tbuckley/cabot-search huggingface dataset:
Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage
Authors: Arne Thiele, Katja Luettges, Daniel Ritter, Niklas Beyhoff, Elia Smeir, Jana Grune, Julia S Steinhoff, Michael Schupp, Robert Klopfleisch, Michael Rothe, Nicola Wilck, Hendrik Bartolomaeus, Anna K Migglautsch, Rolf Breinbauer, Erin E Kershaw, Gernot F Grabner, Rudolf Zechner, Ulrich Kintscher, Anna Foryst-Ludwig
Journal: Cardiovascular Research (2021)

Heart failure (HF) is characterized by an overactivation of β-adrenergic signalling that directly contributes to impairment of myocardial function. Moreover, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently, we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressure-mediated HF in mice. In this study, we investigated the cardioprotective effects of a new pharmacological inhibitor of ATGL, Atglistatin, predominantly targeting ATGL in adipose tissue, on catecholamine-induced cardiac damage.
CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis
Authors: Masatoshi Kudo, Ana Matilla, Armando Santoro, Ignacio Melero, Antonio Cubillo Gracián, Mirelis Acosta-Rivera, Su-Pin Choo, Anthony B. El-Khoueiry, Ryoko Kuromatsu, Bassel El-Rayes, Kazushi Numata, Yoshito Itoh, Francesco Di Costanzo, Oxana Crysler, Maria Reig, Yun Shen, Jaclyn Neely, Marina Tschaika, Tami Wisniewski, Bruno Sangro
Journal: Journal of Hepatology (2021)

Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status.This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC.Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC.In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population.NCT01658878.
Effect of Rapid Respiratory Virus Testing on Antibiotic Prescribing Among Children Presenting to the Emergency Department With Acute Respiratory Illness
Authors: Suchitra Rao, Molly M. Lamb, Angela Moss, Rakesh D. Mistry, Kathleen Grice, Wasiu Ahmed, Daniela Santos-Cantu, Elizabeth Kitchen, Chandni Patel, Ilaria Ferrari, Samuel R. Dominguez
Journal: JAMA Network Open (2021)

<h3>Importance</h3> There is high usage of antibiotics in the emergency department (ED) for children with acute respiratory illnesses. Studies have reported decreased antibiotic use among inpatients with rapid respiratory pathogen (RRP) testing. <h3>Objective</h3> To determine whether RRP testing leads to decreased antibiotic use and health care use among children with influenzalike illness (ILI) in an ED. <h3>Design, Setting, and Participants</h3> A randomized clinical trial among children aged 1 month to 18 years presenting to an ED with ILI from December 1, 2018, to November 30, 2019, was conducted. Data were analyzed March 23, 2020, to April 2, 2021. All children received a nasopharyngeal swab for RRP testing and were randomized 1:1 to the intervention group or control group (results not given, routine clinical care). Results were available in 45 minutes. Intention-to-treat analyses and modified intention-to-treat (clinician knows results) analyses were conducted using multivariable Poisson regression. <h3>Interventions</h3> Rapid respiratory pathogen test results given to clinicians. <h3>Main Outcomes and Measures</h3> Antibiotic prescribing was the primary outcome; influenza antiviral prescribing, ED length of stay, hospital admission, and recurrent health care visits were the secondary outcomes. <h3>Results</h3> Among 931 ED visits (intervention group, 452 children group and control group, 456 children after exclusion of those not meeting criteria or protocol violations), a total of 795 RRP test results (85%) were positive. The median age of the children was 2.1 years (interquartile range, 0.9-5.6 years); 509 (56%) were boys. Most children (478 [53%]) were Hispanic, 688 children (76%) received government insurance, and 314 (35%) had a high-risk medical condition. In the intention-to-treat intervention group, children were more likely to receive antibiotics (relative risk [RR], 1.3; 95% CI, 1.0-1.7), with no significant differences in antiviral prescribing, medical visits, and hospitalization. In inverse propensity-weighted modified intention-to-treat analyses, children with test results known were more likely to receive antivirals (RR, 2.6; 95% CI, 1.6-4.5) and be hospitalized (RR, 1.8; 95% CI, 1.4-2.5); there was no significant difference in antibiotic prescribing (RR, 1.1; 95% CI, 0.9-1.4). <h3>Conclusions and Relevance</h3> The use of RRP testing in the ED for ILI did not decrease antibiotic prescribing in this randomized clinical trial. There is a limited role for RRP pathogen testing in children in this setting. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03756753
NICE recommends inducing pregnant women one week earlier
Authors: Jacqui Wise
Journal: BMJ (2021)

Pregnant women should be offered induction one week earlier than the current recommendations in order to improve outcomes during birth, say draft guidance from the National Institute for Health and Care Excellence (NICE).1

Women with uncomplicated singleton pregnancies should be offered induction at 41 weeks, to take place then or as soon as possible afterwards, the guidance says. The previous guideline in 2008 advised induction between 41 and 42 weeks and that women who had chosen not to be induced should be monitored after 42 weeks. Women who choose not to have induction of …
In COVID-19, tocilizumab reduces all-cause mortality at 28 d
Authors: Shannon M. Fernando, Bram Rochwerg
Journal: Annals of Internal Medicine (2021)

Source CitationGhosn L, Chaimani A, Evrenoglou T, et al. Interleukin-6 blocking agents for treating COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;3:CD013881. https://pubmed.ncbi.nlm.nih.gov/33734435/AbstractClinical Impact RatingsHospitalists: Infectious Disease: Critical Care: Pulmonology:
Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer
Authors: Elias Orouji, Ayush T Raman, Anand K Singh, Alexey Sorokin, Emre Arslan, Archit K Ghosh, Jonathan Schulz, Christopher Terranova, Shan Jiang, Ming Tang, Mayinuer Maitituoheti, Scot C Callahan, Praveen Barrodia, Katarzyna Tomczak, Yingda Jiang, Zhiqin Jiang, Jennifer S Davis, Sukhen Ghosh, Hey Min Lee, Laura Reyes-Uribe, Kyle Chang, Yusha Liu, Huiqin Chen, Ali Azhdarinia, Jeffrey Morris, Eduardo Vilar, Kendra S Carmon, Scott E Kopetz, Kunal Rai
Journal: Gut (2021)

Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as ASCL2 and FZD10, was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.
POS0936 TREATMENT OF ANKYLOSING SPONDYLITIS WITH TUMOR NECROSIS FACTOR-ALPHA INHIBITORS LOWERS THE RISK OF RENAL FUNCTION DECLINE
Authors: S. J. Lee, J. S. Lee, U. C. Cha, E. J. Nam
Journal: Annals of the Rheumatic Diseases (2021)

Background: Ankylosing spondylitis (AS) is associated with reduced renal function, possibly due to chronic inflammation or the use of nephrotoxic drugs. However, the long term effect of tumor necrosis factor (TNF) inhibitors on renal function in patients with AS has not been well established. Objectives: We therefore investigated the association of TNF inhibitors treatment and change in estimated glomerular filtration rate (GFR) using the Korean College of Rheumatology Biologics (KOBIO) registry (ClinicalTrials.gov, NCT01965132 ), a prospective nationwide biologics registry. Methods: We enrolled 1846 patients with AS in KOBIO registry and as disease controls, 471 patients with AS who did not take biologics in Kyungpook National University Hospital. The estimated glomerular filter rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation was evaluated in both groups. Renal insufficiency was defined as eGFR &lt;60 mL/min/1.73 m2. Changes and differences of eGFR in each group were assessed at every follow-up year using paired t-test. Risk factors for renal function decline were identified using multivariable analysis. Results: The changes of eGFR values in patients treated with TNF inhibitors were not significantly decreased during 5 years follow up period. However, those in patients not treated with TNF inhibitors were significantly decreased. Moreover, among patients with renal insufficiency, use of TNF inhibitors did not affect further renal function deterioration during follow up period. Using multivariable logistic regression models, patients treated (versus not treated) with TNF inhibitors had a lower risk of renal function decline after 5 years follow up period (p&lt;0.045). Conclusion: The use of TNF inhibitors was independently associated with lower risk of renal function decline and TNF inhibitors may be a safe treatment option in AS patients with renal insufficiency. Disclosure of Interests: None declared
POS1281 HOW DOES OBESITY INFLUENCE THE FEATURES OF KNEE OSTEOARTHRITIS?
Authors: H. Hachfi, D. Khalifa, M. Brahem, N. Ben Chekaya, M. Younes
Journal: Annals of the Rheumatic Diseases (2021)

Background: Knee osteoarthritis and obesity are both major health problems. It is now admitted that the prevalence of knee osteoarthritis gets higher with obesity and that weight loss helps knee function and allows patients to avoid surgery. Objectives: The aim of this study was to study the influence of obesity on knee osteoarthritis features. Methods: A cross-sectional study was conducted in the university hospital Taher Sfar of Tunisia over a period of 6 months. Patients who had knee osteoarthritis confirmed by radiographs were included. Sociodemographic, clinical, radiological and therapeutic data were collected from medical records and visits. Obesity was defined by a body mass index (BMI) ≥30. Functional impairment was assessed by the Womac index and Lequesne index. Results: The study included 186 patients. There were 31 males and 155 femmes. The mean age was 60±10 years. The percentage of obese patients was 53,8%. The mean age was similar in both groups obese and non obese. There were more women in the obese group compared to the non obese group (p=0.0001), more patients who had diabetes mellitus and dyslipidemia (p=0.002). Non-obese patients had a shorter duration of symptoms with no statistical significance (p=0.151). Obese patients had more involvement of both knees (p&lt;0.0001). Obesity did not have an impact on pain severity. Severity of radiological images (p=0,0001) were more frequent in obese patients. Functional impairment was similar in both groups. However, the percentage of patients having a very important functional impairment with Lequesne index was higher in obese patients (p&lt;0.029). Obese patients also needed more physical therapy sessions (p=0.035). Conclusion: Knee osteoarthritis in obese patients is characterized with the femlae gender predominance, bilateral knee involvement, and a more severe images on radiographs. Thus the need for better control of weight and the importance of physical activity. References: [1]Coggon D, Reading I, Croft P, et al. Knee osteoarthritis and obesity. Int J Obes Relat Metab Disord J Int Assoc Study Obes 2001; 25: 622–627. Disclosure of Interests: None declared
Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015–2020
Authors: Niklas Huntemann, Leoni Rolfes, Marc Pawlitzki, Tobias Ruck, Steffen Pfeuffer, Heinz Wiendl, Sven G. Meuth
Journal: Drugs (2021)

In the recent past, a plethora of drugs have been approved for the treatment of multiple sclerosis (MS). These therapeutics are mainly confined to immunomodulatory or immunosuppressive strategies but do not sufficiently address remyelination and neuroprotection. However, several neuroregenerative agents have shown potential in pre-clinical research and entered Phase I to III clinical trials. Although none of these compounds have yet proceeded to approval, understanding the causes of failure can broaden our knowledge about neuroprotection and neuroregeneration in MS. Moreover, most of the investigated approaches are characterised by consistent mechanisms of action and proved convincing efficacy in animal studies. Therefore, learning from their failure will help us to enforce the translation of findings acquired in pre-clinical studies into clinical application. Here, we summarise trials on MS treatment published since 2015 that have either failed or were interrupted due to a lack of efficacy, adverse events, or for other reasons. We further outline the rationale underlying these drugs and analyse the background of failure to gather new insights into MS pathophysiology and optimise future study designs. For conciseness, this review focuses on agents promoting remyelination and medications with primarily neuroprotective properties or unconventional approaches. Failed clinical trials that pursue immunomodulation are presented in a separate article.
AB0733 DADA2 VASCULITIS PRESENTING AS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES): AN ATYPICAL PRESENTATION
Authors: M. Mamadapur, S. Mahadevan, A. Singh, R. Chakravarthy C H, R. S, T. T N
Journal: Annals of the Rheumatic Diseases (2021)

Background: Deficiency of Adenosine Aminase deficiency 2 is monogenic disease presenting with multisystem involvement of vasculitis,Stroke 1 ,hematological manifestations. We hereby present a young child who presented with PRES initially and later diagnosed as DADA2.Only one case of DADA2 presenting as PRES is reported so far 2 .This case highlights the atypical presentation of DADA2. Objectives: A case report to highlight the rare presentation of DADA2 vasculits. Methods: 8 year old developmentally normal male child,born out of consanguineous marriage presented with with fever,abdominal pain, seizures 1 year back.Ultrasound of abdomen revelaed mesenteric lymphadenitis and MRI Brain was suggestive of Meningoencephalitis.He was managed with antivirals and antibiotics then. 6 months later,he had fever,skin rash,pain abdomen,status epilepticus,hypertension followed by gangrene of fingers and toes.APLA,ANA,ANCA workup was negative. Complete Hemogram was normal. CRP was 130mg/dl. CT Abdomen was normal and no evidence of aneurysms. Renal Doppler Ultrasound was normal.CT upper limb showed left radial and ulnar artery significant narrowing with patchy occlusion. MRI Brain showed bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical T2W FLAIR hyperintensity without diffusion restriction suggestive of PRES. He was diagnosed as Childhood Polyarteritis Nodosa and treated with cyclophosphamide. Genetic Analysis of ADA2(CECR1) gene mutation by Sanger Sequencing of exons 2 to 10 showed a known variant (rs202134424) in ADA2 gene. Figure 1. Gangrene of left 1-5 th digits and right 4 th and 5 th digit resorption Figure 2. T2W FLAIR image showing bilateral fronto parietal,occipital,putamen,left insula and subcortical and cortical hyperintensity without diffusion restriction suggestive of PRES. Results: He was started on Infliximab and is on follow up. No further events noted so far.Rehabilitation of left upper hand was done. Conclusion: DADA2 can present with varied CNS manifestations like infarct,hemorrhage,aneurysms and PRES.High index of suspicion and early recognition can help in maintaining vascular integrity. References: [1]Ganhão S, Loureiro G, Oliveira D, dos-Reis-Maia R, Aguiar F, Quental R et al. Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review. Clinical Rheumatology. 2020;39(12):3853-3860. [2]Sharma A, Naidu G, Sharma V, Jha S, Dhooria A, Dhir V et al. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India. Arthritis &amp; Rheumatology. 2020;73(2):276-285. Disclosure of Interests: None declared
AICAR decreases acute lung injury by phosphorylating AMPK and upregulating heme oxygenase-1
Authors: Israr Ahmad, Adam Molyvdas, Ming-Yuan Jian, Ting Zhou, Amie M. Traylor, Huachun Cui, Gang Liu, Weifeng Song, Anupam Agarwal, Tamas Jilling, Saurabh Aggarwal, Sadis Matalon
Journal: European Respiratory Journal (2021)

Aim We investigated the mechanisms by which N1-(β-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase (AMPK), decreases lung injury and mortality when administered to mice post exposure to bromine gas (Br 2 ). Methods We exposed male C57BL/6 mice and heme oxygenase-1 (HO-1)-deficient (HO-1 −/− ) and corresponding wild-type (WT) littermate mice to Br 2 (600 ppm for 45 or 30 min, respectively) in environmental chambers and returned them to room air. AICAR was administered 6 h post exposure (10 mg·kg −1 , intraperitoneal). We assessed survival, indices of lung injury, high mobility group box 1 (HMGB1) in the plasma, HO-1 levels in lung tissues and phosphorylation of AMPK and its upstream liver kinase B1 (LKB1). Rat alveolar type II epithelial (L2) cells and human club-like epithelial (H441) cells were also exposed to Br 2 (100 ppm for 10 min). After 24 h we measured apoptosis and necrosis, AMPK and LKB1 phosphorylation, and HO-1 expression. Results There was a marked downregulation of phosphorylated AMPK and LKB1 in lung tissues and in L2 and H441 cells post exposure. AICAR increased survival in C57BL/6 but not in HO-1 −/− mice. In WT mice, AICAR decreased lung injury and restored phosphorylated AMPK and phosphorylated LKB1 to control levels and increased HO-1 levels in both lung tissues and cells exposed to Br 2 . Treatment of L2 and H441 cells with small interfering RNAs against nuclear factor erythroid 2-related factor 2 or HO-1 abrogated the protective effects of AICAR. Conclusions Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is the upregulation of lung HO-1 levels.
AB0050 A NOVEL METHOD FOR ISOLATION OF EXOSOMES FROM SYNOVIAL FLUID
Authors: Y. Liu, Y. Huang, Q. Huang, S. Sun, Z. Ji, W. Deng, T. W. LI
Journal: Annals of the Rheumatic Diseases (2021)

Background: Exosomes in synovial fluid (SF) has a close relationship with the pathogenesis of rheumatiod arthritis. As a complex biological fluid, SF presents challenges for exosomes isolation using standard methods, such as Exoquick TM kit and ultracentrifugation. Objectives: The study aims to compared the quality of exosomes separated by Exoquick TM kit (TM), Exoquick TM kit+Exoquick TC kit (TM-TC), ultracentrifugation (UC) and TM-TC+UC(TM-TC-UC) from SF. Methods: Exosomes was separated by TM, TM-TC, UC and TM-TC-UC respectively. The size and concentrations of exosomes were detected by high sensitivity flow cytometry for nanoparticle analysis. Total protein and RNA were extracted from exosomes. SDS-PAGE was used to detect the protein distribution of exosomes. Western blot was used to examine the level of albumin and exosomes marker (TSG101 and CD81). Results: There was no statistic difference in the diameters of exosomes separated by the four methods. The concentrations of exosomes in TM, TM-TC, TM-TC-UC and UC were (5.65±0.93), (3.02±1.19), (1.67±0.25) and (4.61±0.73) *10 9 Particles/mL. The protein concentrations of exosomes separated by the four methods were consistent with the concentrations of exosomes. SDS-PAGE showed that the protein distribution of exosomes separated by the four methods were different. Low levels of albumin were detected in TM-TC and TM-TC-UC, while high levels of albumin in TM and UC. Total RNA concentrations from exosomes in TM-TC was higher than other groups. Conclusion: TM-TC can be used to obtain higher quality exosomes from SF for the study of exosome-enriched components. References: [1]Helwa I, et al, A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents. PloS one, 2017. 12(1): p. e0170628-e0170628. Figure 1. A : SDS-PAGE showed the protein distribution of exosomes; B : the detection of albumin, TSG101 and CD81 by western blot. Disclosure of Interests: None declared