductase (AKR1B3; AR) an enzyme that catalyzes the detoxification of lipid carbonyls in modulating the cardiac stress responses in WT and AR-null mice hearts that were subjected to transverse aortic constriction (TAC). Two weeks after the TAC cardiac enlargement in the AR-null TAC mice was more prominent compared with WT TAC mice. Hemodynamic analysis of the AR-null TAC mice demonstrated left ventricular dilatation and severe contractile dysfunction compared with WT TAC mice. Expression levels of molecular marker for hypertrophy (ANF) increased 2-3 fold in AR-null TAC compared with the WT-TAC. Western blot analysis of the heart homogenates using anti-4 hydroxy-trans-2-nonenal (HNE) antibody showed that the formation of HNE-protein adduct (300KDa) increased 100-fold and the bands corresponding to molecular weights of 75KDa, 40KDa increased 2 to 3-fold after the TAC in WT hearts and the intensity of these bands in AR-null TAC hearts was significantly higher compared with WT TAC. Immuno-blot analysis of the heart homogenates revealed an increase in the LC3-I to LC3-II conversion in banded hearts compared with sham-operated controls and the autophagic activity was more prominent in the AR-null compared to the WT banded hearts. Isolated adult cardiomyocytes from WT and AR-null hearts perfused with HNE resulted in an increase in autophagy and the increase in autophagic activity was robust in AR-null than in WT myocytes. These data establish that TAC-induced hypertrophy increases protein-HNE-adduct formation and autophagic activity and the deletion of akr1b3 gene exacerbates these responses to pressure overload.
Norman Orentreich, The Father of Hair Transplantation
Authors: Noman Choudhry, Anshum Sood, Stephanie Steinweg
Journal: JAMA Dermatology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Diaphragm Atrophy and Weakness in the Absence of Mitochondrial Dysfunction in the Critically Ill
Authors: Marloes van den Berg, Pleuni E. Hooijman, Albertus Beishuizen, Monique C. de Waard, Marinus A. Paul, Koen J. Hartemink, Hieronymus W. H. van Hees, Michael W. Lawlor, Lorenza Brocca, Roberto Bottinelli, Maria A. Pellegrino, Ger J. M. Stienen, Leo M. A. Heunks, Rob C. I. Wüst, Coen A. C. Ottenheijm
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency and increases morbidity, duration of hospital stay, and health care costs. The mechanisms underlying diaphragm weakness are unknown, but might include mitochondrial dysfunction and oxidative stress.We hypothesized that weakness of diaphragm muscle fibers in critically ill patients is accompanied by impaired mitochondrial function and structure, and by increased markers of oxidative stress.To test these hypotheses, we studied contractile force, mitochondrial function, and mitochondrial structure in diaphragm muscle fibers. Fibers were isolated from diaphragm biopsies of 36 mechanically ventilated critically ill patients and compared with those isolated from biopsies of 27 patients with suspected early-stage lung malignancy (control subjects).Diaphragm muscle fibers from critically ill patients displayed significant atrophy and contractile weakness, but lacked impaired mitochondrial respiration and increased levels of oxidative stress markers. Mitochondrial energy status and morphology were not altered, despite a lower content of fusion proteins.Critically ill patients have manifest diaphragm muscle fiber atrophy and weakness in the absence of mitochondrial dysfunction and oxidative stress. Thus, mitochondrial dysfunction and oxidative stress do not play a causative role in the development of atrophy and contractile weakness of the diaphragm in critically ill patients.
PTH-117 Subcortical brain morphology differences in gastrointestinal disorders may be confounded by baseine autonomic function
Authors: JK Ruffle, SJ Coen, V Giampietro, Scr Williams, AD Farmer, Q Aziz
Journal: Gut (2017)

Introduction  The autonomic nervous system (ANS) modulates numerous processes, including metabolic control and visceral pain processing. Accumulating evidence purports that ANS function is disturbed in both inflammatory bowel disease and irritable bowel syndrome (IBS). Whilst the brain is a central hub for regulating autonomic function, the association between resting autonomic activity and subcortical morphology has not been comprehensively studied and thus we sought to address this knowledge gap.  Method  In twenty-seven healthy subjects (14 male and 13 female; mean age 30 years (range 22–53 years)), we quantified resting cardiac sympathetic index (CSI) and parasympathetic cardiac vagal tone (CVT) using a Neuroscope. Autonomic parameters were recorded as per international recommendations. In addition, high resolution structural magnetic resonance imaging scans were acquired using a GE Signa HDxt3.0 Tesla scanner. Subcortical shape differences, i.e. “deformation”, contingent on resting ANS activity were studied using FSL-FIRST, by means of positive and negative linear contrasts.  Results  CSI was significantly associated with outward deformation of the brainstem, right nucleus accumbens, right amygdala and bilateral pallidum (family-wise error (FWE) corrected p  Conclusion  Our study provides novel evidence that resting autonomic state is associated with differences in the shape and/or volume of subcortical nuclei. The Rome working group have highlighted that inter-individual differences are a key limiting factor in the neuroimaging of visceral pain, these data suggest that resting autonomic function reflects an additional important variable. Given that perturbations in autonomic function and brain morphological differences are well described in IBS, our findings suggest that future studies should control for resting autonomic tone as covariates.  Disclosure of Interest  J. Ruffle: None Declared, S Coen: None Declared, V Giampietro: None Declared, S Williams: None Declared, A Farmer Conflict with: Medical Research Council Grant, Q Aziz Conflict with: Medical Research Council Grant
Promoter DNA methylation of CD10 in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene
Authors: Y. Ikawa, N. Sugimoto, S. Koizumi, A. Yachie, Y. Saikawa
Journal: Journal of Clinical Oncology (2009)

10045 Background: Infant ALL displays distinct biologic and clinical features with a poor prognosis. The CD10-negative immunophenotype of infant ALL is a hallmark and provides a predictable signature of MLL rearrangements. While CD10 negativity reflects an earlier stage of B-cell development, complete IgH gene rearrangements (VDJ H ) show more mature IgH status. Discordance between immunophenotype and genotype of infant ALL suggests an aberrant process in immunophenotypic steps of differentiation or a secondary down-regulation of CD 10 expression associated with MLL rearrangements. We performed methylation analysis of full promoter regions of the CD10 gene to investigate epigenetic mechanisms responsible for CD10 negativity. Methods: CD10-negative infant ALL with MLL/AF4, CD10-positive infant ALL with germ-line MLL, CD10-positive pre-B ALL cell line, infant AML (M5) with MLL/AF9 and pediatric AML (M2) with AML1/ETO were analyzed for VDJ H status and methylation of CD10 gene promoters. Results: Three of 4 cases with infant ALL revealed complete rearrangements of VDJ H gene with productive joints. Bisulfite sequencing of CD 10 type 1 and 2 promoters identified more than 84% of methylated CpG dinucleotides in all three CD10-negative infant ALL cases with MLL/AF4. The CpG dinucleotides distributed in the clusters of putative Sp 1 binding sites and functionally active regulatory regions of the promoters were fully methylated. In contrast, none or a few of the CpG dinucleotides were methylated in the CD10-positive ALL, AML (M5) with MLL/AF9 or AML (M2) with AML1/ETO. Conclusions: Structural evidence of dense methylation in the CD 10 gene promoter suggested that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism. [Table: see text] No significant financial relationships to disclose.
白血病:単一細胞トランスクリプトミクスによって明らかになった,慢性骨髄性白血病の幹細胞で見られる異なる分子シグネチャー
Authors: Giustacchini Alice, Thongjuea Supat, Barkas Nikolaos, Povinelli Benjamin J, Booth Christopher A G, Sopp Paul, Norfo Ruggiero, Rodriguez‐Meira Alba, Ashley Neil, Jamieson Lauren, Vyas Paresh, Jacobsen Sten Eirik W, Mead Adam J, Woll Petter S, Anderson Kristina, Segerstolpe Asa, Sandberg Rickard, Qian Hong, Olsson‐Stroemberg Ulla, Mustjoki Satu
Journal: Nature Medicine (2017)