tbuckley/cabot-search huggingface dataset:
Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells
Authors: Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma
Journal: Journal of Clinical Investigation (2024)

Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated lymphocyte antigen 6 complex, locus A+ ( LY6A+, also known as stem cell antigen 1 [Sca-1]) revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced the upregulation of ribosomal protein S14 (RPS14) via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, analysis of clinical CRC cohorts revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum/LY6A/RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.
Chlorthalidone vs Hydrochlorothiazide and Kidney Outcomes in Patients With Hypertension
Authors: Areef Ishani, Cynthia Hau, Srihari Raju, Jessica K. Wise, Peter A. Glassman, Addison A. Taylor, Ryan E. Ferguson, William C. Cushman, Sarah M. Leatherman
Journal: JAMA Network Open (2024)

Hypertension is a risk factor for the development and progression of chronic kidney disease (CKD). It is unclear whether different thiazide diuretics have a differential impact on kidney outcomes.
Allostatic Load, Educational Attainment, and Risk of Cancer Mortality Among US Men
Authors: Cynthia Li, Sydney P. Howard, Charles R. Rogers, Sydney Andrzejak, Keon L. Gilbert, Keith J. Watts, Malcolm S. Bevel, Myles D. Moody, Marvin E. Langston, Judah V. Doty, Adetunji T. Toriola, Darwin Conwell, Justin X. Moore
Journal: JAMA Network Open (2024)

Health disparities among racial and ethnic minoritized populations, particularly for cancer mortality rates, remain a major public health concern. Men from underrepresented backgrounds (Black and Hispanic men, specifically) face the pervasive effects of discrimination in their daily lives, which also contribute to the complex associations among allostatic load (a marker of chronic stress), educational opportunities, and elevated risks of cancer mortality.
Time to Command-Following and Outcomes After Traumatic Brain Injury
Authors: Samuel B. Snider, Hansen Deng, Flora M. Hammond, Robert G. Kowalski, William C. Walker, Ross D. Zafonte, David O. Okonkwo, Joseph T. Giacino, Ava M. Puccio, Yelena G. Bodien
Journal: JAMA Network Open (2024)

This cohort study examines the association of time to command-following with death or dependency at 1 year among individuals with moderate-severe traumatic brain injury (TBI).
Agent-Based Model of Combined Community- and Jail-Based Take-Home Naloxone Distribution
Authors: Eric Tatara, Jonathan Ozik, Harold A. Pollack, John A. Schneider, Samuel R. Friedman, Nina T. Harawa, Basmattee Boodram, Elizabeth Salisbury-Afshar, Anna Hotton, Larry Ouellet, Mary Ellen Mackesy-Amiti, Nicholson Collier, Charles M. Macal
Journal: JAMA Network Open (2024)

Importance Opioid-related overdose accounts for almost 80 000 deaths annually across the US. People who use drugs leaving jails are at particularly high risk for opioid-related overdose and may benefit from take-home naloxone (THN) distribution. Objective To estimate the population impact of THN distribution at jail release to reverse opioid-related overdose among people with opioid use disorders. Design, Setting, and Participants This study developed the agent-based Justice-Community Circulation Model (JCCM) to model a synthetic population of individuals with and without a history of opioid use. Epidemiological data from 2014 to 2020 for Cook County, Illinois, were used to identify parameters pertinent to the synthetic population. Twenty-seven experimental scenarios were examined to capture diverse strategies of THN distribution and use. Sensitivity analysis was performed to identify critical mediating and moderating variables associated with population impact and a proxy metric for cost-effectiveness (ie, the direct costs of THN kits distributed per death averted). Data were analyzed between February 2022 and March 2024. Intervention Modeled interventions included 3 THN distribution channels: community facilities and practitioners; jail, at release; and social network or peers of persons released from jail. Main Outcomes and Measures The primary outcome was the percentage of opioid-related overdose deaths averted with THN in the modeled population relative to a baseline scenario with no intervention. Results Take-home naloxone distribution at jail release had the highest median (IQR) percentage of averted deaths at 11.70% (6.57%-15.75%). The probability of bystander presence at an opioid overdose showed the greatest proportional contribution (27.15%) to the variance in deaths averted in persons released from jail. The estimated costs of distributed THN kits were less than $15 000 per averted death in all 27 scenarios. Conclusions and Relevance This study found that THN distribution at jail release is an economical and feasible approach to substantially reducing opioid-related overdose mortality. Training and preparation of proficient and willing bystanders are central factors in reaching the full potential of this intervention.
Comparative Analysis of Indices for Social Determinants of Health in Pediatric Surgical Populations
Authors: Caroline Q. Stephens, Ava Yap, Lan Vu, Jacqueline M. Saito, Dwight Barry, Amy M. Shui, Hannah Cockrell, Sarah Cairo, Derek Wakeman, Loren Berman, Sarah Greenberg, Allison F. Linden, Jonathan Kohler, KuoJen Tsao, Nicole A. Wilson
Journal: JAMA Network Open (2024)

Conclusions vary substantially among studies examining associations between area-based social determinants of health (SDOH) and pediatric health disparities based on the selected patient population and SDOH index. Most national studies use zip codes, which encompass a wide distribution of communities, limiting the generalizability of findings.
Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation
Authors: Subash Chand Verma, Emmanuelle Enée, Kanchanadevi Manasse, Feriel Rebhi, Axelle Penc, David Romeo-Guitart, Cuc Bui Thi, Matthias Titeux, Franck Oury, Simon Fillatreau, Roland Liblau, Julien Diana
Journal: Journal of Clinical Investigation (2024)

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at an early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that were required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1-39 at the peak of EAE promoted disease remission. In vitro, CRAMP1-39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR) 2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors 2/3 (FFAR2/3), and prevented EAE. This study shows that CRAMP produced by different cell types has opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.
Integration of lipidomics with targeted, single cell, and spatial transcriptomics defines an unresolved pro-inflammatory state in colon cancer
Authors: Ramani Soundararajan, Michelle M Maurin, Jetsen Rodriguez-Silva, Gunjan Upadhyay, Ashley J Alden, Siddabasave Gowda B Gowda, Michael J Schell, Mingli Yang, Noah Jhad Levine, Divyavani Gowda, Punith M Sundaraswamy, Shu-Ping Hui, Lance Pflieger, Heiman Wang, Jorge Marcet, Carolina Martinez, Robert David Bennett, Allen Chudzinski, Andreas Karachristos, Timothy M Nywening, Paul M Cavallaro, Matthew Linley Anderson, Robert J Coffey, Michael V Nebozhyn, Andrey Loboda, Domenico Coppola, Warren Jackson Pledger, Ganesh Halade, Timothy J Yeatman
Journal: Gut (2024)

Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).
Layperson-Delivered Interventions for Glycemic Control in Diabetes
Authors: Brett D. Thombs, Kanika Bharthi, Louise Vidricaire
Journal: JAMA Network Open (2024)

Maninder K. Kahlon, PhD; Nazan S. Aksan, PhD; Rhonda Aubrey, MHI; Nicole Clark, MBA; Maria Cowley-Morillo, MPH; Carolina DuBois, BS; Carlos Garcia, BS; Julia Guerra, MSc; David Pereira, BS; Mathew Sither, MS; Steven Tomlinson, PhD; Sandy Valenzuela, Med; M. Renee Valdez, MD, PhD
Take-Home Naloxone, Release From Jail, and Opioid Overdose—A Piece of the Puzzle
Authors: Dylan Rose Balter, Benjamin A. Howell
Journal: JAMA Network Open (2024)

Eric Tatara, PhD; Jonathan Ozik, PhD; Harold A. Pollack, PhD; John A. Schneider, MD, MPH; Samuel R. Friedman, PhD; Nina T. Harawa, PhD, MPH; Basmattee Boodram, PhD, MPH; Elizabeth Salisbury-Afshar, MD, MPH; Anna Hotton, PhD; Larry Ouellet, PhD; Mary Ellen Mackesy-Amiti, PhD; Nicholson Collier, PhD; Charles M. Macal, PhD
Acute myeloid leukemia management and research in 2025
Authors: Hagop M. Kantarjian, Courtney D. DiNardo, Tapan M. Kadia, Naval G. Daver, Jessica K. Altman, Eytan M. Stein, Elias Jabbour, Charles A. Schiffer, Amy Lang, Farhad Ravandi
Journal: CA A Cancer Journal for Clinicians (2024)

Abstract The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high‐dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody–drug conjugate); midostaurin, gilteritinib, and quizartinib (fms‐like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine‐cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody–drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.
Distinct immune microenvironment of venous tumor thrombus in hepatocellular carcinoma at single-cell resolution
Authors: Kai-Qian Zhou, Yu-Cheng Zhong, Ming-Fang Song, Yun-Fan Sun, Wei Zhu, Jian-Wen Cheng, Yang Xu, Ze-Fan Zhang, Peng-Xiang Wang, Zheng Tang, Jian Zhou, Li-Ye Zhang, Jia Fan, Xin-Rong Yang
Journal: Hepatology (2024)

Portal vein tumor thrombus (PVTT) worsens the prognosis of hepatocellular carcinoma by increasing intrahepatic dissemination and inducing portal vein hypertension. However, the immune characteristics of PVTT remain unclear. Therefore, this study aims to explore the immune microenvironment in PVTT. Time-of-flight mass cytometry (CyTOF) revealed that macrophages and monocytes were the dominant immune cell type in PVTT, with a higher proportion than in primary tumor (PT) and blood (54.1% vs. 26.3% and 9.1%, p<0.05). The differentially enriched clustering of inhibitory and regulatory immune cells in PVTT indicated an immune-suppressive environment. According to the single-cell RNA sequencing (scRNA-seq), TAM-C5AR1 was characterized by leukocyte chemotaxis and was the most common subpopulation in PVTT (36.7%). Multiple immunofluorescence staining showed that the C5aR+ TAM/Mφ were enriched in PVTT compared to both PT and liver, and positively correlated with C5a (r=0.559, p<0.001). Notably, THP-1 (monocyte cell line) was recruited by CSQT2 (PVTT cell line) and exhibited up-regulation of CD163, CD206, and PD-L1 upon stimulation. C5aR antagonist could reverse this. C5aR+ TAMs could also inhibit Granzyme B in CD8+ T cells. High infiltration of C5aR+ TAMs in PVTT correlated with poor differentiation (p<0.009), and was a risk factor for overall survival (p=0.003) and for re-formation of PVTT after resection (p=0.007). TAMs, especially C5aR+ TAMs, were enriched in PVTT. C5aR+ TAMs contribute to the development of PVTT and poor prognosis by reshaping the immunosuppressive environment.
Therapeutic Targeting and Structural Characterization of a Sotorasib-Modified KRAS G12C-MHC I complex Demonstrates the Antitumor Efficacy of Hapten-Based Strategies
Authors: Apurva Pandey, Peter J. Rohweder, Lieza M. Chan, Chayanid Ongpipattanakul, Dong hee Chung, Bryce Paolella, Fiona M. Quimby, Ngoc Nguyen, Kliment A. Verba, Michael J. Evans, Charles S. Craik
Journal: Cancer Research (2024)

Abstract Antibody-based therapies have emerged as a powerful strategy for the management of diverse cancers. Unfortunately, tumor-specific antigens remain challenging to identify and target. Recent work established that inhibitor-modified peptide adducts derived from KRAS G12C are competent for antigen presentation via MHC I and can be targeted by antibody-based therapeutics, offering a means to directly target an intracellular oncoprotein at the cell surface with combination therapies. Here, we validated antigen display of “haptenated” KRAS G12C peptide fragments on tumors in mouse models treated with the FDA-approved KRAS G12C covalent inhibitor Sotorasib using PET/CT imaging of an 89Zr-labeled P1B7 IgG antibody, which selectively binds Sotorasib-modified KRAS G12C MHC I complexes. Targeting this peptide-MHC I complex with radioligand therapy using 225Ac- or 177Lu-P1B7 IgG effectively inhibited tumor growth in combination with Sotorasib. Elucidation of the 3.1 Å cryo-EM structure of P1B7 bound to a haptenated KRAS G12C peptide-MHC I complex confirmed that the Sotorasib-modified KRAS G12C peptide is presented via a canonical binding pose and showed that P1B7 binds the complex in a T-cell receptor-like manner. Together, these findings demonstrate the potential value of targeting unique oncoprotein-derived, haptenated MHC I complexes with radioligand therapeutics and provide a structural framework for developing next generation antibodies.
CCDC134 controls TLR biogenesis through the ER chaperone Gp96
Authors: Léa Bernaleau, Michaela Drobek, Fenja Blank, Philipp Walch, Maeva Delacrétaz, Ales Drobek, Marta Monguió-Tortajada, Petr Broz, Olivia Majer, Manuele Rebsamen
Journal: The Journal of Experimental Medicine (2024)

Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses. CCDC134 deficiency impaired endolysosomal TLR-induced NF-κB, MAPK, and IRF5 activation, as well as downstream production of proinflammatory cytokines and type I interferons. We further demonstrated that CCDC134 is an endoplasmic reticulum (ER)-resident interactor of Gp96 (HSP90B1/Grp94), an ER chaperone essential for folding and trafficking of plasma membrane and endolysosomal TLRs. CCDC134 controlled Gp96 stability as its loss led to Gp96 hyperglycosylation and ER-associated protein degradation (ERAD)-mediated clearance. Accordingly, CCDC134 deficiency impaired the folding, maturation, and trafficking of TLRs, resulting in blunted inflammatory responses upon stimulation. Altogether, this study reveals CCDC134 as a central regulator of the chaperone Gp96, thereby controlling TLR biogenesis and responses.
An erythroid-specific lentiviral vector improves anemia and iron metabolism in a new model of XLSA.
Authors: Carlo Castruccio Castracani, Laura Breda, Tyler Ellis Papp, Amaliris Guerra, Enrico Radaelli, Charles-Antoine Assenmacher, Giovanni Finesso, Barbara L Mui, Ying K. Tam, Simona Fontana, Chiara Riganti, Veronica Fiorito, Sara Petrillo, Emanuela Tolosano, Hamideh Parhiz, Stefano Rivella
Journal: Blood (2024)
Intimate Partner Violence–Related Homicides of Hispanic and Latino Persons — National Violent Death Reporting System, United States, 2003–2021
Authors: Sarah Treves-Kagan, Yanet Ruvalcaba, Daniel T. Corry, Colleen M. Ray, Vi D. Le, Rosalyn D. Lee, Carlos Siordia, Melissa C. Mercado, Lianne Fuino Estefan, Tatiana M. Vera, Megan C. Kearns, Laura M. Mercer Kollar, Delight E. Satter, Ana Penman-Aguilar, José T. Montero
Journal: MMWR Surveillance Summaries (2024)

In 2022, homicide was the second leading cause of death for Hispanic and Latino persons aged 15-24 years in the United States, the third leading cause of death for those aged 25-34 years, and the fourth leading cause of death for those aged 1-14 years. The majority of homicides of females, including among Hispanic and Latino persons, occur in the context of intimate partner violence (IPV). This report summarizes data from CDC's National Violent Death Reporting System (NVDRS) on IPV-related homicides of Hispanic and Latino persons in the United States.
Inflammation-driven NFκB signaling represses Ferroportin transcription in macrophages via HDAC 1 and 3
Authors: Oriana Marques, Natalie K. Horvat, Laura Zechner, Silvia Colucci, Richard Sparla, Stefan Zimmermann, Christopher J. Neufeldt, Sandro Altamura, Ruiyue Qiu, Katja Müdder, Günter Weiss, Matthias W. Hentze, Martina U. Muckenthaler
Journal: Blood (2024)

Anemia of inflammation is a prevalent comorbidity in patients with chronic inflammatory disorders. Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting ferroportin (FPN)-mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface expression of FPN is reduced by hepcidin-induced degradation and/or by repression of FPN (Slc40a1) transcription via cytokine and Toll-like receptor (TLR) stimulation. Although the mechanisms underlying hepcidin-mediated control of FPN have been extensively studied, those inhibiting Slc40a1 messenger RNA (mRNA) expression remain unknown. We applied targeted RNA interference and pharmacological screens in macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signaling regulators of Slc40a1 mRNA repression downstream of TLRs and NF-κB signaling. Interestingly, the NF-κB regulatory hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand lipopolysaccharide, the cytokine tumor necrosis factor β/lymphotoxin-alpha (LTA), and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed Staphylococcus aureus recruits the histone deacetylases (HDACs) HDAC1 and HDAC3 to the antioxidant response element (ARE) located in the Slc40a1 promoter. Accordingly, pretreatment with a pan-HDAC inhibitor abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act downstream of NF-κB to repress Slc40a1 transcription. Consistently, recruitment of HDAC1 and HDAC3 to the Slc40a1 ARE after stimulation with heat-killed S aureus is dependent on NF-κB signaling. These results support a model in which the ARE integrates the transcriptional responses of Slc40a1 triggered by signals from redox, metabolic, and inflammatory pathways. This work identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation, paving the way for therapeutic interventions at this critical juncture.
IFN-I promotes T cell-independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD
Authors: Shan Su, Weili Bao, Yunfeng Liu, Patricia A Shi, Deepa Manwani, Irina Murakhovskaya, Sally Campbell Lee, Cheryl A Lobo, Avital Mendelson, Xiuli An, Hui Zhong, Woelsung Yi, Karina Yazdanbakhsh
Journal: Blood (2024)
Structural barriers to accessing gender-affirming care for transgender and gender diverse (TGD) individuals in the United States
Authors: Ellesse-Roselee L. Akré, Harry Barbee, Nik M. Lampe
Journal: International Journal of Transgender Health (2024)

Background: Access to gender-affirming care (GAC) is important for the health of transgender and gender-diverse (TGD) populations, but many encounter significant barriers. This study examines the experiences of TGD individuals in accessing GAC. Methods: Between September 2022 and March 2023, the first author administered a Qualtrics online survey, incorporating a series of open-ended and closed-ended questions. Participants included adults (18 years or older) who identify as TGD and reside in the United States. We employed purposive social network and snowball sampling methods, utilizing social media platforms for recruitment. Modified grounded theory was employed to examine participants' open-ended responses. Results: Findings illuminate key structural barriers that hindered TGD respondents' access to GAC. Three themes emerged: (1) geographic isolation from GAC; (2) insurance and administrative challenges; and (3) unsatisfactory experience, style, and knowledge of practitioners. Results also indicate several positive perceptions of accessing GAC. Conclusion: Our findings underscore the urgency of policy reforms addressing geographic, financial, and practitioner-related barriers to accessing GAC. By dismantling these barriers, policymakers can ensure GAC is accessible, and beneficial for all TGD individuals, ultimately improving health outcomes within this population.
Effectiveness and use of home high flow nasal cannula in Portugal: Where are we?
Authors: Cristina Jácome, Mónica Duarte, João Carlos Winck, Salvador Díaz Lobato, Cátia Caneiras
Journal: Pulmonology (2024)

KEYWORDS: High flow nasal cannula (HFNC)home careinterstitial lung diseaseneoplasynon-invasive ventilation (NIV)