tbuckley/cabot-search huggingface dataset:
NAD<sup>+</sup>-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin
Authors: Dong-Jie Li, Si-Jia Sun, Jiang-Tao Fu, Shen-Xi Ouyang, Qin-Jie Zhao, Li Su, Qing-Xi Ji, Di-Ynag Sun, Jia-Hui Zhu, Guo-Yan Zhang, Jia-Wei Ma, Xiu-Ting Lan, Yi Zhao, Jie Tong, Guo-Qiang Li, Fu-Ming Shen, Pei Wang
Journal: Theranostics (2021)

Rationale: Nicotinamide adenine dinucleotide+ (NAD+)-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD). Methods: NAD+-boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and Fndc5-/- mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted in vivo and in vitro to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment. Results: NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in Fndc5-/- mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD+-dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5. Conclusions: The findings from this research for the first time demonstrate that NAD+-boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus between physical exercise and NAD+-boosting therapy in metabolic pathophysiology.
BSE and BCOS Guideline for Transthoracic Echocardiographic Assessment of Adult Cancer Patients Receiving Anthracyclines and/or Trastuzumab
Authors: Rebecca Dobson, Arjun K. Ghosh, Bonnie Ky, Tom Marwick, Martin Stout, Allan Harkness, Rick Steeds, Shaun Robinson, David Oxborough, David Adlam, Susannah Stanway, Bushra Rana, Thomas Ingram, Liam Ring, Stuart Rosen, Chris Plummer, Charlotte Manisty, Mark Harbinson, Vishal Sharma, Keith Pearce, Alexander R. Lyon, Daniel X. Augustine
Journal: JACC CardioOncology (2021)

The subspecialty of cardio-oncology aims to reduce cardiovascular morbidity and mortality in patients with cancer or following cancer treatment. Cancer therapy can lead to a variety of cardiovascular complications, including left ventricular systolic dysfunction, pericardial disease, and valvular heart disease. Echocardiography is a key diagnostic imaging tool in the diagnosis and surveillance for many of these complications. The baseline assessment and subsequent surveillance of patients undergoing treatment with anthracyclines and/or human epidermal growth factor receptor (HER) 2-positive targeted treatment (e.g., trastuzumab and pertuzumab) form a significant proportion of cardio-oncology patients undergoing echocardiography. This guideline from the British Society of Echocardiography and British Cardio-Oncology Society outlines a protocol for baseline and surveillance echocardiography of patients undergoing treatment with anthracyclines and/or trastuzumab. The methodology for acquisition of images and the advantages and disadvantages of techniques are discussed. Echocardiographic definitions for considering cancer therapeutics-related cardiac dysfunction are also presented.
New WHO Guideline for Treating Chronic Pain in Children
Authors: Bridget M. Kuehn
Journal: JAMA (2021)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Pancreatic ductal deletion of S100A9 alleviates acute pancreatitis by targeting VNN1-mediated ROS release to inhibit NLRP3 activation
Authors: Hong Xiang, Fangyue Guo, Xufeng Tao, Qi Zhou, Shilin Xia, Dawei Deng, Lunxu Li, Dong Shang
Journal: Theranostics (2021)

Recent studies have proven that the overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also duct cells, however, pancreatic duct contribution in acinar cells homeostasis is poorly known and the molecular mechanisms leading to acinar insult and acute pancreatitis (AP) are unclear. Our previous work also showed that S100A9 protein level was notably increased in AP rat pancreas through iTRAQ-based quantitative proteomic analysis. Therefore, we investigated the actions of injured duct cells on acinar cells and the S100A9-related effects and mechanisms underlying AP pathology in the present paper. Methods: In this study, we constructed S100A9 knockout (s100a9-/-) mice and an in vitro coculture system for pancreatic duct cells and acinar cells. Moreover, a variety of small molecular inhibitors of S100A9 were screened from ChemDiv through molecular docking and virtual screening methods. Results: We found that the upregulation of S100A9 induces cell injury and inflammatory response via NLRP3 activation by targeting VNN1-mediated ROS release; and loss of S100A9 decreases AP injury in vitro and in vivo. Moreover, molecular docking and mutant plasmid experiments proved that S100A9 has a direct interaction with VNN1 through the salt bridges formation of Lys57 and Glu92 residues in S100A9 protein. We further found that compounds C42H60N4O6 and C28H29F3N4O5S can significantly improve AP injury in vitro and in vivo through inhibiting S100A9-VNN1 interaction. Conclusions: Our study showed the important regulatory effect of S100A9 on pancreatic duct injury during AP and revealed that inhibition of the S100A9-VNN1 interaction may be a key therapeutic target for this disease.
FP14.02 A Phase II Study of Osimertinib versus Combination of Osimertinib and Chemotherapy for EGFR and T790M-Mutation Positive NSCLC
Authors: A. Mouri, K. Tanaka, H. Asahina, J. Kishimoto, M. Okada, K. Watanabe, K. Hamai, T. Harada, Y. Tsubata, S. Sugawara, K. Kobayashi, K. Sugio, S. Oizumi, I. Okamoto
Journal: Journal of Thoracic Oncology (2021)
The CD33 short isoform is a gain-of-function variant that enhances Aβ1–42 phagocytosis in microglia
Authors: Abhishek Bhattacherjee, Jaesoo Jung, Sameera Zia, Madelene Ho, Ghazaleh Eskandari-Sedighi, Chris D. St. Laurent, Kelli A. McCord, Arjun Bains, Gaurav Sidhu, Susmita Sarkar, Jason R. Plemel, Matthew S. Macauley
Journal: Molecular Neurodegeneration (2021)

Abstract Background CD33 is genetically linked to Alzheimer’s disease (AD) susceptibility through differential expression of isoforms in microglia. The role of the human CD33 short isoform (hCD33m), preferentially encoded by an AD-protective CD33 allele (rs12459419T), is unknown. Here, we test whether hCD33m represents a loss-of-function or gain-of-function variant. Methods We have developed two models to test the role of hCD33m. The first is a new strain of transgenic mice expressing hCD33m in the microglial cell lineage. The second is U937 cells where the CD33 gene was disrupted by CRISPR/Cas9 and complemented with different variants of hCD33. Primary microglia and U937 cells were tested in phagocytosis assays and single cell RNA sequencing (scRNAseq) was carried out on the primary microglia. Furthermore, a new monoclonal antibody was developed to detect hCD33m more efficiently. Results In both primary microglia and U937 cells, we find that hCD33m enhances phagocytosis. This contrasts with the human CD33 long isoform (hCD33M) that represses phagocytosis, as previously demonstrated. As revealed by scRNAseq, hCD33m + microglia are enriched in a cluster of cells defined by an upregulated expression and gene regulatory network of immediate early genes, which was further validated within microglia in situ. Using a new hCD33m-specific antibody enabled hCD33m expression to be examined, demonstrating a preference for an intracellular location. Moreover, this newly discovered gain-of-function role for hCD33m is dependent on its cytoplasmic signaling motifs, dominant over hCD33M, and not due to loss of glycan ligand binding. Conclusions These results provide strong support that hCD33m represents a gain-of-function isoform and offers insight into what it may take to therapeutically capture the AD-protective CD33 allele.
Narrative Ethics in Response to Unbearable Suffering—the Dutch Slippery Slope Is Nonexistent—Reply
Authors: Diane E. Meier
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Development of an antibody-like T-cell engager based on VH-VL heterodimer formation and its application in cancer therapy
Authors: Seil Jang, Jaeho Song, NaYoung Kim, Jeonghyeon Bak, Keehoon Jung, Young Woo Park, Bum-Chan Park, Ho Min Kim
Journal: Biomaterials (2021)

Following the clinical success of immunotherapeutic antibodies, bispecific antibodies for cytotoxic effector cell redirection, tumor-targeted immunomodulation and dual immunomodulation, have received particular attentions. Here, we developed a novel bispecific antibody platform, termed Antibody-Like Cell Engager (ALiCE), wherein the Fc domain of each heavy chain of immunoglobulin G (IgG) is replaced by the VH and VL domains of an IgG specific to a second antigen while retaining the N-terminal Fab of the parent antibody. Because of specific interactions between the substituted VH and VL domains, the C-terminal stem Fv enables ALiCE to assemble autonomously into hetero-tetramers, thus simultaneously binding to two distinct antigens but with different avidities. This design strategy was used to generate ACE-05 (two anti-PD-L1 Fab × anti-CD3 Fv) and ACE-31 (two anti-CD3 Fab × anti-PD-L1 Fv), both of which bound PD-L1 and CD3. However, ACE-05 was more effective than ACE-31 in reducing off-target toxicity caused by the indiscriminate activation of T cells. Moreover, in cell-based assays and PBMC-reconstituted humanized mice harboring human non-small-cell lung cancer tumors, ACE-05 showed marked antitumor efficacy, causing complete tumor regression at a dose of 0.05 mg/kg body weight. The dual roles of ACE-05 in immune checkpoint inhibition and T-cell redirection, coupled with reduced off-target toxicity, suggest that ACE-05 may be a promising anti-cancer therapeutic agent. Moreover, the bispecific ALiCE platform can be further used for tumor-targeted or multiple immunomodulation applications.
P89.08 Real-World Impact of Plasma Cell-Free DNA Next-Generation Sequencing to Detect Actionable Genomic Alterations in Advanced NSCLC
Authors: B. Ahn, S. Lee, S. Olsen, D. Mehta, S.M. Lim, M.H. Hong, H.R. Kim, B.C. Cho
Journal: Journal of Thoracic Oncology (2021)
STK3/STK4 signalling in adipocytes regulates mitophagy and energy expenditure
Authors: Yoon Keun Cho, Yeonho Son, Abhirup Saha, Doeun Kim, Cheoljun Choi, Minsu Kim, Ji-Hyun Park, Hyeonyeong Im, Juhyeong Han, Kyungmin Kim, Young-Suk Jung, Jeanho Yun, Eun Ju Bae, Je Kyung Seong, Mi-Ock Lee, Sangkyu Lee, James G. Granneman, Yun-Hee Lee
Journal: Nature Metabolism (2021)
Клинико-патогенетические аспекты хронического панкреатита в сочетании с вегетативной дисфункцией
Authors: L.S. Babinets, Z.I. Sabat
Journal: GASTROENTEROLOGY (2019)

Актуальность. В статье проанализированы особенности состояния вегетативной нервной системы у больных хроническим панкреатитом (ХП). Проведенные исследования показали, что наличие вегетативной дисфункции (ВД) осложняет течение хронического панкреатита. Все органы и системы нашего тела находятся под постоянным контролем вегетативной нервной системы. Проблема хронического панкреатита остается одной из наиболее актуальных проблем в современной гастроэнтерологии. Несмотря на внедрение новых методов, наблюдается низкая эффективность лечения ХП, что, вероятно, обусловлено недостаточностью знаний об определенных механизмах патогенеза, в частности о роли ВД в развитии и прогрессировании ХП. Итак, особенности состояния вегетативной нервной системы при хроническом панкреатите представляют значительный научный интерес. Цель исследования: изучить степень вегетативных нарушений и их клиническое течение у больных с хроническим панкреатитом. Материалы и методы. Обследовано 45 пациентов с ХП, проходивших лечение в дневном стационаре и гастроэнтерологическом отделении Тернопольской городской клинической больницы № 2. Диагноз «хронический панкреатит» выставляли на основе клинического протокола, принятого в соответствии с приказом № 638 МЗ Украины от 10.09.2014 г. Общеклинические и биохимические обследования проводили больным ХП в фазе обострения и нестойкой ремиссии (10–14 день пребывания в условиях дневного стационара). Результаты. По данным опросника Вейна, у 91,1 % (n = 41) больных ХП обнаружены признаки вегетативной дисфункции, которые сопровождались наиболее выраженными диспеп­тическим ((3,2 ± 1,0) балла) и болевым ((2,9 ± 1,3) балла) синдромами по данным гастроэнтерологического опросника (GSRS). Наличие вегетативной дисфункции у больных ХП сопровождалось повышением реактивной (среднее значение — (45,0 ± 5,7)) и личной (среднее значение — (43,0 ± 5,2)) тревожности, а также ростом нейротизма (среднее значение — (14,7 ± 2,4)) у 75,6 % больных. У больных ХП с ВД по индексу Кердо констатировано преобладание состояния ваготонии (56 %) над симпатикотонией (31 %) при уровне эйтонии 13 %. По результатам клиноортостатической пробы у 13 % пациентов с ХП установлена нормальная реакция гемодинамики на ее проведение, у 6,5 % — гиперсимпатикотонический и гипердиастолический варианты, у 74 % — асимпатикотонический, что указывает на истощение компенсаторных механизмов регуляции вегетативного тонуса. Выводы. По оценке данных исследования, установлено негативное влияние вегетативной дисфункции на течение хронического панкреатита.
Abstract P21: Saliva as a testing specimen with or without pooling for SARS-CoV-2 detection by multiplex RT-PCR test
Authors: Qing Sun, Jonathan Li, Hui Ren, Larry Pastor, Yulia Loginova, Joseph Wong, Zhao Zhang, Aiguo Zhang, Chuanyi Mark Lu, Michael Sha
Journal: Clinical Cancer Research (2021)

Abstract Objectives Sensitive and high throughput molecular testing availability is essential during the COVID-19 pandemic. The vast majority of the SARS-CoV-2 molecular assays use nasopharyngeal or oropharyngeal swab specimens collected from suspected individuals. However, collecting these specimens has apparent drawbacks, including discomfort to patients and exposure risk to healthcare workers. Methods We developed and validated of QuantiVirus™ SARS-CoV-2 multiplex test using saliva as the testing specimens with pooling. Results The analytical sensitivity (LOD) was confirmed to be 100-200 copies/mL. For clinical evaluation, 85 known positive and 90 knowns negative NPS specimens were showed a positive predictive agreement of 100% and a negative predictive agreement of 98.9%. Twenty paired NPS and saliva samples were tested and showed overall 80% concordance rate without significant difference between NPS and saliva specimens by Wilcoxon signed-rank test (p=0.13). On a large scale of saliva-based population screening, the positive test rate was 1.79% among 389 saliva specimens. Furthermore, saliva sample pooling up to 6 samples for SARS-CoV-2 detection is feasible with sensitivity of 94.8% and specificity of 100%. Conclusions These results demonstrated that the clinical performance of saliva-based testing is comparable to that of NPS-based testing, and that pooling of saliva specimens for SARS-CoV-2 detection is feasible. Citation Format: Qing Sun, Jonathan Li, Hui Ren, Larry Pastor, Yulia Loginova, Joseph Wong, Zhao Zhang, Aiguo Zhang, Chuanyi Mark Lu, Michael Sha. Saliva as a testing specimen with or without pooling for SARS-CoV-2 detection by multiplex RT-PCR test [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P21.
Idarubicin Intensified Bucy Regimen in Allogeneic Peripheral Blood Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia: A Multicenter, Randomized Study (NCT 01766375)
Authors: Qiaochuan Li, Meiqing Wu, Zhongming Zhang, Lianjin Liu, Lingling Shi, Qifa Liu, Yongrong Lai
Journal: Blood (2017)
P38.06 Evaluation of Non-invasive Transcutaneous Bioconductance Measurement - a Risk-Stratification Biomarker for Suspicious Pulmonary Lesions
Authors: D. Yang, J. Sung, X. Zhang, X. Zheng, H. Wang, Y. Gu, Y. Zhang, D. Teng, N. Zhou, M. Garff, R. Yung, C. Bai
Journal: Journal of Thoracic Oncology (2021)
VCAM-1: closing the gap between lipotoxicity and endothelial dysfunction in nonalcoholic steatohepatitis
Authors: Rotonya M. Carr
Journal: Journal of Clinical Investigation (2021)

Nonalcoholic fatty liver disease (NAFLD) results in the accumulation of fat in the liver and can progress as an inflammatory disorder with considerable vascular endothelial dysfunction known as nonalcoholic steatohepatitis (NASH). Inflammatory signals can trigger the expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells. VCAM-1 is a surface protein that induces adherence and extravasation of monocytes to blood vessels. In this issue of the JCI, Furuta et al. report on their sequencing of RNA transcripts from the livers of mice fed a NASH-inducing diet. VCAM-1 was upregulated in the whole liver as well as liver sinusoidal endothelial cells (LSECs). When the researchers incubated LSECs with palmitate, a toxic lipid, VCAM-1 was upregulated. Notably, inhibiting VCAM-1 in the NASH model reduced VCAM-1 expression, lessened infiltrating macrophages, and mitigated fibrosis. This study connects steatosis to endothelial dysfunction and inflammation and suggests that targeting VCAM-1 may address fibrosis in patients with NASH.
Post-acute COVID-19 syndrome
Authors: Ani Nalbandian, Kartik Sehgal, Aakriti Gupta, Mahesh V. Madhavan, Claire McGroder, Jacob S. Stevens, Joshua R. Cook, Anna S. Nordvig, Daniel Shalev, Tejasav S. Sehrawat, Neha Ahluwalia, Behnood Bikdeli, Donald Dietz, Caroline Der-Nigoghossian, Nadia Liyanage-Don, Gregg F. Rosner, Elana J. Bernstein, Sumit Mohan, Akinpelumi A. Beckley, David S. Seres, Toni K. Choueiri, Nir Uriel, John C. Ausiello, Domenico Accili, Daniel E. Freedberg, Matthew Baldwin, Allan Schwartz, Daniel Brodie, Christine Kim Garcia, Mitchell S. V. Elkind, Jean M. Connors, John P. Bilezikian, Donald W. Landry, Elaine Y. Wan
Journal: Nature Medicine (2021)