The disruption of ferroptosis,an emerging form of programmed cell death,is crucial in the development and aggressiveness of tumors.Meanwhile,the mechanisms and treatments that control ferroptosis in neuroblastoma(NB),...The disruption of ferroptosis,an emerging form of programmed cell death,is crucial in the development and aggressiveness of tumors.Meanwhile,the mechanisms and treatments that control ferroptosis in neuroblastoma(NB),a prevalent extracranial cancer in children,are still unknown.In this study,forkhead box C1(FOXC1)and O-GlcNAc transferase(OGT)are identified as regulators of asparagine-and alanine-mediated ferroptosis repression in NB.Mechanistically,OGT facilitates FOXC1 stabilization via inducing O-GlcNAcylation in liquid condensates to increase the expression of asparagine synthetase(ASNS)and glutamate pyruvate transaminase 2(GPT2),resulting in asparagine and alanine biogenesis,and subsequent synthesis of cystathionineβ-synthase(CBS)or ferritin heavy chain 1(FTH1).Meanwhile,exonic circular OGT RNA(ecircOGT)is able to encode a novel protein(OGT-570aa)containing domain essential for binding of OGT to FOXC1,which competitively decreases the OGT-FOXC1 interaction.Preclinically,miconazole nitrate facilitates the interaction of OGT-570aa with FOXC1,suppresses ferroptosis resistance of NB cells,and inhibits their growth,invasion,and metastasis.In clinical NB cases,higher OGT,FOXC1,ASNS,GPT2,CBS,or FTH1 levels are correlated with worse survival,while lower ecircOGT or OGT-570aa expression is associated with tumor progression.These results indicate that targeting the ecircOGT/OGT/FOXC1 axis inhibits asparagine-and alanine-mediated ferroptosis repression in NB progression.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
BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where tr...BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where treatment with IM fails,there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage.This approach will enhance clinical decision-making and optimize patient outcomes.AIM To investigate IM plasma concentration’s role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure.METHODS Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed.Patients were categorized into a low plasma(LP)concentration group(LP group,<1100 ng/mL)and high plasma(HP)concentration group(HP group,≥1100 ng/mL).Each group was further subdivided into Group A(dose-escalation group)and Group B(drug-switch group).Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients.RESULTS Seventy-five patients were included in the analysis.For the LP group(n=28),Group A(n=14)had longer overall survival(OS)than Group B(n=14)(P=0.02).No differences were observed between the two subgroups in disease control rate(DCR),objective response rate,and progression-free survival(PFS)(P>0.05).For the HP group(n=47),Group B(n=18)had a higher DCR and longer PFS than Group A(n=29)(P=0.008 and P=0.03,respectively).No difference in OS was observed between the two subgroups(P>0.05).CONCLUSION Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is<1100 ng/mL.Switching tyrosine kinase inhibitors may improve DCR and PFS if≥1100 ng/mL.展开更多
Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significant...Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.展开更多
基金supported by the Major Program of National Natural Science Foundation of China(82293663)the National Natural Science Foundation of China(82072801,82173316,and 82473092).
文摘The disruption of ferroptosis,an emerging form of programmed cell death,is crucial in the development and aggressiveness of tumors.Meanwhile,the mechanisms and treatments that control ferroptosis in neuroblastoma(NB),a prevalent extracranial cancer in children,are still unknown.In this study,forkhead box C1(FOXC1)and O-GlcNAc transferase(OGT)are identified as regulators of asparagine-and alanine-mediated ferroptosis repression in NB.Mechanistically,OGT facilitates FOXC1 stabilization via inducing O-GlcNAcylation in liquid condensates to increase the expression of asparagine synthetase(ASNS)and glutamate pyruvate transaminase 2(GPT2),resulting in asparagine and alanine biogenesis,and subsequent synthesis of cystathionineβ-synthase(CBS)or ferritin heavy chain 1(FTH1).Meanwhile,exonic circular OGT RNA(ecircOGT)is able to encode a novel protein(OGT-570aa)containing domain essential for binding of OGT to FOXC1,which competitively decreases the OGT-FOXC1 interaction.Preclinically,miconazole nitrate facilitates the interaction of OGT-570aa with FOXC1,suppresses ferroptosis resistance of NB cells,and inhibits their growth,invasion,and metastasis.In clinical NB cases,higher OGT,FOXC1,ASNS,GPT2,CBS,or FTH1 levels are correlated with worse survival,while lower ecircOGT or OGT-570aa expression is associated with tumor progression.These results indicate that targeting the ecircOGT/OGT/FOXC1 axis inhibits asparagine-and alanine-mediated ferroptosis repression in NB progression.
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.
文摘BACKGROUND For patients with advanced gastrointestinal stromal tumors(GISTs)carrying the ckit exon 11 mutation,imatinib(IM)at a standard dosage of 400 mg per day is the preferred first-line treatment.In cases where treatment with IM fails,there is an urgent need for a more precise assessment method to determine whether to switch therapies or escalate the IM dosage.This approach will enhance clinical decision-making and optimize patient outcomes.AIM To investigate IM plasma concentration’s role in second-line treatment decisions for c-kit 11-mutated advanced GISTs post-IM failure.METHODS Patients with advanced GIST harboring c-kit 11 mutation who experienced failure with IM 400 mg per day as first-line treatment at our hospital were retrospectively analyzed.Patients were categorized into a low plasma(LP)concentration group(LP group,<1100 ng/mL)and high plasma(HP)concentration group(HP group,≥1100 ng/mL).Each group was further subdivided into Group A(dose-escalation group)and Group B(drug-switch group).Baseline characteristics were compared and Kaplan-Meier curves were used to analyze the survival of patients.RESULTS Seventy-five patients were included in the analysis.For the LP group(n=28),Group A(n=14)had longer overall survival(OS)than Group B(n=14)(P=0.02).No differences were observed between the two subgroups in disease control rate(DCR),objective response rate,and progression-free survival(PFS)(P>0.05).For the HP group(n=47),Group B(n=18)had a higher DCR and longer PFS than Group A(n=29)(P=0.008 and P=0.03,respectively).No difference in OS was observed between the two subgroups(P>0.05).CONCLUSION Increasing IM dosage for c-kit 11-mutated advanced GISTs post-IM failure may prolong OS if plasma concentration is<1100 ng/mL.Switching tyrosine kinase inhibitors may improve DCR and PFS if≥1100 ng/mL.
文摘Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.
