摘要：Ovarian reserve is essential for fertility and influences healthy aging in women.Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes.The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered.In this review,we highlight some of critical factors that impact oocyte quantity and quality during aging.Germ cell and follicle reserve at birth de-termines reproductive lifespan and timing the menopause in female mammals.Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency.Poor oocyte quality with increasing age could result from chro-mosomal cohesion deterioration and misaligned chromo-somes,telomere shortening,DNA damage and associated genetic mutations,oxidative stress,mitochondrial dysfunc-tion and epigenetic alteration.We also discuss the interven-tion strategies to delay ovarian aging.Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed.Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells.We propose directions for future interventions.As couples increasingly begin delaying parenthood in life worldwide,understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.

摘要：Recurrent pregnancy loss(RPL)has become an important reproductive health issue worldwide.RPL affects about 2%-3%of reproductive-aged women,and makes serious threats to women's physical and mental health.However,the etiology of approximately 50%of RPL cases remains unknown(unexplained RPL),which poses a big challenge for clinical management of these patients.RPL has been widely regarded as a complex disease where its etiology has been attributed to numerous factors.Heretofore,various risk factors for RPL have been identified,such as maternal ages,genetic factors,anatomical structural abnormalities,endocrine dysfunction,prethrombotic state,immunological fac-tors,and infection.More importantly,development and applications of next generation sequencing technology have significantly expanded opportunities to discover chromosomal aberrations and single gene variants respon-sible for RPL,which provides new insight into its pathogenic mechanisms.Furthermore,based upon patients'diagnostic evaluation and etiologic diagnosis,specific therapeutic recommendations have been established.This review will highlight current understanding and recent advances on RPL,with a special focus on the immunological and genetic etiologies,clinical diagnosis and therapeutic management.

摘要：Immune checkpoint inhibitors(ICIs)like pro-grammed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor have shown considerable efficacy in several important cancers including primary liver cancer(PLC)like hepatocellular carcinoma and cholangiocarcinoma.However,only some patients with PLC will benefit,so com-bination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important.Herein,we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark(Mk.)1.0,2.0,and 3.0.We illustrated the significance of ICI monotherapy(Mk.1.0),offering combinational approaches with traditional strategies(Mk.2.0)and additional locoregional therapy(Mk.3.0)to achieve longer survival and even meet the"No Evidence of Disease"status.We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies.Multidisci-plinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.

摘要：Genome-wide association studies(GWASs)have shown that the genetic architecture of cancers are highly polygenic and enabled researchers to identify genetic risk loci for cancers.The genetic variants associated with a cancer can be combined into a polygenic risk score(PRS),which captures part of an individual's genetic suscepti-bility to cancer.Recently,PRSs have been widely used in cancer risk prediction and are shown to be capable of identifying groups of individuals who could benefit from the knowledge of their probabilistic susceptibility to can-cer,which leads to an increased interest in understanding the potential utility of PRSs that might further refine the assessment and management of cancer risk.In this context,we provide an overview of the major discoveries from cancer GWASs.We then review the methodologies used for PRS construction,and describe steps for the development and evaluation of risk prediction models that include PRS and/or conventional risk factors.Potential utility of PRSs in cancer risk prediction,screening,and precision prevention are illustrated.Challenges and prac-tical considerations relevant to the implementation of PRSs in health care settings are discussed.

摘要：In the field of biomedical research,organoids represent a remarkable advancement that has the potential to revolutionize our approach to studying human diseases even before clinical trials.Organoids are essentially miniature 3D models of specific organs or tissues,enabling scientists to investigate the causes of diseases,test new drugs,and explore personalized medicine within a controlled laboratory setting.Over the past decade,organoid technology has made sub-stantial progress,allowing researchers to create highly detailed environments that closely mimic the human body.These organoids can be generated from various sources,including pluripotent stem cells,specialized tissue cells,and tumor tissue cells.This versatility enables scientists to replicate a wide range of diseases affecting different organ systems,effectively creating disease replicas in a laboratory dish.This exciting capability has provided us with unprece-dented insights into the progression of diseases and how we can develop improved treatments.In this paper,we will provide an overview of the progress made in utilizing organoids as preclinical models,aiding our understanding and providing a more effective approach to addressing various human diseases.

摘要：Sepsis is a complex and heterogeneous syndrome that remains a serious challenge to healthcare worldwide.Patients afflicted by severe sepsis or septic shock are customarily placed under intensive care unit(ICU)super-vision,where a multitude of apparatus is poised to produce high-granularity data.This reservoir of high-quality data forms the cornerstone for the integration of AI into clinical practice.However,existing reviews currently lack the inclusion of the latest advancements.This review examines the evolving integration of artificial intelligence(AI)in sepsis management.Applications of artificial intelligence include early detection,subtyping analysis,precise treat-ment and prognosis assessment.AI-driven early warning systems provide enhanced recognition and intervention capabilities,while profiling analyzes elucidate distinct sepsis manifestations for targeted therapy.Precision medicine harnesses the potential of artificial intelligence for pathogen identification,antibiotic selection,and fluid optimization.In conclusion,the seamless amalgamation of artificial intelligence into the domain of sepsis management heralds a transformative shift,ushering in novel prospects to elevate diagnostic precision,therapeutic efficacy,and prognostic acumen.As AI technologies develop,their impact on shaping the future of sepsis care warrants ongoing research and thoughtful implementation.

摘要：Maintaining bile acid homeostasis is essential for metabolic health.Bile acid homeostasis encompasses a complex interplay between biosynthesis,conjugation,secretion,and reabsorption.Beyond their vital role in digestion and absorption of lipid-soluble nutrients,bile acids are pivotal in systemic metabolic regulation.Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases,including obesity,type 2 diabetes melli-tus(T2DM),and metabolic dysfunction-associated steatotic liver disease(MASLD).Bile acids are essential signaling molecules that regulate many critical biological processes,including lipid metabolism,energy expenditure,insulin sensitivity,and glucose metabolism.Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms,hormonal dysregu-lation,interactions with the gut microbiota,and changes in the expression and function of bile acid transporters and receptors.This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity,T2DM,and MASLD.We aim to underscore the significance of bile acids as potential diag-nostic markers and therapeutic agents in the context of metabolic diseases,providing insights into their application in translational medicine.

摘要：Gene editing nucleases(GENs),represented by CRISPR/Cas9,have become major tools in biomedical research and offer potential cures for many human diseases.Gene editing therapy(GETx)studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9(PCSK9),apolipoprotein C3(APOC3),angiopoietin Like 3(ANGPTL3)and inducible degrader of the low-density lipoprotein receptor(IDOL)have demonstrated the benefits and advantages of GETx in managing atherosclerosis.Here we present our views on this brand new therapeutic option for cardiovascular diseases(CVD).

摘要：Our gut microbiome is constituted by trillions of microorganisms including bacteria,archaea and eukary-otic microbes.Nowadays,gut microbiome has been grad-ually recognized as a new organ system that systemically and biochemically interact with the host.Accumulating evidence suggests that the imbalanced gut microbiome contributes to the dysregulation of immune system and the disruption of cardiovascular homeostasis.Specific micro-biome profiles and altered intestinal permeability are often observed in the pathophysiology of cardiovascular diseases.Gut-derived metabolites,toxins,peptides and immune cell-derived cytokines play pivotal roles in the induction of inflammation and the pathogenesis of dysfunction of heart and vasculature.Impaired crosstalk between gut microbiome and multiple organ systems,such as gut-vascular,heart-gut,gut-liver and brain-gut axes,are associated with higher cardiovascular risks.Medications and strategies that restore healthy gut microbiome might therefore represent novel therapeutic options to lower the incidence of cardiovascular and metabolic disorders.

摘要：Advancements in genome editing enable per-manent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing has been applied and achieved significant progress in treating inherited genetic disorders that remain incurable by conventional therapy.Here,we present a review of various programmable genome editing systems with their principles,advantages,and limitations.We introduce their recent applications for treating inherited diseases in the clinic,including sickle cell disease(SCD),β-thalassemia,Leber congenital amaurosis(LCA),heterozygous familial hypercholester-olemia(HeFH),etc.We also discuss the paradigm of ex vivo and in vivo editing and highlight the promise of somatic editing and the challenge of germline editing.Finally,we propose future directions in delivery,cut-ting,and repairing to improve the scope of clinical applications.

摘要：Antibodies,as one of the most important compo-nents of host adaptive immune system,play an important role in defense of infectious disease,immune surveillance,and autoimmune disease.Due to the development of re-combinant antibody technology,antibody therapeutics become the largest and rapidly expanding drug to provide major health benefits to patients,especially for the treat-ment of cancer patients.Many antibody-based therapeutic strategies have been developed including monoclonal anti-bodies,antibody-drug conjugates,bispecific and trispecific antibodies and pro-antibodies with promising results from both clinical and pre-clinical trials.However,the response rate and side-effect still vary between patients with unde-fined mechanisms.Here,we summarized the current and future perspectives of antibody-based cancer immunother-apeutic strategies for designing next-generation drugs.

摘要：Adiponectin is an adipokine predominantly produced by fat cells,circulates and exerts insulin-sensitizing,cardioprotective and anti-inflammatory ef-fects.Dysregulation of adiponectin and/or adiponectin signaling is implicated in a number of metabolic diseases such as obesity,insulin resistance,diabetes,and cardio-vascular diseases.However,while the insulin-sensitizing and cardioprotective effects of adiponectin have been widely appreciated in the field,the obesogenic and anti-inflammatory effects of adiponectin are still of much debate.Understanding the physiological function of adi-ponectin is critical for adiponectin-based therapeutics for the treatment of metabolic diseases.

摘要：Acutely,pain serves to protect us from poten-tially harmful stimuli,however damage to the somato-sensory system can cause maladaptive changes in neurons leading to chronic pain.Although acute pain is fairly well controlled,chronic pain remains difficult to treat.Chronic pain is primarily a neuropathic condition,but studies examining the mechanisms underlying chronic pain are now looking beyond afferent nerve lesions and exploring new receptor targets,immune cells,and the role of the autonomic nervous system in contributing chronic pain conditions.The studies outlined in this review reveal how chronic pain is not only confined to alterations in the nervous system and presents findings on new treatment targets and for this debilitating disease.

摘要：This perspective discussed the available evidence on the involvement of mTOR pathway in antiphospholipid syndrome(APS),from the aspects of endothelial cells,platelets,monocytes and anti-phospholipid antibodies(PLs),which may lead to future therapeutic applications of mTOR inhibition in APS.

摘要：This review thoroughly explores the multifaceted roles of sexual hormones,emphasizing their impact beyond reproductive functions and underscoring their significant influence on cardiometabolic regulation.It analyzes the broader physiological implications of estrogen,testosterone,and progesterone,highlighting their effects on metabolic syndrome,lipid metabolism,glucose homeostasis,and car-diovascular health.Drawing from diverse molecular,clin-ical,and therapeutic studies,the paper delves into the intricate interplay between these hormones and car-diometabolic processes.By presenting a comprehensive analysis that goes beyond traditional perspectives,and recognizing sexual hormones as more than reproductive agents,the review sheds light on their broader significance in health and disease management,advocating for holistic and personalized medical approaches.

摘要：Incretins are gut-produced peptide-hormones that potentiate insulin secretion,especially after food intake.The concept of incretin was formed more than 100 years ago,even before insulin was isolated and utilized in the treatment of subjects with type 1 diabetes.The first incretin,glucose-dependent insulinotropic polypeptide(GIP),was identified during later 1960's and early 1970's;while the second one,known as glucagon-like peptide-1(GLP-1),was recognized during 1980's.Today,GLP-1-based therapeutic agents[also known as GLP-1 receptor(GLP-1R)agonists,GLP-1RAs]are among the first line drugs for type 2 diabetes.In addition to serving as incretin,extra-pancreatic functions of GLP-1RAs have been broadly recognized,including those in the liver,despite the absence of GLP-1R in hepatic tissue.The existence of insulin-independent or gut-pancreas-liver axis-independent hepatic function of GLP-1RAs explains why those therapeutic agents are effective in subjects with insulin resistance and their profound effect on lipid homeostasis.Following a brief review on the discovery of GLP-1,we reviewed literature on the exploration of hepatic function of GLP-1 and GLP-1RAs and discussed recent studies on the role of hepatic hormone fibroblast growth factor 21(FGF21)in mediating function of GLP-1RAs in animal models.This was followed by presenting our perspective views.

摘要：Chronic Mountain Sickness(CMS),characterized by increased red blood cells above average values traditionally attributed to chronic hypobaric hypoxia exposure,is being redefined in light of recent research and clinical experience.We propose a shift in perspective,viewing CMS not as a singular entity but as Poly-erythrocythemia(PEH),as the Hematocrit/Hemoglobin/Red Blood Cells(Ht/Hb/RBCs)increase constitutes a sign,not a disease reflecting a spectrum of oxygen transport alterations in multiple diseases in the chronic hypoxia envi-ronment in high-altitude populations.Drawing on over five decades of experience at the High Altitude Pulmonary and Pa-thology Institute(HAPPI-IPPA)in Bolivia,we advocate for altitude-specific blood parameter norms and emphasize the importance of correct etiological diagnosis for effective man-agement.This updated understanding not only aids in managing chronically hypoxemic patients at various altitudes but also of-fers valuable insights into global health challenges,including the recovery from COVID-19.

摘要：Post-traumatic stress disorder(PTSD)is a severe and heterogenous psychiatric disorder that was first defined as a mental disorder in 1980.Currently,the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition(DSM-5)and the International Classification of Diseases 11th Edition(ICD-11)offer the most widely accepted diagnostic guidelines for PTSD.In both diag-nostic categories,experiencing a traumatic event(TE)is the necessary criterion for diagnosing PTSD.The TEs described in the DSM-5 include actual or threatened death,serious injury,sexual violence,and other extreme stressors,either directly or indirectly.More than 70%of adults worldwide are exposed to a TE at least once in their lifetime,and approximately 10%of individuals develop PTSD after experiencing a TE.The important features of PTSD are intrusion or re-experiencing fear memories,pervasive sense of threat,active avoidance,hyperarousal symptoms,and negative alterations of cognition and mood.Individuals with PTSD have high comorbidities with other psychiatric diseases,including major depres-sive disorder,generalized anxiety disorder,and sub-stance use disorder.Multiple lines of evidence suggest that the pathophysiology of PTSD is complex,involving abnormal neural circuits,molecular mechanisms,and genetic mechanisms.A combination of both psychother-apy and pharmacotherapy is used to treat PTSD,but has limited efficacy in patients with refractory PTSD.Because of the high prevalence,heavy burden,and limited treat-ments,PTSD is a psychiatric disorder that requires urgent attention.In this review,we summarize and discuss the diagnosis,prevalence,TEs,pathophysiology,and treat-ments of PTSD and draw attention to its prevention.

摘要：Pain is a main symptom in inflammation,and inflammation induces pain via inflammatory mediators acting on nociceptive neurons.Macrophages and microglia are distinct cell types,representing immune cells and glial cells,respectively,but they share similar roles in pain regulation.Macrophages are key regulators of inflammation and pain.Macrophage polarization plays different roles in inducing and resolving pain.Notably,macrophage polarization and phago-cytosis can be induced by specialized pro-resolution mediators(SPMs).SPMs also potently inhibit inflammatory and neuro-pathic pain via immunomodulation and neuromodulation.In this review,we discuss macrophage signaling involved in pain induction and resolution,as well as in maintaining physio-logical pain.Microglia are macrophage-like cells in the central nervous system(CNS)and drive neuroinflammation and pathological pain in various inflammatory and neurological disorders.Microglia-produced inflammatory cytokines can potently regulate excitatory and inhibitory synaptic trans-mission as neuromodulators.We also highlight sex differences in macrophage and microglial signaling in inflammatory and neuropathic pain.Thus,targeting macrophage and microglial signaling in distinct locations via pharmacological approaches,including immunotherapies,and non-pharmacological ap-proaches will help to control chronic inflammation and chronic pain.

摘要：Medical device technology develops rapidly,and the life cycle of a medical device is much shorter than drugs.It is necessary to evaluate the safety and effective-ness of a medical device in a timely manner to keep up with technology flux.Bayesian methods provides an efficient approach to addressing this challenge.In this article,we review the characteristics of the Bayesian approach and some Bayesian designs that were commonly used in med-ical device regulatory setting,including Bayesian adaptive design,Bayesian diagnostic design,Bayesian multiregional design,and Bayesian label expansion study.We illustrate these designs with medical devices approved by the US Food and Drug Administration(FDA).We also review several innovative Bayesian information borrowing methods,and briefly discuss the challenges and future directions of the Bayesian application in medical device trials.Our objective is to promote the use of the Bayesian approach to accelerate the development of innovative medical devices and their accessibility to patients for effective disease diagnoses and treatments.