tbuckley/cabot-search huggingface dataset:
Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model
Authors: Yifan Zhu, Chenyu Jiang, Jian He, Chen He, Xingliang Zhou, Xu Huang, Yi Shen, Liwei Wu, Yongnan Li, Bei Feng, Yi Yan, Jun Li, Hao Zhang, Yiwei Liu
Journal: Journal of Clinical Investigation (2024)

Hypothermia is commonly used to protect donor hearts during transplantation. However, patients transplanted with aged donor hearts still have severe myocardial injury and decreased survival rates, but the underlying mechanism remains unknown. Because aged hearts are not considered suitable for donation, the number of patients awaiting heart transplants is increasing. In this study, we examined whether hypothermic cardioprotection was attenuated in aged donor hearts during transplantation and evaluated potential therapeutic targets. Using a rat heart transplantation model, we found that hypothermic cardioprotection was impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq showed that cold-inducible RNA-binding protein (Cirbp) expression was decreased in aged donor hearts, and these hearts showed severe ferroptosis after transplantation. The young donor hearts from Cirbp-KO rats exhibited attenuated hypothermic cardioprotection, but Cirbp overexpression in aged donor hearts ameliorated hypothermic cardioprotection. Cardiac proteomes revealed that dihydroorotate dehydrogenase (DHODH) expression was significantly decreased in Cirbp-KO donor hearts during transplantation. Consequently, DHODH-mediated ubiquinone reduction was compromised, thereby exacerbating cardiac lipid peroxidation and triggering ferroptosis after transplantation. A cardioplegic solution supplemented with CIRBP agonists improved hypothermic cardioprotection in aged donor hearts, indicating that this method has the potential to broaden the indications for using aged donor hearts in transplantation.
A step closer to understanding how a diet high in simple carbohydrates may cause dysbiosis
Authors: Shrinivas Bishu, John Y. Kao
Journal: Journal of Clinical Investigation (2024)

The gut microbiota is an integral part of the human metaorganism that is required to shape physiologic host immune responses including host defense against pathogens. Disease-associated gut dysbiosis has been characterized by blooms of pathobionts, which are bacterial species that can drive disease under certain conditions. Pathobionts like Enterobacteriaceae often bloom during flares of inflammatory bowel disease (IBD) and are causally linked with IBD in murine models. In this issue of the JCI, Hecht and colleagues investigated how simple carbohydrates are causally linked to the bloom of the gut pathobiont Klebsiella pneumoniae, which belong to the Enterobacteriaceae family. Notably, the presence of fiber reduced the dissemination of K. pneumoniae into the blood and liver in a colitis model. Their findings provide a diet-related mechanism for gut dysbiosis, which has implications in the management of IBD and other conditions in which gut dysbiosis is an underlying factor.
Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending
Authors: Kathryn R. Tringale, Andrew Lin, Alexandra M. Miller, Atif Khan, Linda Chen, Melissa Zinovoy, Yoshiya Yamada, Yao Yu, Luke R.G. Pike, Brandon S. Imber
Journal: Journal of the National Comprehensive Cancer Network (2024)

Background: For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare &amp; Medicaid Services data. Methods: Radiation modality, year, age (65–74, 75–84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11–20 fractions) versus LCRT (21–30 or 31–40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. Results: From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65–74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1–1.2) and was associated with older age (≥85 vs 65–74 years; OR, 6.8; 95% CI, 5.5–8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4–5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3–1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3–3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1–1.3; P &lt;.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites ( P =.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care ( P =.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0–1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted β for LCRT = +$8,649; 95% CI, $8,544–$8,755), whereas spending modestly increased with systemic therapy (adjusted β for systemic therapy = +$270; 95% CI, $176–$365). Conclusions: Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.
A therapeutic leap: how myosin inhibitors moved from cardiac interventions to skeletal muscle myopathy solutions
Authors: Julius Bogomolovas, Ju Chen
Journal: Journal of Clinical Investigation (2024)

The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac hypercontractility. This therapeutic mechanism has proven effective for patients with HCM independent of having a primary gene mutation in myosin. In this issue of the JCI, Buvoli et al. report that muscle hypercontractility is a mechanism of pathogenesis underlying muscle dysfunction in Laing distal myopathy, a disorder characterized by mutations altering the rod domain of β myosin heavy chain. The authors performed detailed physiological, molecular, and biomechanical analyses and demonstrated that myosin ATPase inhibition can correct a large extent of muscle abnormalities. The findings offer a therapeutic avenue for Laing distal myopathy and potentially other myopathies. This Commentary underscores the importance of reevaluating myosin activity's role across myopathies in general for the potential development of targeted myosin inhibitors to treat skeletal muscle disorders.
Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in England from 2008 to 2018: a cohort study
Authors: Rikisha Gupta, Ann Dorothy Morgan, Peter M George, Jennifer K Quint
Journal: Thorax (2024)

Background Owing to discrepancies in methodologies and how idiopathic pulmonary fibrosis (IPF) is diagnosed it is challenging to establish a consistent understanding of the disease burden In the UK, over 10 years ago, the incidence and prevalence of IPF were reported as 2.8–8.7 per 100 000 person-years (from 2000 to 2012) and 39 per 100 000 persons (in 2012), respectively. Here, we estimated the incidence and prevalence of IPF in England from 2008 to 2018 and investigated IPF mortality. Methods Using Clinical Practice Research Datalink Aurum and Hospital Episode Statistics (HES) linked datasets, we estimated incidence and prevalence using four validated diagnostic-code-based algorithms. Using the registered number of deaths (from Office of National Statistics) with the underlying cause being recorded as IPF, we estimated IPF mortality for the same period. Results Using Aurum-based definitions, incidence increased over time by 100% for Aurum narrow (3–6.1 per 100 000 person-years) and by 25% for Aurum broad (22.4–28.6 per 100 000 person-years). However, using HES-based definitions showed a decrease in incidence over the same period and lay between the two extremes derived for Aurum-based definition. IPF mortality in 2018 was 7.9 per 100 000 person-years and increased by 53% between 2008 and 2018. Interpretation When using best-case definitions, incidence rose throughout the study period. Scaling this to England’s population (2018), our best estimate would be in the range of 8000–9000 new cases per year which is higher than previously reported estimates (5000–6000). This increased burden in the new cases of IPF each year impacts future health service planning and resource allocation.
Enhancing anticancer activity of macrophages through rational drug combinations
Authors: Gordon B Mills, Marilyne Labrie
Journal: Journal of Clinical Investigation (2024)

Targeting tumor-associated macrophages (TAMs) is an emerging approach being tested in multiple clinical trials. TAMs, depending on their differentiation state, can exhibit pro- or antitumorigenic functions. For example, the M2-like phenotype represents a protumoral state that can stimulate tumor growth, angiogenesis, metastasis, therapy resistance, and immune evasion by expressing immune checkpoint proteins. In this issue of the JCI, Vaccaro and colleagues utilized an innovative drug screen approach to demonstrate that targeting driver oncogenic signaling pathways concurrently with anti-CD47 sensitizes tumor cells, causing them to undergo macrophage-induced phagocytosis. The combination treatment altered expression of molecules on the tumor cells that typically limit phagocytosis. It also reprogrammed macrophages to an M1-like antitumor state. Moreover, the approach was generalizable to tumor cells with different oncogenic pathways, opening the door to precision oncology-based rationale combination therapies that have the potential to improve outcomes for patients with oncogene-driven lung cancers and likely other cancer types.
Enteropathogenic viruses associated with acute gastroenteritis among African children under 5 years of age: A systematic review and meta-analysis
Authors: Cornelius Arome Omatola, Ropo Ebenezer Ogunsakin, Anyebe Bernard Onoja, Martin-Luther Oseni Okolo, Joseph Abraham-Oyiguh, Kehinde Charles Mofolorunsho, Phoebe Queen Akoh, Omebije Patience Adejo, Joshua Idakwo, Therisa Ojomideju Okeme, Danjuma Muhammed, David Moses Adaji, Sunday Ocholi Samson, Ruth Foluke Aminu, Monday Eneojo Akor, Emmanuel Edegbo, Andrew Musa Adamu
Journal: Journal of Infection (2024)

s u m m a r y Gastroenteritis viruses are the leading etiologic agents of diarrhea in children worldwide.We present data from thirty-three (33) eligible studies published between 2003 and 2023 from African countries bearing the brunt of the virus-associated diarrheal mortality.Random effects meta-analysis with proportion, subgroups, and metaregression analyses were employed.Overall, rotavirus with estimated pooled prevalence of 31.0 % (95 % CI 24.0-39.0)predominated in all primary care visits and hospitalizations, followed by norovirus, adenovirus, sapovirus, astrovirus, and aichivirus with pooled prevalence estimated at 15.0 % (95 % CI 12.0-20.0),10 % (95 % CI 6-15), 4.0 % (95 % CI 2.0-6.0), 4 % (95 % CI 3-6), and 2.3 % (95 % CI 1-3), respectively.Predominant rotavirus genotype was G1P[8] (39 %), followed by G3P[8] (11.7 %), G9P[8] (8.7 %), and G2P[4] (7.1 %); although, unusual genotypes were also observed, including G3P[6] (2.7 %), G8P [6] (1.7 %), G1P [6] (1.5 %), G10P[8] (0.9 %), G8P[4] (0.5 %), and G4P[8] (0.4 %).The genogroup II norovirus predominated over the genogroup I-associated infections (84.6 %, 613/725 vs 14.9 %, 108/725), with the GII.4 (79.3 %) being the most prevalent circulating genotype.In conclusion, this review showed that rotavirus remains the leading driver of viral diarrhea requiring health care visits and hospitalization among under-five years children in Africa.Thus, improved rotavirus vaccination in the region and surveillance to determine the residual burden of rotavirus and the evolving trend of other enteric viruses are needed for effective control and management of cases.
A Randomized Trial of Choice Architecture and Mailed Colorectal Cancer Screening Outreach in a Community Health Setting
Authors: Shivan J Mehta, Sanjay Palat, Caitlin McDonald, Catherine Reitz, Evelyn Okorie, Keyirah Williams, Jinming Tao, Pamela A Shaw, Karen Glanz, David A Asch
Journal: Clinical Gastroenterology and Hepatology (2024)
Induction of antiviral interferon-stimulated genes by neuronal STING promotes the resolution of pain in mice
Authors: Manon Defaye, Amyaouch Bradaia, Nasser S Abdullah, Francina Agosti, Mircea Iftinca, Mélissa Delanne-Cuménal, Vanessa Soubeyre, Kristofer Svendsen, Gurveer Gill, Aye Ozmaeian, Nadine Gheziel, Jérémy Martin, Gaetan Poulen, Nicolas Lonjon, Florence Vachiery-Lahaye, Luc Bauchet, Lilian Basso, Emmanuel Bourinet, Isaac M Chiu, Christophe Altier
Journal: Journal of Clinical Investigation (2024)

Inflammation and pain are intertwined responses to injury, infection, or chronic diseases. While acute inflammation is essential in determining pain resolution and opioid analgesia, maladaptive processes occurring during resolution can lead to the transition to chronic pain. Here we found that inflammation activates the cytosolic DNA-sensing protein stimulator of IFN genes (STING) in dorsal root ganglion nociceptors. Neuronal activation of STING promotes signaling through TANK-binding kinase 1 (TBK1) and triggers an IFN-β response that mediates pain resolution. Notably, we found that mice expressing a nociceptor-specific gain-of-function mutation in STING exhibited an IFN gene signature that reduced nociceptor excitability and inflammatory hyperalgesia through a KChIP1-Kv4.3 regulation. Our findings reveal a role of IFN-regulated genes and KChIP1 downstream of STING in the resolution of inflammatory pain.
Developmental endothelial locus-1 protects from hypertension-induced cardiovascular remodeling via immunomodulation
Authors: Theresa Failer, Michael Amponsah-Offeh, Aleš Neuwirth, Ioannis Kourtzelis, Pallavi Subramanian, Peter Mirtschink, Mirko Peitzsch, Klaus Matschke, Sems M. Tugtekin, Tetsuhiro Kajikawa, Xiaofei Li, Anne Steglich, Florian Gembardt, Annika C. Wegner, Christian Hugo, George Hajishengallis, Triantafyllos Chavakis, Andreas Deussen, Vladimir Todorov, Irakli Kopaliani
Journal: Journal of Clinical Investigation (2024)
Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts
Authors: Robert F. Hillary, Hong Kiat Ng, Daniel L. McCartney, Hannah R. Elliott, Rosie M. Walker, Archie Campbell, Felicia Huang, Kenan Direk, Paul Welsh, Naveed Sattar, Janie Corley, Caroline Hayward, Andrew M. McIntosh, Cathie Sudlow, Kathryn L. Evans, Simon R. Cox, John C. Chambers, Marie Loh, Caroline L. Relton, Riccardo E. Marioni, Paul D. Yousefi, Matthew Suderman
Journal: Cell Genomics (2024)

Highlights•Existing DNAm predictors explain 10% of variance in circulating CRP levels•An elastic-net-based predictor outperforms existing models and explains 20% of variance•Newly described predictor is consistent across life course and ancestries•This predictor outperforms CRP and existing methods in health outcome associationsSummaryChronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.Graphical abstract
BAP1 is required prenatally for differentiation and maintenance of postnatal murine enteric nervous system
Authors: Sabine Schneider, Jessica B Anderson, Rebecca P Bradley, Katherine Beigel, Christina M Wright, Beth A Maguire, Guang Yan, Deanne M Taylor, J William Harbour, Robert O Heuckeroth
Journal: Journal of Clinical Investigation (2024)

Epigenetic regulatory mechanisms are underappreciated, yet are critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage caused severe postnatal bowel dysfunction and early death in Tyrosinase-Cre Bap1fl/fl mice. Bap1-depleted ENS appeared normal in neonates; however, by P15, Bap1-deficient enteric neurons were largely absent from the small and large intestine of Tyrosinase-Cre Bap1fl/fl mice. Bowel motility became markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 showed that fetal Bap1 loss in Tyrosinase-Cre Bap1fl/fl mice markedly altered the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for early enteric neuron survival, a finding that may be relevant to the recently described human BAP1-associated neurodevelopmental disorder.
Short-term aid or long-term gains? Harnessing Sudan's humanitarian response for the resilience of its health system
Authors: Maisoon Elbukhari Ibrahim, Dell D Saulnier, Karl Blanchet
Journal: The Lancet Global Health (2024)

The Sudan 2023 Humanitarian Response Plan was revised in May, 2023, due to the escalating violence in the country.This revision increased the scale of assistance and protection activities and suspended the funding allocated for access to livelihood, access to basic services, and for the implementation of resilience solutions.We call to rethink Sudan's current humanitarian response through a pro-resilience and people-centred approach.A pro-resilience approach prioritises investments in national systems and institutions capable of delivering aid and anticipates, prevents, mitigates, and manages imminent and simultaneous shocks.A people-centred humanitarian response involves meaningful engagement of communities and collaborations with civil society organisations, which continue to be the key responders to the ongoing conflict in Sudan.Finally, we propose approaches to effectively operationalise health system resilience to enhance immediate and long-term health outcomes.
Long-term outcomes after treatment of delirium during critical illness with antipsychotics (MIND-USA): a randomised, placebo-controlled, phase 3 trial
Authors: Matthew F Mart, Leanne M Boehm, Amy L Kiehl, Michelle N Gong, Atul Malhotra, Robert L Owens, Babar A Khan, Margaret A Pisani, Gregory A Schmidt, R Duncan Hite, Matthew C Exline, Shannon S Carson, Catherine L Hough, Peter Rock, Ivor S Douglas, Daniel J Feinstein, Robert C Hyzy, William D Schweickert, David L Bowton, Andrew Masica, Onur M Orun, Rameela Raman, Brenda T Pun, Cayce Strength, Mark L Rolfsen, Pratik P Pandharipande, Nathan E Brummel, Christopher G Hughes, Mayur B Patel, Joanna L Stollings, E Wesley Ely, James C Jackson, Timothy D Girard
Journal: The Lancet Respiratory Medicine (2024)
Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses
Authors: Fan Huang, Christophe Gonçalves, Margarita Bartish, Joelle Rémy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galán, Tomasz Rzymski, Milena Mazan, Magdalena Masiejczyk, Jacek Faber, Elie Khoury, Alexandre Benoit, Natascha Gagnon, David Dankort, Fabrice Journe, Ghanem E. Ghanem, Connie M. Krawczyk, H. Uri Saragovi, Ciriaco A. Piccirillo, Nahum Sonenberg, Ivan Topisirovic, Christopher E. Rudd, Wilson H. Miller, Sonia V. del Rincón
Journal: Journal of Clinical Investigation (2024)
CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication
Authors: Pablo Tebas, Julie K. Jadlowsky, Pamela A. Shaw, Lifeng Tian, Erin Esparza, Andrea L. Brennan, Sukyung Kim, Soe Yu Naing, Max W. Richardson, Ashley N. Vogel, Colby R. Maldini, Hong Kong, Xiaojun Liu, Simon F. Lacey, Anya M. Bauer, Felicity Mampe, Lee P. Richman, Gary Lee, Dale Ando, Bruce L. Levine, David L. Porter, Yangbing Zhao, Don L. Siegel, Katharine J. Bar, Carl H. June, James L. Riley
Journal: Journal of Clinical Investigation (2024)
Leveraging functional genomic annotations and genome coverage to improve polygenic prediction of complex traits within and between ancestries
Authors: Zhili Zheng, Shouye Liu, Julia Sidorenko, Ying Wang, Tian Lin, Loic Yengo, Patrick Turley, Alireza Ani, Rujia Wang, Ilja M Nolte, Harold Snieder, Jian Yang, Naomi R Wray, Michael E Goddard, Peter M Visscher, Jian Zeng
Journal: Nature Genetics (2024)

Abstract We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP density and annotation information, suggesting whole-genome sequence variants with annotations may further improve prediction. Functional partitioning analysis highlights a major contribution of evolutionary constrained regions to prediction accuracy and the largest per-SNP contribution from nonsynonymous SNPs.
DISSECT: deep semi-supervised consistency regularization for accurate cell type fraction and gene expression estimation
Authors: Robin Khatri, Pierre Machart, Stefan Bonn
Journal: Genome biology (2024)

Abstract Cell deconvolution is the estimation of cell type fractions and cell type-specific gene expression from mixed data. An unmet challenge in cell deconvolution is the scarcity of realistic training data and the domain shift often observed in synthetic training data. Here, we show that two novel deep neural networks with simultaneous consistency regularization of the target and training domains significantly improve deconvolution performance. Our algorithm, DISSECT, outperforms competing algorithms in cell fraction and gene expression estimation by up to 14 percentage points. DISSECT can be easily adapted to other biomedical data types, as exemplified by our proteomic deconvolution experiments.