Purpose:To compare self-reported diabetes treatments among Chinese urban residents,rural migrants in urban settings,and rural residents.Methods:Data from 993 diabetics at least 45 years of age were collected from the ...Purpose:To compare self-reported diabetes treatments among Chinese urban residents,rural migrants in urban settings,and rural residents.Methods:Data from 993 diabetics at least 45 years of age were collected from the China Health and Retirement Longitudinal Study conducted in 2011.Multiple logistic regressions were performed to examine the associations between individual characteristics and diabetes treatments.Results:In total,719/993(72.4%)of the respondents received treatment for diabetes;of which<8% used insulin therapy.Urban residents were more likely than rural residents to use insulin therapy[odds ratio(OR)=0.44,confidence interval(CI):0.20-0.99;p<0.05],and more likely to use traditional Chinese medicine than migrants(OR=0.30,CI:0.10-0.96;p<0.05).Overall,rural residents showed lower treatment rates than urban and migrant populations.Conclusion:Efforts to improve and enhance diabetes treatments,particularly among rural residents,are urgently needed in China.展开更多
T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway.Recent studies have revealed that posttranslational modificatio...T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway.Recent studies have revealed that posttranslational modifications,such as ubiquitination,regulate NOTCH1 stability,activity,and localization.However,the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished.Here,we report that ubiquitin-specific protease 7(USP7)can stabilize NOTCH1.USP7 deubiquitinated NOTCH1 in vivo and in vitro,whereas knockdown of USP7 increased the ubiquitination of NOTCH1.USP7 interacted with NOTCH1 protein in T-ALL cells,and the MATH and UBL domains of USP7 were responsible for this interaction.Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo,accompanied by downregulation of the NOTCH1 protein level.Similarly,pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells.More importantly,we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples,and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells,indicating the clinical relevance of these findings.Overall,our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1.Therefore,USP7 may be a promising therapeutic target in the currently incurable T-ALL.展开更多
Deubiquitinates(DUBs) alter the stabilities, localizations or activities of substrates by removing their ubiquitin conjugates,which are closely related to the development of inflammatory response. Here, we show that u...Deubiquitinates(DUBs) alter the stabilities, localizations or activities of substrates by removing their ubiquitin conjugates,which are closely related to the development of inflammatory response. Here, we show that ubiquitin-specific protease 47(USP47) prevents inflammation development in inflammatory bowel disease(IBD). Compared with wild-type mice, Usp47 knockout mice are more susceptible to dextran sodium sulfate(DSS)-induced acute and chronic colitis with higher inflammatory cytokines expression and severe intestinal tissue damage. Chimeric mouse experiments suggest that non-hematopoietic cells mainly contribute to the phenotype. And, DSS-induced colitis of the Usp47 knockout mice depends on commensal bacteria.Mechanistically, down-regulation of USP47 aggravates the activation of NF-κB signaling pathway by increasing the K63-linked poly-ubiquitination of tumor necrosis factor receptor-associated factor 6(TRAF6) in intestinal epithelial cells. Furthermore, the expression of USP47, negatively correlated with the degree of inflammation, is lower at colonic inflammatory lesions than that non-inflammatory sites from the intestine from ulcerative colitis(UC) and Crohn's disease(CD) patients. These data, taken together, indicate that USP47 regulates intestinal inflammation through de-ubiquitination of K63-linked poly-ubiquitination TRAF6 in intestinal epithelial cells.展开更多
Background Emergency medical services(EMS)is a critical link in the chain of stroke survival.We aimed to assess EMS use for stroke in Singapore,identify characteristics associated with EMS use and the association of E...Background Emergency medical services(EMS)is a critical link in the chain of stroke survival.We aimed to assess EMS use for stroke in Singapore,identify characteristics associated with EMS use and the association of EMS use with stroke evaluation and treatment.Methods The Singapore Stroke Registry combines nationwide EMS and public hospital data for stroke cases in Singapore.Multivariate regressions with the generalised estimating equations were performed to examine the association between EMS use and timely stroke evaluation and treatment.results Of 3555 acute ischaemic patients with symptom onset within 24 hours admitted to all five public hospitals between 2015 and 2016,68%arrived via EMS.Patients who used EMS were older,were less likely to be female,had higher stroke severity by National Institute of Health Stroke Scale and had a higher prevalence of atrial fibrillation or peripheral arterial disease.Patients transported by EMS were more likely to receive rapid evaluation(door-to imaging time≤25 min 34.3%vs 11.1%,OR=2.74(95%CI 1.40 to 5.38))and were more likely to receive intravenous tissue plasminogen activator(tPA,22.8%vs 4.6%,OR=4.61(95%CI 3.52 to 6.03)).Among patients treated with tPA,patients who arrived via EMS were more likely to receive timely treatment than self-transported patients(door-to needle time≤60 min 52.6%vs 29.4%,OR=2.58(95%CI 1.35 to 4.92)).Conclusions EMS use is associated with timely stroke evaluation and treatment in Singapore.Seamless EMS-Hospital stroke pathways and targeted public campaigns to advocate for appropriate EMS use have the potential to improve acute stroke care.展开更多
Dear Editor,c-Myc is highly associated with poor prognosis and aggressive progression of diffuse large B cell lymphoma(DLBCL)and is thus a desirable drug target.Moreover,studies indicate that 5–15%of DLBCL patients h...Dear Editor,c-Myc is highly associated with poor prognosis and aggressive progression of diffuse large B cell lymphoma(DLBCL)and is thus a desirable drug target.Moreover,studies indicate that 5–15%of DLBCL patients harbor MYC and BCL-2 translocations,while 20–35%DLBCL patients simultaneously overexpress of c-Myc and BCL-2 proteins without gene rearrangements.1 These two types of DLBCL are referred as“double-hit”lymphoma(DHL)and“double-expressor”lymphoma(DEL),respectively.Both DHL and DEL lymphomas have inferior clinical outcomes and are refractory to R-CHOP or even hematopoietic stem cell transplant.2 Thus,targeting both c-Myc and BCL-2 is a promising strategy to treat high-risk DLBCLs.3 Although BCL-2 inhibitors are clinically available,c-Myc remains to be“undruggable”owing to its lack of kinase activity and intrinsically disordered structure.4 Thus,developing clinically applicable c-Myc inhibitor remains challenging.展开更多
The stability of Ikaros family zinc finger protein 1(Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon(CRBN)ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.Ho...The stability of Ikaros family zinc finger protein 1(Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon(CRBN)ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.However,other stabilization mechanisms of Ikaros have yet to be elucidated.In this study,we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia(AML)cells.Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros,which is accompanied with the increased ubiquitination of Ikaros.Moreover,Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein(CHIP),which mediates the STA-9090-induced ubiquitination of Ikaros.In addition,the knockdown of Ikaros effectively inhibits the proliferation of leukemia cells,but this phenomenon could be rescued by Ikaros overexpression.Collectively,our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells,which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.展开更多
文摘Purpose:To compare self-reported diabetes treatments among Chinese urban residents,rural migrants in urban settings,and rural residents.Methods:Data from 993 diabetics at least 45 years of age were collected from the China Health and Retirement Longitudinal Study conducted in 2011.Multiple logistic regressions were performed to examine the associations between individual characteristics and diabetes treatments.Results:In total,719/993(72.4%)of the respondents received treatment for diabetes;of which<8% used insulin therapy.Urban residents were more likely than rural residents to use insulin therapy[odds ratio(OR)=0.44,confidence interval(CI):0.20-0.99;p<0.05],and more likely to use traditional Chinese medicine than migrants(OR=0.30,CI:0.10-0.96;p<0.05).Overall,rural residents showed lower treatment rates than urban and migrant populations.Conclusion:Efforts to improve and enhance diabetes treatments,particularly among rural residents,are urgently needed in China.
基金This work was supported in part by grants from the National Key Research and Development Program of China(no.2017YFA0505200)the National Basic Research Program of China(973 Program)(no.2015CB910403)+3 种基金the National Natural Science Foundation of China(81700475,81670139,81570118,and 81570112)Natural Science Foundation of Shanghai(16ZR1427800)the Science and Technology Committee of Shanghai(15401901800)the Innovation Program of Shanghai Municipal Education Commission(13YZ028).
文摘T-cell acute lymphoblastic leukemia(T-ALL)is a highly aggressive leukemia that is primarily caused by aberrant activation of the NOTCH1 signaling pathway.Recent studies have revealed that posttranslational modifications,such as ubiquitination,regulate NOTCH1 stability,activity,and localization.However,the specific deubiquitinase that affects NOTCH1 protein stability remains unestablished.Here,we report that ubiquitin-specific protease 7(USP7)can stabilize NOTCH1.USP7 deubiquitinated NOTCH1 in vivo and in vitro,whereas knockdown of USP7 increased the ubiquitination of NOTCH1.USP7 interacted with NOTCH1 protein in T-ALL cells,and the MATH and UBL domains of USP7 were responsible for this interaction.Depletion of USP7 significantly suppressed the proliferation of T-ALL cells in vitro and in vivo,accompanied by downregulation of the NOTCH1 protein level.Similarly,pharmacologic inhibition of USP7 led to apoptosis of T-ALL cells.More importantly,we found that USP7 was significantly upregulated in human T-ALL cell lines and patient samples,and a USP7 inhibitor exhibited cell cytotoxicity toward primary T-ALL cells,indicating the clinical relevance of these findings.Overall,our results demonstrate that USP7 is a novel deubiquitinase that stabilizes NOTCH1.Therefore,USP7 may be a promising therapeutic target in the currently incurable T-ALL.
基金supported in part by the National Key Research and Development Program of China (2017YFA0505202)the National Natural Science Foundation of China (81700475)the Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases and the State Key Laboratory of Oncogenes and Related Genes (KF2107)。
文摘Deubiquitinates(DUBs) alter the stabilities, localizations or activities of substrates by removing their ubiquitin conjugates,which are closely related to the development of inflammatory response. Here, we show that ubiquitin-specific protease 47(USP47) prevents inflammation development in inflammatory bowel disease(IBD). Compared with wild-type mice, Usp47 knockout mice are more susceptible to dextran sodium sulfate(DSS)-induced acute and chronic colitis with higher inflammatory cytokines expression and severe intestinal tissue damage. Chimeric mouse experiments suggest that non-hematopoietic cells mainly contribute to the phenotype. And, DSS-induced colitis of the Usp47 knockout mice depends on commensal bacteria.Mechanistically, down-regulation of USP47 aggravates the activation of NF-κB signaling pathway by increasing the K63-linked poly-ubiquitination of tumor necrosis factor receptor-associated factor 6(TRAF6) in intestinal epithelial cells. Furthermore, the expression of USP47, negatively correlated with the degree of inflammation, is lower at colonic inflammatory lesions than that non-inflammatory sites from the intestine from ulcerative colitis(UC) and Crohn's disease(CD) patients. These data, taken together, indicate that USP47 regulates intestinal inflammation through de-ubiquitination of K63-linked poly-ubiquitination TRAF6 in intestinal epithelial cells.
文摘Background Emergency medical services(EMS)is a critical link in the chain of stroke survival.We aimed to assess EMS use for stroke in Singapore,identify characteristics associated with EMS use and the association of EMS use with stroke evaluation and treatment.Methods The Singapore Stroke Registry combines nationwide EMS and public hospital data for stroke cases in Singapore.Multivariate regressions with the generalised estimating equations were performed to examine the association between EMS use and timely stroke evaluation and treatment.results Of 3555 acute ischaemic patients with symptom onset within 24 hours admitted to all five public hospitals between 2015 and 2016,68%arrived via EMS.Patients who used EMS were older,were less likely to be female,had higher stroke severity by National Institute of Health Stroke Scale and had a higher prevalence of atrial fibrillation or peripheral arterial disease.Patients transported by EMS were more likely to receive rapid evaluation(door-to imaging time≤25 min 34.3%vs 11.1%,OR=2.74(95%CI 1.40 to 5.38))and were more likely to receive intravenous tissue plasminogen activator(tPA,22.8%vs 4.6%,OR=4.61(95%CI 3.52 to 6.03)).Among patients treated with tPA,patients who arrived via EMS were more likely to receive timely treatment than self-transported patients(door-to needle time≤60 min 52.6%vs 29.4%,OR=2.58(95%CI 1.35 to 4.92)).Conclusions EMS use is associated with timely stroke evaluation and treatment in Singapore.Seamless EMS-Hospital stroke pathways and targeted public campaigns to advocate for appropriate EMS use have the potential to improve acute stroke care.
基金supported in part by grants from the National Key Research and Development Program of China(No.2017YFA0505200)Science and Technology Committee of Shanghai(19ZR1428700,15401901800)National Natural Science Foundation of China(81700157,81570118,81700475,81870156).
文摘Dear Editor,c-Myc is highly associated with poor prognosis and aggressive progression of diffuse large B cell lymphoma(DLBCL)and is thus a desirable drug target.Moreover,studies indicate that 5–15%of DLBCL patients harbor MYC and BCL-2 translocations,while 20–35%DLBCL patients simultaneously overexpress of c-Myc and BCL-2 proteins without gene rearrangements.1 These two types of DLBCL are referred as“double-hit”lymphoma(DHL)and“double-expressor”lymphoma(DEL),respectively.Both DHL and DEL lymphomas have inferior clinical outcomes and are refractory to R-CHOP or even hematopoietic stem cell transplant.2 Thus,targeting both c-Myc and BCL-2 is a promising strategy to treat high-risk DLBCLs.3 Although BCL-2 inhibitors are clinically available,c-Myc remains to be“undruggable”owing to its lack of kinase activity and intrinsically disordered structure.4 Thus,developing clinically applicable c-Myc inhibitor remains challenging.
基金supported by the National Key Research and Development Program of China(2017YFA0505200)Science and Technology Committee of Shanghai(19ZR1428700,20ZR1430600)the National Natural Science Foundation of China(81272886,81570118,81570112,81700157,81700475)。
文摘The stability of Ikaros family zinc finger protein 1(Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon(CRBN)ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.However,other stabilization mechanisms of Ikaros have yet to be elucidated.In this study,we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia(AML)cells.Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros,which is accompanied with the increased ubiquitination of Ikaros.Moreover,Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein(CHIP),which mediates the STA-9090-induced ubiquitination of Ikaros.In addition,the knockdown of Ikaros effectively inhibits the proliferation of leukemia cells,but this phenomenon could be rescued by Ikaros overexpression.Collectively,our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells,which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.