BACKGROUND Over 90%of rectal cancer patients develop low anterior resection syndrome(LARS)after sphincter-preserving resection.The current globally recognized evaluation method has many drawbacks and its subjectivity ...BACKGROUND Over 90%of rectal cancer patients develop low anterior resection syndrome(LARS)after sphincter-preserving resection.The current globally recognized evaluation method has many drawbacks and its subjectivity is too strong,which hinders the research and treatment of LARS.AIM To evaluate the anorectal function after colorectal cancer surgery by quantifying the index of magnetic resonance imaging(MRI)defecography,and pathogenesis of LARS.METHODS We evaluated 34 patients using the standard LARS score,and a new LARS evaluation index was established using the dynamic images of MRI defecography to verify the LARS score.RESULTS In the LARS score model,there were 10(29.41%)mild and 24(70.58%)severe cases of LARS.The comparison of defecation rate between the two groups was 29.36±14.17%versus 46.83±18.62%(P=0.004);and MRI-rectal compliance(MRI-RC)score was 3.63±1.96 versus 7.0±3.21(P=0.001).Severe and mild LARS had significant differences using the two evaluation methods.There was a significant negative correlation between LARS and MRI-RC score(P<0.001),and they had a negative correlation with defecation rate(P=0.028).CONCLUSION MRI defecography and standard LARS score can both be used as an evaluation index to study the pathogenesis of LARS.展开更多
Few effective therapies have been developed for the treatment of lung squamous cell carcinoma(SQCC), in part due to a lack of understanding regarding the mechanisms underlying the initiation and development of this di...Few effective therapies have been developed for the treatment of lung squamous cell carcinoma(SQCC), in part due to a lack of understanding regarding the mechanisms underlying the initiation and development of this disease. Whole transcriptome sequencing not only provides insight into the expression of all transcribed genes, but offers an efficient approach for identifying genetic variations,including gene fusions, mutations and alternative splicing. In this study, we performed whole transcriptome sequencing of 10 patients with stage IIIA lung SQCC, and discovered a large number of single nucleotide variants(SNVs; mean of 12.2 SNVs/Mb), with C>T/G>A and A>G/T>C transitions being the most frequently observed. Additionally, a total of 132 gene fusions were identified based upon Top Hat alignments, 70.5%(93/132) of which occurred as a result of intra-chromosomal rearrangements. Based on the number of supporting reads for each fusion, we further validated 20 of the 26 top gene fusions by RT-PCR and Sanger sequencing. Taken together, these data provide an in-depth view of transcriptional alterations in lung SQCC patients, and may be useful for identification of new therapeutic targets.展开更多
Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kina...Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.展开更多
文摘BACKGROUND Over 90%of rectal cancer patients develop low anterior resection syndrome(LARS)after sphincter-preserving resection.The current globally recognized evaluation method has many drawbacks and its subjectivity is too strong,which hinders the research and treatment of LARS.AIM To evaluate the anorectal function after colorectal cancer surgery by quantifying the index of magnetic resonance imaging(MRI)defecography,and pathogenesis of LARS.METHODS We evaluated 34 patients using the standard LARS score,and a new LARS evaluation index was established using the dynamic images of MRI defecography to verify the LARS score.RESULTS In the LARS score model,there were 10(29.41%)mild and 24(70.58%)severe cases of LARS.The comparison of defecation rate between the two groups was 29.36±14.17%versus 46.83±18.62%(P=0.004);and MRI-rectal compliance(MRI-RC)score was 3.63±1.96 versus 7.0±3.21(P=0.001).Severe and mild LARS had significant differences using the two evaluation methods.There was a significant negative correlation between LARS and MRI-RC score(P<0.001),and they had a negative correlation with defecation rate(P=0.028).CONCLUSION MRI defecography and standard LARS score can both be used as an evaluation index to study the pathogenesis of LARS.
基金supported by the grants from the National Natural Science Foundation of China (No. 81272618) to YiLong WuGuangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No. 2012A061400006)Special Fund for Research in the Public Interest from National Health and Family Planning Commission of PRC (No. 201402031)
文摘Few effective therapies have been developed for the treatment of lung squamous cell carcinoma(SQCC), in part due to a lack of understanding regarding the mechanisms underlying the initiation and development of this disease. Whole transcriptome sequencing not only provides insight into the expression of all transcribed genes, but offers an efficient approach for identifying genetic variations,including gene fusions, mutations and alternative splicing. In this study, we performed whole transcriptome sequencing of 10 patients with stage IIIA lung SQCC, and discovered a large number of single nucleotide variants(SNVs; mean of 12.2 SNVs/Mb), with C>T/G>A and A>G/T>C transitions being the most frequently observed. Additionally, a total of 132 gene fusions were identified based upon Top Hat alignments, 70.5%(93/132) of which occurred as a result of intra-chromosomal rearrangements. Based on the number of supporting reads for each fusion, we further validated 20 of the 26 top gene fusions by RT-PCR and Sanger sequencing. Taken together, these data provide an in-depth view of transcriptional alterations in lung SQCC patients, and may be useful for identification of new therapeutic targets.
基金This study was supported by the research grant from National Key R&D Program of China(2018YFC0910203)
文摘Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.
