tbuckley/cabot-search huggingface dataset:
Sleepless nights and social plights: medial septum GABAergic hyperactivity in a neuroligin 3–deficient autism model
Authors: Claire E. Cho, Dahee Jung, Reesha R. Patel
Journal: Journal of Clinical Investigation (2024)

Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.
Half-Dose Tenecteplase or Primary Percutaneous Coronary Intervention in Older Patients With ST-Elevation Myocardial Infarction: STREAM-2 1-Year Mortality Follow-Up
Authors: Peter R. Sinnaeve, Robert C. Welsh, Alexandra Arias Mendoza, Arsen D. Ristić, Oleg V. Averkov, Yves Lambert, José F. Kerr Saraiva, Pablo Sepulveda, Fernando Rosell-Ortiz, John K. French, Ljilja B. Musić, Katleen Vandenberghe, Kris Bogaerts, Thierry Danays, Kevin R. Bainey, Paul W. Armstrong, Frans Van de Werf
Journal: Circulation (2024)
Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer
Authors: Xiaolin Zhu, Tatyanah Farsh, Daniël Vis, Ivan Yu, Haolong Li, Tianyi Liu, Martin Sjöström, Raunak Shrestha, Jeroen Kneppers, Tesa Severson, Meng Zhang, Arian Lundberg, Thaidy Moreno Rodriguez, Alana S Weinstein, Adam Foye, Niven Mehra, Rahul R Aggarwal, Andries M Bergman, Eric J Small, Nathan A Lack, Wilbert Zwart, David A Quigley, Michiel S van der Heijden, Felix Y Feng
Journal: Journal of Clinical Investigation (2024)

BACKGROUNDAndrogen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODSTo investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTSWe confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSIONOur findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDINGNational Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.
Distinct landscape and clinical implications of therapy-related clonal hematopoiesis
Authors: Koichi Takahashi, Daisuke Nakada, Margaret Goodell
Journal: Journal of Clinical Investigation (2024)

Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.
Clonal hematopoiesis and atherosclerosis
Authors: Ohad Oren, Aeron M Small, Peter Libby
Journal: Journal of Clinical Investigation (2024)

Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.
The Effect on Travel Distance of a Statewide Regionalization Policy for Initial Breast Cancer Surgery
Authors: Nina A. Bickell, Ann B. Nattinger, Emily L. McGinley, Maria J. Schymura, Purushottam W. Laud, Liliana E. Pezzin
Journal: Journal of Clinical Oncology (2024)

PURPOSE Reimbursement strategies to regionalize care can be effective for improving patient outcomes but may adversely affect access to care. We sought to determine the effect on travel distance for surgical treatment of a 2009 New York State (NYS) policy restricting Medicaid reimbursement for breast cancer surgery at low-volume hospitals. PATIENTS AND METHODS From a linked data set merging the NYS tumor registry with hospital discharge data, we identified women younger than 65 years with stage I-III first breast tumors from pre- and post-policy periods. We classified patients by urbanicity of their residence into four geographic areas (New York City, other large urban core, suburban/large town, and small town/rural). A multivariable difference-in-difference-in-differences model was used to estimate the policy effect on the distance traveled by Medicaid and non-Medicaid insured patients before and after the policy, by area of residence. RESULTS Among the 46,029 study sample, 13.5% were covered by Medicaid. Regardless of insurance, women treated more recently traveled longer distances to their surgical facility than those in the prepolicy period. Regardless of time period, Medicaid beneficiaries drove fewer miles to treatment than women with other insurance. Although all women traveled greater distances postpolicy, the increase was not significantly different by insurance status (Medicaid or not), except for those living in suburban areas in which Medicaid patients traveled further postpolicy (+7.7 miles compared with +3.4 miles for non-Medicaid; P = .007). CONCLUSION After a policy regionalizing surgical care, only suburban Medicaid patients experienced a statistically significant (albeit small) increase in travel distance compared with non-Medicaid patients. In the state of NY, regionalization of breast cancer care yielded improved outcomes with minimal decrease in access.
Circulating Tumor DNA Sequencing for Biologic Classification and Individualized Risk Stratification in Patients With Hodgkin Lymphoma
Authors: Jan-Michel Heger, Laman Mammadova, Julia Mattlener, Sophia Sobesky, Melita Cirillo, Janine Altmüller, Elisabeth Kirst, Sarah Reinke, Wolfram Klapper, Paul J. Bröckelmann, Justin Ferdinandus, Helen Kaul, Gundolf Schneider, Jessica Schneider, Julia Katharina Schleifenbaum, Roland T. Ullrich, Max Freihammer, Sabine Awerkiew, Mia Lohmann, Florian Klein, Peter Nürnberg, Michael Hallek, Davide Rossi, Christine Mauz-Körholz, Stefan Gattenlöhner, Andreas Bräuninger, Peter Borchmann, Bastian von Tresckow, Sven Borchmann
Journal: Journal of Clinical Oncology (2024)

PURPOSE Current clinical challenges in Hodgkin lymphoma (HL) include difficult-to-treat relapsed/refractory disease and considerable long-term toxicities of treatment. Since clinical risk factors lack discriminatory power, intensity of therapy is mainly based on tumor burden. Exploring HL genetics and tumor microenvironment (TME) might provide valuable insights for improved risk stratification. MATERIALS AND METHODS In this study, we applied circulating tumor DNA sequencing to 243 patients obtained from pivotal German Hodgkin Study Group trials to identify subtypes of HL. Independent validation of the subtypes was performed in 96 patients treated in the EuroNet-PHL-C2 study. Outcome differences of subtypes were assessed in an event-enriched clinical validation cohort comprising 72 patients from the HD21 trial, using a refined, validated, and clinically feasible assay. RESULTS We propose a biologic classification of HL consisting of three distinct subtypes: inflammatory immune escape HL is characterized by frequent copy-number variations including immune escape variants such as high-level amplifications of the PD-L1 locus and an inflammatory TME. Virally-driven HL is associated with Epstein-Barr virus and/or human herpesvirus 6 and an inflammatory TME with neutrophils and macrophages, while the tumor mutational burden (TMB) is low. Oncogene-driven HL is defined by a high TMB, recurrent mutations in oncogenic drivers such as TNFAIP3 , ITPKB , and SOCS1 , and a cold TME. A refined and validated assay version aiming at clinically feasible risk stratification showed significant progression-free survival differences between subtypes. In addition, assessment of minimal residual disease (MRD) allowed for the detection of patients at very high risk of relapse within the subtypes. CONCLUSION We propose a clinically feasible, noninvasive method for individualized risk stratification and MRD monitoring in patients with HL on the basis of circulating tumor DNA sequencing.
National Institutes of Health COVID-19 Treatment Guidelines Panel: Perspectives and Lessons Learned
Authors: Roy M. Gulick, Alice K. Pau, Eric Daar, Laura Evans, Rajesh T. Gandhi, Pablo Tebas, Renée Ridzon, Henry Masur, H. Clifford Lane, Adaora A. Adimora, Jason Baker, Lisa Baumann Kreuziger, Roger Bedimo, Pamela Belperio, Anoopindar Bhalla, Timothy Burgess, Danielle Campbell, Stephen Cantrill, Kara Chew, Kathleen Chiotos, Craig Coopersmith, Richard Davey, Amy Dzierba, Derek Eisnor, Gregory Eschenauer, Joseph Francis, John Gallagher, David Glidden, Neil Goldenberg, Birgit Grund, Alison Han, Erica Hardy, Carly Harrison, Lauren Henderson, Elizabeth Higgs, Carl Hinkson, Brenna Hughes, Steven Johnson, Marla Keller, Arthur Kim, Richard Knight, Safia Kuriakose, Jeffrey Lennox, Andrea Lerner, Mitchell Levy, Jonathan Li, Christine MacBrayne, Greg Martin, Nandita Nadig, Martha Nason, Pragna Patel, Andrew Pavia, Michael Proschan, Grant Schulert, Nitin Seam, Virginia Sheikh, Steven Simpson, Kanal Singh, Susan Swindells, Phyllis Tien, Timothy Uyeki, Alpana Waghmare, Cameron Wolfe, Jinoos Yazdany, Judith Aberg, Renée Ridzon, Roy Gulick, Alice Pau, Eric Daar, Laura Evans, Rajesh T. Gandhi, Pablo Tebas, Henry Masur, H. Clifford Lane, Adaora A. Adimora, Jason Baker, Lisa Baumann Kreuziger, Roger Bedimo, Pamela Belperio, Anoopindar Bhalla, Timothy Burgess, Danielle Campbell, Stephen Cantrill, Kara Chew, Kathleen Chiotos, Craig Coopersmith, Richard Davey, Amy Dzierba, Derek Eisnor, Gregory Eschenauer, Joseph Francis, John Gallagher, David Glidden, Neil Goldenberg, Birgit Grund, Alison Han, Erica Hardy, Carly Harrison, Lauren Henderson, Elizabeth Higgs, Carl Hinkson, Brenna Hughes, Steven Johnson, Marla Keller, Arthur Kim, Richard Knight, Safia Kuriakose, Jeffrey Lennox, Andrea Lerner, Mitchell Levy, Jonathan Li, Christine MacBrayne, Greg Martin, Nandita Nadig, Martha Nason, Pragna Patel, Andrew Pavia, Michael Proschan, Grant Schulert, Nitin Seam, Virginia Sheikh, Steven Simpson, Kanal Singh, Susan Swindells, Phyllis Tien, Timothy Uyeki, Alpana Waghmare, Cameron Wolfe, Jinoos Yazdany, Judith Aberg
Journal: Annals of Internal Medicine (2024)

In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective.
Time-Restricted Eating in Adults With Metabolic Syndrome
Authors: Emily N.C. Manoogian, Michael J. Wilkinson, Monica O’Neal, Kyla Laing, Justina Nguyen, David Van, Ashley Rosander, Aryana Pazargadi, Nikko R. Gutierrez, Jason G. Fleischer, Shahrokh Golshan, Satchidananda Panda, Pam R. Taub
Journal: Annals of Internal Medicine (2024)

Time-restricted eating (TRE), limiting daily dietary intake to a consistent 8 to 10 hours without mandating calorie reduction, may provide cardiometabolic benefits.
Shortfalls in Follow-up Albuminuria Quantification After an Abnormal Result on a Urine Protein Dipstick Test
Authors: Yunwen Xu, Jung-Im Shin, Amelia Wallace, Juan J. Carrero, Lesley A. Inker, Amrita Mukhopadhyay, Saul B. Blecker, Leora I. Horwitz, Morgan E. Grams, Alexander R. Chang
Journal: Annals of Internal Medicine (2024)
Pharmacogenetic Panel Testing: A Review of Current Practice and Potential for Clinical Implementation
Authors: R. Mosch, M. van der Lee, H.J. Guchelaar, J.J. Swen
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation.
Genetically Enriched Clinical Trials for Precision Development of Noncancer Therapeutics: A Scoping Review
Authors: Benoît Delabays, Chiara De Paoli, Andrea Miller-Nesbitt, Vincent Mooser
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Genetically driven clinical trial enrichment has been proposed to accelerate and reduce the cost of developing new therapeutics. Usage of this approach has not been comprehensively reviewed. We searched Ovid MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP for articles published between 2010 and 2023. Excluding absorption, distribution, metabolism, and elimination pharmacogenetic studies and anti-infectives, we found 95 completed, 4 terminated, and 22 ongoing prospective genetically enriched trials on 110 drugs for 48 nononcology, nonrare syndromic indications. Trial sizes ranged from 4 to 6,147 participants (median 72) and covered numerous disease areas, particularly neurology (30), metabolism (22), and psychiatry (17). Fifty-six completed studies (60%) met their primary end point. Overall, this scoping review demonstrates that genetically enriched trials are feasible and scalable across disease areas and provide critical information for further development, or attrition, of investigational drugs. Large, appropriately designed disease-, hospital-, or population-based biobanks will undoubtedly facilitate this type of precision drug development approach.
BPP43_05035 is a <i>Brachyspira pilosicoli</i> cell surface adhesin that weakens the integrity of the epithelial barrier during infection
Authors: Anandi Rajan, Pablo Gallego, Brendan Dolan, Piyush Patel, Chinmay Dwibedi, Ana S. Luis, Sergio Trillo-Muyo, Liisa Arike, Sjoerd van der Post, Magnus Simrén, Thaher Pelaseyed
Journal: Gut Microbes (2024)

The anaerobic spirochete
Characterization of regeneration initiating cells during Xenopus laevis tail regeneration
Authors: Radek Sindelka, Ravindra Naraine, Pavel Abaffy, Daniel Zucha, Daniel Kraus, Jiri Netusil, Karel Smetana, Lukas Lacina, Berwini Beduya Endaya, Jiri Neuzil, Martin Psenicka, Mikael Kubista
Journal: Genome biology (2024)
Progranulin protects against <i>Clostridioides difficile</i> infection by enhancing IL-22 production
Authors: Jun Huang, Bichen Liu, Yi Liu, Wenxian You, Ping Zhao, Yuhan Liu, Kehan Wang, Xiaofei Lai, Banglao Xu, Ju Cao
Journal: Gut Microbes (2024)

Enhanced mortality, relapse rates, and increased prevalence of
Loss of Lateral suppressor gene is associated with evolution of root nodule symbiosis in Leguminosae
Authors: Tengfei Liu, Zhi Liu, Jingwei Fan, Yaqin Yuan, Haiyue Liu, Wenfei Xian, Shuaiying Xiang, Xia Yang, Yucheng Liu, Shulin Liu, Min Zhang, Yuannian Jiao, Shifeng Cheng, Jeff J Doyle, Fang Xie, Jiayang Li, Zhixi Tian
Journal: Genome biology (2024)
FGFR Inhibition in Urothelial Carcinoma
Authors: Roger Li, Joshua Linscott, James W F Catto, Siamak Daneshmand, Bishoy M Faltas, Ashish M Kamat, Joshua J Meeks, Andrea Necchi, Benjamin Pradere, Jeffrey S Ross, Michiel S van der Heijden, Bas W G van Rhijn, Yohann Loriot
Journal: European Urology (2024)
Regulation of plasma soluble receptors of TNF and IL-1 in patients with COVID-19 differs from that observed in sepsis
Authors: Muhammed D Aksu, Tijmen van der Ent, Zhenhua Zhang, Anca L Riza, Aline H de Nooijer, Isis Ricaño-Ponce, Nico Janssen, Job J Engel, Ioana Streata, Helga Dijkstra, Heidi Lemmers, Inge Grondman, Valerie A C M Koeken, Eleni Antoniadou, Nikolaos Antonakos, Frank L van de Veerdonk, Yang Li, Evangelos J Giamarellos-Bourboulis, Mihai G Netea, Athanasios Ziogas
Journal: Journal of Infection (2024)
FABP5+ lipid-loaded macrophages process tumor-derived unsaturated fatty acid signal to suppress T-cell antitumor immunity
Authors: Xuguang Yang, Bo Deng, Weiwei Zhao, Yangyang Guo, Yaqi Wan, Zhihao Wu, Sheng Su, Jingyan Gu, Xiaoqian Hu, Wenxue Feng, Chencheng Hu, Jia Li, Yanyong Xu, Xiaowu Huang, Yuli Lin
Journal: Journal of Hepatology (2024)
Effect of a campaign with oral polio vaccine on general health: A cluster-randomised trial in rural Guinea-Bissau
Authors: Line M Nanque, Anshu Varma, Sanne M Thysen, Christine S Benn, Justiniano Sd Martins, Aksel Kg Jensen, Claudino Correia, Sören Möller, Anita Van den Biggelaar, None Peter Aaby, Ane B Fisker
Journal: Journal of Infection (2024)
Risk of fungal infection in patients with psoriasis receiving biologics: a retrospective single-center cohort study
Authors: Yoshihito Minami, Junichiro Hiruma, Kazuharu Harada, Kazuki Fujimori, Risa Suzuki, Miho Mori, Masahiro Okura, Namiko Abe, Kazutoshi Harada, Yukari Okubo
Journal: Journal of the American Academy of Dermatology (2024)
Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice
Authors: Emmanuel Dauda Dixon, Thierry Claudel, Alexander Daniel Nardo, Alessandra Riva, Claudia Fuchs, Veronika Mlitz, Georg Busslinger, Hubert Schnarnagl, Tatjana Stojakovic, Joana Senéca, Helga Hinteregger, Gernot F Grabner, Dagmar Kratky, Henkjan Verkade, Robert Zimmermann, Guenter Haemmerle, Michael Trauner
Journal: Journal of Hepatology (2024)
Commentary: Response to “Dupilumab therapy for atopic dermatitis is associated with increased risk of cutaneous T cell lymphoma: a retrospective cohort study”
Authors: Tien V Nguyen, Andrea Fleisch Marcus, Sarah-Jo Sinnott, Anna Coleman, Carlos Peralta, Stephane Levy, Prashant Kushwaha, Debra Sierka, Marius Ardeleanu, Ana B Rossi
Journal: Journal of the American Academy of Dermatology (2024)
Application of a deep-learning marker for morbidity and mortality prediction derived from retinal photographs: a cohort development and validation study
Authors: Simon Nusinovici, Tyler Hyungtaek Rim, Hengtong Li, Marco Yu, Mihir Deshmukh, Ten Cheer Quek, Geunyoung Lee, Crystal Chun Yuen Chong, Qingsheng Peng, Can Can Xue, Zhuoting Zhu, Emily Y Chew, Charumathi Sabanayagam, Tien-Yin Wong, Yih-Chung Tham, Ching-Yu Cheng
Journal: The Lancet Healthy Longevity (2024)
Evolving Approaches for Pharmacological Therapy of Obesity
Authors: Ariana M. Chao, Simeon Taylor, Molly Moore, Anastassia Amaro, Thomas A. Wadden
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Obesity is a global health concern. Progress in understanding the physiology of obesity and weight reduction has provided new drug targets. Development and testing of new antiobesity medications (AOMs) has the potential to quickly expand options for treatment. In this review, we briefly summarize the physiology of obesity and weight reduction, as well as medications currently approved for weight management. We highlight the increasing use of incretin and nutrient-stimulated hormone-based therapies. We conclude with an overview of AOMs progressing through the pipeline and discuss their implications for the rapidly evolving field of obesity management.