tbuckley/cabot-search huggingface dataset:
DNA methylation–mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation
Authors: Ding Xiao, Liang Fang, Zhongting Liu, Yonghua He, Jun Ying, Haocheng Qin, Aiwu Lu, Meng Shi, Tiandao Li, Bo Zhang, Jianjun Guan, Cuicui Wang, Yousef Abu-Amer, Jie Shen
Journal: Journal of Clinical Investigation (2023)

Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cell was one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, consequently leading to Rbpjk upregulation via hypomethylation within its promoter region. We also showed that Dnmt3b loss-of-function mice phenotypically recapitulated the fracture repair defects observed in Ikk2ca mice, whereas Dnmt3b transgenic mice alleviated fracture repair defects induced by Ikk2ca. Moreover, Rbpjk ablation restored fracture repair in both Ikk2ca mice and Dnmt3b loss-of-function mice. Altogether, this work elucidates a common mechanism involving NFkB/Dnmt3b/Rbpjk axis within the context of inflamed bone regeneration. Building upon this mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in RA mice and showed a functional restoration of bone regeneration under inflammatory condition through an increase in progenitor differentiation potential.
Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism
Authors: Dongping Li, Yu Chen, Meijuan Wan, Fengyi Mei, Fangzhao Wang, Peng Gu, Xianglong Zhang, Rongjuan Wei, Yunong Zeng, Hanzhao Zheng, Bangguo Chen, Qingquan Xiong, Tao Xue, Tianshan Guan, Jiayin Guo, Yuanxin Tian, Li-Yan Zeng, Zhanguo Liu, Hang Yuan, Ling Yang, Hongbin Liu, Lei Dai, Yao Yu, Yifeng Qiu, Peng Wu, Sanda Win, Tin Aung Than, Riqing Wei, Bernd Schnabl, Neil Kaplowitz, Yong Jiang, Qiang Ma, Peng Chen
Journal: Cell Host & Microbe (2023)
A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs
Authors: Wouter J. Venema, Sanne Hiddingh, Jorg van Loosdregt, John Bowes, Brunilda Balliu, Joke H. de Boer, Jeannette Ossewaarde-van Norel, Susan D. Thompson, Carl D. Langefeld, Aafke de Ligt, Lars T. van der Veken, Peter H.L. Krijger, Wouter de Laat, Jonas J.W. Kuiper
Journal: Cell Genomics (2023)

Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
Reporting of Factorial Randomized Trials
Authors: Brennan C. Kahan, Sophie S. Hall, Elaine M. Beller, Megan Birchenall, An-Wen Chan, Diana Elbourne, Paul Little, John Fletcher, Robert M. Golub, Beatriz Goulao, Sally Hopewell, Nazrul Islam, Merrick Zwarenstein, Edmund Juszczak, Alan A. Montgomery
Journal: JAMA (2023)

Importance Transparent reporting of randomized trials is essential to facilitate critical appraisal and interpretation of results. Factorial trials, in which 2 or more interventions are assessed in the same set of participants, have unique methodological considerations. However, reporting of factorial trials is suboptimal. Objective To develop a consensus-based extension to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement for factorial trials. Design Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the CONSORT extension for factorial trials was developed by (1) generating a list of reporting recommendations for factorial trials using a scoping review of methodological articles identified using a MEDLINE search (from inception to May 2019) and supplemented with relevant articles from the personal collections of the authors; (2) a 3-round Delphi survey between January and June 2022 to identify additional items and assess the importance of each item, completed by 104 panelists from 14 countries; and (3) a hybrid consensus meeting attended by 15 panelists to finalize the selection and wording of items for the checklist. Findings This CONSORT extension for factorial trials modifies 16 of the 37 items in the CONSORT 2010 checklist and adds 1 new item. The rationale for the importance of each item is provided. Key recommendations are (1) the reason for using a factorial design should be reported, including whether an interaction is hypothesized, (2) the treatment groups that form the main comparisons should be clearly identified, and (3) for each main comparison, the estimated interaction effect and its precision should be reported. Conclusions and Relevance This extension of the CONSORT 2010 Statement provides guidance on the reporting of factorial randomized trials and should facilitate greater understanding of and transparency in their reporting.
Foreign Letters
Journal: JAMA (2023)

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
Sending positive signals and good (calcium) vibes
Authors: David Dominguez-Sola
Journal: The Journal of Experimental Medicine (2023)

In this issue of JEM, Yada et al. (https://doi.org/10.1084/jem.20222178) demonstrate that effective antibody affinity selection in germinal centers relies on the store-operated calcium entry (SOCE) component of the B cell receptor (BCR) signaling network. Therefore, active BCR signaling is as relevant to positive selection as the function of BCRs as endocytic receptors, answering a question that had puzzled experts for a while. These findings transform our understanding of the mechanisms supporting adaptive immune responses (to vaccines, for example) and have important implications for interpreting the genomics and pathogenesis of germinal center-derived B cell lymphomas.
Politicians, experts, and patient representatives call for the UK government to reverse the rate of antidepressant prescribing
Authors: James Davies, John Read, Danny Kruger, Nigel Crisp, Norman Lamb, Michael Dixon, Sam Everington, Sheila Hollins, Joanna Moncrieff, Bogdan Chiva Giurca, Chris van Tulleken, Guy Chouinard, Michael Dooley, Anne Guy, Mark Horowitz, Peter Kinderman, Lucy Johnstone, Luke Montagu, Antonio E Nardi, Sarah Stacey, Martin Bell, Andrew Tresidder, Jo Watson, Stevie Lewis, Marcantonio Spada, Rupert Payne, Naveed Akhtar, Christian Buckland, Jon Levett, Sue Whitcombe, Laura Marshall-Andrews
Journal: BMJ (2023)

We, a group of medical professionals, researchers, patient representatives, and politicians, call for the UK government to commit to a reversal
Some of Us
Authors: Patricia Lynne Moody
Journal: JAMA (2023)

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
Dengue and Zika RNA-RNA interactomes reveal pro- and anti-viral RNA in human cells
Authors: Kuo-Chieh Liao, Xuping Xie, Anna Karin Beatrice Sundstrom, Xin Ni Lim, Kiat Kee Tan, Yu Zhang, Jing Zou, Amanda Makha Bifani, Hui Xian Poh, Jia Jia Chen, Wy Ching Ng, Su Ying Lim, Eng Eong Ooi, October M. Sessions, Yvonne Tay, Pei-Yong Shi, Roland G. Huber, Yue Wan
Journal: Genome biology (2023)

Abstract Background Identifying host factors is key to understanding RNA virus pathogenicity. Besides proteins, RNAs can interact with virus genomes to impact replication. Results Here, we use proximity ligation sequencing to identify virus-host RNA interactions for four strains of Zika virus (ZIKV) and one strain of dengue virus (DENV-1) in human cells. We find hundreds of coding and non-coding RNAs that bind to DENV and ZIKV viruses. Host RNAs tend to bind to single-stranded regions along the virus genomes according to hybridization energetics. Compared to SARS-CoV-2 interactors, ZIKV-interacting host RNAs tend to be downregulated upon virus infection. Knockdown of several short non-coding RNAs, including miR19a-3p, and 7SK RNA results in a decrease in viral replication, suggesting that they act as virus-permissive factors. In addition, the 3′UTR of DYNLT1 mRNA acts as a virus-restrictive factor by binding to the conserved dumbbell region on DENV and ZIKV 3′UTR to decrease virus replication. We also identify a conserved set of host RNAs that interacts with DENV, ZIKV, and SARS-CoV-2, suggesting that these RNAs are broadly important for RNA virus infection. Conclusions This study demonstrates that host RNAs can impact virus replication in permissive and restrictive ways, expanding our understanding of host factors and RNA-based gene regulation during viral pathogenesis.
Primary care needs to rise to the challenge of caring for patients during climate disasters
Authors: Alexander Azan
Journal: BMJ (2023)

Primary care needs to rise to the challenge of caring for patients during climate disasters Alexander Azan describes how this year's wildfires were an urgent reminder of how primary care needs to adapt to the threat climate change poses to health and health equity Alexander Azan internal medicine physician and climate health research fellow As a primary care physician and climate health research fellow, I'm alarmed by how unprepared I was to counsel and care for my patients during an air quality emergency in New York City earlier this year.In June 2023, air pollution from wildfires raging in Canada moved into regions of the northeastern United States.As a result, communities in New York City were exposed to the worst air quality in the city's recorded history. 1 The first day wildfire smoke blanketed New York City, I was seeing patients.Daylight had quickly turned into a dim, hazy, orange glow, and the air inside my clinic began to smell like burning campfire wood.I work at a federally qualified health centre, which is federally funded to provide preventive medical care to underserved communities in the US.Many of my patients have multiple, chronic health conditions that increase their risk of severe health outcomes from exposure to poor air quality.Without informed guidance to advise them, many of my patients arrived at their appointments unmasked and in notable respiratory distress.Outside, the air quality index (AQI) neared its maximum of 500, 2 far beyond the AQI of 101-150 that is deemed unhealthy for sensitive populations.
Advances in the management of chronic kidney disease
Authors: Teresa K Chen, Melanie P Hoenig, Dorothea Nitsch, Morgan E Grams
Journal: BMJ (2023)

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.
Hot “Dissolving” Extrusion of Lurasidone with Natural Liquid Small Molecule for Amorphous Solid Dispersion Based Self‐Assembled Submicron Emulsion
Authors: Peiya Shen, Enshi Hu, Chunfeng Zhang, Yuan Gao, Shuai Qian, Weili Heng, Jianjun Zhang, Yuanfeng Wei
Journal: Advanced Healthcare Materials (2023)

Nowadays, ≈90% of new drug candidates under development are poorly bioavailable due to their low solubility and/or permeability. Herein, a natural liquid small molecule trans-anethole (TA) is introduced into the drug-polymer system lurasidone (LUS)-poly (1-vinylpyrrolidone-co-vinyl acetate) (VA64), notably improving the compatibility of components for the successful preparation of amorphous solid dispersion (ASD) and facilitating the formation of self-emulsifying drug delivery system (SEDDS) during dissolution. LUS-TA-VA64 ASD shows enhanced supersaturation with a long maintenance time of at least 24 h over pure LUS. The strong non-covalent force between VA64 (as emulsifier) and TA (as oil phase)/ water promotes the self-assembly of submicron emulsion and ensures its stability for at least 10 h. Compared to the commercial salt form of LUS, the ASD shows twofold increase in peak plasma concentration (C
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Authors: Jayesh Desai, Guzman Alonso, Se Hyun Kim, Andres Cervantes, Thomas Karasic, Laura Medina, Einat Shacham-Shmueli, Rasha Cosman, Alejandro Falcon, Eelke Gort, Tormod Guren, Erminia Massarelli, Wilson H. Miller, Luis Paz-Ares, Hans Prenen, Alessio Amatu, Chiara Cremolini, Tae Won Kim, Victor Moreno, Sai-Hong I. Ou, Alessandro Passardi, Adrian Sacher, Armando Santoro, Rafal Stec, Susanna Ulahannan, Kathryn Arbour, Patricia Lorusso, Jia Luo, Manish R. Patel, Yoonha Choi, Zhen Shi, Sandhya Mandlekar, Mark T. Lin, Stephanie Royer-Joo, Julie Chang, Tomi Jun, Neekesh V. Dharia, Jennifer L. Schutzman, Sae-Won Han
Journal: Nature Medicine (2023)

Abstract KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRA S G12C -positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS–MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRA S G12C -positive CRC ( n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients ( n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRA S G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRA S G12C -positive CRC. ClinicalTrials.gov identifier: NCT04449874
Integration of datasets for individual prediction of DNA methylation-based biomarkers
Authors: Charlotte Merzbacher, Barry Ryan, Thibaut Goldsborough, Robert F. Hillary, Archie Campbell, Lee Murphy, Andrew M. McIntosh, David Liewald, Sarah E. Harris, Allan F. McRae, Simon R. Cox, Timothy I. Cannings, Catalina A. Vallejos, Daniel L. McCartney, Riccardo E. Marioni
Journal: Genome biology (2023)

Abstract Background Epigenetic scores (EpiScores) can provide biomarkers of lifestyle and disease risk. Projecting new datasets onto a reference panel is challenging due to separation of technical and biological variation with array data. Normalisation can standardise data distributions but may also remove population-level biological variation. Results We compare two birth cohorts (Lothian Birth Cohorts of 1921 and 1936 — n LBC1921 = 387 and n LBC1936 = 498) with blood-based DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examine the effect of 16 normalisation methods on a novel BMI EpiScore (trained in an external cohort, n = 18,413), and Horvath’s pan-tissue DNA methylation age, when the cohorts are normalised separately and together. The BMI EpiScore explains a maximum variance of R 2 =24.5% in BMI in LBC1936 (SWAN normalisation). Although there are cross-cohort R 2 differences, the normalisation method makes a minimal difference to within-cohort estimates. Conversely, a range of absolute differences are seen for individual-level EpiScore estimates for BMI and age when cohorts are normalised separately versus together. While within-array methods result in identical EpiScores whether a cohort is normalised on its own or together with the second dataset, a range of differences is observed for between-array methods. Conclusions Normalisation methods returning similar EpiScores, whether cohorts are analysed separately or together, will minimise technical variation when projecting new data onto a reference panel. These methods are important for cases where raw data is unavailable and joint normalisation of cohorts is computationally expensive.
Inflammation-induced subcutaneous neovascularization for the long-term survival of encapsulated islets without immunosuppression
Authors: Long-Hai Wang, Braulio A. Marfil-Garza, Alexander U. Ernst, Rena L. Pawlick, Andrew R. Pepper, Kento Okada, Boris Epel, Navin Viswakarma, Mrignayani Kotecha, James Arthur Flanders, Ashim K. Datta, Hong-Jie Gao, Ye-Zi You, Minglin Ma, A. M. James Shapiro
Journal: Nature Biomedical Engineering (2023)
Efficient 3D imaging and pathological analysis of the human lymphoma tumor microenvironment using light-sheet immunofluorescence microscopy
Authors: Liting Chen, Jiao Meng, Yao Zhou, Fang Zhao, Yifan Ma, Wenyang Feng, Xingyu Chen, Jin jin, Shimeng Gao, Jianchao Liu, Man Zhang, Aichun Liu, Zhenya Hong, Jiang Tang, Dong Kuang, Liang Huang, Yicheng Zhang, Peng Fei
Journal: Theranostics (2023)

The composition and spatial structure of the lymphoma tumor microenvironment (TME) provide key pathological insights for tumor survival and growth, invasion and metastasis, and resistance to immunotherapy. However, the 3D lymphoma TME has not been well studied owing to the limitations of current imaging techniques. In this work, we take full advantage of a series of new techniques to enable the first 3D TME study in intact lymphoma tissue.