tbuckley/cabot-search huggingface dataset:
Pharmacological induction of chromatin remodeling drives chemosensitization in triple-negative breast cancer
Authors: Meisam Bagheri, Gadisti Aisha Mohamed, Mohammed Ashick Mohamed Saleem, Nevena B. Ognjenovic, Hanxu Lu, Fred W. Kolling, Owen M. Wilkins, Subhadeep Das, Ian S. LaCroix, Shivashankar H. Nagaraj, Kristen E. Muller, Scott A. Gerber, Todd W. Miller, Diwakar R. Pattabiraman
Journal: Cell Reports Medicine (2024)

Targeted therapies have improved outcomes for certain cancer subtypes, but cytotoxic chemotherapy remains a mainstay for triple-negative breast cancer (TNBC). The epithelial-to-mesenchymal transition (EMT) is a developmental program co-opted by cancer cells that promotes metastasis and chemoresistance. There are no therapeutic strategies specifically targeting mesenchymal-like cancer cells. We report that the US Food and Drug Administration (FDA)-approved chemotherapeutic eribulin induces ZEB1-SWI/SNF-directed chromatin remodeling to reverse EMT that curtails the metastatic propensity of TNBC preclinical models. Eribulin induces mesenchymal-to-epithelial transition (MET) in primary TNBC in patients, but conventional chemotherapy does not. In the treatment-naive setting, but not after acquired resistance to other agents, eribulin sensitizes TNBC cells to subsequent treatment with other chemotherapeutics. These findings provide an epigenetic mechanism of action of eribulin, supporting its use early in the disease process for MET induction to prevent metastatic progression and chemoresistance. These findings warrant prospective clinical evaluation of the chemosensitizing effects of eribulin in the treatment-naive setting.
Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis
Authors: Katariina Nurmi, Kristiina Silventoinen, Salla Keskitalo, Kristiina Rajamäki, Vesa-Petteri Kouri, Matias Kinnunen, Sami Jalil, Rocio Maldonado, Kirmo Wartiovaara, Elma Inés Nievas, Silvina Paola Denita-Juárez, Christopher J.A. Duncan, Outi Kuismin, Janna Saarela, Inka Romo, Timi Martelius, Jukka Parantainen, Arzu Beklen, Marcelina Bilicka, Sampsa Matikainen, Dan C. Nordström, Meri Kaustio, Ulla Wartiovaara-Kautto, Outi Kilpivaara, Christoph Klein, Fabian Hauck, Tiina Jahkola, Timo Hautala, Markku Varjosalo, Goncalo Barreto, Mikko R.J. Seppänen, Kari K. Eklund
Journal: Cell Reports Medicine (2024)

In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients' macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1β secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-β (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1β and/or IFN-I signaling could represent a therapeutic approach for these patients.
A Novel Coacervate Embolic Agent for Tumor Chemoembolization
Authors: Menghui Liu, Yang Sun, Yitong Zhou, Yanlv Chen, Meng Yu, Liujun Li, Leye Yan, Yajun Yuan, Jiayao Chen, Kaixiang Zhou, Hong Shan, Xin Peng
Journal: Advanced Healthcare Materials (2024)

Transcatheter arterial chemoembolization (TACE) has proven effective in blocking tumor-supplied arteries and delivering localized chemotherapeutic treatment to combat tumors. However, traditional embolic TACE agents exhibit certain limitations, including insufficient chemotherapeutic drug-loading and sustained-release capabilities, non-biodegradability, susceptibility to aggregation, and unstable mechanical properties. This study introduces a novel approach to address these shortcomings by utilizing a complex coacervate as a liquid embolic agent for tumor chemoembolization. By mixing oppositely charged quaternized chitosan (QCS) and gum arabic (GA), a QCS/GA polymer complex coacervate with shear-thinning property is obtained. Furthermore, the incorporation of the contrast agent Iohexol (I) and the chemotherapeutic doxorubicin (DOX) into the coacervate leads to the development of an X-ray-opaque QCS/GA/I/DOX coacervate embolic agent capable of carrying drugs. This innovative formulation effectively embolizes the renal arteries without recanalization. More importantly, the QCS/GA/I/DOX coacervate can successfully embolize the supplying arteries of the VX2 tumors in rabbit ear and liver. Coacervates can locally release DOX to enhance its therapeutic effects, resulting in excellent antitumor efficacy. This coacervate embolic agent exhibits substantial potential for tumor chemoembolization due to its shear-thinning performance, excellent drug-loading and sustained-release capabilities, good biocompatibility, thrombogenicity, biodegradability, safe and effective embolic performance, and user-friendly application.
Public Health Relevance of US EPA Air Quality Index Activity Recommendations
Authors: Robert D. Brook, Sanjay Rajagopalan, Sadeer Al-Kindi
Journal: JAMA Network Open (2024)

Importance Reducing exposure to fine particulate matter (&amp;amp;lt;2.5 μm [PM 2.5 ]) air pollution improves cardiopulmonary morbidity and mortality. However, the public health relevance of air quality index (AQI) activity guidelines under present-day environmental conditions in the US has not been critically assessed. Objective To evaluate the public health relevance of following PM 2.5 AQI activity guidance in preventing serious atherosclerotic cardiovascular disease (ASCVD) and pulmonary events among adults in the US. Design, Setting, and Participants This cross-sectional modeling study involved the general adult population and sensitive individuals as designated by the US Environmental Protection Agency (EPA), including adults with preexisting ASCVD or lung disease (asthma or chronic obstructive pulmonary disease). The study was conducted between August 1, 2023, and January 31, 2024. Exposures Daily AQI strata for PM 2.5 and the corresponding activity recommendations. Main Outcomes and Measures The main outcome was the number needed to treat (NNT) per day by following activity guidance across daily AQI strata to prevent 1 serious ASCVD or pulmonary event among relevant populations. To calculate PM 2.5 -induced excess disease event rates per day, estimated baseline disease-specific daily event rates for each group were multiplied by the increase in risks due to PM 2.5 levels at each AQI stratum. The number of events prevented per day was calculated by multiplying each excess disease event rate by the percentage in exposure reduction plausibly incurred by following population-specific activity guidance at each AQI level. The NNT is the reciprocal of the number of events prevented. Results The NNT to prevent ASCVD events was high for the general population and for patients with ASCVD across all AQI strata. The range of values was comparatively lower to prevent pulmonary events among adults with lung disease. During most days (96%) when activity recommendations were promulgated due to elevated PM 2.5 (AQI, 101-200), the NNT to prevent a serious disease event remained very high for the general population (&amp;amp;gt;18 million), patients with ASCVD (approximately 1.6-5 million), and adults with lung disease (approximately 66 000-202 000). Conclusions and Relevance These findings suggest that existing PM 2.5 AQI activity recommendations are of questionable public health relevance in present-day conditions and merit consideration for updating to improve their potential effectiveness.
Tunable In Situ Synthesis of Ultrathin Extracellular Matrix‐Derived Membranes in Organ‐on‐a‐Chip Devices
Authors: Jeremy D. Newton, Yuetong Song, Siwan Park, Kayshani R. Kanagarajah, Amy P. Wong, Edmond W. K. Young
Journal: Advanced Healthcare Materials (2024)

Thin cell culture membranes in organ-on-a-chip (OOC) devices are used to model a wide range of thin tissues. While early and most current platforms use microporous or fibrous elastomeric or thermoplastic membranes, there is an emerging class of devices using extra-cellular matrix (ECM) protein-based membranes to improve their biological relevance. These ECM-based membranes present physiologically relevant properties, but they are difficult to integrate into OOC devices due to their relative fragility. Additionally, the specialized fabrication methods developed to date make comparison between methods difficult. This work presents the development and characterization of a method to produce ultrathin matrix-derived membranes (UMM) in OOC devices that requires only a preassembled thermoplastic device and a micropipette, decoupling the device and UMM fabrication processes. Control over the thickness and permeability of the UMM is demonstrated, along with integration of the UMM in a device enabling high-resolution on-chip microscopy. The reliability of the UMM fabrication method is leveraged to develop a medium-throughput well-plate format device with 32 independent UMM-integrated samples. Finally, proof-of-concept cell culture experiments are demonstrated. Due to its simplicity and controllability, the presented method has the potential to overcome technical barriers preventing wider adoption of physiologically relevant ECM-based membranes in OOC devices.
Antibiotic-Sparing Prevention of Urinary Tract Infections—New Evidence Regarding <scp>d</scp>-Mannose
Authors: Eva Raphael, Alison J. Huang
Journal: JAMA Internal Medicine (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 Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast 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) 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 Internal Medicine journal
Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection
Authors: Lucy Cooper, Hui Xu, Jack Polmear, Liam Kealy, Christopher Szeto, Ee Shan Pang, Mansi Gupta, Alana Kirn, Justin J. Taylor, Katherine J.L. Jackson, Benjamin J. Broomfield, Angela Nguyen, Catarina Gago da Graça, Nicole La Gruta, Daniel T. Utzschneider, Joanna R. Groom, Luciano Martelotto, Ian A. Parish, Meredith O’Keeffe, Christopher D. Scharer, Stephanie Gras, Kim L. Good-Jacobson
Journal: Immunity (2024)
Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells
Authors: Gabriele Picco, Yanhua Rao, Angham Al Saedi, Yang Lee, Sara F. Vieira, Shriram Bhosle, Kieron May, Carmen Herranz-Ors, Samantha J. Walker, Raynold Shenje, Cansu Dincer, Freddy Gibson, Ruby Banerjee, Zoe Hewitson, Thilo Werner, Joshua E. Cottom, Yang Peng, Nanhua Deng, Youyou Zhang, Eldridge N. Nartey, Leng Nickels, Philip Landis, Daniela Conticelli, Katrina McCarten, Jacob Bush, Mamta Sharma, Howard Lightfoot, David House, Emma Milford, Emma K. Grant, Michal P. Glogowski, Craig D. Wagner, Marcus Bantscheff, Anna Rutkowska-Klute, Francesca Zappacosta, Jonathan Pettinger, Syd Barthorpe, H. Christian Eberl, Brian T. Jones, Jessica L. Schneck, Dennis J. Murphy, Emile E. Voest, Joshua P. Taygerly, Michael P. DeMartino, Matthew A. Coelho, Jonathan Houseley, Geeta Sharma, Benjamin Schwartz, Mathew J. Garnett
Journal: Cancer Discovery (2024)

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.
Future proofing health in response to climate change and rapid urbanisation in Africa
Authors: Monika Kamkuemah, Olalekan Ayo-Yusuf, Tolu Oni
Journal: BMJ (2024)

Community oriented, integrated climate and health systems should include indigenous knowledge systems and capitalise on Africa's young demographic, harnessing mobile technology to unleash a cadre of youth community climate health workers, argue <b>Monika Kamkuemah and colleagues</b>
Tying health taxes to health promotion is popular and effective in Thailand
Authors: Viroj Tangcharoensathien, Prakit Vathesatogkit, Supakorn Buasai
Journal: BMJ (2024)

The ringfencing of alcohol and tobacco consumption taxes for spending on health promotion has coincided with reductions in risk factors for non-communicable disease, the ThaiHealth programme shows, write <b>Viroj Tangcharoensathien</b>, <b>Prakit Vathesatogkit</b>, and <b>Supakorn Buasai</b>
Capacity for the management of kidney failure in the International Society of Nephrology North and East Asia region: report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)
Authors: Winston Wing-Shing Fung, Hyeong Cheon Park, Yosuke Hirakawa, Silvia Arruebo, Aminu K. Bello, Fergus J. Caskey, Sandrine Damster, Jo-Ann Donner, Vivekanand Jha, David W. Johnson, Adeera Levin, Charu Malik, Masaomi Nangaku, Ikechi G. Okpechi, Marcello Tonelli, Seiji Ueda, Feng Ye, Yusuke Suzuki, Angela Yee-Moon Wang, Atefeh Amouzegar, Guangyan Cai, Jer-Ming Chang, Hung-Chun Chen, Yuk Lun Cheng, Yeoungjee Cho, M. Razeen Davids, Sara N. Davison, Hassane M. Diongole, Smita Divyaveer, Kent Doi, Udeme E. Ekrikpo, Isabelle Ethier, Kei Fukami, Anukul Ghimire, Ghenette Houston, Htay Htay, Kwaifa Salihu Ibrahim, Takahiro Imaizumi, Georgina Irish, Kailash Jindal, Naoki Kashihara, Dearbhla M. Kelly, Rowena Lalji, Bi-Cheng Liu, Shoichi Maruyama, Aisha M. Nalado, Brendon L. Neuen, Jing Nie, Akira Nishiyama, Timothy O. Olanrewaju, Mohamed A. Osman, Anna Petrova, Parnian Riaz, Syed Saad, Aminu Muhammad Sakajiki, Emily See, Stephen M. Sozio, Sydney C.W. Tang, Sophanny Tiv, Somkanya Tungsanga, Andrea Viecelli, Marina Wainstein, Motoko Yanagita, Chih-Wei Yang, Jihyun Yang, Emily K. Yeung, Xueqing Yu, Deenaz Zaidi, Hong Zhang, Lili Zhou
Journal: Kidney International Supplements (2024)
Can current interlinked crises stimulate the structural and policy choices required for healthy societies?
Authors: Kumanan Rasanathan, Yogan Pillay
Journal: BMJ (2024)

<b>Kumanan Rasanathan and colleagues</b> argue that governments and other societal actors, including the health sector, must ensure current global crises lead to choices and action to build healthy societies that enhance social, economic, and environmental equity and sustainability
A comprehensive benchmark of graph-based genetic variant genotyping algorithms on plant genomes for creating an accurate ensemble pipeline
Authors: Ze-Zhen Du, Jia-Bao He, Wen-Biao Jiao
Journal: Genome biology (2024)

Abstract Background Although sequencing technologies have boosted the measurement of the genomic diversity of plant crops, it remains challenging to accurately genotype millions of genetic variants, especially structural variations, with only short reads. In recent years, many graph-based variation genotyping methods have been developed to address this issue and tested for human genomes. However, their performance in plant genomes remains largely elusive. Furthermore, pipelines integrating the advantages of current genotyping methods might be required, considering the different complexity of plant genomes. Results Here we comprehensively evaluate eight such genotypers in different scenarios in terms of variant type and size, sequencing parameters, genomic context, and complexity, as well as graph size, using both simulated and real data sets from representative plant genomes. Our evaluation reveals that there are still great challenges to applying existing methods to plants, such as excessive repeats and variants or high resource consumption. Therefore, we propose a pipeline called Ensemble Variant Genotyper (EVG) that can achieve better genotyping performance in almost all experimental scenarios and comparably higher genotyping recall and precision even using 5× reads. Furthermore, we demonstrate that EVG is more robust with an increasing number of graphed genomes, especially for insertions and deletions. Conclusions Our study will provide new insights into the development and application of graph-based genotyping algorithms. We conclude that EVG provides an accurate, unbiased, and cost-effective way for genotyping both small and large variations and will be potentially used in population-scale genotyping for large, repetitive, and heterozygous plant genomes.
Safety and Efficacy of Metabolic Modulation With Ninerafaxstat in Patients With Nonobstructive Hypertrophic Cardiomyopathy
Authors: Martin S. Maron, Masliza Mahmod, Azlan Helmy Abd Samat, Lubna Choudhury, Daniele Massera, Dermot M.J. Phelan, Sharon Cresci, Matthew W. Martinez, Ahmad Masri, Theodore P. Abraham, Eric Adler, Omar Wever-Pinzon, Sherif F. Nagueh, Gregory D. Lewis, Paul Chamberlin, Jai Patel, Arash Yavari, Hakim-Moulay Dehbi, Rizwan Sarwar, Betty Raman, Ladislav Valkovič, Stefan Neubauer, James E. Udelson, Hugh Watkins
Journal: Journal of the American College of Cardiology (2024)

In nonobstructive hypertrophic cardiomyopathy (nHCM), there are no approved medical therapies. Impaired myocardial energetics is a potential cause of symptoms and exercise limitation. Ninerafaxstat, a novel cardiac mitotrope, enhances cardiac energetics. To evaluate the safety and efficacy of ninerafaxstat in nHCM. Patients with HCM and left ventricular (LV) outflow gradient <30 mmHg, ejection fraction ≥50% and peak VO2 <80% predicted, were randomized to ninerafaxstat 200 mg BID or placebo (1:1) for 12 weeks. Primary endpoint was safety and tolerability with efficacy outcomes also assessed as secondary endpoints. A total of 67 patients with nHCM were enrolled at 12 centers (57 yrs ± 11.8; 55% women). Serious adverse events occurred in 11.8% (4/34) in the ninerafaxstat group and 6.1% of patients (2/33) in placebo. From baseline to 12 weeks, ninerafaxstat was associated with significantly better ventilatory efficiency (VE/VCO2 slope) compared to placebo with a least square (LS) mean difference between the groups of -2.1 (95% CI, -3.4, -0.6; p=0.006), with no significant difference in pVO2 (p=0.9). KCCQ-CCS was directionally though not significantly improved with ninerafaxstat vs. placebo (LS mean, 3.2 [95% CI, -2.9, 9.2; p=0.2]), though was statistically significant when analyzed post-hoc in the 35 patients with baseline KCCQ-CSS ≤80 (LS mean, 9.4 [95% CI, 0.2, 18.5; p=0.04]). In symptomatic nHCM, novel drug therapy targeting myocardial energetics was safe and well tolerated and associated with better exercise performance and health status among those most symptomatically limited. The findings support assessing ninerafaxstat in a Phase 3 study.
Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy
Authors: James L. Januzzi, Javed Butler, Stefano Del Prato, Justin A. Ezekowitz, Nasrien E. Ibrahim, Carolyn S.P. Lam, Gregory D. Lewis, Thomas H. Marwick, Riccardo Perfetti, Julio Rosenstock, Scott D. Solomon, W.H. Wilson Tang, Faiez Zannad
Journal: Journal of the American College of Cardiology (2024)
Cardiovascular Concerns, Cancer Treatment, and Biological and Chronological Aging in Cancer
Authors: Dina Ioffe, Sanjana C. Bhatia-Patel, Sakshi Gandhi, Eman A. Hamad, Efrat Dotan
Journal: JACC CardioOncology (2024)

Cardiovascular disease (CVD) and cancer are leading causes of death globally, particularly among the rapidly growing population of older adults (OAs). CVD is a leading cause of mortality among cancer survivors, often accelerated by cancer treatments associated with short- or long-term cardiotoxicity. Moreover, there is a dynamic relationship among CVD, cancer, and aging, characterized by shared risk factors and biological hallmarks, that plays an important role in caring for OAs, optimizing treatment approaches, and developing preventive strategies. Assessment of geriatric domains (eg, functional status, comorbidities, cognition, polypharmacy, nutritional status, social support, psychological well-being) is critical to individualizing treatment of OAs with cancer. The authors discuss considerations in caring for an aging population with cancer, including methods for the assessment of OAs with CVD and/or cardiovascular risk factors planned for cancer therapy. Multidisciplinary care is critical in optimizing patient outcomes and maintaining quality of life in this growing vulnerable population.
PMF-GRN: a variational inference approach to single-cell gene regulatory network inference using probabilistic matrix factorization
Authors: Claudia Skok Gibbs, Omar Mahmood, Richard Bonneau, Kyunghyun Cho
Journal: Genome biology (2024)

Abstract Inferring gene regulatory networks (GRNs) from single-cell data is challenging due to heuristic limitations. Existing methods also lack estimates of uncertainty. Here we present Probabilistic Matrix Factorization for Gene Regulatory Network Inference (PMF-GRN). Using single-cell expression data, PMF-GRN infers latent factors capturing transcription factor activity and regulatory relationships. Using variational inference allows hyperparameter search for principled model selection and direct comparison to other generative models. We extensively test and benchmark our method using real single-cell datasets and synthetic data. We show that PMF-GRN infers GRNs more accurately than current state-of-the-art single-cell GRN inference methods, offering well-calibrated uncertainty estimates.