tbuckley/cabot-search huggingface dataset:
Implication of the deacetylase sirtuin-1 on synovial angiogenesis and persistence of experimental arthritis
Authors: Agathe Leblond, Sonia Pezet, Anne Cauvet, Claudine Casas, Julie Pires Da Silva, Roxane Hervé, Gaelle Clavel, Sébastien Dumas, Sylvia Cohen-Kaminsky, Natacha Bessis, Luca Semerano, Christophe Lemaire, Yannick Allanore, Jérôme Avouac
Journal: Annals of the Rheumatic Diseases (2020)

To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA).RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis.RA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis.These results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.
EMPAGLIFLOZIN IS ASSOCIATED WITH A LOWER RISK OF POST-ACUTE HEART FAILURE RE-HOSPITALIZATION AND MORTALITY: INSIGHTS FROM THE EMPA-REG OUTCOME TRIAL
Authors: Javed Butler, Gianluigi Savarese, Naveed Sattar, James Januzzi, Subodh Verma, Lars H. Lund, David Fitchett, Cordula Zeller, Jyothis T. George, Martina Brueckmann, Anne Pernille Ofstad, Silvio E. Inzucchi, Christoph Wanner, Bernard Zinman
Journal: Journal of the American College of Cardiology (2019)
54. Lentiviral-Mediated Silencing of SOD1 through RNA Interference Delays Disease Onset and Progression in a Mouse Model of ALS
Journal: Molecular Therapy (2005)

Over 100 mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to approximately 20% of familial ALS cases. Many strands of evidences suggest that SOD1 mutations cause motoneuron death by a gain of novel toxic property(ies). The therapeutic approach we propose consist in knocking down mutated SOD1, the primary element governing the whole pathogenic processes, via a viral-based delivery of small hairpin RNA specific to SOD1.
Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials
Authors: Donghua Shi, Yaoping Shi, Ahmed O. Kaseb, Xingxing Qi, Yuan Zhang, Jiachang Chi, Qing Lu, Huiping Gao, Hua Jiang, Huamao Wang, Daijing Yuan, Hong Ma, Hongyang Wang, Zonghai Li, Bo Zhai
Journal: Clinical Cancer Research (2020)

Our preclinical studies demonstrated the potential of chimeric antigen receptor (CAR)-glypican-3 (GPC3) T-cell therapy for hepatocellular carcinoma (HCC). We report herein the first published results of CAR-GPC3 T-cell therapy for HCC.In two prospective phase I studies, adult patients with advanced GPC3+ HCC (Child-Pugh A) received autologous CAR-GPC3 T-cell therapy following cyclophosphamide- and fludarabine-induced lymphodepletion. The primary objective was to assess the treatment's safety. Adverse events were graded using the Common Terminology Criteria for Adverse Events (version 4.03). Tumor responses were evaluated using the RECIST (version 1.1).A total of 13 patients received a median of 19.9 × 108 CAR-GPC3 T cells by a data cutoff date of July 24, 2019. We observed pyrexia, decreased lymphocyte count, and cytokine release syndrome (CRS) in 13, 12, and nine patients, respectively. CRS (grade 1/2) was reversible in eight patients. One patient experienced grade 5 CRS. No patients had grade 3/4 neurotoxicity. The overall survival rates at 3 years, 1 year, and 6 months were 10.5%, 42.0%, and 50.3%, respectively, according to the Kaplan-Meier method. We confirmed two partial responses. One patient with sustained stable disease was alive after 44.2 months. CAR T-cell expansion tended to be positively associated with tumor response.This report demonstrated the initial safety profile of CAR-GPC3 T-cell therapy. We observed early signs of antitumor activity of CAR-GPC3 T cells in patients with advanced HCC.
Safety of 80 antidepressants, antipsychotics, anti‐attention‐deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta‐review of 78 adverse effects
Authors: Marco Solmi, Michele Fornaro, Edoardo G. Ostinelli, Caroline Zangani, Giovanni Croatto, Francesco Monaco, Damir Krinitski, Paolo Fusar‐Poli, Christoph U. Correll
Journal: World Psychiatry (2020)

Mental disorders frequently begin in childhood or adolescence. Psychotropic medications have various indications for the treatment of mental dis-orders in this age group and are used not infrequently off-label. However, the adverse effects of these medications require special attention during developmentally sensitive periods of life. For this meta-review, we systematically searched network meta-analyses and meta-analyses of randomized controlled trials (RCTs), individual RCTs, and cohort studies reporting on 78 a priori selected adverse events across 19 categories of 80 psychotropic medications - including antidepressants, antipsychotics, anti-attention-deficit/hyperactivity disorder (ADHD) medications and mood stabilizers - in children and adolescents with mental disorders. We included data from nine network meta-analyses, 39 meta-analyses, 90 individual RCTs, and eight cohort studies, including 337,686 children and adolescents. Data on ≥20% of the 78 adverse events were available for six antidepressants (sertraline, escitalopram, paroxetine, fluoxetine, venlafaxine and vilazodone), eight antipsychotics (risperidone, quetiapine, aripiprazole, lurasidone, paliperidone, ziprasidone, olanzapine and asenapine), three anti-ADHD medications (methylphenidate, atomoxetine and guanfacine), and two mood stabilizers (valproate and lithium). Among these medications with data on ≥20% of the 78 adverse events, a safer profile emerged for escitalopram and fluoxetine among antidepressants, lurasidone for antipsychotics, methylphenidate among anti-ADHD medications, and lithium among mood stabilizers. The available literature raised most concerns about the safety of venlafaxine, olanzapine, atomoxetine, guanfacine and valproate. Nausea/vomiting and discontinuation due to adverse event were most frequently associated with antidepressants; sedation, extrapyramidal side effects, and weight gain with antipsychotics; anorexia and insomnia with anti-ADHD medications; sedation and weight gain with mood stabilizers. The results of this comprehensive and updated quantitative systematic meta-review of top-tier evidence regarding the safety of antidepressants, antipsychotics, anti-ADHD medications and mood stabilizers in children and adolescents can inform clinical practice, research and treatment guidelines.
A lifelong preoccupation with the sociality of moral obligation
Authors: Zoe Liberman, John W Du Bois
Journal: Behavioral and Brain Sciences (2020)

Abstract Tomasello provides compelling evidence that children understand that people are morally obligated toward members of their social group. We call for expanding the scope of inquiry to encompass the full developmental trajectory of humans’ understanding of the relation between moral obligation, sociality, and stancetaking in interaction. We suggest that humans display a lifelong preoccupation with the sociality of moral obligation.
Abstract 15126: Cardiorespiratory Fitness and Atrial Fibrillation: A Population-based Follow-up Study
Authors: Danesh K Kella, Jari Laukkanen, Michael S Lloyd, Sudhir Kuir, Rainer Rauramaa, Javed Butler, Hassan Khan
Journal: Circulation (2014)

Background: Atrial fibrillation (AF) is the most common arrhythmia worldwide and has a complex association with exercise capacity. The relationship of atrial fibrillation with cardiorespiratory fitness (CRF) has not been previously investigated. Methods: Cardiorespiratory fitness, as assessed by maximal oxygen uptake (VO2max), was measured at baseline in 1,950 middle-aged men (mean 52.6 ± 5.1 years) from the Kuopio Ischaemic Heart Disease Study (KIHD). Results: During an average follow-up of 19.5 years, there were 305 incident AF cases (annual AF rate of 65.1/1000 person-years, 95% CI: 58.2 to 72.8). Overall a non-linear association was observed between CRF and incident atrial fibrillation. Rate of incident AF varied from 11.5 (95% CI: 9.4-14.0) for the first quartile of CRF, to 9.1 (95% CI: 7.4-11.2) for second quartile, 5.7 (95% CI: 4.4-7.4) for third quartile and 6.3 (95% CI: 5.0-8.0) for the fourth quartile respectively, Figure 1. Usual levels of CRF were non-linearly associated with AF risk, Figure 2. Age-adjusted HR comparing top versus bottom fourth of usual CRF levels was 0.67(95% CI: 0.48-0.95), which attenuated to 0.98 (95% CI: 0.66-1.43) upon further adjustment for several risk factors. These findings were comparable across age, body mass index, history of smoking, diabetes and cardiovascular disease status at baseline. Conclusions: Improved fitness as indicated by higher levels of CRF is protective of atrial fibrillation within an optimal range, beyond which the risk of atrial fibrillation rises again. Our findings are congruent with emerging data on the complex relationship between physical fitness and incident AF.
Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer
Authors: Di Zhao, Li Cai, Xin Lu, Xin Liang, Jiexi Li, Peiwen Chen, Michael Ittmann, Xiaoying Shang, Shan Jiang, Haoyan Li, Chenling Meng, Ivonne Flores, Jian H. Song, James W. Horner, Zhengdao Lan, Chang-Jiun Wu, Jun Li, Qing Chang, Ko-Chien Chen, Guocan Wang, Pingna Deng, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho
Journal: Cancer Discovery (2020)

Abstract Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identified CHD1 as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic understanding of, the essential role of CHD1 in PTEN-deficient prostate cancer. In Pten and Pten/Smad4 genetically engineered mouse models, prostate-specific deletion of Chd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identified IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. Given the prominent role of MDSCs in suppressing responsiveness to immune checkpoint inhibitors (ICI), our genetic and tumor biological findings support combined testing of anti-IL6 and ICI therapies, specifically in PTEN-deficient prostate cancer. Significance: We demonstrate a critical role of CHD1 in MDSC recruitment and discover CHD1/IL6 as a major regulator of the immunosuppressive TME of PTEN-deficient prostate cancer. Pharmacologic inhibition of IL6 in combination with immune checkpoint blockade elicits robust antitumor responses in prostate cancer. This article is highlighted in the In This Issue feature, p. 1241
PTH-053 Endocuff assisted colonoscopy significantly improve ADR comparing to cap assisted colonoscopy: a randomised study (detect)
Authors: Rajaratnam Rameshshanker, Zacharias Tsiamoulos, Ana Wilson, Brian Saunders
Journal: Endoscopy (2018)

<h3>Introduction</h3> Adenoma miss rate during colonoscopy is considered as a key indicator of post colonoscopy cancer. One of the main reason for missed adenoma is poor visualisation of proximal folds and flexures during standard colonoscopy. Disposable distal attachments such as cap and Endocuff showed promising results to visualise proximal aspects of folds and to improve adenoma detection. There are no comparative randomised controlled trials of those two devices in the literature to date. <h3>Aim</h3> Primary aim of this study was to compare adenoma miss rate between Endocuff assisted colonoscopy (EAC) and Cap assisted colonoscopy (CAC). <h3>Methods</h3> All Patients referred for a colonoscopy via symptomatic services were invited to participate in the study. This is a randomised, single centre, tandem colonoscopy trial performed by the same endoscopist, on the same day first with Endocuff Vision followed by cap or vice-versa. All procedures were performed by Gastroenterology fellows who had performed more than 1500 colonoscopies each. <h3>Results</h3> A total of 154 patients were recruited. 78 of them had CAC as their first procedure. The mean age of participant was 61 years (male: female was 1:1). Polyp miss rate was significantly lower in EAC (8.4%) when compared with CAC (26.1%, p&lt;0.001). Adenoma miss rate showed similar trend (EAC vs CAC, 6%, vs 19%, p=0.002). Miss rate for diminutive adenomas where significantly lower in EAC group (1.8% vs 19.6%, p&lt;0.001), however, there was no significant differences in the miss rates for small (3.7% vs 2.9%, p=0.69) or adenomas larger than 10 mm (2.6% vs 1.6%, p=0.98). There was no significant difference in cancer, advanced adenoma or serrated polyps miss rate. The mean number adenoma per procedure was significantly higher in EAC group when compared to CAC (1.5 vs 0.8, p&lt;0.001). Caecal intubation time were significantly shorter in the EAC group than CAC group (median 6 vs 7 mins, p=0.01) Conversely, withdrawal time (median 10 vs 8 mins, p=0.01) was significantly longer in the EAC group. This difference could be due to more polyps were detected and resected in EAC group. While introducing the colonoscope via anus the discomfort score was higher in EAC (55% vs 10%, p&lt;0.001). However, majority of them reported only a mild discomfort During the first procedure, Endocuff was removed in 5/76 (6.6%) patients' due to difficulties to pass the Endocuff through a fixed or narrowed sigmoid colon. There were no difficulties to negotiate the sigmoid colon when cap was used. There were no other colonoscopy related complications reported during the procedure. <h3>Conclusions</h3> Our randomised, back to back study demonstrates that Endocuff assisted colonoscopy has significantly lower adenoma miss rate than cap assisted colonoscopy. Use of Endocuff appear to improve efficiency of the colonoscopy.
THE MEDICAL PROFESSION AND THE NATIONAL INSURANCE ACT.
Authors: H.H. Mills, Christopher Addison, Clifford Allbutt, Clement Belcher, C.J. Bond, John Collie, Adam Hamilton, M.St.L. Harford, Herbert Jones, Arthur Latham, H.H. Mills, ShirleyF. Murphy, George Reid, John Robertson, G.Sims Woodhead, Christopher Addison, Christopher Addison, M.S. Harford, B. Hall
Journal: The Lancet (1912)
Inactivation of <i>Fbxw7</i> Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade
Authors: Cécile Gstalder, David Liu, Diana Miao, Bart Lutterbach, Alexander L. DeVine, Chenyu Lin, Megha Shettigar, Priya Pancholi, Elizabeth I. Buchbinder, Scott L. Carter, Michael P. Manos, Vanesa Rojas-Rudilla, Ryan Brennick, Evisa Gjini, Pei-Hsuan Chen, Ana Lako, Scott Rodig, Charles H. Yoon, Gordon J. Freeman, David A. Barbie, F. Stephen Hodi, Wayne Miles, Eliezer M. Van Allen, Rizwan Haq
Journal: Cancer Discovery (2020)

The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG1, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy. SIGNIFICANCE: Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti-PD-1 therapy. Fbxw7 loss promotes resistance to anti-PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.This article is highlighted in the In This Issue feature, p. 1241.
Abstract 9887: Metformin Improves Metabolic, Functional, and Structural Abnormalities in Spontaneously Hypertensive Rat Hearts
Authors: Jie Li, Krzysztof Minczuk, James Massey, Jack Roy, Soumen Paul, James Patrie, Robert Carey, Heinrich Taegtmeyer, Susanna Keller, Bijoy Kundu
Journal: Circulation (2019)

Introduction: In a chronic hypertension model [spontaneously hypertensive rats (SHR)], we observed profound myocardial metabolic changes during early hypertension, before or concomitant with cardia...
Prevalence and Clinical Outcomes for Patients With ALK Gene Rearrangement in Europe: Preliminary Results from the European Thoracic Oncology Platform Lungscape Project
Authors: F. Blackhall, S. Peters, K.M. Kerr, K. O'Byrne, H. Hager, A. Sejda, A. Soltermann, C. Dooms, E. Felip, A. Marchetti, E.-J.M. Speel, N. Price, S. Savic, J. de Jong, M. Martorell, E. Thunnissen, L. Bubendorf, O. Dafni, R. Rosell, R.A. Stahel
Journal: Annals of Oncology (2012)
The Association Between Dietary Patterns at Midlife and Health in Aging
Authors: Cécilia Samieri, Qi Sun, Mary K. Townsend, Stephanie E. Chiuve, Olivia I. Okereke, Walter C. Willett, Meir Stampfer, Francine Grodstein
Journal: Annals of Internal Medicine (2013)

Healthy eating is associated with lower mortality and lower incidence of some chronic diseases, but the relationship of diet to healthy aging is less well-defined. This large observational study fo...
Evaluation of commercial and automated SARS-CoV-2 IgG and IgA ELISAs using coronavirus disease (COVID-19) patient samples
Authors: Anne J Jääskeläinen, Eliisa Kekäläinen, Hannimari Kallio-Kokko, Laura Mannonen, Elisa Kortela, Olli Vapalahti, Satu Kurkela, Maija Lappalainen
Journal: Eurosurveillance (2020)

Antibody-screening methods to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) need to be validated. We evaluated SARS-CoV-2 IgG and IgA ELISAs in conjunction with the EUROLabworkstation (Euroimmun, Lübeck, Germany). Overall specificities were 91.9% and 73.0% for IgG and IgA ELISAs, respectively. Of 39 coronavirus disease patients, 13 were IgG and IgA positive and 11 IgA alone at sampling. IgGs and IgAs were respectively detected at a median of 12 and 11 days after symptom onset.
Added value of chest computed tomography in suspected COVID-19: an analysis of 239 patients
Authors: Daniël A. Korevaar, Ruud S. Kootte, Loek P. Smits, Joost G. van den Aardweg, Peter I. Bonta, Janke Schinkel, René M. Vigeveno, Inge A.H. van den Berk, Maeke J. Scheerder, Bregtje A. Lemkes, Abraham Goorhuis, Ludo F.M. Beenen, Jouke T. Annema
Journal: European Respiratory Journal (2020)

<b>In a high-prevalence emergency department setting, chest CT showed a high probability of COVID-19 in 30% of patients with a negative or indeterminate initial RT-PCR result</b>https://bit.ly/38hLDzR
Airway abundance of <i>Haemophilus influenzae</i> predicts response to azithromycin in adults with persistent uncontrolled asthma
Authors: Steven L. Taylor, Kerry L. Ivey, Peter G. Gibson, Jodie L. Simpson, Geraint B. Rogers
Journal: European Respiratory Journal (2020)

Long-term azithromycin treatment reduced exacerbations in adults with persistent symptomatic asthma in the AMAZES trial (Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235) [1]. However, response to treatment was variable between participants and the characteristics of those who experience most clinical benefit have not been determined. The inability to define a specific population who are more responsive limits the ability to personalise this therapy, which is the goal for airways disease management [2]. With recent studies identifying airway Haemophilus influenzae colonisation as a candidate marker for asthma subgrouping [3, 4], we assessed whether H. influenzae abundance, measured using quantitative PCR (qPCR) [5, 6], predicted the ability of azithromycin therapy to reduce the incidence of acute asthma exacerbations. Sputum Haemophilus influenzae load predicts response to azithromycin in adults with persistent uncontrolled asthma: secondary findings from the AMAZES trial <https://bit.ly/3f3tJ71> The following investigators constitute the AMAZES Investigators Group: Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James, Christine Jenkins, Matthew J. Peters, Melissa Baraket and Guy B. Marks.
Safety and feasibility of intradermal injection with tolerogenic dendritic cells pulsed with proinsulin peptide—for type 1 diabetes
Authors: Tatjana Nikolic, Jaap J Zwaginga, Bas S Uitbeijerse, Nicky J Woittiez, Eelco J de Koning, Henk-Jan Aanstoot, Bart O Roep
Journal: The Lancet Diabetes & Endocrinology (2020)