Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeu...Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.展开更多
Epilepsy is one of the most common neurological disorders characterized by epileptic seizures.The anti-epileptic drugs(AEDs)are the main form of treatment for people with epilepsy.Classically,people thought that AEDs ...Epilepsy is one of the most common neurological disorders characterized by epileptic seizures.The anti-epileptic drugs(AEDs)are the main form of treatment for people with epilepsy.Classically,people thought that AEDs modify the activities of ion channels to suppress epileptic seizures.However,accumulating evidence suggests that targeting at ion channels cannot completely account for the numerous effects of the AEDs on its broad clinical activity in epileptic patients.In our study,proteomic methods were used to quantify the proteome of hippocampal tissues from patients who were treated or not treated by AEDs(Carbamazepine).Further bioinformatics methods,including Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,were utilized to analyze the differences between two patient groups.We found that more than 400 proteins,including metabolism and immune related proteins,had a higher expression level in the carbamazepine-treated group compared with the controls.These altered proteins were considered to be involved in many different biological pathways.Among these pathways,immune-system related pathway modulated by complement C3 and microglia was highly remarkable,which regulated the synapses elimination in physiological condition.In epilepsy,the carbamazepine induced up-regulation of complement C3 might decrease the abnormal synaptic connections between neurons and thus contribute to the therapeutic role of carbamazepine.The results of our study suggested that apart from ion channels,carbamazepine exerted numerous effects on human epileptic foci,which might be the fundamental mechanisms of AEDs for treatment,adverse-effects and pharmacoresistance of epilepsy.展开更多
For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy(a subtype of membranoproliferative glomerulonephritis), have mostly been comp...For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy(a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases.Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.展开更多
文摘Objectives:Colorectal cancer(CRC)remains a major contributor to global cancer mortality,ranking second worldwide for cancer-related deaths in 2022,and is characterized by marked heterogeneity in prognosis and therapeutic response.We sought to construct a machine-learning prognosticmodel based on a complement-related risk signature(CRRS)and to situate this signature within the CRC immune microenvironment.Methods:Transcriptomic profiles with matched clinical annotations from TCGA and GEO CRC cohorts were analyzed.Prognostic CRRS genes were screened using Cox proportional hazards modeling alongside machine-learning procedures.A random survival forest(RSF)predictor was trained and externally validated.Comparisons of immune infiltration,mutational burden,pathway enrichment,and drug sensitivity were made between risk groups.The function of FAM84A,a key model gene,was examined in CRC cell lines.Results:The six-gene CRRS model accurately stratified patients by survival outcomes.Low-risk patients exhibited greater immune cell infiltration and higher predicted response to immunotherapy and chemotherapy,while high-risk patients showed enrichment of complement activation and matrix remodeling pathways.FAM84A was shown to promote CRC cell proliferation,migration,and epithelial–mesenchymal transition.Conclusion:CRRS is a critical modulator of the CRC immune microenvironment.The developed model enables precise risk prediction and supports individualized therapeutic decisions in CRC.
基金The Ministry of Science and Technology of China(Grant No.2015CB559200)the National Natural Science Foundation of China(Grant No.81371432).
文摘Epilepsy is one of the most common neurological disorders characterized by epileptic seizures.The anti-epileptic drugs(AEDs)are the main form of treatment for people with epilepsy.Classically,people thought that AEDs modify the activities of ion channels to suppress epileptic seizures.However,accumulating evidence suggests that targeting at ion channels cannot completely account for the numerous effects of the AEDs on its broad clinical activity in epileptic patients.In our study,proteomic methods were used to quantify the proteome of hippocampal tissues from patients who were treated or not treated by AEDs(Carbamazepine).Further bioinformatics methods,including Gene Ontology(GO)annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis,were utilized to analyze the differences between two patient groups.We found that more than 400 proteins,including metabolism and immune related proteins,had a higher expression level in the carbamazepine-treated group compared with the controls.These altered proteins were considered to be involved in many different biological pathways.Among these pathways,immune-system related pathway modulated by complement C3 and microglia was highly remarkable,which regulated the synapses elimination in physiological condition.In epilepsy,the carbamazepine induced up-regulation of complement C3 might decrease the abnormal synaptic connections between neurons and thus contribute to the therapeutic role of carbamazepine.The results of our study suggested that apart from ion channels,carbamazepine exerted numerous effects on human epileptic foci,which might be the fundamental mechanisms of AEDs for treatment,adverse-effects and pharmacoresistance of epilepsy.
文摘For decades, kidney diseases related to inappropriate complement activity, such as atypical hemolytic uremic syndrome and C3 glomerulopathy(a subtype of membranoproliferative glomerulonephritis), have mostly been complicated by worsened prognoses and rapid progression to end-stage renal failure. Alternative complement pathway dysregulation, whether congenital or acquired, is well-recognized as the main driver of the disease process in these patients. The list of triggers include: surgery, infection, immunologic factors, pregnancy and medications. The advent of complement activation blockade, however, revolutionized the clinical course and outcome of these diseases, rendering transplantation a viable option for patients who were previously considered as non-transplantable cases.Several less-costly therapeutic lines and likely better efficacy and safety profiles are currently underway. In view of the challenging nature of diagnosing these diseases and the long-term cost implications, a multidisciplinary approach including the nephrologist, renal pathologist and the genetic laboratory is required to help improve overall care of these patients and draw the optimum therapeutic plan.
