tbuckley/cabot-search huggingface dataset:
Abstract 14: Computer-aided discovery of small-molecule inhibitors targeting neural transcription factor BRN2 in neuroendocrine prostate tumors
Authors: Ravi Munuganti, Daksh Thaper, Adeleke Aguda, Soojin Kim, Olena Sivak, Amina Zoubeidi
Journal: Clinical Cancer Research (2020)

Abstract Therapies targeting tumor-fueling androgens have been mainstay treatments of advanced prostate cancer for almost 5 decades. While the androgen receptor (AR) inhibitor enzalutamide (ENZ) prolongs survival of castration-resistant prostate cancer patients (CRPC), ENZ-resistant (ENZR) tumors rapidly recur. Our laboratory has identified that ENZ resistance can occur both in the presence and absence of continued classical AR activity. Lack of AR activity is clinically relevant, as it has been estimated that up to 25% of men who die from advanced CRPC have non-AR driven disease and lethal AR inactive neuroendocrine and anaplastic phenotypes of CRPC emerge after hormone therapy. Recently our group identified the neural transcription factor BRN2 as a major clinically relevant driver of neuroendocrine prostate cancer (NEPC). Hence, using the integrated power of computational drug discovery platform and biologic testing, we identified first-in-field inhibitors for BRN2. First, a homology model of BRN2 protein was generated and used as an input to perform large-scale virtual screening and virtual hits were tested in a series of experiments. Cpd 18-14, a lead BRN2 inhibitor, exhibited profound inhibition of BRN2 in transcriptional assay and binding to the BRN2 in cellular and in vitro assays. Furthermore, Cpd18-14 reduced the expression of neuroendocrine genes SOX2 and NCAM1. Importantly, Cpd18-14 displayed antiproliferative activity specifically in patient-derived BRN2hi NCI-H660 and in house-developed 42DENZRcells while displaying no effect on BRN2low 16DCRPC and LNCaP cells. Further, the most stable binding orientation of Cpd18-14 was determined using molecular dynamics simulations and was used to carry out structure-based lead optimization. As a result, we developed several synthetic derivatives with significant improvement in antiproliferative activity and metabolic stability. Finally, Cpd18-94 reduced the growth of NCI-H660 and 42DENZR NEPC tumors significantly in xenograft models. We anticipate that the developed drug prototypes will lay a foundation for the development of small-molecule therapies capable of combating highly aggressive and lethal form of neuroendocrine tumors. Citation Format: Ravi Munuganti, Daksh Thaper, Adeleke Aguda, Soojin Kim, Olena Sivak, Amina Zoubeidi. Computer-aided discovery of small-molecule inhibitors targeting neural transcription factor BRN2 in neuroendocrine prostate tumors [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 14.
Oligodendrocytes Provide Antioxidant Defense Function for Neurons by Secreting Ferritin Heavy Chain
Authors: Chaitali Mukherjee, Tina Kling, Belisa Russo, Kerstin Miebach, Eva Kess, Martina Schifferer, Liliana D. Pedro, Ulrich Weikert, Maryam K. Fard, Nirmal Kannaiyan, Moritz Rossner, Marie-Louise Aicher, Sandra Goebbels, Klaus-Armin Nave, Eva-Maria Krämer-Albers, Anja Schneider, Mikael Simons
Journal: Cell Metabolism (2020)
Sirt6 Alleviated Liver Fibrosis by Deacetylating Conserved Lysine 54 on Smad2 in Hepatic Stellate Cells
Authors: Jinhang Zhang, Yanping Li, Qinhui Liu, Ya Huang, Rui Li, Tong Wu, Zijing Zhang, Jian Zhou, Hui Huang, Qin Tang, Cuiyuan Huang, Yingnan Zhao, Guorong Zhang, Wei Jiang, Li Mo, Jian Zhang, Wen Xie, Jinhan He
Journal: Hepatology (2020)

Backgrounds and Aims Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. This study aimed to elucidate the role of the deacetylase sirtuin 6 (Sirt6) in HSC activation and liver fibrosis. Approach and Results Gain‐of‐function and loss‐of‐function models were used to study the function of Sirt6 in HSC activation. Mass spectrometry was used to determine the specific acetylation site. The lecithin retinol acyltransferase–driven cyclization recombination recombinase construct (CreERT2) mouse line was created to generate HSC‐specific conditional Sirt6‐knockout mice (Sirt6 △HSC ). We found that Sirt6 is most abundantly expressed in HSCs as compared with other liver cell types. The expression of Sirt6 was decreased in activated HSCs and fibrotic livers of mice and humans. Sirt6 knockdown and Sirt6 overexpression increased and decreased fibrogenic gene expression, respectively, in HSCs. Mechanistically, Sirt6 inhibited the phosphorylation and nuclear localization of mothers against decapentaplegic homolog (Smad) 2. Further study demonstrated that Sirt6 could directly interact with Smad2, deacetylate Smad2, and decrease the transcription of transforming growth factor β/Smad2 signaling. Mass spectrometry revealed that Sirt6 deacetylated conserved lysine 54 on Smad2. Mutation of lysine 54 to Arginine in Smad2 abolished the regulatory effect of Sirt6. In vivo , specific ablation of Sirt6 in HSCs exacerbated hepatocyte injury and cholestasis‐induced liver fibrosis in mice. With targeted delivery of the Sirt6 agonist MDL‐800, its concentration was 9.28‐fold higher in HSCs as compared with other liver cells and alleviated hepatic fibrosis. Conclusions Sirt6 plays a key role in HSC activation and liver fibrosis by deacetylating the profibrogenic transcription factor Smad2. Sirt6 may be a potential therapeutic target for liver fibrosis.
Rare loss-of-function mutations of <i>PTGIR</i> are enriched in fibromuscular dysplasia
Authors: Adrien Georges, Juliette Albuisson, Takiy Berrandou, Délia Dupré, Aurélien Lorthioir, Valentina D’Escamard, Antonio F Di Narzo, Daniella Kadian-Dodov, Jeffrey W Olin, Ewa Warchol-Celinska, Aleksander Prejbisz, Andrzej Januszewicz, Patrick Bruneval, Anna A Baranowska, Tom R Webb, Stephen E Hamby, Nilesh J Samani, David Adlam, Natalia Fendrikova-Mahlay, Stanley Hazen, Yu Wang, Min-Lee Yang, Kristina Hunker, Nicolas Combaret, Pascal Motreff, Antoine Chédid, Béatrice Fiquet, Pierre-François Plouin, Elie Mousseaux, Arshid Azarine, Laurence Amar, Michel Azizi, Heather L Gornik, Santhi K Ganesh, Jason C Kovacic, Xavier Jeunemaitre, Nabila Bouatia-Naji
Journal: Cardiovascular Research (2020)

Abstract Aims Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods and results We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C&amp;gt;G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10−4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.
Can Covid Catalyze an Educational Transformation? Competency-Based Advancement in a Crisis
Authors: Mary Ellen J. Goldhamer, Martin V. Pusic, John Patrick T. Co, Debra F. Weinstein
Journal: New England Journal of Medicine (2020)

Can Covid Catalyze an Educational Transformation? The Covid-19 pandemic presents an urgent imperative to rethink residency graduation requirements and an opportunity to implement the competency-bas...
<i>Fgfr3</i> mutation disrupts chondrogenesis and bone ossification in zebrafish model mimicking CATSHL syndrome partially via enhanced Wnt/β-catenin signaling
Authors: Xianding Sun, Ruobin Zhang, Hangang Chen, Xiaolan Du, Shuai Chen, Junlan Huang, Mi Liu, Meng Xu, Fengtao Luo, Min Jin, Nan Su, Huabing Qi, Jing Yang, Qiaoyan Tan, Dali Zhang, Zhenhong Ni, Sen Liang, Bin Zhang, Di Chen, Xin Zhang, Lingfei Luo, Lin Chen, Yangli Xie
Journal: Theranostics (2020)

CATSHL syndrome, characterized by camptodactyly, tall stature and hearing loss, is caused by loss-of-function mutations of fibroblast growth factor receptors 3 (FGFR3) gene. Most manifestations of patients with CATSHL syndrome start to develop in the embryonic stage, such as skeletal overgrowth, craniofacial abnormalities, however, the pathogenesis of these phenotypes especially the early maldevelopment remains incompletely understood. Furthermore, there are no effective therapeutic targets for this skeleton dysplasia.
AB0201 IMPACT OF TREATMENT INITIATION DELAY ON DISEASE ACTIVITY DURING RHEUMATOID ARTHRITIS
Authors: H. Bettaieb, A. Fazaa, S. Miladi, M. Sellami, O. Kmar, L. Souabni, S. Kassab, S. Chikili, Z. Leith, K. Ben Abdelghani, A. Laatar
Journal: Annals of the Rheumatic Diseases (2020)

Background: During rheumatoid arthritis (RA), initiating conventional synthetic Disease Modifying Anti-Rheumatic Drug (csDMARD) at the early stages of the disease is a mandatory condition to achieve DMARD-free sustained remission (1). Limited data studying the relationship between RA treatment delay and disease activity are available. Objectives: The aim of this study was to assess the impact of csDMARD initiation delay during RA on disease activity. Methods: This is a cross-sectional study including patients with RA (ACR/EULAR criteria).Delays were collected from patients’ interview and were represented respectively by D1, D2 and D3. D1 stands for the lag time separating the first RA symptom onset and rheumatologist consultation. D2 stands for the lag time separating the first RA symptom onset and RA diagnosis. D3 stands for lag time separating the first RA symptom onset and csDMARD initiation. Disease activity was evaluated by: Visual Analogue Scale for pain (VAS), number of tender joints, number of swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and Disease Activity Score28 (DAS28).The data were analyzed with descriptive statistics, Student’s t test, chi (2) test, and Spearman correlation using the SPSS statistical package. A p value &lt; 0.05 was considered significant. Results: The study included 100 RA patients (86 women and 14 men), with a mean age of 56.5 ± 12.4 years. The mean age at the onset of RA was 47.5 ± 12.4 years. Median D1, D2 and D3 were respectively 12 months [0-242], 15.7 months [2-252] and 18 months [2-270].Methotrextate was prescribed in 86% of cases. At RA diagnosis, the median values for the following parameters were: VAS 80 [30-100], number of tender joints 10[0-28], number of swollen joints 5 [0-17], ESR 43mm/hour [6-133], CRP 14.1 mg/l [1-120], DAS28 (ESR) 5.22 [2-7.52] and DAS28 (CRP) 4.6 [1-6.93]. After one year of follow-up, the median parameters of the disease activity were respectively: VAS 60 [0-100], number of tender joints 6[0-28], number of swollen joints 2 [0-22], ESR 32 mm/hour [2-106], CRP 7.5 mg/l [1.2-94], DAS28 (ESR) 4.1 [1.4-7.1] and DAS28 (CRP) 3.7 [1.68-6.22]. Significant positive correlation was found between delays in csDMARD initiation and DAS28 (CRP) scores over the first year (p=0.02, r=0.29). Conclusion: In this study, delays in treatment were associated with higher DAS28 (CRP) scores after one year of follow-up. Our results suggest that early identification and treatment of RA leads to improved outcomes and even improved rates of drug-free remission. References: [1]Van Nies JA, Krabben A, Schoones JW, et al. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis 2014;73:861–70. Disclosure of Interests: None declared
Toward the elimination of medical oncology admissions
Authors: D. M. Mintzer, S. Zheng, J. Sprandio
Journal: Journal of Clinical Oncology (2009)

e20740 Background: While medical oncology is growing in volume, it is increasingly becoming an outpatient enterprise. Issues leading to hospital admissions in the past are commonly either prevented or managed on an outpatient basis. We sought out trends within our practice on the frequency and reasons for hospital admissions. Methods: Computerized office visit and hospital admissions data were obtained on admissions by physician and year, for Pa. Oncology-Hematology Associates from 2000–2007. A retrospective chart review was also done for one physician from 6/08–12/08 to determine the reasons for admission. Results: While the total number of patients seen per year increased by 40% over the review period from 2000–2007, the relative number of admissions has steadily declined. Adjusting the number of admissions per patients in the practice (since the overall increase in volume partially masks the decline in admission frequency), the reduction in admissions is further evident. The frequency of admissions for the 4 senior oncologists showed a 50% reduction in admissions per patient over the past 8 years. Of 56 admissions reviewed from 6/08–12/08, 20 were related to infections (although only a minority were neutropenic), 13 for symptom management of disease progression, 6 for anemia/bleeding, 3 for bowel obstruction, 3 for non-infectious complications of treatment, and only 1 for chemotherapy administration. Conclusions: Trends in our practice indicate a continued decline in the frequency of admissions per patient. Elective admissions for diagnosis, work-up, and chemotherapy are rare. Improved medications for symptoms related to cancer, its complications and treatment-related toxicities and improvements in palliative care (psychosocial support, communication about prognosis and treatment goals, and end-of-life care) have contributed to decreased admissions. Increasingly, even patients with incurable disease are managed from diagnosis to death entirely as outpatients. Optimizing outpatient management and avoiding admissions in medical oncology has major implications for practice quality, patient quality of life, cost and allocation of health care resources. No significant financial relationships to disclose.
Human postprandial responses to food and potential for precision nutrition
Authors: Sarah E. Berry, Ana M. Valdes, David A. Drew, Francesco Asnicar, Mohsen Mazidi, Jonathan Wolf, Joan Capdevila, George Hadjigeorgiou, Richard Davies, Haya Al Khatib, Christopher Bonnett, Sajaysurya Ganesh, Elco Bakker, Deborah Hart, Massimo Mangino, Jordi Merino, Inbar Linenberg, Patrick Wyatt, Jose M. Ordovas, Christopher D. Gardner, Linda M. Delahanty, Andrew T. Chan, Nicola Segata, Paul W. Franks, Tim D. Spector
Journal: Nature Medicine (2020)
Home Noninvasive Positive Pressure Ventilation for Chronic Obstructive Pulmonary Disease
Authors: Robert L. Owens, Simon Oczkowski, Bram Rochwerg
Journal: JAMA (2020)

To the Editor Dr Wilson and colleagues reviewed bilevel positive airway pressure (BPAP) and home mechanical ventilation for chronic obstructive pulmonary disease (COPD).1 We are concerned about certain issues related to their methodology.
Annals Graphic Medicine - COVID-19, Telemedicine, and My Stethoscope
Authors: Satyajeet Roy
Journal: Annals of Internal Medicine (2020)

Web Exclusives16 June 2020Annals Graphic Medicine - COVID-19, Telemedicine, and My StethoscopeFREESatyajeet Roy, MDSatyajeet Roy, MDCooper University Hospital, Cherry Hill, New Jersey (S.R.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G20-0062 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Author, Article, and Disclosure InformationAuthors: Satyajeet Roy, MDAffiliations: Cooper University Hospital, Cherry Hill, New Jersey (S.R.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G20-0062.Author/Illustrator Information: Satyajeet Roy, MD; e-mail, roy-satyajeet@cooperhealth.edu.This article was published at Annals.org on 16 June 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byA Graphic Transformation: A Qualitative Study of Transformative Learning in Medical Trainees during COVID-19 Using Comics as Data Presentation 21 July 2020Volume 173, Issue 2 Page: W44-W45 Keywords COVID-19 Disclosure Health care Telemedicine ePublished: 16 June 2020 Issue Published: 21 July 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction
Authors: Chunmei Xu, Xiaojun Zhou, Tianyue Xie, Yuan Zhou, Qian Zhang, Shan Jiang, Rui Zhang, Lin Liao, Jianjun Dong
Journal: Theranostics (2020)

Diabetic nephropathy (DN) is mainly regarded as diabetic glomerulopathy, and its progression is tightly correlated with tubular epithelial lesions. However, the underlying molecular mechanisms linking tubular damage and glomerulopathy are poorly understood. Methods: We previously reported that the upregulation of Bim mediated proximal tubular epithelial cell (PTEC) apoptosis and was crucial in the early stages of DN. Herein we modulated Bim expression in PTECs and subsequently determined podocyte (PC) cytoskeletal arrangement by building a Transwell co-culture system in high glucose (HG). Results: Compared to normal glucose, exposure to 40 mM of HG for 48 h induced significant expression of Bim in PTECs and disorganization in the PC cytoskeleton. When cocultured with PTECs in HG, exacerbated filamentous actin (F-actin) rearrangement and reduced synaptopodin levels were detected in PCs. In contrast, gene knockdown of Bim in PTECs was correlated with the absence of PC cytoskeletal disorganization. NFAT2 level and its nuclear translocation in PTECs were decreased by suppressing Bim expression. Upregulating NFAT2 disrupted the beneficial effects on F-actin organization in PCs obtained by inhibiting Bim. LncRNA microarray analysis identified NONHSAT179542.1, which was implicated in Bim-mediated PC cytoskeletal disorder. Conclusion: Our study clarified the functional role of Bim, a pro-apoptotic factor, which is involved in the crosstalk between PTECs and PCs. Bim promotes NFAT2 activation in PTECs, inducing the downregulation of lncRNA NONHSAT179542.1 in PCs, contributing to the cytoskeletal damage. Identification of the role of the Bim/NFAT2 pathway may represent a promising research direction for a better understanding of DN development.
The perennial issue of gender discrepancy in publications on chest diseases
Authors: Fatma Tokgoz Akyil, Emre Saygili, Mustafa Akyil
Journal: European Respiratory Journal (2020)

<b>This letter gives a concrete picture of the lack of equal opportunities for women in academia, and raises awareness for professionals and policy makers to level the playing field and to enable women to contribute more to the accumulation of knowledge.</b>https://bit.ly/2UumeNK
異常肉柱(aberrant papillary muscle)により心室中部閉塞と心尖部の壁運動異常をきたした1例
Authors: 正岡佳子, 三浦健太郎, 石橋堅, 三戸森児, 岡田武規, 豊福守, 平尾秀和, 村岡裕司, 作間忠道
Journal: Circulation (2004)
Impact of the COVID-19 pandemic on admission rates for, and management of, acute coronary syndromes in England.
Authors: B Casadei, M M Mafham, E Spata, R Goldacre, D Gair, P Curnow, M Bray, S Hollings, C Roebuck, C P Gale, M A Mamas, J E Deanfield, M A de Belder, T F Luescher, T Denwood, M Landray, C Baigent, J Emberson, R E Collins, Morris Eja.
Journal: The Lancet (2020)
Abstract 703: HIF-1{alpha} Dependent Expression of iNOS in Bone Marrow Stem Cells Mediates Protection of Cardiomyocytes against Ischemia
Authors: Ying Dai, Muhammad Ashraf, Yigang Wang, Meifeng Xu
Journal: Circulation (2007)

We hypothesized that inducible nitric oxide synthase (iNOS) upregulated in bone marrow stem cells (BMSCs) protect ischemic cardiomyocytes via hypoxia inducible factor-1α (HIF-1α) pathway. Methods: ...
Natural History of Asymptomatic SARS-CoV-2 Infection
Authors: Aki Sakurai, Toshiharu Sasaki, Shigeo Kato, Masamichi Hayashi, Sei-ichiro Tsuzuki, Takuma Ishihara, Mitsunaga Iwata, Zenichi Morise, Yohei Doi
Journal: New England Journal of Medicine (2020)

Natural History of Asymptomatic SARS-CoV-2 Infection The outbreak on the cruise ship Diamond Princess led to the identification of 96 persons who were infected with SARS-CoV-2 but were asymptomatic...
Stromal LAG-3<sup>+</sup>cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture
Authors: Han Zeng, Quan Zhou, Zewei Wang, Hongyu Zhang, Zhaopei Liu, Qiuren Huang, Jiajun Wang, Yuan Chang, Qi Bai, Yu Xia, Yiwei Wang, Le Xu, Bo Dai, Jianming Guo, Li Liu, Yu Zhu, Jiejie Xu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Lymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3 + cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment. Methods 141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8 + T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration. Results In Kaplan-Meier analyses and Cox regression models, stromal LAG-3 + cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3 + cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8 + T cells correlated its dysfunctional state with LAG-3 + cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway. Conclusions Stromal LAG-3 + cells abundance indicated an immunoevasive contexture with dysfunctional CD8 + T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3 + cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.