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Social Isolation, loneliness, and Quality of life Among Food-Insecure Adults

AMERICAN JOURNAl OF PREVENTIVE MEDICINE 2024年第1期67卷 120-123页

作者： Park, Sungchul Berkowitz, Seth A. Korea Univ Coll Hlth Sci Dept Hlth Policy & Management Seoul South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Seoul South Korea Univ N Carolina Sch Med Div Gen Med & Clin Epidemiol Dept Med Chapel Hill NC USA Univ N Carolina Cecil G Sheps Ctr Hlth Serv Res Chapel Hill NC USA

Introduction: Food insecurity is associated with adverse health outcomes, but may also have a detrimental effect on social relationships, potentially exacerbating social isolation and loneliness, and consequently affecting health-related quality of life. This study examined the associations of food insecurity with social isolation, loneliness, and health-related quality of life among U.S. adults. Methods: A retrospective cohort study was conducted using panel data from the 2020-2021 - 2021 Medical Expenditure Panel Survey. Regression models were used to assess the associations of food insecurity in 1 year with the outcomes of interest in the subsequent year while adjusting for baseline individual-level characteristics. Analysis was conducted in December 2023. Results: Experiencing food insecurity in 2020 was significantly fi cantly associated with increased reports of social isolation (3.1 percentage points [95% CI: 1.2-5.1]) - 5.1]) and loneliness (9.7 percentage points [95% CI: 1.0-18.3]) - 18.3]) in 2021. Additionally, food insecurity in 2020 was significantly fi cantly associated with lower self-reported good mental health (-2.9- 2.9 percentage points [95% CI:- 5.1,- 0.6]) and mental component summary score from the Short Form-12 health Survey (-3.3- 3.3 points [95% CI- 3.8,- 2.9]) in 2021. However, there were no or small associations with physical health-related quality of life. Conclusions: Food insecurity is associated with worse social and mental well-being among U.S. adults. This suggests that food insecurity interventions should not focus too narrowly on nutrition, but instead give holistic consideration to the multiple ways food insecurity harms health-not - not only via lower quality diets, but through worse mental health and impairing the ability to participate in social life. Am J Prev Med 2024;67(1):120-123. - 123. (c) 2024 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

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How do nursing home nurses conceptualize the management of behavioral and psychological symptoms of dementia? A phenomenographic study

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NURSING & health SCIENCES 2024年第1期26卷 e13079-e13079页

作者： Kim, Dayeong Choi, Young-Rim lee, Ye-Na Chang, Sung Ok Korea Univ Coll Nursing 145 Anam Ro Seoul 02841 South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Seoul South Korea Univ Suwon Dept Nursing Hwaseong Si South Korea

The behavioral and psychological symptoms of dementia (BPSD) present complex challenges for nursing home (NH) nurses, leading to confusion and difficulties in providing effective care. To address these issues, investigating how NH nurses perceive and manage the BPSD is crucial since it can lead to the development of tailored and effective care plans. This study therefore aimed to explore the ways in which NH nurses approach the management of the BPSD by using phenomenography. The study identified five categories of assessment and four categories of intervention in managing the BPSD, with their hierarchical structure represented as an outcome space. Each category's description provides a clear conceptualization of the complex and challenging nature of the BPSD care, offering insights into how NH nurses perceive the BPSD management. The study's findings can enhance NH nurse education and lead to effective care plans for residents with BPSD.

关键词： continuing education dementia nursing home phenomenography qualitative research

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Entosis: the core mechanism and crosstalk with other cell death programs

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EXPERIMENTAl AND MOlECUlAR MEDICINE 2024年第4期56卷 870页

作者： Kim, Sunghoon lee, Donghyuk Kim, Sung Eun Overholtzer, Michael Korea Univ Dept Biosyst & Biomed Sci Coll Hlth Sci Seoul South Korea Korea Univ Coll Hlth Sci Dept Integrated Biomed & Life Sci Seoul South Korea L HOPE Program Community Based Total Learning Hlth Seoul South Korea Yonsei Univ Coll Med Dept Pharmacol & Brain Korea Project Med Sci 21 Seoul South Korea Sloan Kettering Inst Canc Res Cell Biol Program New York NY 10065 USA Mem Sloan Kettering Canc Ctr Louis V Gerstner Jr Grad Sch Biomed Sci New York NY 10021 USA Weill Cornell Med Coll BCMB Allied Program New York NY 10065 USA

Cell death pathways play critical roles in organism development and homeostasis as well as in the pathogenesis of various diseases. While studies over the last decade have elucidated numerous different forms of cell death that can eliminate cells in various contexts, how certain mechanisms impact physiology is still not well understood. Moreover, recent studies have shown that multiple forms cell death can occur in a cell population, with different forms of death eliminating individual cells. Here, we aim to describe the known molecular mechanisms of entosis, a non-apoptotic cell engulfment process, and discuss signaling mechanisms that control its induction as well as its possible crosstalk with other cell death mechanisms. Cell death, a complex process, can happen through various mechanisms, including entosis. Entosis, first identified as a non-apoptotic cell death program, involves one cell engulfing another, causing the death of the internalized cell. However, the exact molecular mechanisms and factors controlling entosis are unclear. In this study, the authors review recent findings uncovering the molecular regulation of entosis and dicuss its potential implications in cancer. They discuss how entosis is controlled by a network of regulations involving cell adhesion, the RhoA-ROCK signaling pathway, and actomyosin contraction. Interestingly, entosis can occur alongside other cell death forms in populations, suggesting it may influence how cell groups respond to stress. The study concludes that entosis may contribute to aggressive cancers' development by favoring cells with low tension setpoints, promoting the creation of aneuploid cell lineages, and supporting cell lineages with large scavenged nutrient *** summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

关键词： Entosis Tumour heterogeneity

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An integrative single-cell atlas for exploring the cellular and temporal specificity of genes related to neurological disorders during human brain development

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EXPERIMENTAl AND MOlECUlAR MEDICINE 2024年第10期56卷 2271-2282页

作者： Kim, Seoyeon lee, Jihae Koh, In Gyeong Ji, Jungeun Kim, Hyun Jung Kim, Eunha Park, Jihwan Park, Jong-Eun An, Joon-Yong Korea Univ Dept Integrated Biomed & Life Sci Seoul South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Seoul South Korea Korea Univ Coll Hlth Sci Sch Biosyst & Biomed Sci Seoul South Korea Korea Univ Coll Med Dept Biomed Sci Seoul South Korea Korea Univ Coll Med Dept Anat Seoul South Korea Korea Univ Coll Med Dept Neurosci Seoul South Korea Korea Univ Coll Med Dept Biomed Sci Grad Program BK21 Seoul South Korea Gwangju Inst Sci & Technol GIST Sch Life Sci Gwangju South Korea Korea Adv Inst Sci & Technol KAIST Grad Sch Med Sci & Engn Daejeon South Korea

Single-cell technologies have enhanced comprehensive knowledge regarding the human brain by facilitating an extensive transcriptomic census across diverse brain regions. Nevertheless, understanding the cellular and temporal specificity of neurological disorders remains ambiguous due to developmental variations. To address this gap, we illustrated the dynamics of disorder risk gene expression under development by integrating multiple single-cell RNA sequencing datasets. We constructed a comprehensive single-cell atlas of the developing human brain, encompassing 393,060 single cells across diverse developmental stages. Temporal analysis revealed the distinct expression patterns of disorder risk genes, including those associated with autism, highlighting their temporal regulation in different neuronal and glial lineages. We identified distinct neuronal lineages that diverged across developmental stages, each exhibiting temporal-specific expression patterns of disorder-related genes. lineages of nonneuronal cells determined by molecular profiles also showed temporal-specific expression, indicating a link between cellular maturation and the risk of disorder. Furthermore, we explored the regulatory mechanisms involved in early brain development, revealing enriched patterns of fetal cell types associated with neuronal disorders indicative of the prenatal stage's influence on disease determination. Our findings facilitate unbiased comparisons of cell type-disorder associations and provide insight into dynamic alterations in risk genes during development, paving the way for a deeper understanding of neurological disorders. The growth of the human brain is a complicated process that begins before birth and continues into young adulthood. Researchers focused on how genes related to brain disorders are expressed in different cells over time. They gathered data from 114 human brain samples, creating a single-cell atlas that traces brain growth from early fetal stages to adulthoo

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Air pollution and survival in patients with malignant mesothelioma and asbestos-related lung cancer: a follow-up study of 1591 patients in South Korea

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ENVIRONMENTAl health 2024年第1期23卷 56-56页

作者： Huh, Da-An Choi, Yun-Hee Kim, lita Park, Kangyeon lee, Jiyoun Hwang, Se Hyun Moon, Kyong Whan Kang, Min-Sung lee, Yong-Jin Korea Univ Inst Hlth Sci Anam Ro 145 Seoul 02841 South Korea Korea Univ Coll Med Dept Ophthalmol Dept Biostat Anam ro 145 Seoul 02841 South Korea Korea Univ Dept Hlth & Safety Convergence Sci Anam ro 145 Seoul 02841 South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Anam ro 145 Seoul 02841 South Korea Korea Univ Sch Hlth & Environm Sci Anam ro 145 Seoul 02841 South Korea Soonchunhyang Univ Cheonan Hosp Environm Hlth Ctr Asbestos 31 Suncheonhyang 6-gil Cheonan Si 31151 South Korea Soonchunhyang Univ Dept Occupat & Environm Med 31 Suncheonhyang 6-gil Cheonan Si 31151 South Korea

Background Despite significant advancements in treatments such as surgery, radiotherapy, and chemotherapy, the survival rate for patients with asbestos-related cancers remains low. Numerous studies have provided evidence suggesting that air pollution induces oxidative stress and inflammation, affecting acute respiratory diseases, lung cancer, and overall mortality. However, because of the high case fatality rate, there is limited knowledge regarding the effects of air pollution exposures on survival following a diagnosis of asbestos-related cancers. This study aimed to determine the effect of air pollution on the survival of patients with malignant mesothelioma and asbestos-related lung cancer. Methods We followed up with 593 patients with malignant mesothelioma and 998 patients with lung cancer identified as asbestos victims between 2009 and 2022. Data on five air pollutants-sulfur dioxide, carbon monoxide, nitrogen dioxide, fine particulate matter with a diameter < 10 mu m, and fine particulate matter with a diameter < 2.5 mu m-were obtained from nationwide atmospheric monitoring stations. Cox proportional hazard models were used to estimate the association of cumulative air pollutant exposure with patient mortality, while adjusting for potential confounders. Quantile-based g-computation was used to assess the combined effect of the air pollutant mixture on mortality. Results The 1-, 3-, and 5-year survival rates for both cancer types decreased with increasing exposure to all air pollutants. The estimated hazard ratios rose significantly with a 1-standard deviation increase in each pollutant exposure level. A quartile increase in the pollutant mixture was associated with a 1.99-fold increase in the risk of malignant mesothelioma-related mortality (95% confidence interval: 1.62, 2.44). For lung cancer, a quartile increase in the pollutant mixture triggered a 1.87-fold increase in the mortality risk (95% confidence interval: 1.53, 2.30). Conclusion These findings su

关键词： Air pollution Exposure mixtures lung cancer Malignant mesothelioma Survival analysis

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Whole-genome sequencing analyses suggest novel genetic factors associated with Alzheimer's disease and a cumulative effects model for risk liability

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Nature communications 2025年第1期16卷 4870页

作者： Jun Pyo Kim Minyoung Cho Chanhee Kim Hyunwoo lee Beomjin Jang Sang-Hyuk Jung Yujin Kim In Gyeong Koh Seoyeon Kim Daeun Shin Eun Hye lee Jong-Young lee YoungChan Park Hyemin Jang Bo-Hyun Kim Hongki Ham Beomsu Kim A-Hyun Cho Towfique Raj Hee Jin Kim Duk l Na Sang Won Seo Joon-Yong An Hong-Hee Won Alzheimer's Disease Convergence Research Center Samsung Medical Center Seoul Republic of Korea. Department of Neurology Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Republic of Korea. Neuroscience Center Samsung Medical Center Seoul Republic of Korea. Department of Digital Health Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University Seoul Republic of Korea. Department of Integrated Biomedical and Life Science Korea University Seoul Republic of Korea. L-HOPE Program for Community-Based Total Learning Health Systems Korea University Seoul Republic of Korea. Department of Health Sciences and Technology Samsung Advanced Institute for Health Sciences & Technology (SAIHST) Sungkyunkwan University Seoul Republic of Korea. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York NY USA. Nash Family Department of Neuroscience & Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York NY USA. Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York NY USA. Department of Medical Informatics Kangwon National University College of Medicine Chuncheon Republic of Korea. Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis IN USA. Indiana Alzheimer Disease Research Center Indiana University School of Medicine Indianapolis IN USA. Oneomics Co. Ltd Gyeonggi-do Republic of Korea. Division of Bio Bigdata Department of Precision Medicine Korea National Institution of Health Cheongju Republic of Korea. Department of Neurology Seoul National University Hospital Seoul National University School of Medicine Seoul Republic of Korea. Icahn Institute for Data Science and Genomic Technology Icahn School of Medicine at Mount Sinai New York NY USA. Estelle and Daniel Maggin Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA. Alzheimer's Disease Convergen

Genome-wide association studies (GWAS) on Alzheimer's disease (AD) have predominantly focused on identifying common variants in Europeans. Here, we performed whole-genome sequencing (WGS) of 1,559 individuals from a Korean AD cohort to identify various genetic variants and biomarkers associated with AD. Our GWAS analysis identified a previously unreported locus for common variants (APCDD1) associated with AD. Our WGS analysis was extended to explore the less-characterized genetic factors contributing to AD risk. We identified rare noncoding variants located in cis-regulatory elements specific to excitatory neurons associated with cognitive impairment. Moreover, structural variation analysis showed that short tandem repeat expansion was associated with an increased risk of AD, and copy number variant at the HPSE2 locus showed borderline statistical significance. APOE ε4 carriers with high polygenic burden or structural variants exhibited severe cognitive impairment and increased amyloid beta levels, suggesting a cumulative effects model of AD risk.

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Association of food insecurity with health, access to care, affordability of care, fi nancial burden of care, and fi nancial hardships among US adults during the COVID-19 pandemic

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PUBlIC health 2024年 230卷 183-189页

作者： Park, S. Ortega, A. N. Chen, J. Mortensen, K. Bustamante, A. V. Korea Univ Coll Hlth Sci Dept Hlth Policy & Management 145 Anam Ro Seoul 02841 South Korea Korea Univ Grad Sch Dept Healthcare Sci 145 Anam Ro Seoul 02841 South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth 145 Anam Ro Seoul 02841 South Korea Univ Hawaii Manoa Thompson Sch Social Work & Publ Hlth 2430 Campus Rd Honolulu HI 96822 USA Univ Maryland Sch Publ Hlth Dept Hlth Policy & Management 4200 Valley Dr College Pk MD 20742 USA Univ Miami Herbert Business Sch Dept Hlth Management & Policy 5250 Univ Dr Coral Gables FL 33146 USA UCLA UCLA Latino Policy & Polit Inst Fielding Sch Publ Hlth Dept Hlth Policy & Management 650 Charles Young Dr S Los Angeles CA 90095 USA Korea Univ Coll Hlth Sci BK21 FOUR R&E Ctr Learning Hlth Syst Dept Hlth Policy & Management 145 Anam Ro Seoul 02841 South Korea

Objectives: To examine the associations between food insecurity and health, access to care, affordability of care, financial burden of care, and financial hardships among US adults during the COVID-19 pandemic and examine whether the associations were less pronounced among adults with safety nets. Study design: We conducted a retrospective longitudinal cohort study using the 2020-2021 Medical Expenditure Panel Survey. Methods: linear probability models were used to assess the associations between food insecurity in one year and the outcomes of interest in the following year while adjusting for baseline characteristics. We performed the analyses for the entire population and then conducted stratified analyses for adults with and without Supplemental Nutrition Assistance program (SNAP) benefits or Medicaid coverage. Results: Compared with food -secure adults, food -insecure adults were 9.1 percentage points less likely to report life satisfaction and 9.9, 10.2, and 13.2 percentage points more likely to experience delays in getting medical care, postpone or forgo medical care because of cost, and struggle with paying medical bills. Food -insecure adults were 30.4, 27.2, and 23.5 percentage points more likely to face challenges in affording necessities, paying utility bills, and meeting rent or mortgage payments on time than foodsecure adults. Notably, the strengths of these associations were attenuated among adults with SNAP benefits or Medicaid coverage. Conclusions: Food insecurity was associated with poor health, limited access to and affordability of care, and a greater financial burden of care among US adults during the pandemic. Nevertheless, safety net programs can play a critical role in alleviating adverse consequences.

关键词： Food insecurity Access to care Affordability of care Financial burden of care COVID-19 pandemic

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Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder

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PSYCHIATRY AND ClINICAl NEUROSCIENCES 2024年第7期78卷 405-415页

作者： Kim, Jae Hyun Koh, In Gyeong lee, Hyeji lee, Gang-Hee Song, Da-Yea Kim, Soo-Whee Kim, Yujin Han, Jae Hyun Bong, Guiyoung lee, Jeewon Byun, Heejung Son, Ji Hyun Kim, Ye Rim lee, Yoojeong Kim, Justine Jaewon Park, Jung Woo Kim, Il Bin Choi, Jung Kyoon Jang, Ja-Hyun Trost, Brett lee, Junehawk Kim, Eunjoon Yoo, Hee Jeong An, Joon-Yong Korea Univ Dept Integrated Biomed & Life Sci Seoul South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Seoul South Korea Seoul Natl Univ Bundang Hosp Dept Psychiat Seongnam South Korea Seoul Natl Univ Coll Med Dept Psychiat Seoul South Korea Soonchunhyang Univ Cheonan Hosp Coll Med Dept Pediat Cheonan South Korea Soonchunhyang Univ Dept Psychiat Coll Med Asan South Korea Seoul Metropolitan Childrens Hosp Dept Neuropsychiat Seoul South Korea Korea Inst Sci & Technol Informat Ctr Biomed Comp Div Natl Supercomp Daejeon South Korea Hanyang Univ Dept Psychiat Guri Hosp Guri South Korea Korea Adv Inst Sci & Technol Dept Bio & Brain Engn Daejeon South Korea Sungkyunkwan Univ Sch Med Samsung Med Ctr Dept Lab Med & Genet Seoul South Korea Hosp Sick Children Mol Med Program Toronto ON Canada Hosp Sick Children Genet & Genome Biol Program Toronto ON Canada Ctr Synapt Brain Dysfunct Inst Basic Sci Daejeon South Korea Korea Adv Inst Sci & Technol Dept Biol Sci Daejeon South Korea Korea Univ Coll Hlth Sci Sch Biosyst & Biomed Sci Seoul South Korea

AimShort tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD *** analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR *** ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to *** tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

关键词： autism biological psychiatry genetics in psychiatry tandem repeat whole genome sequencing

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Chemical exposure from the Hebei spirit oil spill accident and its long-term effects on mental health

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ECOTOXICOlOGY AND ENVIRONMENTAl SAFETY 2024年 284卷 116938页

作者： Kim, lita Huh, Da-An Kang, Min-Sung Park, Kangyeon lee, Jiyoun Hwang, Se Hyun Choi, Hyeon Jeong lim, Woohyun Moon, Kyong Whan lee, Yong-Jin Korea Univ Grad Sch Dept Hlth & Safety Convergence Sci Seoul South Korea L HOPE Program Community Based Total Learning Hlth Seoul South Korea Korea Univ Inst Hlth Sci Anam Ro 145 Seoul 02841 South Korea Soonchunhyang Univ Inst Environm Med Cheonan Hosp 31 Suncheonhyang 6 Gil Cheonan Si 31151 South Korea Baylor Univ Dept Environm Sci Waco TX USA Korea Univ Sch Hlth & Environm Sci Seoul South Korea Soonchunhyang Univ Cheonan Hosp Reg Environm Hlth Ctr Cheonan South Korea Soonchunhyang Univ Dept Occupat & Environm Med Cheonan South Korea

While evidence indicates that exposure to oil spill incidents can affect mental health, it is unclear whether the mental health effects result from the incident itself or from exposure to associated chemicals. Oil contains chemicals that can impact mental health and these chemicals may have long-term effects due to their persistence in the environment. To address the gap in current knowledge, we conducted cross-sectional and prospective analyses of data from adults who participated in the health Effects of the Hebei Spirit Oil Spill study. To assess chemical exposure from oil spills, we used indirect exposure indicators such as distance from the contaminated oil band to residences and duration of clean-up work, along with direct exposure indicators such as urine metabolite concentrations of volatile organic compounds and polycyclic aromatic hydrocarbons. Mental health assessments covered posttraumatic stress disorder (PTSD), depression, state anxiety, and trait anxiety. In the cross-sectional analyses, all four mental health issues were found to be associated with proximity to the oil band (p-value<0.05) and showed a positive association with clean-up work duration (p-value<0.05). Cox regression analysis revealed that higher urinary t, t-muconic acid levels were associated with an increased risk of depression (Hazard Ratio [HR] = 1.55, 95 % Confidence Interval [CI] = 1.05-2.28), and elevated 1-hydroxypyrene levels increased the risk of PTSD (HR = 1.60, 95 % CI = 1.03-2.48). Additionally, higher urinary 2-naphthol levels were associated with increased state anxiety (HR = 1.39, 95 % CI = 1.00-1.93) and trait anxiety (HR = 1.64, 95 % CI = 1.15-2.32). These associations persisted even after controlling for distance and duration variables related to psychosocial exposure. Our findings suggest that environmental disaster response plans should prioritize minimizing chemical exposure while also considering the duration and nature of the mental health impacts.

关键词： Hebei Spirit long-term effect Mental health Oil spill Polycyclic aromatic hydrocarbons Volatile organic compounds

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RNA N⁶-Methyladenosine-Binding Protein YTHDFs Redundantly Attenuate Cancer Immunity by Downregulating IFN-γ Signaling in Gastric Cancer

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ADVANCED SCIENCE 2024年第3期12卷 e2410806页

作者： Jang, Dongjun Hwa, Chanwoong Kim, Seoyeon Oh, Jaeik Shin, Seungjae lee, Soo-Jin Kim, Jiwon lee, Sang Eun Yang, Yoojin Kim, Dohee lee, Seoho Jung, Hae Rim Oh, Yumi Kim, Kyunggon lee, Hye Seung An, Joon-Yong Cho, Sung-Yup Seoul Natl Univ Coll Med Dept Biomed Sci Seoul 03080 South Korea Korea Univ L HOPE Program Community Based Total Learning Hlth Seoul 02841 South Korea Korea Univ Dept Integrated Biomed & Life Sci Seoul 02841 South Korea Seoul Natl Univ Coll Med Dept Translat Med Seoul 03080 South Korea Seoul Natl Univ Genom Med Inst Coll Med Med Res Ctr Seoul 03080 South Korea Univ Ulsan Coll Med Dept Biomed Sci Seoul 05505 South Korea Seoul Natl Univ Coll Med Dept Pathol Seoul 03080 South Korea Seoul Natl Univ Canc Res Inst Seoul 03080 South Korea Korea Univ Coll Hlth Sci Sch Biosyst & Biomed Sci Seoul 02841 South Korea

Immunotherapy holds potential as a treatment for gastric cancer (GC), though immune checkpoint inhibitor (ICI) resistance remains an obstacle. One resistance mechanism involves defects in interferon-gamma (IFN-gamma) signaling, in which IFN-gamma is linked to improved responsiveness to ICIs. Herein, the roles of RNA N-6-methyladenosine (m6A) modifications in regulation of IFN-gamma signaling and the responsiveness to ICIs are unveiled. The m6A-binding protein YTH N-6-methyladenosine RNA-binding protein F1 (YTHDF1) is overexpressed in GC tissues, correlating with the suppression of cancer immunity and poorer survival rates. YTHDF1 overexpression impaired the responsiveness to IFN-gamma in GC cells, and knockdown studies indicated the redundant effects of YTHDF2 and YTHDF3 with YTHDF1 in IFN-gamma responsiveness. RNA immunoprecipitation sequencing revealed YTHDFs directly target interferon regulatory factor 1 (IRF1) mRNA, a master regulator of IFN-gamma signaling, leading to reduced RNA stability and consequent downregulation of IFN-gamma signaling. Furthermore, in mouse syngeneic tumor models, Ythdf1 depletion in cancer cells resulted in reduced tumor growth and increased tumor-infiltrating lymphocytes, which are attributed to the augmentation of IFN-gamma signaling. Collectively, these findings highlight how YTHDFs modulate cancer immunity by influencing IFN-gamma signaling through IRF1 regulation, suggesting their viability as therapeutic targets in cancer immunotherapy.

关键词： cancer immunity gastric cancer interferon-gamma signaling N-6-methyladenosine YTHDF proteins

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