We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma（RCC） patients and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase...We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma（RCC） patients and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched.We included phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively.The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals（CI）, were calculated using fixed-or random-effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and 22 were associated with sorafenib. The incidences of hypertension（24.9%vs. 7.9%）, fatigue（8.2% vs. 6.6%）, and gastrointestinal toxicity（17.6% vs. 11.3%） were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower in patients receiving axitinib versus those receiving sorafenib（9.5% vs. 13.3%）. In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy.展开更多
Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic pa...Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic patients and 352 healthy volunteers from the same area of southeast China. Genotyping of each selected SNP was performed using multiplex PCR in conjunction with tagged array single base extension technology. We conducted case-control and case-only association studies between the selected SNPs in TLR7 and TLR8 and asthma or asthma-related phenotypes. Results： The T allele of rs5935436 SNP in TLR7 was protective from developing asthma in males （adjusted ORs = 0.126, 95% CIs = 0.016-0.995）. The CT/TT genotype of rs5935436 was less frequent in female asthmatics with allergic rhinitis （adjusted ORs = 0.18, 95% CIs = 0.04-0.90）. The homozygote AA of rs3761623 and GG of rs3764880 were positively associated with lower FEV1% and asthma severity in female asthmatics. These results were confirmed by haplotype analysis. Conclusion：TLR7 and TLR8 polymorphisms may play an important role in the pathogenesis of asthma that is gender-dependent. This could be clinically useful, both for identifying patients at risk of asthma and for preventing its occurrence.展开更多
Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distributio...Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distribution, an expectation-maximization（EM） algorithm of the hazard ratio was derived, and several simulation studies were used to verify its applications. The method had obvious variation in the hazard ratio estimates and overestimation for the relatively small hazard ratios. Our studies showed that the stability of the EM estimation results directly correlated with the sample size, the convergence of the EM algorithm was impacted by the initial values, and a balanced design produced the best estimates. No reliable blinded sample size re-estimation inference can be made in our studies, but the results provide useful information to steer the practitioners in this field from repeating the same endeavor.展开更多
Objective:Cardiovascular disease(CVD)is one of the leading causes of death worldwide,and answers are urgently needed regarding many aspects,particularly risk identification and prognosis prediction.Real-world studies ...Objective:Cardiovascular disease(CVD)is one of the leading causes of death worldwide,and answers are urgently needed regarding many aspects,particularly risk identification and prognosis prediction.Real-world studies with large numbers of observations provide an important basis for CVD research but are constrained by high dimensionality,and missing or unstructured data.Machine learning(ML)methods,including a variety of supervised and unsupervised algorithms,are useful for data governance,and are effective for high dimensional data analysis and imputation in real-world studies.This article reviews the theory,strengths and limitations,and applications of several commonly used ML methods in the CVD field,to provide a reference for further application.Methods:This article introduces the origin,purpose,theory,advantages and limitations,and applications of multiple commonly used ML algorithms,including hierarchical and k-means clustering,principal component analysis,random forest,support vector machine,and neural networks.An example uses a random forest on the Systolic Blood Pressure Intervention Trial(SPRINT)data to demonstrate the process and main results of ML application in CVD.Conclusion:ML methods are effective tools for producing real-world evidence to support clinical decisions and meet clinical needs.This review explains the principles of multiple ML methods in plain language,to provide a reference for further application.Future research is warranted to develop accurate ensemble learning methods for wide application in the medical field.展开更多
Spinal cord injury(SCI)is a severe disease of the nervous system that causes irreparable damage and loss of function,for which no effective treatments are available to date.Engineered extracellular vesicles(EVs)carryi...Spinal cord injury(SCI)is a severe disease of the nervous system that causes irreparable damage and loss of function,for which no effective treatments are available to date.Engineered extracellular vesicles(EVs)carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy.In this study,we demonstrated the design of a drug delivery system of peptide CAQK-modified,siRNA-loaded EVs(C-EVs-siRNA)for SCI-targeted therapy.The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells(iNSCs).CCL2-siRNA was then loaded into the EVs through electroporation.The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo.C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells.C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA,thus enhancing the therapeutic effect against SCI.The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI,promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI.Thus,engineered EVs are a potentially feasible and efficacious treatment for SCI,and may also be used to develop targeted treatments for other diseases.展开更多
To improve the logic stability of conventional multi-valued logic（MVL） circuits designed with a GaNbased resonate tunneling diode（RTD）, we proposed a GaN/InGaN/AlGaN multi-quantum well（MQW） RTD. The proposed RTD...To improve the logic stability of conventional multi-valued logic（MVL） circuits designed with a GaNbased resonate tunneling diode（RTD）, we proposed a GaN/InGaN/AlGaN multi-quantum well（MQW） RTD. The proposed RTD was simulated through solving the coupled Schrodinger and Poisson equations in the numerical non-equilibrium Green＇s function（NEGF） method on the TCAD platform. The proposed RTD was grown layer by layer in epitaxial technologies. Simulated results indicate that its current-voltage characteristic appears to have a wider total negative differential resistance region than those of conventional ones and an obvious hysteresis loop at room temperature. To increase the Al composite of AIGaN barrier layers properly results in increasing of both the total negative differential resistance region width and the hysteresis loop width, which is helpful to improve the logic stability of MVL circuits. Moreover, the complement resonate tunneling transistor pair consisted of the proposed RTDs or the proposed RTD and enhanced mode HEMT controlled RTD8 is capable of generating versatile MVL modes at different supply voltages less than 3.3 V, which is very attractive for implementing more complex MVL function digital integrated circuits and systems with less devices, super high speed linear or nonlinear ADC and voltage sensors with a built-in super high speed ADC function.展开更多
Background:Accurate diagnosis of intrahepatic cholangiocarcinoma(ICC)caused by intrahepatic lithiasis(IHL)is crucial for timely and effective surgical intervention.The aim of the present study was to develop a nomogra...Background:Accurate diagnosis of intrahepatic cholangiocarcinoma(ICC)caused by intrahepatic lithiasis(IHL)is crucial for timely and effective surgical intervention.The aim of the present study was to develop a nomogram to identify ICC associated with IHL(IHL-ICC).Methods:The study included 2,269 patients with IHL,who received pathological diagnosis after hepatectomy or diagnostic biopsy.Machine learning algorithms including Lasso regression and random forest were used to identify important features out of the available features.Univariate and multivariate logistic regression analyses were used to reconfirm the features and develop the nomogram.The nomogram was externally validated in two independent cohorts.Results:The seven potential predictors were revealed for IHL-ICC,including age,abdominal pain,vomiting,comprehensive radiological diagnosis,alkaline phosphatase(ALK),carcinoembryonic antigen(CEA),and cancer antigen(CA)19-9.The optimal cutoff value was 2.05μg/L for serum CEA and 133.65 U/mL for serum CA 19-9.The accuracy of the nomogram in predicting ICC was 82.6%.The area under the curve(AUC)of nomogram in training cohort was 0.867.The AUC for the validation set was 0.881 from The Second Affiliated Hospital of Wenzhou Medical University,and 0.938 from The First Affiliated Hospital of Fujian Medical University.Conclusions:The nomogram holds promise as a novel and accurate tool to predict IHL-ICC,which can identify lesions in IHL in time for hepatectomy or avoid unnecessary surgical resection.展开更多
Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we cond...Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we conducted a multicenter,randomized,phase 3 study to compare the efficacy and safety of cis-platin plus Lipusu(LP)versus cisplatin plus gemcitabine(GP)as first-line treat-ment in locally advanced or metastatic LSCC.Methods:Patients enrolled were aged between 18 to 75 years,had locally advanced(clinical stage IIIB,ineligible for concurrent chemoradiation or surgery)or metastatic(Stage IV)LSCC,had no previous systemic chemother-apy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors(version 1.1)before administration of the trial drug.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety profiles.To explore the possible predictive value of plasma cytokines for LP treatment,plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology.The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.Results:The median duration of follow-up was 15.4 months.237 patients in the LP group and 253 patients in the GP group were included in the per protocol set(PPS).In the PPS,the median PFS was 5.2 months versus 5.5 months in the LP and GP group(hazard rtio[HR]:1.03,P=0.742)respectively.The median OS was 14.6 months versus 12.5 months in the LP and GP group(HR:0.83,P=0.215).The ORR(41.8%versus 45.9%,P=0.412)and DCR(90.3%versus 88.1%,P=0.443)were also similar between the LP and GP group.A significantly lower proportion of patients in the LP group experienced adverse events(AEs)leading to treatment interruptions(10.9%versus 26.4%,P<0.001)or treatment termination(14.3%versus 23.1%,P=0.011).The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR,and 15 cytokines were associated with improved PFS,with 14 cytokines,including TNF-a,IFN-y,IL-6,and IL-8,demonstrating an overlapping trend.Conclusion:The LP regimen demonstrated similar PFS,OS,ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles.The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.展开更多
基金supported by grants from the National Natural Science Foundation of China (81773554 to H. Yu)the National Natural Science Foundation of China Grant for Young Scientists (81302512 to J. Bai)
文摘We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma（RCC） patients and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched.We included phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively.The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals（CI）, were calculated using fixed-or random-effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and 22 were associated with sorafenib. The incidences of hypertension（24.9%vs. 7.9%）, fatigue（8.2% vs. 6.6%）, and gastrointestinal toxicity（17.6% vs. 11.3%） were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower in patients receiving axitinib versus those receiving sorafenib（9.5% vs. 13.3%）. In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy.
基金supported by grants from the National Natural Science Foundation of China 30400191 and 30570797
文摘Objective： To evaluate the effects of polymorphisms in TLR7 and TLRS（as potential candidate genes） on asthma risk and asthma-related phenotypes. Methods： We consecutively recruited 318 unrelated adult asthmatic patients and 352 healthy volunteers from the same area of southeast China. Genotyping of each selected SNP was performed using multiplex PCR in conjunction with tagged array single base extension technology. We conducted case-control and case-only association studies between the selected SNPs in TLR7 and TLR8 and asthma or asthma-related phenotypes. Results： The T allele of rs5935436 SNP in TLR7 was protective from developing asthma in males （adjusted ORs = 0.126, 95% CIs = 0.016-0.995）. The CT/TT genotype of rs5935436 was less frequent in female asthmatics with allergic rhinitis （adjusted ORs = 0.18, 95% CIs = 0.04-0.90）. The homozygote AA of rs3761623 and GG of rs3764880 were positively associated with lower FEV1% and asthma severity in female asthmatics. These results were confirmed by haplotype analysis. Conclusion：TLR7 and TLR8 polymorphisms may play an important role in the pathogenesis of asthma that is gender-dependent. This could be clinically useful, both for identifying patients at risk of asthma and for preventing its occurrence.
基金supported by the National Natural Science Foundation of China(81273184)the National Natural Science Foundation of China Grant for Young Scientists (81302512)
文摘Sample size re-estimation is essential in oncology studies. However, the use of blinded sample size reassessment for survival data has been rarely reported. Based on the density function of the exponential distribution, an expectation-maximization（EM） algorithm of the hazard ratio was derived, and several simulation studies were used to verify its applications. The method had obvious variation in the hazard ratio estimates and overestimation for the relatively small hazard ratios. Our studies showed that the stability of the EM estimation results directly correlated with the sample size, the convergence of the EM algorithm was impacted by the initial values, and a balanced design produced the best estimates. No reliable blinded sample size re-estimation inference can be made in our studies, but the results provide useful information to steer the practitioners in this field from repeating the same endeavor.
基金This study was funded by the National Natural Science Foundation of China(project No.82173620 to Y.Z.,82204156 to D.Y.)This study was also funded by the Priority Academic Program Development of Jiangsu Higher Education Institution(PAPD).
文摘Objective:Cardiovascular disease(CVD)is one of the leading causes of death worldwide,and answers are urgently needed regarding many aspects,particularly risk identification and prognosis prediction.Real-world studies with large numbers of observations provide an important basis for CVD research but are constrained by high dimensionality,and missing or unstructured data.Machine learning(ML)methods,including a variety of supervised and unsupervised algorithms,are useful for data governance,and are effective for high dimensional data analysis and imputation in real-world studies.This article reviews the theory,strengths and limitations,and applications of several commonly used ML methods in the CVD field,to provide a reference for further application.Methods:This article introduces the origin,purpose,theory,advantages and limitations,and applications of multiple commonly used ML algorithms,including hierarchical and k-means clustering,principal component analysis,random forest,support vector machine,and neural networks.An example uses a random forest on the Systolic Blood Pressure Intervention Trial(SPRINT)data to demonstrate the process and main results of ML application in CVD.Conclusion:ML methods are effective tools for producing real-world evidence to support clinical decisions and meet clinical needs.This review explains the principles of multiple ML methods in plain language,to provide a reference for further application.Future research is warranted to develop accurate ensemble learning methods for wide application in the medical field.
基金This work was sponsored by the National Natural Science Foundation of China(grant No.81974335,82172426).We would like to thank the Core Facility of the First Affiliated Hospital of Nanjing Medical University for its help in the experiment.
文摘Spinal cord injury(SCI)is a severe disease of the nervous system that causes irreparable damage and loss of function,for which no effective treatments are available to date.Engineered extracellular vesicles(EVs)carrying therapeutic molecules hold promise as an alternative SCI therapy depending on the specific functionalized EVs and the appropriate engineering strategy.In this study,we demonstrated the design of a drug delivery system of peptide CAQK-modified,siRNA-loaded EVs(C-EVs-siRNA)for SCI-targeted therapy.The peptide CAQK was anchored through a chemical modification to the membranes of EVs isolated from induced neural stem cells(iNSCs).CCL2-siRNA was then loaded into the EVs through electroporation.The modified EVs still maintained the basic properties of EVs and showed favorable targeting and therapeutic effects in vitro and in vivo.C-EVs-siRNA specifically delivered siRNA to the SCI region and was taken up by target cells.C-EVs-siRNA used the inherent anti-inflammatory and neuroreparative functions of iNSCs-derived EVs in synergy with the loaded siRNA,thus enhancing the therapeutic effect against SCI.The combination of targeted modified EVs and siRNA effectively regulated the microenvironmental disturbance after SCI,promoted the transformation of microglia/macrophages from M1 to M2 and limited the negative effects of the inflammatory response and neuronal injury on functional recovery in mice after SCI.Thus,engineered EVs are a potentially feasible and efficacious treatment for SCI,and may also be used to develop targeted treatments for other diseases.
基金Project supported by the National Natural Science Foundation of China(Nos.61302009,61571171)
文摘To improve the logic stability of conventional multi-valued logic（MVL） circuits designed with a GaNbased resonate tunneling diode（RTD）, we proposed a GaN/InGaN/AlGaN multi-quantum well（MQW） RTD. The proposed RTD was simulated through solving the coupled Schrodinger and Poisson equations in the numerical non-equilibrium Green＇s function（NEGF） method on the TCAD platform. The proposed RTD was grown layer by layer in epitaxial technologies. Simulated results indicate that its current-voltage characteristic appears to have a wider total negative differential resistance region than those of conventional ones and an obvious hysteresis loop at room temperature. To increase the Al composite of AIGaN barrier layers properly results in increasing of both the total negative differential resistance region width and the hysteresis loop width, which is helpful to improve the logic stability of MVL circuits. Moreover, the complement resonate tunneling transistor pair consisted of the proposed RTDs or the proposed RTD and enhanced mode HEMT controlled RTD8 is capable of generating versatile MVL modes at different supply voltages less than 3.3 V, which is very attractive for implementing more complex MVL function digital integrated circuits and systems with less devices, super high speed linear or nonlinear ADC and voltage sensors with a built-in super high speed ADC function.
文摘Background:Accurate diagnosis of intrahepatic cholangiocarcinoma(ICC)caused by intrahepatic lithiasis(IHL)is crucial for timely and effective surgical intervention.The aim of the present study was to develop a nomogram to identify ICC associated with IHL(IHL-ICC).Methods:The study included 2,269 patients with IHL,who received pathological diagnosis after hepatectomy or diagnostic biopsy.Machine learning algorithms including Lasso regression and random forest were used to identify important features out of the available features.Univariate and multivariate logistic regression analyses were used to reconfirm the features and develop the nomogram.The nomogram was externally validated in two independent cohorts.Results:The seven potential predictors were revealed for IHL-ICC,including age,abdominal pain,vomiting,comprehensive radiological diagnosis,alkaline phosphatase(ALK),carcinoembryonic antigen(CEA),and cancer antigen(CA)19-9.The optimal cutoff value was 2.05μg/L for serum CEA and 133.65 U/mL for serum CA 19-9.The accuracy of the nomogram in predicting ICC was 82.6%.The area under the curve(AUC)of nomogram in training cohort was 0.867.The AUC for the validation set was 0.881 from The Second Affiliated Hospital of Wenzhou Medical University,and 0.938 from The First Affiliated Hospital of Fujian Medical University.Conclusions:The nomogram holds promise as a novel and accurate tool to predict IHL-ICC,which can identify lesions in IHL in time for hepatectomy or avoid unnecessary surgical resection.
基金Nanjing Luye Pharmaceutical Co.Ltd,Nanjing,China,Grant/Award Number:2017ZZ02012sponsored by Nanjing Luye Pharmaceu-tical Co.Ltd,Nanjing,China,and supported in part by grants from Shanghai Key disciplines of Respiratory(No.2017ZZ02012)and Shanghai Major Diseases Multidisci-plinary Cooperation Diagnosis and Treatment Construc-tion Project.
文摘Background:Lipusu is the first commercialized liposomal formulation of pacli-taxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma(LSCC)in a small-scale study.Here,we conducted a multicenter,randomized,phase 3 study to compare the efficacy and safety of cis-platin plus Lipusu(LP)versus cisplatin plus gemcitabine(GP)as first-line treat-ment in locally advanced or metastatic LSCC.Methods:Patients enrolled were aged between 18 to 75 years,had locally advanced(clinical stage IIIB,ineligible for concurrent chemoradiation or surgery)or metastatic(Stage IV)LSCC,had no previous systemic chemother-apy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors(version 1.1)before administration of the trial drug.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),disease control rate(DCR),overall survival(OS),and safety profiles.To explore the possible predictive value of plasma cytokines for LP treatment,plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology.The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses.Results:The median duration of follow-up was 15.4 months.237 patients in the LP group and 253 patients in the GP group were included in the per protocol set(PPS).In the PPS,the median PFS was 5.2 months versus 5.5 months in the LP and GP group(hazard rtio[HR]:1.03,P=0.742)respectively.The median OS was 14.6 months versus 12.5 months in the LP and GP group(HR:0.83,P=0.215).The ORR(41.8%versus 45.9%,P=0.412)and DCR(90.3%versus 88.1%,P=0.443)were also similar between the LP and GP group.A significantly lower proportion of patients in the LP group experienced adverse events(AEs)leading to treatment interruptions(10.9%versus 26.4%,P<0.001)or treatment termination(14.3%versus 23.1%,P=0.011).The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR,and 15 cytokines were associated with improved PFS,with 14 cytokines,including TNF-a,IFN-y,IL-6,and IL-8,demonstrating an overlapping trend.Conclusion:The LP regimen demonstrated similar PFS,OS,ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles.The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.
