tbuckley/cabot-search huggingface dataset:
Novel Liver Injury Phenotypes and Outcomes in Clinical Trial Participants with Pulmonary Hypertension
Authors: Jacqueline V. Scott, Jude Moutchia, Robin L McClelland, Nadine Al-Naamani, Ethan Weinberg, Harold I Palevsky, Jasleen Minhas, Dina K. Appleby, Akaya Smith, Steven C Pugliese, Corey E Ventetuolo, Steven M Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Rationale: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) cause right ventricular dysfunction, which can impact other solid organs. However, the profiles and consequences of hepatic injury resulting from PAH and CTEPH have not been well studied. Objectives: We aimed to identify underlying patterns of liver injury in a cohort of patients with PAH and CTEPH enrolled in 15 randomized clinical trials conducted between 1998 and 2014. Methods: We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity. Measurements and Main Results: Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin data. Using k-means clustering, we identified phenotypes with no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns. Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and the highest risk of mortality. The cholestatic injury group also experienced the greatest placebo-corrected treatment effect on 6-minute-walk distance. Randomization to the experimental arm transitioned patients to a healthier liver status. Conclusions: Liver injury was associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment had beneficial effects on liver health compared with placebo. The role of liver disease (often subclinical) in determining outcomes warrants prospective studies.
Advances in targeting histone deacetylase for treatment of solid tumors
Authors: Mu-Qi Shi, Ying Xu, Xin Fu, De-Si Pan, Xian-Ping Lu, Yi Xiao, Yi-Zhou Jiang
Journal: Journal of Hematology & Oncology (2024)

Abstract Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors.
GFI1B specifies developmental potential of innate lymphoid cell progenitors in the lungs
Authors: Qiutong Huang, Wang H. J. Cao, Sophie Curio, Huiyang Yu, Renae Denman, Evelyn Chen, Jaring Schreuder, James Dight, M. Chaudhry, Nicolas Jacquelot, Verena C. Wimmer, Cyril Seillet, Tarik Möröy, Gabrielle T. Belz
Journal: Science Immunology (2024)

Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B
The tumor-intrinsic role of the m <sup>6</sup> A reader YTHDF2 in regulating immune evasion
Authors: Sai Xiao, Shoubao Ma, Baofa Sun, Wenchen Pu, Songqi Duan, Jingjing Han, Yaqun Hong, Jianying Zhang, Yong Peng, Chuan He, Ping Yi, Michael A. Caligiuri, Jianhua Yu
Journal: Science Immunology (2024)

Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m
Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause late-onset primary lymphedema
Authors: Pascal Brouillard, Aino Murtomäki, Veli-Matti Leppänen, Marko Hyytiäinen, Sandrine Mestre, Lucas Potier, Laurence M. Boon, Nicole Revencu, Arin Greene, Andrey Anisimov, Miia H. Salo, Reetta Hinttala, Lauri Eklund, Isabelle Quéré, Kari Alitalo, Miikka Vikkula
Journal: Journal of Clinical Investigation (2024)

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation and fibrosis, results from defective lymphatic vessels or valves caused by mutations in genes involved in development, maturation and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor-like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodelling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR-Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2-TIE1 pathway in lymphatic function.
Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in COPDGene
Authors: Eileen M. Harder, Pietro Nardelli, Carrie L. Pistenmaa, Samuel Y Ash, Aparna Balasubramanian, Russell P. Bowler, Monica Iturrioz Campo, Alejandro A Diaz, Paul M. Hassoun, Jane A. Leopold, Fernando J. Martinez, Steven D Nathan, Imre Noth, Anna J. Podolanczuk, Rajan Saggar, Rúben San José Estépar, Oksana A. Shlobin, Wei Wang, Aaron B. Waxman, Rachel K Putman, George R Washko, Bina Choi, Raúl San José Estépar, Farbod N Rahaghi
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown.
Highlighting equity in physical activity, sport and clinical practice
Authors: Jenna M Schulz, Jane S Thornton
Journal: British Journal of Sports Medicine (2024)

Health equity, as defined by the WHO, ensures that all participants, regardless of background or ability can access and benefit from the essential elements of health and well-being. 1 For physical activity and sport, equity often involves breaking down barriers to participation, whether they be financial, cultural or physical.This edition of the BJSM focuses on these three key areas of equity within sport and exercise medicine (SEM).
Relevance of Echocardiography-derived Phenotyping in Patients with Pulmonary Arterial Hypertension Treated with Initial Oral Combination Therapy: An Italian Pulmonary Hypertension Network (iPHNET) Study
Authors: Roberto Badagliacca, Stefano Ghio, Michele D’Alto, Pietro Ameri, Michele Correale, Domenico Filomena, Claudia Raineri, Davide Stolfo, Robert Naeije, Carmine Dario Vizza, Paola Argiento, Natale Daniele Brunetti, Gavino Casu, Nadia Cedrone, Marco Confalonieri, Marco Corda, Carlo D’Agostino, Gaetano M. De Ferrari, Elisabetta De Tommasi, Giuseppe Galgano, Alessandra Greco, Massimo Grimaldi, Carlo Lombardi, Rosalinda Madonna, Giovanna Manzi, Valentina Mercurio, Alexandra Mihai, Massimiliano Mulè, Giuseppe Paciocco, Silvia Papa, Tommaso Recchioni, Antonella Romaniello, Emanuele Romeo, Marco Vatrano, Patrizio Vitulo
Journal: American Journal of Respiratory and Critical Care Medicine (2024)
Discovery and Validation of a Volatile Signature of Eosinophilic Airway Inflammation in Asthma
Authors: Rosa Peltrini, Rebecca L. Cordell, Michael Wilde, Shahd Abuhelal, Eleanor Quek, Nazanin Zounemat-Kermani, Wadah Ibrahim, Matthew Richardson, Paul Brinkman, Florence Schleich, Pierre-Hugues Stefanuto, Hnin Aung, Neil Greening, Sven Erik Dahlen, Ratko Djukanovic, Ian M Adcock, Christopher Brightling, Paul Monks, Salman Siddiqui
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Volatile organic compounds (VOCs) in asthmatic breath may be associated with sputum eosinophilia. We developed a volatile biomarker signature to predict sputum eosinophilia in asthma.
Aloe emodin promotes mucosal healing by modifying the differentiation fate of enteroendocrine cells via regulating cellular free fatty acid sensitivity
Authors: Weilian Bao, Jiaren Lyu, Guize Feng, Linfeng Guo, Dian Zhao, Keyuan You, Yang Liu, Haidong Li, Peng Du, Daofeng Chen, Xiaoyan Shen
Journal: Acta Pharmaceutica Sinica B (2024)

The proper differentiation and reorganization of the intestinal epithelial cell population is critical to mucosal regeneration post injury. Label retaining cells (LRCs) expressing SRY-box transcription factor 9 (SOX9) promote epithelial repair by replenishing LGR5
MetALD: Does it require a different therapeutic option?
Authors: George W. Marek, Harmeet Malhi
Journal: Hepatology (2024)

New guidelines for the definitions of steatotic liver disease have named the entity of metabolic dysfunction and alcohol-associated liver disease (MetALD) as an overlap condition of metabolic dysfunction–associated steatotic liver disease (MASLD) and alcohol-associated liver disease. There is a broad range of therapeutics in all stages of development for MASLD, but these therapeutics, in general, have not been studied in patients with significant ongoing alcohol use. In this review, we discuss the current understanding of the endogenous and exogenous risks for MASLD and MetALD. Rational strategies for therapeutic intervention in MetALD include biopsychosocial interventions, alcohol use cessation strategies, including the use of medications for alcohol use disorder, and judicious use of therapeutics for steatotic liver disease. Therapeutics with promise for MetALD include incretin-based therapies, FGF21 agonists, thyroid hormone receptor beta agonists, sodium-glucose co-transporter 2 inhibitors, and agents to modify de novo lipogenesis. Currently, glucagon-like peptide 1 receptor agonists and peroxisome proliferator–activated receptor γ agonists have the largest body of literature supporting their use in MASLD, and there is a paucity of agents in trials for alcohol-associated liver disease. From existing studies, it is not clear if unique therapeutics or a combinatorial approach are needed for MetALD. Further elucidation of the safety and benefits of MASLD-related therapies is of paramount importance for advancing therapeutics for MetALD in carefully designed inclusive clinical trials.
MondoA and AKI and AKI-to-CKD Transition
Authors: Shihomi Maeda, Shinsuke Sakai, Yoshitsugu Takabatake, Takeshi Yamamoto, Satoshi Minami, Jun Nakamura, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Hiroaki Yonishi, Sho Matsui, Atsuhiro Imai, Ryuya Edahiro, Hitomi Yamamoto-Imoto, Isao Matsui, Seiji Takashima, Ryoichi Imamura, Norio Nonomura, Motoko Yanagita, Yukinori Okada, Andrea Ballabio, Shuhei Nakamura, Tamotsu Yoshimori, Yoshitaka Isaka
Journal: Journal of the American Society of Nephrology (2024)

Key Points The expression of MondoA was decreased in the renal tubules of patients with CKD. Genetic ablation of MondoA in proximal tubules inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the transcription factor EB-peroxisome proliferator-activated receptor- γ coactivator-1 α axis. Background Elderly individuals and patients with CKD are at a higher risk of AKI. The transcription factor MondoA is downregulated in the kidneys of aged individuals or patients with AKI; however, its roles in AKI development and the AKI-to-CKD transition remain unknown. Methods We investigated the expression of MondoA in human kidney biopsy samples, ischemia-reperfusion–injured (IRI) mouse kidneys, and cultured proximal tubular epithelial cells under hypoxia/reoxygenation. The role of MondoA during the initial and recovery phases after IRI was evaluated using proximal tubule–specific MondoA knockout mice and MondoA -deficient proximal tubular epithelial cells. Furthermore, we explored the involvement of Rubicon and transcription factor EB (TFEB), both of which are downstream factors of MondoA. Results MONDOA expression was decreased in the renal tubules of patients with CKD. In mouse kidneys, MondoA expression was decreased under ischemia, whereas its expression was increased during reperfusion. Genetic ablation of MondoA in proximal tubular epithelial cells inhibited autophagy and increased vulnerability to AKI through increased expression of Rubicon. Ablation of Rubicon in MondoA -deficient IRI kidneys activated autophagy and protected mitochondrial function. MondoA ablation during the recovery phase after ischemia-reperfusion aggravated kidney injury through downregulation of the TFEB-peroxisome proliferator-activated receptor- γ coactivator-1 α axis. Pharmacological upregulation of TFEB contributed to maintaining mitochondrial biogenesis and increased peroxisome proliferator-activated receptor- γ coactivator-1 α transcription. Conclusions Our findings demonstrate that MondoA protected against vulnerability to AKI by maintaining autophagy and subsequently supporting mitochondrial function to prevent progression to CKD.
Preoperative GLP-1 Receptor Agonists and Risk of Postoperative Respiratory Complications
Authors: Ion A. Hobai
Journal: JAMA (2024)

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 Journals 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 2024 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
Identification of novel small-molecule inhibitors of SARS-CoV-2 by chemical genetics
Authors: Chris Chun-Yiu Chan, Qian Guo, Jasper Fuk-Woo Chan, Kaiming Tang, Jian-Piao Cai, Kenn Ka-Heng Chik, Yixin Huang, Mei Dai, Bo Qin, Chon Phin Ong, Allen Wing-Ho Chu, Wan-Mui Chan, Jonathan Daniel Ip, Lei Wen, Jessica Oi-Ling Tsang, Tong-Yun Wang, Yubin Xie, Zhenzhi Qin, Jianli Cao, Zi-Wei Ye, Hin Chu, Kelvin Kai-Wang To, Xing-Yi Ge, Tao Ni, Dong-Yan Jin, Sheng Cui, Kwok-Yung Yuen, Shuofeng Yuan
Journal: Acta Pharmaceutica Sinica B (2024)

There are only eight approved small molecule antiviral drugs for treating COVID-19. Among them, four are nucleotide analogues (remdesivir, JT001, molnupiravir, and azvudine), while the other four are protease inhibitors (nirmatrelvir, ensitrelvir, leritrelvir, and simnotrelvir-ritonavir). Antiviral resistance, unfavourable drug‒drug interaction, and toxicity have been reported in previous studies. Thus there is a dearth of new treatment options for SARS-CoV-2. In this work, a three-tier cell-based screening was employed to identify novel compounds with anti-SARS-CoV-2 activity. One compound, designated
Preoperative GLP-1 Receptor Agonists and Risk of Postoperative Respiratory Complications
Authors: David A. Milder, Tamara Y. Milder, Peter Kam
Journal: JAMA (2024)

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 Journals 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 2024 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
Preoperative GLP-1 Receptor Agonists and Risk of Postoperative Respiratory Complications—Reply
Authors: Anjali A. Dixit, Brian T. Bateman, Eric C. Sun
Journal: JAMA (2024)

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 Journals 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 2024 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
Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function
Authors: Alia Hassan, Nareman Khalaily, Rachel Kilav-Levin, Barbara Del Castello, Nancy Ruth Manley, Iddo Z. Ben-Dov, Tally Naveh-Many
Journal: Journal of the American Society of Nephrology (2024)

Key Points Maintaining parathyroid gland integrity is a dynamic process regulated by the parathyroid microRNA–mechanistic target of rapamycin complex 1 axis. This axis is essential for preserving intact parathyroid glands throughout life, with relevance to CKD-induced secondary hyperparathyroidism. Background Secondary hyperparathyroidism of CKD contributes significantly to patient morbidity and mortality. The underlining mechanisms of CKD-induced secondary hyperparathyroidism remain elusive. We previously demonstrated that PT- Dicer −/− mice, with parathyroid-specific deletion of the microRNA (miRNA)-processing enzyme Dicer and consequently miRNA, maintain normal basal serum parathyroid hormone (PTH) levels but do not develop secondary hyperparathyroidism induced by CKD. In addition, we showed that the parathyroid mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in CKD. We now explored the roles of Dicer/miRNA and mTORC1 in parathyroid development and function. Methods We generated mice with parathyroid-specific Dicer (PT- Dicer −/− ), mechanistic target of rapamycin (PT- mTOR −/− ), or tuberous sclerosis complex 1 (PT- Tsc1 −/− ) deficiency combined with yellow fluorescent protein (YFP) or tdTomato expression to identify the parathyroids by fluorescence microscopy. CKD was induced by an adenine-rich high-phosphate diet. Results Despite normal basal serum PTH levels, PT- Dicer −/− mice displayed apoptotic loss of intact parathyroid glands postnatally and reduced mechanistic target of rapamycin activity. PT- mTOR −/− mice lacked intact parathyroid glands yet maintained normal serum PTH levels, mirroring the phenotype of PT- Dicer −/− mice. Conversely, PT- Tsc1 −/− mice with hyperactivated mTORC1 exhibited enlarged glands along with elevated basal serum PTH and calcium levels. Significantly, PT- Dicer −/− ;Tsc1 −/− double knockout mice preserved intact parathyroid glands and reinstated CKD-induced secondary hyperparathyroidism. Conclusions mTORC1 operates downstream of Dicer and miRNA in the parathyroid and is essential for maintaining postnatal parathyroid gland integrity throughout life and for the pathogenesis of CKD-induced secondary hyperparathyroidism.
Tirzepatide—New Evidence for the Treatment of Obesity From China
Authors: Weiping Jia, Jianzhong Xiao, Juliana C.N. Chan
Journal: JAMA (2024)

Lin Zhao, MD; Zhifeng Cheng, MD; Yibing Lu, MD; Ming Liu, MD; Hong Chen, MD; Min Zhang, MD; Rui Wang, MD; Yuan Yuan, PhD; Xiaoying Li, MD