Background This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.Methods ...Background This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.Methods Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing.We analyzed the patients’convulsions and treatment with antiepileptic drugs.The patients were followed up at different time periods after ketogenic diet therapies.Results Six patients with SLC2A1 mutations were included in this study.The patients had seizures of different types and frequencies,and they took antiepileptic drugs to relieve their symptoms.They were then treated with a ketogenic diet for at least four months.We analyzed epilepsy control rates at 1,2,3,6,and 12 months after ketogenic diet treatment.All patients were seizure-free within a month of receiving the diet therapy.All patients were followed up for six months,three were followed up for 12 months after the treatment,and there was no recurrence of epilepsy during this period.After antiepileptic drug withdrawal,none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone.No severe adverse events occurred during the therapy.Conclusions Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations.Therefore,patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.展开更多
Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still large...Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.展开更多
Angiogenic factor with G-patch and FHA domains 1(AGGF1) exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis, but the biological significance and underlying mechan...Angiogenic factor with G-patch and FHA domains 1(AGGF1) exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis, but the biological significance and underlying mechanism of this nucleocytoplasmic transport remains unknown. Here, we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function. To search the structural bases for this nucleocytoplasmic transport, we characterized three potential nuclear localization regions, one potential nuclear export region, forkhead-associated(FHA), and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis, and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization. The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β. Binding of AGGF1 via FHA domain to 14-3-3α/β is required to complete the transport. Thus, we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.展开更多
基金supported by grants from National Key R&D Program of China(2019YFA0801900)Epilepsy Research Fund of China Association Against Epilepsy(CJ-B-2021-21)+5 种基金The Interdisciplinary Program of Shanghai Jiao Tong University(YG2021QN108)Emerging Frontier Technology Project of Shanghai Hospital(SHDC12015113)Research Funds of Shanghai Health and Family Planning Commission(20204Y0339)Shanghai Hospital Development Center Foundation(SHDC12022626,SHDC2022CRS052)Shanghai“Rising Stars of Medical Talent”Youth Development Program-Youth Medical Talents-Clinical Pharmacist Program(SHWRS(2020)_087)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212800).
文摘Background This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.Methods Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing.We analyzed the patients’convulsions and treatment with antiepileptic drugs.The patients were followed up at different time periods after ketogenic diet therapies.Results Six patients with SLC2A1 mutations were included in this study.The patients had seizures of different types and frequencies,and they took antiepileptic drugs to relieve their symptoms.They were then treated with a ketogenic diet for at least four months.We analyzed epilepsy control rates at 1,2,3,6,and 12 months after ketogenic diet treatment.All patients were seizure-free within a month of receiving the diet therapy.All patients were followed up for six months,three were followed up for 12 months after the treatment,and there was no recurrence of epilepsy during this period.After antiepileptic drug withdrawal,none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone.No severe adverse events occurred during the therapy.Conclusions Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations.Therefore,patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.
基金supported by the National Natural Science Foundation of China (No.81830086, 81988101, 81802780)Beijing Municipal Administration of Hospital’s Mission Plan (No.SML20181101)+1 种基金Beijing Nova Program (No.Z191100001119038)Beijing Hospitals Authority Youth Programme (No.QML20191104)。
文摘Objective: Solute carrier family 38(SLC38 s) transporters play important roles in amino acid transportation and signaling transduction. However, their genetic alterations and biological roles in tumors are still largely unclear.This study aimed to elucidate the genetic signatures of SLC38 s transporters and their implications in esophageal squamous cell carcinoma(ESCC).Methods: Analyses on somatic mutation and copy number alterations(CNAs) of SLC38 A3 were performed as described. Immunohistochemistry(IHC) assay and Western blot assay were used to detect the protein expression level. MTS assay, colony formation assay, transwell assay and wound healing assay were used to explore the malignant phenotypes of ESCC cells. Immunofluorescence assay was used to verify the colocalization of two indicated proteins and immunopreciptation assay was performed to confirm the interaction of proteins.Results: Our findings revealed that SLC38 s family was significantly disrupted in ESCC, with high frequent CNAs and few somatic mutations. SLC38 A3 was the most frequent loss gene among them and was linked to poor survival and lymph node metastasis. The expression of SLC38 A3 was lower in tumor tissues compared to that in normal tissues, which was also significantly associated with worse clinical outcome. Further experiments revealed that depletion of SLC38 A3 could promote EMT in ESCC cell lines, and the interaction of SLC38 A3 and SETDB1 might lead to the reduced transcription of Snail. Pharmacogenomic analyses demonstrated that fifteen inhibitors were showed significantly correlated with SLC38 A3 expression.Conclusions: Our investigations have provided insights that SLC38 A3 could act as a suppressor in EMT pathway and serve as a prognostic factor and predictor of differential drug sensitivities in ESCC.
基金This work was supported by grants from the National Natural Science Foundation of China(30730047,81070262,81130003 and 81630034).
文摘Angiogenic factor with G-patch and FHA domains 1(AGGF1) exhibits a dynamic distribution from the nucleus to the cytoplasm in endothelial cells during angiogenesis, but the biological significance and underlying mechanism of this nucleocytoplasmic transport remains unknown. Here, we demonstrate that the dynamic distribution is essential for AGGF1 to execute its angiogenic function. To search the structural bases for this nucleocytoplasmic transport, we characterized three potential nuclear localization regions, one potential nuclear export region, forkhead-associated(FHA), and G-patch domains to determine their effects on nucleocytoplasmic transport and angiogenesis, and we show that AGGF1 remains intact during the dynamic subcellular distribution and the region from 260 to 288 amino acids acts as a signal for its nuclear localization. The distribution of AGGF1 in cytoplasm needs both FHA domain and 14-3-3α/β. Binding of AGGF1 via FHA domain to 14-3-3α/β is required to complete the transport. Thus, we for the first time established structural bases for the nucleocytoplasmic transport of AGGF1 and revealed that the FHA domain of AGGF1 is essential for its nucleocytoplasmic transport and angiogenesis.
