Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
Microglia are the macrophages that populate the brain parenchyma.Research in the past decades has identified them as both essential guardians of the brain and significant contributors to various neurological diseases....Microglia are the macrophages that populate the brain parenchyma.Research in the past decades has identified them as both essential guardians of the brain and significant contributors to various neurological diseases.A highly versatile cell type,microglia have been shown to fulfill a multitude of critical roles in the central nervous system,including facilitating neurogenesis and myelination,pruning synapses,removing debris and waste,modulating neuronal activity,supporting the blood-brain barrier,repairing tissue damage,and surveilling against microbial invasions under physiological conditions(Prinz et al.,2021;Paolicelli et al.,2022).展开更多
Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
BACKGROUND Edwardsiella tarda(E.tarda)belongs to the family Enterobacteriaceae and is generally seen to cause infections mainly in fish,but is also capable of infecting humans.Extraintestinal infections occur in patie...BACKGROUND Edwardsiella tarda(E.tarda)belongs to the family Enterobacteriaceae and is generally seen to cause infections mainly in fish,but is also capable of infecting humans.Extraintestinal infections occur in patients with certain risk factors,including immunocompromised status.We recently diagnosed a case of spontaneous bacterial peritonitis(SBP)due to E.tarda in an immuno-compromised dialysis patient.CASE SUMMARY Patient was a 55-year-old male,with a history of diabetic nephropathy being treated with hemodialysis three times a week.He was referred to our hospital due to an increased volume of ascites,and blood examination revealed increased inflammatory reaction.At our emergency department,he developed fever,disturbance of consciousness,abdominal distension,and abdomen-wide pain.In addition,a dialysis shunt was confirmed in his right forearm,and the shunt site showed no signs of inflammation.No wounds were confirmed on or in his body.A blood examination revealed increased values of white blood cells,C-reactive protein,and creatinine.Plain chest and abdominal computed tomography scanning revealed increased ascites volume.Abdominal paracentesis was performed and a Gram stain revealed Gramnegative bacillus.These findings prompted diagnosis of SBP.The patient was admitted and treated with cefmetazole,causing fever resolution and symptom improvements.Later,E.tarda was identified in ascites culture.The patient improved with decreased inflammatory response and was discharged on the 12th day of hospitalization.The antibiotic was terminated after 14 days of treatment.SBP in this case may have developed from chronic renal failure and diabetes mellitus.CONCLUSION We report the first known case of SBP due to E.tarda in an immuno-compromised dialysis patient.展开更多
Gastrointestinal tumors require personalized treatment strategies due to their heterogeneity and complexity.Multimodal artificial intelligence(AI)addresses this challenge by integrating diverse data sources-including ...Gastrointestinal tumors require personalized treatment strategies due to their heterogeneity and complexity.Multimodal artificial intelligence(AI)addresses this challenge by integrating diverse data sources-including computed tomography(CT),magnetic resonance imaging(MRI),endoscopic imaging,and genomic profiles-to enable intelligent decision-making for individualized therapy.This approach leverages AI algorithms to fuse imaging,endoscopic,and omics data,facilitating comprehensive characterization of tumor biology,prediction of treatment response,and optimization of therapeutic strategies.By combining CT and MRI for structural assessment,endoscopic data for real-time visual inspection,and genomic information for molecular profiling,multimodal AI enhances the accuracy of patient stratification and treatment personalization.The clinical implementation of this technology demonstrates potential for improving patient outcomes,advancing precision oncology,and supporting individualized care in gastrointestinal cancers.Ultimately,multimodal AI serves as a transformative tool in oncology,bridging data integration with clinical application to effectively tailor therapies.展开更多
BACKGROUND Post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP)is a prevalent and potentially serious complication in patients undergoing endoscopic retrograde cholangiopancreatography.AIM To comprehe...BACKGROUND Post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP)is a prevalent and potentially serious complication in patients undergoing endoscopic retrograde cholangiopancreatography.AIM To comprehensively assess the efficacy of indomethacin therapy in reducing PEP risk.METHODS We searched PubMed,EMBASE,Scopus,and Cochrane Library databases to identify randomized controlled trials(RCTs)that compared rectal indomethacin with a control group to prevent PEP.Duplicates were removed,and studies were included based on the established inclusion criteria.We used the Cochrane Collaboration’s tool to assess the risk of bias in the RCTs.A random-effects model was applied to produce pooled risk ratios(RRs)with 95%confidence intervals(CIs).RESULTS We included a total of 30 RCTs involving 16977 patients.Compared to the control group,rectal indomethacin showed comparable rates of overall PEP(PEP;RR=0.85,95%CI:0.69-1.04,I2=79%)with no statistically significant difference of RR in mild(RR=0.92,95%CI:0.74-1.14),moderate(RR=0.78,95%CI:0.59-1.02),or severe PEP(RR=1.12,95%CI:0.75-1.67).There was also no difference in cases of adverse events(RR=0.97,95%CI:0.69-1.35),abdominal pain(RR=1.14,95%CI:0.80-1.62),bleeding(RR=1.07,95%CI:0.70-1.63),or mortality(RR=0.86,95%CI:0.56-1.33)between the two groups.Subgroup analyses were also performed.CONCLUSION Rectal indomethacin appears to be safe and may offer benefit in selected high-risk patients,though findings should be interpreted with caution due to high heterogeneity.展开更多
Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progre...Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.展开更多
This commentary critically appraises the study by Li et al which pioneered the exploration of the triglyceride-glucose(TyG)index as a prognostic marker in hepatitis B virus-related advanced hepatocellular carcinoma pa...This commentary critically appraises the study by Li et al which pioneered the exploration of the triglyceride-glucose(TyG)index as a prognostic marker in hepatitis B virus-related advanced hepatocellular carcinoma patients undergoing combined camrelizumab and lenvatinib therapy.While we acknowledge the study’s clinical relevance in proposing an easily accessible metabolic biomarker,we delve into the mechanistic plausibility linking insulin resistance to immunotherapy response and angiogenic inhibition.We further critically examine the methodological limitations,including the retrospective design,the populationspecific TyG cut-off value,and unaddressed metabolic confounders.We highlight the imperative for future research to validate its utility across diverse etiologies and treatment settings,and to unravel the underlying immunometabolic pathways.展开更多
Clinically differentiating bipolarⅡdisorder(BD-Ⅱ)from major depressive disorder(MDD)remains a significant challenge in modern psychiatry.These two conditions share substantial clinical symptomatology,making accurate...Clinically differentiating bipolarⅡdisorder(BD-Ⅱ)from major depressive disorder(MDD)remains a significant challenge in modern psychiatry.These two conditions share substantial clinical symptomatology,making accurate diagnosis difficult in routine clinical practice.Misdiagnosis may lead to inappropriate treatment strategies,increased psychological and physical burdens,reduced quality of life,and impaired social functioning.Genetic overlap may partially explain the clinical similarities between MDD and BD-Ⅱ,and biomarkers along with neuroimaging techniques are receiving increasing attention as tools to aid in diagnosis.For example,electroencephalography has been shown to effectively distinguish between unipolar depression and bipolar depression;serum levels of glycogen synthase kinase-3 have also been investigated as a potential tool for differentiating between the two disorders.A comprehensive assessment integrating clinical characteristics,genetic basis research,and multimodal evaluations using neuroimaging and biomarkers through a multidisciplinary approach will help enhance clinicians'ability to distinguish between MDD and BD-Ⅱ.By improving diagnostic accuracy,more personalized and effective treatment strategies can be developed,ultimately improving patients'health outcomes and quality of life.展开更多
BACKGROUND Post-transplant tertiary hyperparathyroidism(PT-tHPT)is a well-recognized complication following kidney transplantation,characterized by persistent excessive secretion of parathyroid hormone(PTH)despite imp...BACKGROUND Post-transplant tertiary hyperparathyroidism(PT-tHPT)is a well-recognized complication following kidney transplantation,characterized by persistent excessive secretion of parathyroid hormone(PTH)despite improved renal function.It is potentially associated with an increased risk of cardiovascular events,renal osteodystrophy,pathologic fractures,graft loss,and mortality.AIM To evaluate the incidence,risk factors,and outcomes of PT-tHPT amongst kidney transplant recipients.METHODS A total of 887 transplant recipients who underwent transplantation between 2000 and 2020 were evaluated.Univariable and multivariable logistic regression was performed to determine the predictors of tertiary hyperparathyroidism.Graft and recipient outcomes were assessed using multivariable Cox regression.A separate multivariable Cox regression was performed to determine the effect of treatment strategies on outcomes.RESULTS PT-tHPT,defined as elevated PTH(>65 ng/L)and persistent hypercalcemia(>2.60 mmol/L),was diagnosed in 14%of recipients.Risk factors for PT-tHPT included older age[odds ratio(OR)=1.36,P<0.001],Asian ethnicity(OR=0.33,P=0.006),total ischemia time(OR=1.03,P=0.048 per hour),pre-transplant serum calcium(OR=1.38,P<0.001)per decile increase,pre-transplant PTH level(OR=1.31,P<0.001)per decile increase,longer dialysis duration(OR=1.12,P=0.002)per year,history of acute rejection(OR=2.37,P=0.012),and slope of estimated glomerular filtration rate change(OR=0.91,P=0.001).There were a 3.4-fold higher risk of death-censored graft loss and a 1.9-fold greater risk of recipient death with PT-tHPT.The three treatment strategies of conservative management,calcimimetic and parathyroidectomy did not significantly change the graft or patient outcome.CONCLUSION Pretransplant elevated calcium and PTH levels,older age and dialysis duration are associated with PT-tHPT.While PT-tHPT significantly affects graft and recipient survival,the treatment strategies did not affect survival.展开更多
BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant rec...BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.展开更多
Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genoty...Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.展开更多
Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend ...Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend against illness,and maintain homeostasis)syndrome is considered a critical syndrome in traditional Chinese medicine(TCM)and is associated with poor prognosis in heart failure(HF).This study investigates the clinical,metabolic,and transcriptomic differences between heart failure patients with and without Qi deficiency syndrome.Methods:56 heart failure patients were evaluated using a Qi deficiency syndrome scale and divided into Qi deficiency syndrome(QD)and non-Qi deficiency(non-QD)groups based on the median score.Clinical characteristics,including baseline N-terminal pro-B-type natriuretic peptide(NT-proBNP),left ventricular ejection fraction(LVEF),total diuretic use during hospitalization,and 90-day rehospitalization rates,were compared between the groups.Differentially expressed genes(DEGs)and differential metabolites were identified,followed by enrichment analyses and validation using qPCR and Western blot in AC16 cardiomyocytes.Results:QD patients exhibited significantly higher NT-proBNP levels,lower LVEF,and increased 90-day rehospitalization rates.Metabolomic profiling revealed lipid metabolism disruptions,notably in linoleic acid and phospholipid pathways.Transcriptomic analysis highlighted 17 DEGs,including CISD2,a critical mitochondrial regulator,which was downregulated in QD patients.Correlation analysis identified significant associations between DEGs(e.g.,CISD2,BPGM)and lipid metabolites such as PC(16:0/P-16:0).Functional knockdown of CISD2 in AC16 cells led to upregulation of lipid oxidation enzymes ALOX15 and CYP1A2,linking CISD2 dysfunction to lipid metabolic dysregulation.Conclusion:Qi deficiency is associated with more severe heart failure symptoms,worse prognosis,and distinct metabolic and transcriptomic profiles,particularly in lipid metabolism.CISD2 emerges as a potential therapeutic target,offering new avenues for integrating molecular insights with TCM approaches to optimize HF management.展开更多
AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induc...AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.展开更多
Silicosis is one of the most serious and prevalent occupational diseases globally,characterized by typical silicotic nodules and fibrosis.Recent studies suggest that the perinodular zone of the lung shares certain cha...Silicosis is one of the most serious and prevalent occupational diseases globally,characterized by typical silicotic nodules and fibrosis.Recent studies suggest that the perinodular zone of the lung shares certain characteristics with the nodules themselves.In this study,a silicotic rat model was established via a single intratracheal in-stillation of a 50 mg/mL silica suspension.Pulmonary anatomical and pathological examinations revealed that silica deposition induced severe alterations in both the nodular and perinodular tissues.Subsequently,pseudo-targeted metabolomics analysis revealed that abnormally elevated ornithine levels were closely associated with the progression of silicosis,from normal to perinodular and finally to nodular tissues.Immunofluorescent stain-ing demonstrated that,in addition to M2 macrophages,silica exposure increased the protein levels of ARG1 in epithelial cells,a finding further confirmed by in vitro experiments using A549 and BEAS-2B cells.Moreover,accumulated ornithine induced epithelial-mesenchymal transition in vitro,increased extracellular matrix expres-sion in NIH 3T3 fibroblasts,and enhanced TGF-β1 levels in RAW264.7 cells.Co-exposure to ornithine and silica significantly induced the aberrant expression of fibrosis-associated proteins compared to silica exposure alone,characterized by increased levels of FN and𝛼-SMA,as well as decreased E-cad expression.These findings sug-gest that silica exposure up-regulates ARG1 in various cells,leading to ornithine accumulation,which in turn accelerates the progression of fibrosis.展开更多
Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesio...Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.展开更多
BACKGROUND Medial dished(MD)liner designs for cruciate-retaining(CR)total knee arthroplasty(TKA)are a relatively novel development.MD tibial inserts have a more constraining medial side,which allows for more similar k...BACKGROUND Medial dished(MD)liner designs for cruciate-retaining(CR)total knee arthroplasty(TKA)are a relatively novel development.MD tibial inserts have a more constraining medial side,which allows for more similar kinematics and function to a native knee.AIM To evaluate the clinical results and patient-reported outcomes after CR TKA procedures utilizing a kinematically designed medial dish system.METHODS A multicenter,retrospective cohort review of 139 primary elective TKAs utilizing a kinematically designed CR Knee System(JOURNEY™II CR MD;Smith and Nephew,Memphis,TN,United States)at three different institutions with a minimum of two years of follow-up.Demographic information,clinical outcomes,and patient-reported outcome measures were collected and analyzed.RESULTS With up to 3.7 years from surgery,overall implant survivorship was 98.6%.There were significant postoperative increases in the average Knee Injury and Osteoarthritis Outcome Score for Joint Replacement scores(17.4 at 6 months,26.1 points at two years or more,P<0.001).CONCLUSION The combination of high implant survivorship and substantial improvements in patient-reported outcome measures suggests that the medial dish tibial insert represents a safe and effective option within TKA.Additional investigation is necessary to evaluate the long-term survivorship of this design.展开更多
Background:Diabetic foot,a severe complication of diabetes,is characterized by chronic refractory wounds.Sanhuang Oil,a topical herbal formula,demonstrates significant therapeutic effects including antibacterial,anti-...Background:Diabetic foot,a severe complication of diabetes,is characterized by chronic refractory wounds.Sanhuang Oil,a topical herbal formula,demonstrates significant therapeutic effects including antibacterial,anti-inflammatory,and immunomodulatory activities.However,its active constituents and mechanisms of action against diabetic foot remain to be elucidated.Methods:In this study,the chemical constituents of Sanhuang Oil were identified using UPLC-QE-Orbitrap-MS.Subsequently,the mechanism by which Sanhuang Oil promotes diabetic foot ulcer healing was predicted by integrating network pharmacology and molecular docking.Additionally,diabetic mouse model was established in ICR mice using a combination of a high-fat diet(HFD)and streptozotocin(STZ)chemical induction.A full-thickness skin defect was created on the dorsum of the mice.Wound healing and the healing rate were observed following Sanhuang Oil intervention.The mechanism underlying Sanhuang Oil’s promotion of diabetic ulcer healing was further investigated using transcriptomics and histopathological examination(H&E staining).Results:A total of 97 active ingredients were identified from Sanhuang Oil.Network pharmacology analysis predicted 543 common targets,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis identified 203 relevant pathways.Molecular docking further confirmed high binding affinity(binding energy≤−5.0 kcal/mol)between specific active components in Sanhuang Oil(e.g.,coptisine,phellodendrine,baicalein)and key targets associated with diabetic foot ulcers(e.g.,EGFR,AKT1,STAT3).In vivo experimental results demonstrated that the wound healing rate was significantly higher in Sanhuang Oil-treated groups compared to the model group(P<0.001).HE staining revealed that the high-dose Sanhuang Oil group exhibited more pronounced epithelial tissue coverage over the wound,reduced inflammatory cell infiltration,and increased collagen deposition and fibroblast proliferation.transcriptomic analysis identified Pdk4,Ttn,Csrp3,Actn2,Myoz2,Tnnc2,Myod1,Myog,Myot,and Myf6 as key regulatory proteins involved in promoting wound healing.Conclusion:Sanhuang Oil promotes wound healing in diabetic ulcer mice,potentially by mitigating inflammation and regulating key targets such as Pdk4 to enhance fibroblast function.These findings provide novel insights into the multi-target,multi-pathway mechanism of Sanhuang Oil for treating diabetic foot ulcers.展开更多
Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving resear...Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.展开更多
BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in comp...BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.展开更多
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金funded by NIH grants HL154720-03S1, AG057587, AG074283, DK122708-03S1, BrightFocus ADR A20183775Brown Foundation 2020 Healthy Aging Initiative (to WC)
文摘Microglia are the macrophages that populate the brain parenchyma.Research in the past decades has identified them as both essential guardians of the brain and significant contributors to various neurological diseases.A highly versatile cell type,microglia have been shown to fulfill a multitude of critical roles in the central nervous system,including facilitating neurogenesis and myelination,pruning synapses,removing debris and waste,modulating neuronal activity,supporting the blood-brain barrier,repairing tissue damage,and surveilling against microbial invasions under physiological conditions(Prinz et al.,2021;Paolicelli et al.,2022).
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
文摘BACKGROUND Edwardsiella tarda(E.tarda)belongs to the family Enterobacteriaceae and is generally seen to cause infections mainly in fish,but is also capable of infecting humans.Extraintestinal infections occur in patients with certain risk factors,including immunocompromised status.We recently diagnosed a case of spontaneous bacterial peritonitis(SBP)due to E.tarda in an immuno-compromised dialysis patient.CASE SUMMARY Patient was a 55-year-old male,with a history of diabetic nephropathy being treated with hemodialysis three times a week.He was referred to our hospital due to an increased volume of ascites,and blood examination revealed increased inflammatory reaction.At our emergency department,he developed fever,disturbance of consciousness,abdominal distension,and abdomen-wide pain.In addition,a dialysis shunt was confirmed in his right forearm,and the shunt site showed no signs of inflammation.No wounds were confirmed on or in his body.A blood examination revealed increased values of white blood cells,C-reactive protein,and creatinine.Plain chest and abdominal computed tomography scanning revealed increased ascites volume.Abdominal paracentesis was performed and a Gram stain revealed Gramnegative bacillus.These findings prompted diagnosis of SBP.The patient was admitted and treated with cefmetazole,causing fever resolution and symptom improvements.Later,E.tarda was identified in ascites culture.The patient improved with decreased inflammatory response and was discharged on the 12th day of hospitalization.The antibiotic was terminated after 14 days of treatment.SBP in this case may have developed from chronic renal failure and diabetes mellitus.CONCLUSION We report the first known case of SBP due to E.tarda in an immuno-compromised dialysis patient.
基金Supported by Xuhui District Health Commission,No.SHXH202214.
文摘Gastrointestinal tumors require personalized treatment strategies due to their heterogeneity and complexity.Multimodal artificial intelligence(AI)addresses this challenge by integrating diverse data sources-including computed tomography(CT),magnetic resonance imaging(MRI),endoscopic imaging,and genomic profiles-to enable intelligent decision-making for individualized therapy.This approach leverages AI algorithms to fuse imaging,endoscopic,and omics data,facilitating comprehensive characterization of tumor biology,prediction of treatment response,and optimization of therapeutic strategies.By combining CT and MRI for structural assessment,endoscopic data for real-time visual inspection,and genomic information for molecular profiling,multimodal AI enhances the accuracy of patient stratification and treatment personalization.The clinical implementation of this technology demonstrates potential for improving patient outcomes,advancing precision oncology,and supporting individualized care in gastrointestinal cancers.Ultimately,multimodal AI serves as a transformative tool in oncology,bridging data integration with clinical application to effectively tailor therapies.
文摘BACKGROUND Post-endoscopic retrograde cholangiopancreatography pancreatitis(PEP)is a prevalent and potentially serious complication in patients undergoing endoscopic retrograde cholangiopancreatography.AIM To comprehensively assess the efficacy of indomethacin therapy in reducing PEP risk.METHODS We searched PubMed,EMBASE,Scopus,and Cochrane Library databases to identify randomized controlled trials(RCTs)that compared rectal indomethacin with a control group to prevent PEP.Duplicates were removed,and studies were included based on the established inclusion criteria.We used the Cochrane Collaboration’s tool to assess the risk of bias in the RCTs.A random-effects model was applied to produce pooled risk ratios(RRs)with 95%confidence intervals(CIs).RESULTS We included a total of 30 RCTs involving 16977 patients.Compared to the control group,rectal indomethacin showed comparable rates of overall PEP(PEP;RR=0.85,95%CI:0.69-1.04,I2=79%)with no statistically significant difference of RR in mild(RR=0.92,95%CI:0.74-1.14),moderate(RR=0.78,95%CI:0.59-1.02),or severe PEP(RR=1.12,95%CI:0.75-1.67).There was also no difference in cases of adverse events(RR=0.97,95%CI:0.69-1.35),abdominal pain(RR=1.14,95%CI:0.80-1.62),bleeding(RR=1.07,95%CI:0.70-1.63),or mortality(RR=0.86,95%CI:0.56-1.33)between the two groups.Subgroup analyses were also performed.CONCLUSION Rectal indomethacin appears to be safe and may offer benefit in selected high-risk patients,though findings should be interpreted with caution due to high heterogeneity.
文摘Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.
文摘This commentary critically appraises the study by Li et al which pioneered the exploration of the triglyceride-glucose(TyG)index as a prognostic marker in hepatitis B virus-related advanced hepatocellular carcinoma patients undergoing combined camrelizumab and lenvatinib therapy.While we acknowledge the study’s clinical relevance in proposing an easily accessible metabolic biomarker,we delve into the mechanistic plausibility linking insulin resistance to immunotherapy response and angiogenic inhibition.We further critically examine the methodological limitations,including the retrospective design,the populationspecific TyG cut-off value,and unaddressed metabolic confounders.We highlight the imperative for future research to validate its utility across diverse etiologies and treatment settings,and to unravel the underlying immunometabolic pathways.
文摘Clinically differentiating bipolarⅡdisorder(BD-Ⅱ)from major depressive disorder(MDD)remains a significant challenge in modern psychiatry.These two conditions share substantial clinical symptomatology,making accurate diagnosis difficult in routine clinical practice.Misdiagnosis may lead to inappropriate treatment strategies,increased psychological and physical burdens,reduced quality of life,and impaired social functioning.Genetic overlap may partially explain the clinical similarities between MDD and BD-Ⅱ,and biomarkers along with neuroimaging techniques are receiving increasing attention as tools to aid in diagnosis.For example,electroencephalography has been shown to effectively distinguish between unipolar depression and bipolar depression;serum levels of glycogen synthase kinase-3 have also been investigated as a potential tool for differentiating between the two disorders.A comprehensive assessment integrating clinical characteristics,genetic basis research,and multimodal evaluations using neuroimaging and biomarkers through a multidisciplinary approach will help enhance clinicians'ability to distinguish between MDD and BD-Ⅱ.By improving diagnostic accuracy,more personalized and effective treatment strategies can be developed,ultimately improving patients'health outcomes and quality of life.
文摘BACKGROUND Post-transplant tertiary hyperparathyroidism(PT-tHPT)is a well-recognized complication following kidney transplantation,characterized by persistent excessive secretion of parathyroid hormone(PTH)despite improved renal function.It is potentially associated with an increased risk of cardiovascular events,renal osteodystrophy,pathologic fractures,graft loss,and mortality.AIM To evaluate the incidence,risk factors,and outcomes of PT-tHPT amongst kidney transplant recipients.METHODS A total of 887 transplant recipients who underwent transplantation between 2000 and 2020 were evaluated.Univariable and multivariable logistic regression was performed to determine the predictors of tertiary hyperparathyroidism.Graft and recipient outcomes were assessed using multivariable Cox regression.A separate multivariable Cox regression was performed to determine the effect of treatment strategies on outcomes.RESULTS PT-tHPT,defined as elevated PTH(>65 ng/L)and persistent hypercalcemia(>2.60 mmol/L),was diagnosed in 14%of recipients.Risk factors for PT-tHPT included older age[odds ratio(OR)=1.36,P<0.001],Asian ethnicity(OR=0.33,P=0.006),total ischemia time(OR=1.03,P=0.048 per hour),pre-transplant serum calcium(OR=1.38,P<0.001)per decile increase,pre-transplant PTH level(OR=1.31,P<0.001)per decile increase,longer dialysis duration(OR=1.12,P=0.002)per year,history of acute rejection(OR=2.37,P=0.012),and slope of estimated glomerular filtration rate change(OR=0.91,P=0.001).There were a 3.4-fold higher risk of death-censored graft loss and a 1.9-fold greater risk of recipient death with PT-tHPT.The three treatment strategies of conservative management,calcimimetic and parathyroidectomy did not significantly change the graft or patient outcome.CONCLUSION Pretransplant elevated calcium and PTH levels,older age and dialysis duration are associated with PT-tHPT.While PT-tHPT significantly affects graft and recipient survival,the treatment strategies did not affect survival.
文摘BACKGROUND The use of induction immunosuppression agents has improved kidney transplant outcomes,but selecting the optimal agent remains a point of debate.AIM To compare the long-term outcomes of kidney transplant recipients receiving alemtuzumab vs basiliximab induction,focusing on graft function,acute rejection,infection,malignancy,post-transplant glomerulonephritis,and survival,using a propensity score matched cohort design.METHODS Kidney transplant recipients who received alemtuzumab or basiliximab induction from 2014 to 2019 across two nephrology centres in Northwest England were evaluated.Propensity score matching at a 1:1.5 ratio ensured comparability between cohorts.Baseline characteristics,immunosuppression regimens,and outcomes were analyzed.Linear,binary logistic and Cox proportional hazard regression models.RESULTS A total of 436 recipients were included,with a median follow-up of 5.2 years.The matched cohort(n=262)had a mean age of 51.1±13.5 years;39%were female and 92%were white.There was no significant difference in the cumulative incidence of acute rejection[odds ratio(OR)=2.10;95%CI:0.9-4.9;P=0.110].Compared with basiliximab,alemtuzumab was associated with lower estimated glomerular filtration rate at 12 months(-6.6 mL/minute/1.73 m2;95%CI:-10.5 to-2.7;P<0.001)and higher risks of cytomegalovirus viremia(OR=3.2;95%CI:1.6-6.5;P<0.001),BK viremia(OR=2.4;95%CI:1.1-5.5;P=0.02),post-transplant malignancy(OR=6.2;95%CI:1.6-29.9;P=0.013),and death-censored graft loss(hazard ratio=3.6;95%CI:1.2-11.4;P=0.03).No significant differences were observed in post-transplant glomerulonephritis or recipient mortality.CONCLUSION In this propensity score-matched analysis,alemtuzumab induction was associated with lower graft function at 12 months and higher risks of viral infection,post-transplant malignancy,and graft loss compared with basiliximab.These findings highlight the need for further studies to confirm the long-term safety and effectiveness of alemtuzumab in kidney transplantation.
基金supported by the National Natural Science Foundation of China(Grant No.82220108002 to F.C.and Grant No.82273737 to R.Z.)the U.S.National Institutes of Health(Grant Nos.CA209414,HL060710,and ES000002 to D.C.C.,Grant Nos.CA209414 and CA249096 to Y.L.)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.
文摘Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.
基金supported by the Sanming Project of Medicine in Shenzhen[SZZYSM202206001]National Natural Science Foundation of China[82004320 and 82374383]+3 种基金Natural Science Foundation of Guangdong Province of China[2022A1515011710 and 2022A1515010679]Shenzhen Science and Technology Innovation Committee[JCYJ20220530141407017 and JCYJ20240813153619026]2024 High-quality Development Research Project of Shenzhen Bao’an Public Hospital[YNXM2024078]and Shenzhen Bao’an Chinese Medicine Hospital Research Program[BAZYY20220702].
文摘Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend against illness,and maintain homeostasis)syndrome is considered a critical syndrome in traditional Chinese medicine(TCM)and is associated with poor prognosis in heart failure(HF).This study investigates the clinical,metabolic,and transcriptomic differences between heart failure patients with and without Qi deficiency syndrome.Methods:56 heart failure patients were evaluated using a Qi deficiency syndrome scale and divided into Qi deficiency syndrome(QD)and non-Qi deficiency(non-QD)groups based on the median score.Clinical characteristics,including baseline N-terminal pro-B-type natriuretic peptide(NT-proBNP),left ventricular ejection fraction(LVEF),total diuretic use during hospitalization,and 90-day rehospitalization rates,were compared between the groups.Differentially expressed genes(DEGs)and differential metabolites were identified,followed by enrichment analyses and validation using qPCR and Western blot in AC16 cardiomyocytes.Results:QD patients exhibited significantly higher NT-proBNP levels,lower LVEF,and increased 90-day rehospitalization rates.Metabolomic profiling revealed lipid metabolism disruptions,notably in linoleic acid and phospholipid pathways.Transcriptomic analysis highlighted 17 DEGs,including CISD2,a critical mitochondrial regulator,which was downregulated in QD patients.Correlation analysis identified significant associations between DEGs(e.g.,CISD2,BPGM)and lipid metabolites such as PC(16:0/P-16:0).Functional knockdown of CISD2 in AC16 cells led to upregulation of lipid oxidation enzymes ALOX15 and CYP1A2,linking CISD2 dysfunction to lipid metabolic dysregulation.Conclusion:Qi deficiency is associated with more severe heart failure symptoms,worse prognosis,and distinct metabolic and transcriptomic profiles,particularly in lipid metabolism.CISD2 emerges as a potential therapeutic target,offering new avenues for integrating molecular insights with TCM approaches to optimize HF management.
基金Supported by the National Natural Science Fundation of China(No.82101107No.81471575).
文摘AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.
基金supported by the National Natural Science Foundation of China(No.81973466)the National Administration of Traditional Chinese Medicine Youth Qihuang Scholars Support Project,and the Program of Graduate Innovation Research in Shanxi Province(No.2023KY019).
文摘Silicosis is one of the most serious and prevalent occupational diseases globally,characterized by typical silicotic nodules and fibrosis.Recent studies suggest that the perinodular zone of the lung shares certain characteristics with the nodules themselves.In this study,a silicotic rat model was established via a single intratracheal in-stillation of a 50 mg/mL silica suspension.Pulmonary anatomical and pathological examinations revealed that silica deposition induced severe alterations in both the nodular and perinodular tissues.Subsequently,pseudo-targeted metabolomics analysis revealed that abnormally elevated ornithine levels were closely associated with the progression of silicosis,from normal to perinodular and finally to nodular tissues.Immunofluorescent stain-ing demonstrated that,in addition to M2 macrophages,silica exposure increased the protein levels of ARG1 in epithelial cells,a finding further confirmed by in vitro experiments using A549 and BEAS-2B cells.Moreover,accumulated ornithine induced epithelial-mesenchymal transition in vitro,increased extracellular matrix expres-sion in NIH 3T3 fibroblasts,and enhanced TGF-β1 levels in RAW264.7 cells.Co-exposure to ornithine and silica significantly induced the aberrant expression of fibrosis-associated proteins compared to silica exposure alone,characterized by increased levels of FN and𝛼-SMA,as well as decreased E-cad expression.These findings sug-gest that silica exposure up-regulates ARG1 in various cells,leading to ornithine accumulation,which in turn accelerates the progression of fibrosis.
基金supported by the Qingdao Medical Health Research Project,No.2023-WJZD212(to XX)。
文摘Recent evidence suggests that ferroptosis plays a crucial role in the occurrence and development of white matter lesions.However,the mechanisms and regulatory pathways involved in ferroptosis within white matter lesions remain unclear.Long non-coding RNAs(lnc RNAs)have been shown to influence the occurrence and development of these lesions.We previously identified lnc_011797 as a biomarker of white matter lesions by high-throughput sequencing.To investigate the mechanism by which lnc_011797 regulates white matter lesions,we established subjected human umbilical vein endothelial cells to oxygenglucose deprivation to simulate conditions associated with white matter lesions.The cells were transfected with lnc_011797 overexpression or knockdown lentiviruses.Our findings indicate that lnc_011797 promoted ferroptosis in these cells,leading to the formation of white matter lesions.Furthermore,lnc_011797 functioned as a competitive endogenous RNA(ce RNA)for mi R-193b-3p,thereby regulating the expression of WNK1 and its downstream ferroptosis-related proteins.To validate the role of lnc_011797 in vivo,we established a mouse model of white matter lesions through bilateral common carotid artery stenosis.The results from this model confirmed that lnc_011797 regulates ferroptosis via WNK1 and promotes the development of white matter lesions.These findings clarify the mechanism by which lnc RNAs regulate white matter lesions,providing a new target for the diagnosis and treatment of white matter lesions.
文摘BACKGROUND Medial dished(MD)liner designs for cruciate-retaining(CR)total knee arthroplasty(TKA)are a relatively novel development.MD tibial inserts have a more constraining medial side,which allows for more similar kinematics and function to a native knee.AIM To evaluate the clinical results and patient-reported outcomes after CR TKA procedures utilizing a kinematically designed medial dish system.METHODS A multicenter,retrospective cohort review of 139 primary elective TKAs utilizing a kinematically designed CR Knee System(JOURNEY™II CR MD;Smith and Nephew,Memphis,TN,United States)at three different institutions with a minimum of two years of follow-up.Demographic information,clinical outcomes,and patient-reported outcome measures were collected and analyzed.RESULTS With up to 3.7 years from surgery,overall implant survivorship was 98.6%.There were significant postoperative increases in the average Knee Injury and Osteoarthritis Outcome Score for Joint Replacement scores(17.4 at 6 months,26.1 points at two years or more,P<0.001).CONCLUSION The combination of high implant survivorship and substantial improvements in patient-reported outcome measures suggests that the medial dish tibial insert represents a safe and effective option within TKA.Additional investigation is necessary to evaluate the long-term survivorship of this design.
基金supported by the Natural Science Foundation of Hubei Provincial Department of Education(D20232101)Shandong Second Medical University 2024 Affiliated Hospital(Teaching Hospital)Scientific Research Development Fund Project(2024FYQ026)+3 种基金the innovative Research Programme of Xiangyang No.1 People’s Hospital(XYY2023ZY01)Faculty Development Grants of Xiangyang No.1 People’s Hospital Affiliated to Hubei University of Medicine(XYY2023D05)Joint supported by Hubei Provincial Natural Science Foundation and Xiangyang of China(2025AFD091)Traditional Chinese Medicine Scientific Research Project of Hubei Provincial Administration of Traditional Chinese Medicine(ZY2025D019).
文摘Background:Diabetic foot,a severe complication of diabetes,is characterized by chronic refractory wounds.Sanhuang Oil,a topical herbal formula,demonstrates significant therapeutic effects including antibacterial,anti-inflammatory,and immunomodulatory activities.However,its active constituents and mechanisms of action against diabetic foot remain to be elucidated.Methods:In this study,the chemical constituents of Sanhuang Oil were identified using UPLC-QE-Orbitrap-MS.Subsequently,the mechanism by which Sanhuang Oil promotes diabetic foot ulcer healing was predicted by integrating network pharmacology and molecular docking.Additionally,diabetic mouse model was established in ICR mice using a combination of a high-fat diet(HFD)and streptozotocin(STZ)chemical induction.A full-thickness skin defect was created on the dorsum of the mice.Wound healing and the healing rate were observed following Sanhuang Oil intervention.The mechanism underlying Sanhuang Oil’s promotion of diabetic ulcer healing was further investigated using transcriptomics and histopathological examination(H&E staining).Results:A total of 97 active ingredients were identified from Sanhuang Oil.Network pharmacology analysis predicted 543 common targets,and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis identified 203 relevant pathways.Molecular docking further confirmed high binding affinity(binding energy≤−5.0 kcal/mol)between specific active components in Sanhuang Oil(e.g.,coptisine,phellodendrine,baicalein)and key targets associated with diabetic foot ulcers(e.g.,EGFR,AKT1,STAT3).In vivo experimental results demonstrated that the wound healing rate was significantly higher in Sanhuang Oil-treated groups compared to the model group(P<0.001).HE staining revealed that the high-dose Sanhuang Oil group exhibited more pronounced epithelial tissue coverage over the wound,reduced inflammatory cell infiltration,and increased collagen deposition and fibroblast proliferation.transcriptomic analysis identified Pdk4,Ttn,Csrp3,Actn2,Myoz2,Tnnc2,Myod1,Myog,Myot,and Myf6 as key regulatory proteins involved in promoting wound healing.Conclusion:Sanhuang Oil promotes wound healing in diabetic ulcer mice,potentially by mitigating inflammation and regulating key targets such as Pdk4 to enhance fibroblast function.These findings provide novel insights into the multi-target,multi-pathway mechanism of Sanhuang Oil for treating diabetic foot ulcers.
基金supported by Key Research and Development Plan of Hunan Province(2024DK2006)the Fundamental Research Funds for the Central Universities of Central South University(1053320221769)+2 种基金Hunan Provincial Respiratory Disease Rehabilitation and Nursing Engineering Research Center Innovation Capacity Building Project(No.202012)the Zhangjiajie Science and Technology Development Key Special Project(No.202304)the National Key Clinical Specialty Major Scientific Research Project(No.20230382).
文摘Background:Glioblastoma(GBM)prognosis has seen little improvement over the past two decades.While immunotherapy has revolutionized cancer treatment,its impact on GBM remains limited.To characterize the evolving research landscape and identify future directions in GBM immunotherapy,we conducted a comprehensive bibliometric review.Methods:All literature related to immunotherapy in GBM from 1999 to 2024 was collected from the Web of Science Core Collection.CtieSpace and VOSviewer were used to conduct bibliometric analysis and visualize the data.Results:Bibliometric analysis identified 5038 publications authored by 23,335 researchers from 4699 institutions across 96 countries/regions,published in 945 journals.The United States produced the highest number of publications,while Switzerland achieved the highest average citation rate.Duke University led in institutional output and citations.John H Sampson was the most productive author,and Roger Stupp was the most cited.Frontiers in Immunology published the most papers,while Clinical Cancer Research was the most cited journal.Research focus centered on adoptive T cell therapy,particularly chimeric antigen receptor(CAR)-T cells with 572 dedicated publications.Within CAR-T research for GBM,the University of Pennsylvania was the leading institution,Frontiers in Immunology the predominant journal,and Christine E Brown(City of Hope National Medical Center)was the most prolific and cited author.Conclusions:There has been a growing interest in GBM immunotherapy over past decades.The United States is the dominant contributor.CAR-T therapy represents the primary research focus.Emerging strategies like chimeric antigen receptor-modified natural killer(CAR-NK)cells,chimeric antigen receptor-engineered macrophages(CAR-M),and cytomegalovirus-specific T cell receptor(CMV-TCR)T cells are gaining prominence,aiming to address limitations in antigen recognition inherent to CAR-T therapy for GBM.
文摘BACKGROUND Complement-mediated thrombotic microangiopathy(TMA)is a rare endothelial injury syndrome caused by dysregulated activation of the alternative complement pathway,often linked to genetic abnormalities in complement factor H(CFH),complement factor I,or complement factor H-related(CFHR)proteins.Both renal transplantation and pregnancy are independent triggers for recurrence.This case highlights a genetically high-risk patient who achieved a successful term pregnancy after renal transplantation without complement inhibition,emphasizing individualized risk stratification,close surveillance,and multidisciplinary management for favourable maternal and graft outcomes.CASE SUMMARY A 32-year-old woman with end-stage renal disease secondary to genetically confirmed complement-mediated TMA—homozygous CFH exon 17 deletion and CFHR3-CFHR1 duplication—was maintained on dialysis for 2.5 years before undergoing a successful live-donor kidney transplant from her mother.Post-transplant immunosuppression included tacrolimus,mycophenolate mofetil,and prednisolone,later modified to azathioprine during pregnancy planning.One-year post-transplant,she conceived spontaneously.Pregnancy was complicated by transient gestational hypertension,controlled with nifedipine,labetalol,and amlodipine.Proteinuria remained<150 mg/day;white blood cell counts 5.8-7.2×109/L without cytopenia.Serum creatinine ranged 0.9-1.1 mg/dL,and tacrolimus trough levels 5-7 ng/mL.At 36 weeks,she delivered a healthy 3 kg infant by elective caesarean section.Postpartum follow-up at three months confirmed stable maternal and graft function.CONCLUSION High-risk complement-mediated TMA patients can achieve successful pregnancy post-transplant through individualized care without mandatory complement blockade.
