tbuckley/cabot-search huggingface dataset:
AB0850 THE LIPID SPECTRUM OF BLOOD, DEPENDING OF BONE MINERAL DENSITY (BMD) IN MEN WITH CORONARY HEART DISEASE (CHD)
Authors: Tatiana Raskina, Anna Voronkina, Marina Letaeva, Olga Barbarash, Vyacheslav Fanaskov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The problem of the relationship between osteoporosis in men and risk factors for atherosclerosis is insufficiently studied. <h3>Objectives</h3> The aim was to assess the lipid profile of the blood depending on the BMD in men with CHD. <h3>Methods</h3> 93 men older than 50 years (mean age – 60.8±6.9 years) with coronary artery disease verified by coronary angiography were examined. The concentration of total cholesterol (OHS), triglycerides (TG), high and low density lipoprotein cholesterol (HDL and LDL cholesterol) in serum was determined by spectrophotometric method. T-criterion of the femoral neck and lumbar spine was used for the assessment of BMD, which was investigated by the method of two-energy absorptiometry (densitometer Excel XR-46, NORLAND, USA). According to the T-criterion, patients were divided into 3 groups: I – 30 patients with osteoporosis (T-criterion ≤-2.5), II – 44 patients with osteopenia (T-criterion from -1 to -2.5) and III – 19 men with normal BMD (T-criterion ≥-1). <h3>Results</h3> Most men with established CHD dyslipidemia (95.7% of patients): hypercholesterolemia – 76.3%, elevated level of LDL cholesterol – 81.7% of the patients, hypertriglyceridemia in 49.5%, a decrease in the concentration of HDL cholesterol – 44.1% of cases. In all three groups of patients hypercholesterolemia (80, 75 and 73.7% of patients in groups I, II and III, p&gt;0.05) and increased LDL-C concentration (83.3, 84.1 and 73.7% of men in groups I, II and III, p&gt;0.05) were revealed. Reduction of HDL cholesterol level was determined in 46.7% of cases in group I, 43.2% in group II and 42.1% in group III (p&gt;0.05). Hypertriglyceridemia was registered in 60% of patients with osteoporosis, 43.2% - with osteopenia and 47.4% – with normal BMD (p&gt;0.05). Correlation analysis of the relationship of lipid metabolism with the T-criterion in all patients included in the study did not reveal significant relationships (p&gt;0.05). <h3>Conclusion</h3> The results of the study indicate the presence of severe dyslipidemia and the absence of dependence of lipid parameters on the state of BMD in men with CHD. <h3>Disclosure of Interests</h3> None declared
Parkin Knockout Inhibits Neuronal Development via Regulation of Proteasomal Degradation of p21
Authors: Mi Hee Park, Hwa-Jeong Lee, Hye Lim Lee, Dong Ju Son, Jung Hoon Ju, Byung Kook Hyun, Sung Hee Jung, Ju-Kyoung Song, Dong-Hoon Lee, Chul Ju Hwang, Sang Bae Han, Sanghyeon Kim, Jin Tae Hong
Journal: Theranostics (2017)

PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in the development of Parkinson's disease (PD).Although the neuroprotective role of parkin is well known, the mechanism of PARK2's function in neural stem differentiation has not yet been thoroughly studied.Co-expressions network analysis showed that synaptosomal-associated protein 25 (SNAP-25) and brain-derived neurotrophic factor (BDNF) were positively correlated with parkin, but negatively correlated with p21 in human patient brain.We investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation.We found that the neurogenesis was lowered in PARK2 knockout (KO) mice compared with non-tg mice.Expression of the marker protein for neural cell differentiation such as class III beta tubulin (TUBBIII), glial fibrillary acidic protein (GFAP) and neurofilament, as well as SNAP25 and BDNF, was down regulated in PARK2 KO mice.Associated with the loss of differentiation function, p21 protein was highly accumulated in the neural stem cells of PARK2 KO mice.We discovered that p21 directly binds with parkin and is ubiquitinated by parkin which resulted in the loss of cell differentiation ability.Introduction of p21 shRNA in PARK2 KO mice significantly rescued the differentiation efficacy as well as SNAP25 and BDNF expression.c-Jun N-terminal kinase (JNK) pathway is implicated in neurogenesis and p21 degradation.We also defined the decreased p21 ubiquitination and differentiation ability were reversed after treatment with JNK inhibitor, SP600125 in PARK2 KO mice derived neural stem cells.Thus, the present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21.
Abstract 257: Oxidative Stress Induces Endothelial Dysfunction: Role of Ubiquitin-Proteasome System
Authors: Jian Xu, Shuangxi Wang, Yong Wu, Ping Song, Miao Zhang, Ming-Hui Zou
Journal: Circulation (2007)

Endothelial Nitric oxide (NO) production is dependent on adequate cellular tetrahydrobiopterin (BH 4 ), a key cofactor for endothelial NO syntheses (eNOS). Reduction of BH 4 levels is reported in diseased vessels and plays a causal role in the development of eNOS uncoupling. However, the mechanisms that lead to BH 4 reduction are not entirely understood. Here we report that angiotensin-II (Ang II) reduced tetrahydrobiopterin (BH 4 ) and eNOS uncoupling by peroxynitrite ONOO − )-triggered proteasome activation. Compared to control, exposure of human umbilical vein endothelial cells (HUVEC) to angiotensin II (Ang II, 100nM) for 6h significantly decreased the levels of total biopterins (BH 4 plus BH 2 ) and BH 4 (−22.0 4.6%, n= 3, p&lt;0.01), indicating decreased synthesis of biopterins. In parallel, Ang II but not vehicle significantly reduced the levels of GTP-cyclohydrolase (GTPCH), a rate-limiting enzyme for de novo synthesis of biopterins, and dihydrofolate reductase (DHFR), a crucial enzyme for BH 4 recycle from BH 2 . Ang II but not vehicle significantly increased the 26S proteasome activity. In addition, administration of proteasome inhibitors, MG132, abolished the Ang II-induced reduction of both GTPCH and DHFR. While Ang II significantly increased O 2 − , the scavenging of O 2 − by Tempol (SOD mimetic), or inhibition of NOS with N -nitro-L-arginine methyl ester hydrochloride (L-NAME) (1mM) significantly attenuated Ang II-induced both 26S proteasome activation and the reduction of both GTPCH and DHFR, suggesting that Ang II via endogenous ONOO − causes 26S proteasome-dependent degradation of both GTPCH and DHFR. Moreover, inhibition of NAD(P)H oxidase with either apocynin or by overexpression of p67 phox -dominant negative mutants ablated Ang II-induced proteasome activation and degradation of both GTPCH and DHFR. Finally, treatment of mice aorta ex vivo with MG132 (0.5 μM for 1h followed by Ang II for 12h) reversed the Ang II-induced reduction of GTPCH, DHFR and BH 4 , and increased acetylcholine-induced endothelium-dependent relaxation. We conclude that Ang II activates NAD(P)H oxidase to release O 2 . − and ONOO − , which activate 26S proteasome resulting in increased degradation of both GTPCH and DHFR, two key enzymes in controlling the levels of BH 4 .
Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis
Authors: Chunqing Lin, Jiri Slama, Paula Gonzalez, Marc T Goodman, Ningshao Xia, Aimée R Kreimer, Ting Wu, Nancy A Hessol, Yurii Shvetsov, Ana P Ortiz, Beatriz Grinsztejn, Anna-Barbara Moscicki, Isabelle Heard, María del Refugio González Losa, Erna M Kojic, Maarten F Schim van der Loeff, Feixue Wei, Adhemar Longatto-Filho, Zizipho A Mbulawa, Joel M Palefsky, Annette H Sohn, Brenda Y Hernandez, Katina Robison, Steve Simpson, Lois J Conley, Alexandra de Pokomandy, Marianne A B van der Sande, Racheal S Dube Mandishora, Lays P B Volpini, Alessandra Pierangeli, Byron Romero, Timothy Wilkin, Silvia Franceschi, Carmen Hidalgo-Tenorio, Reshmie A Ramautarsing, Ina U Park, Fernanda K Tso, Sheela Godbole, Kathleen W M D'Hauwers, Borek Sehnal, Lynette J Menezes, Sandra A Heráclio, Gary M Clifford
Journal: The Lancet Infectious Diseases (2019)
Additional Data From Omitted Study in a Meta-analysis of the Association of Depression and Anxiety With Autoimmune Thyroiditis
Authors: Eva-Maria Siegmann, Teja Wolfgang Grömer
Journal: JAMA Psychiatry (2019)

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 Psychiatry 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 Psychiatry journal
Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation
Authors: Brian S. J. Blagg, Timothy D. Kerr
Journal: Medicinal Research Reviews (2005)

Abstract The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the renaturation of denatured proteins. In transformed cells, numerous mutated and overexpressed proteins rely on the Hsp90 protein folding machinery for tumor progression. The Hsp90‐mediated protein folding process is dependent upon ATP, and when inhibitors of ATP are present, the Hsp90 machinery is unable to fold client proteins into their biologically active form, which results in the degradation of protein substrates via the ubiquitin‐proteasome pathway. Consequently, Hsp90 has evolved into a promising anti‐cancer target because multiple oncogenic proteins can be simultaneously degraded as a consequence of Hsp90 inhibition. This review serves to explain the Hsp90 protein folding process, the impact of Hsp90 inhibition, the identification of natural product inhibitors, and the development of rationally designed inhibitors of the Hsp90 protein folding machinery. © 2005 Wiley Periodicals, Inc.
A decade of clinical development of PARP inhibitors in perspective
Authors: J. Mateo, C.J. Lord, V. Serra, A. Tutt, J. Balmaña, M. Castroviejo-Bermejo, C. Cruz, A. Oaknin, S.B. Kaye, J.S. de Bono
Journal: Annals of Oncology (2019)

Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.
The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis.
Authors: Mahran Shoukier, Hagop M. Kantarjian, Jorge E. Cortes, Elias Jabbour, Farhad Ravandi, Guillermo Garcia-Manero, Tapan M. Kadia, Jairo Matthews, Srdan Verstovsek, Gautam Borthakur
Journal: Journal of Clinical Oncology (2019)

e18539 Background: Tyrosine kinase inhibitors (TKIs) are standard therapy for chronic phase (CP) chronic myeloid leukemia (CML). Up to have patients with CML may develop grade ≥3 thrombocytopenia, leading to treatment interruptions and dose reductions. Similarly, management of thrombocytopenia in myelofibrosis (MF) can be challenging because the condition may result in dose adjustments and interruptions of ruxolitinib. Methods: We conducted a non-randomized, phase II, single-arm study to determine the efficacy of eltrombopag for patients with CML or MF with persistent thrombocytopenia during therapy with a TKI or ruxoltinib. We enrolled 15 CML patients with persistent grade ≥3 thrombocytopenia (platelets ≤50 x 10 9 /l) and six MF patients with platelets &lt; 100 x 10 9 /l after at least 3 months of therapy with a TKI or ruxolitinib. Patients received eltrombopag at a starting dose of 50 mg daily, with dose escalation to a maximum of 300 mg daily according to platelet response. Patients were followed with a weekly complete blood count until a stable platelet count was achieved. The target response was a complete response, defined as a platelet count ≥50 x 10 9 /l for CML and ≥100 x 10 9 /l for MF in at least 30% of subjects, sustained for 3 months while continuing TKIs or ruxolitinib therapy. Results: We enrolled 21 patients (CML = 15, MF = 6), with a median age of 60 years (range, 31-99 years). The median platelet count was 44 (range, 3-49) in patients with CML and 62 (range, 25-91) in those with MF. After a median duration of treatment of 18 months (range, 5-77 months), 11 of the 15 patients with CML achieved a complete platelet response at eltrombopag doses of 50–300 mg per day. The median peak platelet count among responders was 133 (range, 6-1225) x 10 9 /l. Nine patients with CML experienced an improvement in cytogenetic response. In 5 patients with CML, the TKIs dose was increased and maintained while continuing eltrombopag. None of the 5 patients with MF had a sustained increase in platelet count to ≥100 x 10 9 /l. No progression of disease was documented in any patient. Therapy was generally well tolerated. One patient (CML) discontinued therapy secondary to toxicity (persistent transaminitis with an accompanying lack of response). Conclusions: Eltrombopag demonstrated clinical efficacy in some patients with CML who were treated with TKIs. No similar benefit was observed in patients with MF who were treated with ruxolitinib. Eltrombopag might be a useful adjunct for patients with CML experiencing persistent thrombocytopenia. Clinical trial information: NCT01428635.
Abstract P366: Repeatability of Cardio-Ankle Vascular Index in Morbidly Obese Individuals
Authors: Chao Yang, Josef Coresh, Chiadi Ndumele, Kunihiro Matsushita
Journal: Circulation (2018)

Background: The AHA 2016 Statement for arterial stiffness evaluation introduced several novel parameters. Cardio-ankle vascular index (CAVI) is one of them and has a unique property of being largely independent of blood pressure (BP) at the time of examination. The repeatability of CAVI has been confirmed in healthy population but not in morbidly obese individuals. Methods: We investigated 76 participants (mean age 44 years, and mean BMI 48 kg/m 2 [ranged from 36-70]) in the BARI-Heart Study, who underwent 2 standardized visits (1-10 months apart) before bariatric surgery. CAVI was measured twice 5-minute apart at each visit using oscillometric device VaSera VS-1500 (Fukuda Denshi, Tokyo, Japan) at a supine position. We calculated intra-class correlation coefficient (ICC), minimal detectable change (MDC 95 ) and minimal detectable difference (MDD) using a nested random-effects analysis of variance model for CAVI. As a contrast, we also calculated these repeatability statistics for brachial and ankle BP measured using the same device when CAVI was measured. Results: At the first visit, average CAVI was 6.2 (SD 1.1) and average brachial systolic and diastolic BP was 146 mmHg (SD 13) and 86 mmHg (SD 7). For short-term repeatability in 5 minutes at the first visit, the ICCs were very high for both CAVI and brachial and ankle BPs (all with ICC ≥ 0.82 bilaterally). When we observed longer term repeatability over several months, the ICCs were fair for BPs (ranged from 0.42-0.57) but remained very high for CAVI with ≥0.72 for both sides. The MDC 95 between repeated measures within an individual across two visits was 1.6-1.7 for CAVI and 15-35 mmHg for BP parameters. In this scenario, the MDD for two independent samples of 100 per group was ~0.5 for CAVI and 4-8 mmHg for BP parameters. Conclusion: The short- and longer-term repeatability of CAVI was overall good even among morbidly obese individuals. Our results suggest that a longitudinal change of CAVI by 1.6-1.7 indicates a change beyond the measurement error.
Rationale and design of the EMPERIAL‐Preserved and EMPERIAL‐Reduced trials of empagliflozin in patients with chronic heart failure
Authors: William T. Abraham, Piotr Ponikowski, Martina Brueckmann, Cordula Zeller, Hemani Macesic, Barbara Peil, Michèle Brun, Anastasia Ustyugova, Waheed Jamal, Afshin Salsali, JoAnn Lindenfeld, Stefan D. Anker
Journal: European Journal of Heart Failure (2019)

Aims Heart failure (HF) is associated with considerable symptom burden and impairment in physical functioning and quality of life. The sodium–glucose co‐transporter 2 inhibitor empagliflozin reduced the risk of HF hospitalisation and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease in the EMPA‐REG OUTCOME trial, and could potentially improve congestion symptoms and exercise capacity in patients with HF. We describe the designs of the EMPERIAL‐Preserved and EMPERIAL‐Reduced trials of empagliflozin in patients with chronic stable HF, with or without type 2 diabetes. Methods EMPERIAL‐Preserved and EMPERIAL‐Reduced are randomised, placebo‐controlled trials designed to investigate the effects of empagliflozin on exercise capacity and patient‐reported outcomes in patients with chronic stable HF with preserved ejection fraction [HFpEF; left ventricular ejection fraction (LVEF) &gt; 40%] and HF with reduced ejection fraction (HFrEF; LVEF ≤ 40%), respectively. In each trial, approximately 300 patients will be randomised 1:1 to receive empagliflozin 10 mg or placebo once daily for 12 weeks. In both trials, the primary endpoint is the change from baseline in 6‐min walk test distance at week 12. Key secondary endpoints are the change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score and change from baseline in dyspnoea score of the Chronic Heart Failure Questionnaire at week 12. Conclusion The EMPERIAL‐Preserved and EMPERIAL‐Reduced trials will determine the effects of empagliflozin on exercise capacity and patient‐reported outcomes in patients with HFpEF and HFrEF, respectively, and provide insight into the potential of empagliflozin in the treatment of patients with HF. Clinical Trial Registration: ClinicalTrials.gov ID: NCT03448406 (EMPERIAL‐Preserved), NCT03448419 (EMPERIAL‐Reduced).
AB1335 AGE-RELATED MUSCULOSKELETAL STIFFNESS AMONGST HEALTHY SUBJECTS
Authors: Hugh Watson, Amalie Lynggard, Lars-Erik Bartels
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> A patient questionnaire for evaluating musculoskeletal stiffness (MSQ) has been developed for rheumatoid arthritis (RA) (Halls 2015) and also tested in chikungunya disease. Joint stiffness is associated with older age in adults. <h3>Objectives:</h3> The aim of this study was to evaluate the variation in MSQ scores with age in a cohort of healthy adults. <h3>Methods:</h3> Subjects ≥18 years old were enrolled at two sites. Subjects were engaged in, or had completed, tertiary education. Subjects with a diagnosis of joint disease, Parkinson's disease or multiple sclerosis were excluded. Each subject completed a 21-item questionnaire designed to evaluate the severity of musculoskeletal stiffness, its physical impact and psychosocial impact, and to provide an overall stiffness score. Results are expressed as a percentage of the maximum possible score. <h3>Results:</h3> Two hundred and fifty-eight subjects were included, 120 males and 138 females. Subjects were &gt;95% Caucasian. The mean age of subjects was 40±16 years. No differences were seen in the stiffness scores between males and females. The percentage of subjects reporting any stiffness was over 50% in every age group, and markedly higher in those aged ≥60 years (Table). The average overall MSQ scores and those of its three components were low and showed little variation between the three lower age cohorts, but scores increased in the upper age cohort (Table). <h3>Conclusion:</h3> The prevalence of musculoskeletal stiffness in healthy subjects as measured with this questionnaire is not negligible. Overall stiffness scores in this study were low in the subjects aged 18-59 years when compared to those in RA and chikungunya disease. However, the high frequency of stiffness and the higher average scores in the upper age cohort suggest that the background joint stiffness amongst older subjects should be considered when interpreting stiffness scores in patients. <h3>References</h3> [1] Halls S, Dures E, Kirwan J, et al. AB1128-HPR Developing A New Rheumatoid Arthritis (RA) Stiffness Patient Reported Outcome Measure (PROM). Ann Rheum Dis2016; 75: 1317 <h3>Disclosure of Interests:</h3> Hugh Watson Shareholder of: Sanofi, Employee of: Sanofi, Amalie Lynggard: None declared, Lars-Erik Bartels: None declared
Abstract 14224: Effect of Regadenoson Vasodilator Stress on Left Ventricular Strain
Authors: Ellianna Hoff, Samuel Kulifay, Selena Chandler, Jordan Long, Venkat Tondapu, J. Ronald Mikolich
Journal: Circulation (2018)

Introduction: Pharmacologic stress cardiac MRI is a well-established non-invasive test for evaluating coronary athersclerotic disease (CAD). Dobutamine is a pharmacologic stress agent which is comm...