BACKGROUND:Steroid-induced osteonecrosis of the femoral head(SANFH)is a severe orthopedic disease characterized by interruption of the blood supply to the femoral head and necrosis of subchondral bone,leading to joint dysfunction.Long-term use of glucocorticoids is the main cause of SANFH,and its pathogenesis involves multiple factors,including intravascular coagulation and osteocyte apoptosis.Vascular endothelial growth factor A(VEGF-A),as a key angiogenic factor,has potential value in the treatment of SANFH.OBJECTIVE:To summarize the mechanisms of action of VEGF-A in SANFH,including its progress in promoting angiogenesis,anti-apoptosis,and lipid metabolism regulation,and to discuss the prospects for clinical application of VEGF-A targeted therapy.METHODS:Literature related to VEGF-A targeted regulation of angiogenesis in the treatment of SANFH was identified through searches of PubMed,Web of Science,CNKI,and WanFang databases from database inception to November 2024.After quality assessment,71 articles were selected,data were extracted by independent researchers,and disagreements were resolved through group discussions.RESULTS AND CONCLUSION:(1)VEGF-A binds to its receptors VEGFR-1 and VEGFR-2,activating downstream signaling pathways that promote the proliferation,migration,and angiogenesis of endothelial cells.Therefore,it can promote the formation of collateral circulation and improve blood supply to the area of bone necrosis.(2)Reduced expression of VEGF-A may lead to a decrease in the number of blood vessels within bone tissue,exacerbating the ischemic state of the femoral head.Furthermore,VEGF-A has anti-apoptotic effects and reduce apoptosis in osteocytes and bone marrow cells,thus protecting bone tissue.(3)The role of VEGF-A in regulating lipid metabolism and inflammatory responses,as well as promoting the osteogenic differentiation of bone marrow mesenchymal stem cells,provides a new perspective for the treatment of SANFH.(4)The development of VEGF-A protein delivery systems,such as lipid nanoparticles and exosome-based delivery systems,offers new possibilities for the clinical application of VEGF-A.(5)The research progress of VEGF-A in SANFH treatment has laid a solid foundation for the development of new treatment strategies and has opened up new avenues for future research directions and clinical applications.(6)With further clarification of the mechanisms of action of VEGF-A and continuous advancements in delivery technologies,more effective treatments will be provided for SANFH patients,improving their prognosis.

BACKGROUND:The pathogenesis of steroid-induced osteonecrosis of the femoral head is complex,involving vascular endothelial injury,osteocyte apoptosis,inflammatory responses,and bone metabolism disorders.MicroRNAs(miRNAs),as key regulators of gene expression,play an important role in steroid-induced osteonecrosis of the femoral head.OBJECTIVE:To comprehensively analyze the regulatory role of miRNAs in steroid-induced osteonecrosis of the femoral head and to evaluate their potential as biomarkers and therapeutic tools.METHODS:Relevant literature was retrieved from PubMed,Web of Science,CNKI,and WanFang databases using specific keywords,and articles were selected based on the inclusion and exclusion criteria.By reading titles,abstracts,or full texts,articles with poor relevance or repetitive content were excluded,and 76 articles were finally included for analysis.RESULTS AND CONCLUSION:miRNAs regulate gene expression by binding to the 3'untranslated region of target mRNAs,affecting cell differentiation,proliferation,apoptosis,and stress responses.Specific miRNAs such as miR-33-5p,miR-99a,miR-106b-5p,miR-155,miR-146a,and miR-21 play a central regulatory role in vascular injury,inflammatory responses,osteocyte differentiation,and apoptosis in steroid-induced osteonecrosis of the femoral head.Additionally,the expression patterns of miRNAs are closely related to the pathogenesis of steroid-induced osteonecrosis of the femoral head,showing potential as biomarkers.Although miRNAs shows great potential as biomarkers in therapeutic strategies,the current limitation of sample size and lack of multi-population validation restrict the universality and reliability of the results.Moreover,the efficacy and safety of miRNA therapeutic strategies(including off-target effects and delivery issues)remain major challenges in realizing clinical applications.

BACKGROUND:Steroid-induced osteonecrosis of the femoral head(SANFH)is a severe orthopedic disease characterized by interruption of the blood supply to the femoral head and necrosis of subchondral bone,leading to joint dysfunction.Long-term use of glucocorticoids is the main cause of SANFH,and its pathogenesis involves multiple factors,including intravascular coagulation and osteocyte apoptosis.Vascular endothelial growth factor A(VEGF-A),as a key angiogenic factor,has potential value in the treatment of SANFH.OBJECTIVE:To summarize the mechanisms of action of VEGF-A in SANFH,including its progress in promoting angiogenesis,anti-apoptosis,and lipid metabolism regulation,and to discuss the prospects for clinical application of VEGF-A targeted therapy.METHODS:Literature related to VEGF-A targeted regulation of angiogenesis in the treatment of SANFH was identified through searches of PubMed,Web of Science,CNKI,and WanFang databases from database inception to November 2024.After quality assessment,71 articles were selected,data were extracted by independent researchers,and disagreements were resolved through group discussions.RESULTS AND CONCLUSION:(1)VEGF-A binds to its receptors VEGFR-1 and VEGFR-2,activating downstream signaling pathways that promote the proliferation,migration,and angiogenesis of endothelial cells.Therefore,it can promote the formation of collateral circulation and improve blood supply to the area of bone necrosis.(2)Reduced expression of VEGF-A may lead to a decrease in the number of blood vessels within bone tissue,exacerbating the ischemic state of the femoral head.Furthermore,VEGF-A has anti-apoptotic effects and reduce apoptosis in osteocytes and bone marrow cells,thus protecting bone tissue.(3)The role of VEGF-A in regulating lipid metabolism and inflammatory responses,as well as promoting the osteogenic differentiation of bone marrow mesenchymal stem cells,provides a new perspective for the treatment of SANFH.(4)The development of VEGF-A protein delivery systems,such as lipid nanoparticles and exosome-based delivery systems,offers new possibilities for the clinical application of VEGF-A.(5)The research progress of VEGF-A in SANFH treatment has laid a solid foundation for the development of new treatment strategies and has opened up new avenues for future research directions and clinical applications.(6)With further clarification of the mechanisms of action of VEGF-A and continuous advancements in delivery technologies,more effective treatments will be provided for SANFH patients,improving their prognosis.

BACKGROUND:The pathogenesis of steroid-induced osteonecrosis of the femoral head is complex,involving vascular endothelial injury,osteocyte apoptosis,inflammatory responses,and bone metabolism disorders.MicroRNAs(miRNAs),as key regulators of gene expression,play an important role in steroid-induced osteonecrosis of the femoral head.OBJECTIVE:To comprehensively analyze the regulatory role of miRNAs in steroid-induced osteonecrosis of the femoral head and to evaluate their potential as biomarkers and therapeutic tools.METHODS:Relevant literature was retrieved from PubMed,Web of Science,CNKI,and WanFang databases using specific keywords,and articles were selected based on the inclusion and exclusion criteria.By reading titles,abstracts,or full texts,articles with poor relevance or repetitive content were excluded,and 76 articles were finally included for analysis.RESULTS AND CONCLUSION:miRNAs regulate gene expression by binding to the 3'untranslated region of target mRNAs,affecting cell differentiation,proliferation,apoptosis,and stress responses.Specific miRNAs such as miR-33-5p,miR-99a,miR-106b-5p,miR-155,miR-146a,and miR-21 play a central regulatory role in vascular injury,inflammatory responses,osteocyte differentiation,and apoptosis in steroid-induced osteonecrosis of the femoral head.Additionally,the expression patterns of miRNAs are closely related to the pathogenesis of steroid-induced osteonecrosis of the femoral head,showing potential as biomarkers.Although miRNAs shows great potential as biomarkers in therapeutic strategies,the current limitation of sample size and lack of multi-population validation restrict the universality and reliability of the results.Moreover,the efficacy and safety of miRNA therapeutic strategies(including off-target effects and delivery issues)remain major challenges in realizing clinical applications.

Objective To analyze white matter hyperintensities(WMH)and 11C-CFT PET/CT characteristics in patients with PD,and explore their relationship.Methods A total of 84 PD pa-tients admitted to our department between March 2021 and March 2025 were retrospectively en-rolled,and they were divided into young group(33 cases)and elderly group(aged＞65 years,51 cases)and also into non-WMH group(22 cases)and WMH group(62 cases)based on the severity of WMH.The degree of white matter lesions was scored,including periventricular white matter hyperintense(PVH)score and deep white matter hyperintense(DWMH)score.All patients un-derwent head MRI and 11C-CFT-PET/CT scanning.The T/N value and asymmetry index were calculated.Results The elderly PD patients exhibited significantly advanced age and higher H-Y stages,but lower T/N values of affected side of caudate nucleus,contralateral caudate nucleus,affected side of anterior putamen,contralateral anterior putamen and contralateral posterior puta-men,and posterior putamen asymmetry index than the young patients(P＜0.05,P＜0.01).Simi-lar results were observed in the WMH group when compared with the non-WMH group(P＜0.05,P＜0.01).The PVH score was negatively correlated with the T/N values of affected side of caudate nucleus(r=-0.282,P=0.009),contralateral caudate nucleus(r=-0.215,P=0.049),affected side of anterior putamen(r=-0.249,P=0.022),contralateral anterior putamen(r=-0.280,P=0.010)and contralateral posterior putamen(r=-0.285,P=0.009),and DWMH score was also negatively correlated with the T/N values in the affected side of caudate nucleus and affected side of anterior putamen(P＜0.05).Conclusion Both age and disease severity impact WMH and dopaminergic system in PD patients.A higher WMH load is associated with dopamin-ergic neuronal damage.

Background and Aims:The BRAFV600E mutation is the most common genetic alteration in papillary thyroid carcinoma(PTC)and is widely used to guide surgical extent and risk stratification.However,other genetic variants are increasingly identified in clinical practice,and their association with lymph node metastasis(LNM)remains unclear.Most existing studies have compared BRAFV600E-mutated cases with BRAF wild-type cases without stratifying specific mutation types,potentially affecting the accuracy of risk assessment.This study aimed to compare the lymph node metastatic features between PTC patients with different common genetic alterations and those with the BRAFV600E mutation.Methods:A retrospective analysis was conducted on 4 795 PTC patients who underwent surgery and genetic testing at Fudan University Shanghai Cancer Center from January 2019 to January 2025.Patients with a single genetic alteration were included and grouped accordingly.Propensity score matching(PSM)was used to control for confounding factors including age,sex,and T stage.The number of metastatic lymph nodes and N stage were compared between each mutation group and the BRAFV600E group.Results:After PSM,patients in the CCDC6-RET and NCOA4-RET fusion groups had significantly higher numbers of metastatic lymph nodes and N1b stage rates compared to the BRAFV600E group(all P<0.05).No significant differences were observed between the ETV6-NTRK3 fusion or RAS mutation groups and the BRAFV600E group in terms of lymph node metastasis or N stage(all P>0.05).Conclusion:PTC patients harboring CCDC6-RET or NCOA4-RET fusions exhibit a significantly higher lymph node metastatic burden than those with the BRAFV600E mutation,suggesting more aggressive behavior.In contrast,ETV6-NTRK3 and RAS-mutated PTCs show similar metastatic profiles to BRAFV600E-mutated cases.Preoperative genetic profiling may help identify patients at high risk of metastasis and guide individualized lymph node dissection strategies.

ObjectiveTo investigate the characteristics of mitochondrial translational initiation factor 2 （MTIF2） gene methylation and its association with the development and progression of hepatocellular carcinoma （HCC）. MethodsMethSurv and EWAS Data Hub were used to perform the standardized analysis and the cluster analysis of MTIF2 methylation samples， including survival curve analysis， methylation signature analysis， the association of tumor signaling pathways， and a comparative analysis based on pan-cancer database. The independent-samples t test was used for comparison between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. The Cox proportional hazards model was used to perform the univariate and multivariate survival analyses of methylation level at the CpG site. The Kaplan-Meier method was used to investigate the survival differences between the patients with low methylation level and those with high methylation level， and the Log-likelihood ratio method was used for survival difference analysis. ResultsGlobal clustering of MTIF2 methylation showed that there was no significant difference in MTIF2 gene methylation level between different races， ethnicities， BMI levels， and ages. The Kaplan-Meier survival curve analysis showed that the patients with N-Shore hypermethylation of the MTIF2 gene had a significantly better prognosis than those with hypomethylation （hazard ratio ［HR］=0.492， P<0.001）， while there was no significant difference in survival rate between the patients with different CpG island and S-Shore methylation levels （P>0.05）. The methylation profile of the MTIF2 gene based on different ages， sexes， BMI levels， races， ethnicities， and clinical stages showed that the N-Shore and CpG island methylation levels of the MTIF2 gene decreased with the increase in age， and the Caucasian population had significantly lower N-Shore methylation levels of the MTIF2 gene than the Asian population （P<0.05）； the patients with clinical stage Ⅳ had significantly lower N-Shore and CpG island methylation levels of the MTIF2 gene than those with stage Ⅰ/Ⅱ （P<0.05）. Clinical validation showed that the patients with stage Ⅲ/Ⅳ HCC had a significantly lower methylation level of the MTIF2 gene than those with stage Ⅰ/Ⅱ HCC and the normal population （P<0.05）. ConclusionN-Shore hypomethylation of the MTIF2 gene is a risk factor for the development and progression of HCC.

AIM:To investigate the therapeutic effects and potential mechanism of pachymic acid(PA)on li-popolysaccharide(LPS)-induced acute kidney injury(AKI)in mice.METHODS:(1)Genes related to AKI were screened using the DAVID database.Core genes were identified by intersecting related genes and analyzed using Cyto-scape software.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analyses were performed through the DAVID database for the cross-targets.Molecular docking and activity assays were conducted on the primary core targets.(2)A total of 100 C57BL/6J mice were randomly divided into five groups:normal control(NC),model(LPS),solvent control(LPS+DMSO),and treatment groups(LPS+PA-10 and LPS+PA-20),with 20 mice in each group.The LPS-AKI model was established by intraperitoneal injection of 18 mg/kg LPS.The treatment groups received 10 mg/kg and 20 mg/kg PA,respectively,and the solvent control group was administered an equivalent dose of DMSO.Mice were euthanized 24 h after injection.Serum was collected for biochemical analysis,and Western blot was used to detect neutro-phil gelatinase-associated lipocalin(NGAL),kidney injury molecule-1(KIM-1),caspase-3,cleaved caspase-3,interleu-kin-1β(IL-1β),and monocyte chemoattractant protein-1(MCP-1)protein expression.RT-qPCR was employed to detect inflammatory factor mRNA levels.Molecular docking was used to simulate the optimal binding site of PA to caspase-3.En-zyme activity assays were performed to assess caspase protein activity,and renal lesions were observed via hematoxylin and eosin(HE)staining.Apoptosis was detected by TUNEL staining.RESULTS:(1)Thirty-one potential targets of PA against AKI were identified through network pharmacology.GO and KEGG enrichment analyses indicated that these tar-gets were primarily involved in immune response,inflammatory processes,apoptosis and survival,angiogenesis and hemo-dynamics,oxidative stress,and endoplasmic reticulum stress.Key targets included CASP3(caspase-3),PTGS2,BCL2,CCL2,and CYP219.(2)PA treatment improved renal function and reduced tubular epithelial injury.It significantly de-creased NGAL,KIM-1,and cleaved caspase-3 protein levels,as well as inflammatory factors TNF-α,IL-1β,and MCP-1 mRNA and protein expression.PA also reduced apoptosis of renal tubular epithelial cells.Enzyme activity assays and mo-lecular docking revealed that PA exerted its anti-apoptotic effect by directly binding to caspase-3,thereby inhibiting its ac-tivation by caspase-8.CONCLUSION:PA demonstrated a therapeutic effect in LPS-AKI,potentially through the inhibi-tion of inflammatory factor synthesis and release,as well as the inhibition of caspase-3 activation by caspase-8,reducing apoptosis in renal tubular epithelial cells.

Background and purpose:Thyroid cancer is the most common malignant endocrine tumor,particularly prevalent among the Asian population.The overall survival for thyroid cancer patients is relatively high,but there are significant survival differences among patients.Based on long-term hospital-based cancer registry database,this study analyzed the 10-year observed overall survival(OS)rate of thyroid cancer cases and the distribution of causes of death,providing real-world evidences to further survival management of thyroid cancer in China.Methods:A total of 55343 thyroid cancer patients who underwent treatment at Fudan University Shanghai Cancer center from 2005 to 2021 were included in this study.Clinical information and the follow-up endpoint data were collected through medical records review,telephone visits and death registry data linkage.The last follow-up date was October 31,2024.Kaplan-Meier method was applied in evaluating the OS rate,and survival data were described by different subgroups as age group,gender,treatment period,tumor staging and pathological characteristics.The standardized mortality ratio(SMR)and absolute excess risk(AER)were calculated using general Shanghai population as the reference,and the mortality risk was described by gender,age at diagnosis and histological subtype.Results:With a median follow-up time of 63.01 months,the overall 1-,3-,5-and 10-year OS rates of thyroid cancer patients were 99.67%(95%CI:99.62%-99.72%),99.11%(95%CI:99.03%-99.19%),98.48%(95%CI:98.36%-98.60%)and 95.81%(95%CI:95.50%-96.11%),respectively.The 10-year OS rates of stage Ⅰ,Ⅱ,Ⅲ and Ⅳ were 97.99%(95%CI:97.70%-98.28%),89.80%(95%CI:87.24%-92.37%),77.84%(95%CI:70.76%-84.92%)and 62.95%(95%CI:55.37%-70.54%),respectively.The differences in OS among patients with different age,gender and histological classification were significant.1256(2.27%)deaths occurred,of which 18.63%,50.88%and 7.32%were attributable to thyroid cancer,other cancers and cardiovascular disease(CVD),respectively.Compared with the general population,patients with different subtypes of thyroid cancer had higher all-cause mortality rates,progressively increasing with papillary,follicular,medullary and anaplastic thyroid carcinoma/poorly differentiated carcinoma.Compared with general population,the death risk was 2.24 times higher in papillary thyroid cancer patients(95%CI:2.06-2.44),9.94 times higher in follicular thyroid cancer patients(95%CI:6.79-14.09),12.16 times higher in medullary thyroid cancer patients(95%CI:8.05-17.69),and the highest risk was observed in patients with anaplastic thyroid carcinoma/poorly differentiated carcinoma[SMR=79.67(95%CI:58.38-106.31),AER=766.01/1 000 person-years].Conclusion:The 10-year long survival data and cause of death for thyroid cancer patients with different histological types were reported in China based on a large single institution hospital-based cancer registry database.Staging and histological characteristics were the most important factors directly affected the survival.Early diagnosis and individualized treatment are crucial for improving prognosis.

Background and purpose:The microphthalmia-associated transcription factor(MITF)plays a complex role in melanoma pathogenesis and progression.It is known to regulate multiple processes both in melanocytes and melanoma cells.While numerous studies have explored MITF in cutaneous melanoma(CM),research in acral melanoma(AM)is still limited.This study retrospectively analyzed the correlation between MITF expression and clinical,pathological characteristics and prognosis in AM patients,providing a basis for prognosis evaluation and personalized treatment plan formulation for patients.Methods:Patients who underwent primary resection of AM at Fudan University Shanghai Cancer Center from March 2008 to February 2022 were included.All surgical samples were diagnosed by clinical histopathology and used to construct the tissue microarray(TMA).This study was approved by the medical ethics committee of Fudan University Shanghai Cancer Center(approval number:2203-ZZK-69-3).Cutting complete tissue microarray and evaluating MITF expression levels by immunohistochemistry(IHC)staining were carried out.The results were independently assessed and scored by three pathologists.Clinical and pathological data were collected from the hospital's electronic medical record system,and each patient's data was matched to their corresponding tissue sample on the chip.Patients were stratified into two groups based on MITF expression levels.Statistical analyses were performed to assess differences in clinical,pathological characteristics and survival outcomes between these two groups.Results:A total of 137 AM patients were included.MITF expression was significantly associated with T stage,N stage,American Joint Committee on Cancer(AJCC)stage,clark level,sentinel lymph node status,and presence of ulceration.Among these,N stage and ulceration were independent risk factors for high expression of MITF after adjusting for confounding factors.Survival analysis showed that AM patients with high MITF expression or higher T stage were associated with shorter disease-free survival(DFS).Patients with high MITF expression showed no significant difference in overall survival(OS)between observation or cytokine therapy and adjuvant immune checkpoint inhibitor(ICI)therapy,whereas those with low MITF expression derived significant survival benefits from ICI treatment.Conclusion:A higher N stage or the presence of ulceration indicates high MITF expression in tumor cells,with high MITF levels serving as a warning signal for early recurrence,metastasis,and even death.Patients with low MITF expression could receive improved OS with early adjuvant ICI therapy.MITF could not only serve as an auxiliary diagnostic marker for melanoma but also provide a basis for clinical prognosis assessment and the formulation of personalized treatment plans.