Cancer remains the leading cause of mortality worldwide.Radiotherapy(RT),a cornerstone of oncological treatment for over a century,has achieved great success in various cancers.However,radioresistance remains the prim...Cancer remains the leading cause of mortality worldwide.Radiotherapy(RT),a cornerstone of oncological treatment for over a century,has achieved great success in various cancers.However,radioresistance remains the primary factor leading to the failure of radiotherapy.Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure,either by loosening or tightening it.Here,we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal tissue cells.Furthermore,we discuss the regulatory mechanisms of histone modifications and the enzymes on the recruitment of proteins that recognize histone modifications.Consequently,these processes substantially affect the radiosensitivity of tumors.In addition to cancer cells,we highlight the intricate interplay between histone modification and radiosensitivity,both within and beyond the cancer cells.Meanwhile,various drugs targeting histone modifications emerge as a promising therapeutic strategy to overcome radioresistance of tumors as well as radioprotection.The combination of histone modification inhibitors with radiotherapy presents a novel approach to enhance cancer treatment outcomes in clinical practice.Nevertheless,the underlying mechanisms through which histone modifications influence cancer radiosensitivity require further elucidation to identify novel targets for radiotherapeutic intervention.展开更多
Although the search for appropriate radiation countermeasures has been ongoing for decades,there remains a lack of safe and effective radioprotective pharmaceuticals for preventing,mitigating,or treating acute radiati...Although the search for appropriate radiation countermeasures has been ongoing for decades,there remains a lack of safe and effective radioprotective pharmaceuticals for preventing,mitigating,or treating acute radiation syndrome(ARS)and other severe radiation injuries,and only a handful of drugs have been approved for clinical use with various side-effects.It has been increasingly recognized that valuable radiation countermeasures can be derived from Earth-based species exhibiting resistance to extremely high levels of ionizing radiation.In the pursuit of the mechanisms that govern radiosensitivity,a groundbreaking study in Science has delved into the radiation tolerance mechanisms of the tardigrade Hypsibius henanensis sp.nov.,revealing cross-species radiation defense strategies by integrating genomics,transcriptomics,and proteomic.Three key findings emerged:The horizontal transfer of the 4,5-DOPA dioxygenase gene from bacteria enhanced antioxidant production.The tardigrade-specific protein TRID1 was crucial for DNA double-strand break repair through liquid-liquid sepa-ration.The up-regulation of mitochondrial function-related genes accelerated NAD^(+)regeneration for DNA damage repair.This multi-omics approach not only sheds light on the extraordinary survival strategies of radiotolerant species,but also opens a promising avenue for harnessing cross-species radiation tolerance to develop innovative radioprotective compounds.展开更多
Introduction:This study investigated the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)with clinically significant fibrosis among obese patients with type 2 diabetes mellitus(T2DM).Metho...Introduction:This study investigated the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)with clinically significant fibrosis among obese patients with type 2 diabetes mellitus(T2DM).Methods:This multicenter study enrolled T2DM patients from tertiary hospitals and primary care facilities across 21 cities in China between 2017 and 2024.Clinically significant fibrosis was defined as liver stiffness measurement(LSM)≥8 kPa assessed by vibration-controlled transient elastography(VCTE)or biopsy-confirmed fibrosis stage≥F2.Results:Of the 10,281 patients included,9,725 comprised the VCTE cohort(5,171 from clinics and 4,554 from primary care),while 556 comprised the biopsy cohort.Overall,25.6%were obese.The prevalence of MASLD with clinically significant fibrosis reached 26.7%in obese patients,significantly exceeding that in non-obese patients(8.4%).This prevalence increased progressively with rising body mass index and demonstrated a strong association with the number of cardiometabolic risk factors.Furthermore,a non-invasive model incorporating age,waist circumference,alanine aminotransferase,total bilirubin,and triglycerides exhibited reliable performance in stratifying the risk of MASLD with clinically significant fibrosis among obese patients with T2DM[Area under the receiver operating characteristic curve(AUC):0.799(95%CI:0.767-0.832)].Conclusions:MASLD with clinically significant fibrosis is highly prevalent among obese patients with T2DM,emphasizing the necessity for systematic risk stratification and integrated management of these interconnected metabolic conditions.展开更多
Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution o...Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD,progress in drug development for this condition remains limited.This review highlights the potential of drug-target Mendelian randomisation(MR),a study design that leverages human genetics and genomics,for the discovery,repositioning and safety assessment of drug targets in MASLD.We summarised key aspects of designing and appraising a drug-target MR study,discussing its inherent assumptions and considerations for instrument selection.Furthermore,we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets,repositing existing drug targets,informing adjunctive treatments and addressing issues in paediatric MASLD.展开更多
基金supported by the National Natural Science Foundation of China(82404200 and 82473574)Projects from Sichuan Province(2024ZYD0126,China)+1 种基金Key Innovation Project from Tibet Province(XZ202501ZY0131,China)Sichuan Science and Technology Program(MZGC20240002,China).
文摘Cancer remains the leading cause of mortality worldwide.Radiotherapy(RT),a cornerstone of oncological treatment for over a century,has achieved great success in various cancers.However,radioresistance remains the primary factor leading to the failure of radiotherapy.Histone modifications in cancer cells are known to play a pivotal role in regulating radiosensitivity by modulating chromatin structure,either by loosening or tightening it.Here,we provide a comprehensive summary of the link between aberrant histone modifications and radiation resistance across various cancer and normal tissue cells.Furthermore,we discuss the regulatory mechanisms of histone modifications and the enzymes on the recruitment of proteins that recognize histone modifications.Consequently,these processes substantially affect the radiosensitivity of tumors.In addition to cancer cells,we highlight the intricate interplay between histone modification and radiosensitivity,both within and beyond the cancer cells.Meanwhile,various drugs targeting histone modifications emerge as a promising therapeutic strategy to overcome radioresistance of tumors as well as radioprotection.The combination of histone modification inhibitors with radiotherapy presents a novel approach to enhance cancer treatment outcomes in clinical practice.Nevertheless,the underlying mechanisms through which histone modifications influence cancer radiosensitivity require further elucidation to identify novel targets for radiotherapeutic intervention.
基金The National Natural Science Foundation of China(82473574 and 82404200)the Sichuan Science and Technology Program(25QNJJ4600),China.
文摘Although the search for appropriate radiation countermeasures has been ongoing for decades,there remains a lack of safe and effective radioprotective pharmaceuticals for preventing,mitigating,or treating acute radiation syndrome(ARS)and other severe radiation injuries,and only a handful of drugs have been approved for clinical use with various side-effects.It has been increasingly recognized that valuable radiation countermeasures can be derived from Earth-based species exhibiting resistance to extremely high levels of ionizing radiation.In the pursuit of the mechanisms that govern radiosensitivity,a groundbreaking study in Science has delved into the radiation tolerance mechanisms of the tardigrade Hypsibius henanensis sp.nov.,revealing cross-species radiation defense strategies by integrating genomics,transcriptomics,and proteomic.Three key findings emerged:The horizontal transfer of the 4,5-DOPA dioxygenase gene from bacteria enhanced antioxidant production.The tardigrade-specific protein TRID1 was crucial for DNA double-strand break repair through liquid-liquid sepa-ration.The up-regulation of mitochondrial function-related genes accelerated NAD^(+)regeneration for DNA damage repair.This multi-omics approach not only sheds light on the extraordinary survival strategies of radiotolerant species,but also opens a promising avenue for harnessing cross-species radiation tolerance to develop innovative radioprotective compounds.
基金Supported by grants from the Key Research and Development Program of Jiangsu Province(BE2023767a)the Fundamental Research Fund of Southeast University(3290002303A2)+6 种基金the Changjiang Scholars Talent Cultivation Project of Zhongda Hospital of Southeast University(2023YJXYYRCPY03)the Research Personnel Cultivation Programme of Zhongda Hospital Southeast University(CZXM-GSP-RC125,CZXMGSP-RC119)the China Postdoctoral Science Foundation(2024M750461)the National Natural Science Foundation of China(82402413)the Natural Science Foundation of Jiangsu Province(BK20241681)the Health Research Program of Anhui(AHWJ2023A30169)the Natural Science Foundation of Anhui Province(2508085QH314).
文摘Introduction:This study investigated the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)with clinically significant fibrosis among obese patients with type 2 diabetes mellitus(T2DM).Methods:This multicenter study enrolled T2DM patients from tertiary hospitals and primary care facilities across 21 cities in China between 2017 and 2024.Clinically significant fibrosis was defined as liver stiffness measurement(LSM)≥8 kPa assessed by vibration-controlled transient elastography(VCTE)or biopsy-confirmed fibrosis stage≥F2.Results:Of the 10,281 patients included,9,725 comprised the VCTE cohort(5,171 from clinics and 4,554 from primary care),while 556 comprised the biopsy cohort.Overall,25.6%were obese.The prevalence of MASLD with clinically significant fibrosis reached 26.7%in obese patients,significantly exceeding that in non-obese patients(8.4%).This prevalence increased progressively with rising body mass index and demonstrated a strong association with the number of cardiometabolic risk factors.Furthermore,a non-invasive model incorporating age,waist circumference,alanine aminotransferase,total bilirubin,and triglycerides exhibited reliable performance in stratifying the risk of MASLD with clinically significant fibrosis among obese patients with T2DM[Area under the receiver operating characteristic curve(AUC):0.799(95%CI:0.767-0.832)].Conclusions:MASLD with clinically significant fibrosis is highly prevalent among obese patients with T2DM,emphasizing the necessity for systematic risk stratification and integrated management of these interconnected metabolic conditions.
基金supported by Seed Fund for Basic Science(2302101604),the University of Hong Kong.
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has emerged as the most prevalent cause of chronic liver disease worldwide affecting over one-third of the adult population.Despite the recent evolution of new nomenclature and diagnostic criteria for MASLD,progress in drug development for this condition remains limited.This review highlights the potential of drug-target Mendelian randomisation(MR),a study design that leverages human genetics and genomics,for the discovery,repositioning and safety assessment of drug targets in MASLD.We summarised key aspects of designing and appraising a drug-target MR study,discussing its inherent assumptions and considerations for instrument selection.Furthermore,we presented real-world examples from studies in MASLD which focused on opportunities and challenges in identifying novel drug targets,repositing existing drug targets,informing adjunctive treatments and addressing issues in paediatric MASLD.
