Polymer acceptor configuration and aggregation behavior are critical in determining the photovoltaic performance of all-polymer solar cells(all-PSCs).Effectively manipulating polymer self-aggregation through structura...Polymer acceptor configuration and aggregation behavior are critical in determining the photovoltaic performance of all-polymer solar cells(all-PSCs).Effectively manipulating polymer self-aggregation through structural design to optimize the blend morphology remains challenging.Herein,we present a simple yet effective design strategy to modulate the aggregation behavior of the Y-series-based polymer acceptor PY-V-γby introducing a pendant-fluorinated Y-series acceptor(Y2F-ET)into the main-conjugated backbone.Two random copolymer acceptors(PY-EY-5 and PY-EY-20)were synthesized with varying molar fractions of Y2F-ET pendant monomers.Our findings revealed that both the solution-phase and solid-state aggregation behaviors were progressively suppressed as the Y2F-ET content increased.Compared to the highly self-aggregating PY-V-γ-based all-PSCs,the more amorphous PY-EY-5 enabled devices to achieve an increased device efficiency from 17.31%to 18.45%,which is attributed to the slightly smaller polymer phase-separation domain sizes and reduced molecular aggregation in the PM6:PY-EY-5 blend.Moreover,the finely tuned blend morphology exhibited superior thermal stability,underscoring the significant advantages of the Y-series pendant random copolymerization approach.展开更多
Finding effective molecular design strategies to enable efficient charge generation,high charge transport,and small energy loss is a longstanding challenge for developing high-performance all-polymer solar cells(all-P...Finding effective molecular design strategies to enable efficient charge generation,high charge transport,and small energy loss is a longstanding challenge for developing high-performance all-polymer solar cells(all-PSCs).Here,we designed and synthesized a fused-aromatic-ring-constructed near-infrared(NIR)polymer acceptor(PA)PYT-Tz with fused-ring benzotriazole(BTz)-based A’-DAD-A’structure as electron-deficient-core,n-nonane as alkyl-side-chain and thiophene asπ-bridge,and achieved a power conversion efficiency(PCE)of 15.10%for the all-PSCs with PYT-Tz as acceptor and a wide-bandgap PBDB-T as donor.A control PA PYT reported by our lab recently was introduced for investigating the synergistic effect of the electron-deficient-core and alkyl-side-chain on the optoelectronic properties and photovoltaic performance of the n-type PAs.Compared with PYT,the designed PYT-Tz exhibits intense and red-shifted absorption,upshifted energy levels,high electron mobility and ordered molecular packing in the active layers,and,blended with PBDB-T,yields the efficient hole injection,ultrafast charge generation,and the decreased non-radiative recombination loss of 0.17 eV.Of note is that the PCE of 15.10%is one of the highest PCE values for an all-PSC reported to date.Our results indicate BTz-based fused-aromatic-ring-constructed PAs are promising NIR acceptors in the all-PSCs.展开更多
Circulating tumor cells(CTCs),arising from the spread of primary or metastatic tumors,are crucial in understanding tumor metastasis.Unlike traditional serum biomarkers,CTCs,being actual tumor cells,offer more direct i...Circulating tumor cells(CTCs),arising from the spread of primary or metastatic tumors,are crucial in understanding tumor metastasis.Unlike traditional serum biomarkers,CTCs,being actual tumor cells,offer more direct insight into the specific tumor's biology[1].In the past decade,CTCs proved instrumental in the diagnosis of cancer,as well as for prognostic prediction,and monitoring the response to treatment[2].展开更多
Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ...Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).展开更多
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma(HCC).Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffecti...The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma(HCC).Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib.The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab,cabozantinib,and the most influential,immune checkpoint inhibitors(ICIs).Over the same period combination therapies,including anti-angiogenesis agents with ICIs,dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies,have been extensively investigated and have shown promise and provided the basis for exciting clinical trials.Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance,with the goal of improving the survival of patients with HCC.展开更多
Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis a...Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system （Shanghai Score） for individualized prognosis estimation and adjuvant treatment evaluation. Methods： A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, y-glutamyltransferase, a-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell＇s concordance index （C-index） was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable＇s corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis.Results： Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index （confidence interval [CI]） was 0.74 for overall survival （OS） and 0.68 for recurrence-free survival （RFS） in derivation cohort （4166 patients）, and in the three independent validation cohorts, the CIs for OS ranged 0.70 0.72 and that for RFS ranged 0.63 0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices （transcatheter arterial chemoembolization or interferon-a）. The identified subset of patients at low risk could be ideal candidates for curative surgery, and subsets of patients at moderate or high risk could be recommended with possible adjuvant therapies after surgery. Finally, a web server with individualized outcome prediction and treatment recommendation was constructed. Conclusions： Based on the largest cohort up to date, we established Shanghai Score - an individualized outcome prediction system specifically designed for Chinese HCC patients after surgery. The Shanghai Score web server provides an easily accessible tool to stratify the prognosis of patients undergoing liver resection for HCC.展开更多
Fluorescent probes have emerged as indispensable chemical tools to the field of chemical biology and medicine.The ability to detect intracellular species and monitor physiological processes has not only advanced our k...Fluorescent probes have emerged as indispensable chemical tools to the field of chemical biology and medicine.The ability to detect intracellular species and monitor physiological processes has not only advanced our knowledge in biology but has provided new approaches towards disease diagnosis.In this review,we detail the design criteria and strategies for some recently reported fluorescent probes that can detect a wide range of biologically important species in cells and in vivo.In doing so,we highlight the importance of each biological species and their role in biological systems and for disease progression.We then discuss the current problems and challenges of existing technologies and provide our perspective on the future directions of the research area.Overall,we hope this review will provide inspiration for researchers and prove as useful guide for the development of the next generation of fluorescent probes.展开更多
Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from pr...Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC.In this study,we performed whole-genome sequencing(WGS)on 40 pairs of primary and early-recurrent hepatitis B virus(HBV)-related HCC tumors from patients who received curative resection,and from four patients whose primary and recurrent tumor were extensively sampled.We identified two recurrence patterns:de novo recurrence(18/40),which developed genetically independently of the primary tumor and carried different HCC drivers,and ancestral recurrence(22/40),which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence.We found that the recurrence location was predictive of the recurrence pattern:distant recurrence tended to display the de novo pattern,whereas local recurrence tended to display the ancestral pattern.We then uncovered the evolutionary trajectories based on the subclonal architecture,driver-gene mutations,and mutational processes observed in the primary and recurrent tumors.Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal,monophyletic dissemination in HCC ancestral recurrence.In addition,we identified recurrence-specific mutations and copy-number gains in BCL9,leading to WNT/β-catenin signaling activation and an immuneexcluded tumor microenvironment,which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC.Collectively,our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence,providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.展开更多
Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this disease.Inhibiting MDM2 has been dem...Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this disease.Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC.However,most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding,and have limited efficacy against tumors with mutant or deficient p53.In the present study,we developed a novel MDM2 inhibitor(termed SP141)that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells.We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion,independent of p53.Mechanistically,SP141 directly binds the MDM2 protein and promotes MDM2 degradation.The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib.In addition,in orthotopic and patient-derived xenograft models,SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis,without any host toxicity.Furthermore,the inhibition of MDM2 by SP141 is essential for its anti-HCC activities.These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.展开更多
Objective: This study was designed to develop a method for detecting differences in the chemical composition of Corydalis yanhusuo W. T. Wang using high-performance liquid chromatography with a diode array detector te...Objective: This study was designed to develop a method for detecting differences in the chemical composition of Corydalis yanhusuo W. T. Wang using high-performance liquid chromatography with a diode array detector technology. Materials and Methods: We established a novel quantitative evaluation method for identifying multiple components in natural extracts using a single-marker method quantitative analysis of multi-components by single marker(QAMS). This method was then validated using eight alkaloid phytochemical markers designed to evaluate C. yanhusuo quality. Results: Our evaluations revealed good linearity(R^(2) ≥ 0.9991) within the range of tested concentrations for all eight alkaloids, with recovery ranging from 95.5% to 101.5%. The evaluations also returned stability results that fell within the acceptable range. Cluster analysis and Heatmap analyses were applied to classify and evaluate alkaloids across 21 different production areas. These results revealed a significant difference in the component profiles between samples from different origins. Conclusions: Thus, these data suggest that in the absence of a material reference, QAMS may help facilitate the stable production of C. yanhusuo. In addition, our data suggest that this method may have value as a promising alternative to common quality evaluations for controlling C. yanhusuo composition.展开更多
Background and Aims:The overall survival(OS)of hepatocellular carcinoma(HCC)remains dismal.Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision.This st...Background and Aims:The overall survival(OS)of hepatocellular carcinoma(HCC)remains dismal.Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision.This study aimed to develop a prognostic gene model for HCC.Methods:GSE14520 was retrieved as a training set to identify differential expressed genes(DEGs)between tumor and adjacent liver tissues in HCC patients with different OS.A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model.The area under the receiver operating characteristic curve(AUC)and hazard ratio(HR)of the model for OS were calculated.A model-based nomogram was estab-lished and verified.Results:In the training set,differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation.After univariate Cox and LASSO regression,eight genes(LPCAT1,DHRS1,SORBS2,ALDH5A1,SULT1C2,SPP1,HEY1 and GOLM1)were selected to build the prognostic model.The AUC for 1-,3-and 5-year OS were 0.779,0.736,0.754 in training set and 0.693,0.689,0.693 in the TCGA-LIHC validation set,respectively.The AUC for 1-and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set.Multivariate analysis confirmed the model was an independent prognostic factor(training set:HR=4.422,p<0.001;TCGA-LIHC validation set:HR=2.561,p<0.001;ICGC-LIRI validation set:HR=3.931,p<0.001).Furthermore,a nomogram combining the model and AJCC stage was established and validated,showing increased OS predictive efficacy compared with the prognostic model(p=0.035)or AJCC stage(p<0.001).Conclusions:Our eight-gene prognostic model and the related nomogram represent as reliable prognostic tools for OS prediction in HCC patients.展开更多
We regret that an error was made in“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”(Genes Dis 2019 Dec;694:419e430).In Fig.1C of the original manuscrip...We regret that an error was made in“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”(Genes Dis 2019 Dec;694:419e430).In Fig.1C of the original manuscript,the right panel(showing the migration ability of the MHCCLM3 cells)was erroneously duplicated with the left panel(showing the migration ability of the Huh7 cells)when the figures were assembled.We have now checked the original data and request to replace the right panel with the correct data for MHCCLM3 cells.The corrected Fig.展开更多
Hepatocellular carcinoma(HCC)is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis,which is mainly caused by tumor recurrence and metastasis.Circulating tumor cells(CTCs)a...Hepatocellular carcinoma(HCC)is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis,which is mainly caused by tumor recurrence and metastasis.Circulating tumor cells(CTCs)are tumor cells shed into the bloodstream and regarded as the“seeds”of tumor recurrent or metastatic lesions.Over the past decade,the clinical value of CTC analysis has been extensively explored.CTC analysis is a representative form of liquid biopsy,offering a novel solution that can bypass the problems of invasive biopsy procedures,enabling comprehensive,non-invasive,and real-time disease monitoring.In HCC,CTC analysis has facilitated early detection and prognosis prediction,as well as treatment monitoring and therapeutic intervention guiding.In this review,we summarize available literature and provide an overview of CTC biology,detection technologies,and clinical applications in the diagnosis,prognosis prediction,and personalized treatment of HCC.展开更多
基金supported by the National Natural Science Foundation of China(NSFC)(Nos.22279094 and 22409149)Hubei Provincial Natural Science Foundation(No.2024 AFB068)Fundamental Research Funds for the Central Universities。
文摘Polymer acceptor configuration and aggregation behavior are critical in determining the photovoltaic performance of all-polymer solar cells(all-PSCs).Effectively manipulating polymer self-aggregation through structural design to optimize the blend morphology remains challenging.Herein,we present a simple yet effective design strategy to modulate the aggregation behavior of the Y-series-based polymer acceptor PY-V-γby introducing a pendant-fluorinated Y-series acceptor(Y2F-ET)into the main-conjugated backbone.Two random copolymer acceptors(PY-EY-5 and PY-EY-20)were synthesized with varying molar fractions of Y2F-ET pendant monomers.Our findings revealed that both the solution-phase and solid-state aggregation behaviors were progressively suppressed as the Y2F-ET content increased.Compared to the highly self-aggregating PY-V-γ-based all-PSCs,the more amorphous PY-EY-5 enabled devices to achieve an increased device efficiency from 17.31%to 18.45%,which is attributed to the slightly smaller polymer phase-separation domain sizes and reduced molecular aggregation in the PM6:PY-EY-5 blend.Moreover,the finely tuned blend morphology exhibited superior thermal stability,underscoring the significant advantages of the Y-series pendant random copolymerization approach.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.21702154 and 51773157)We also thank the support of the opening project of Key Laboratory of Materials Processing and Mold and Beijing National Laboratory for Molecular Sciences(No.BNLMS201905).
文摘Finding effective molecular design strategies to enable efficient charge generation,high charge transport,and small energy loss is a longstanding challenge for developing high-performance all-polymer solar cells(all-PSCs).Here,we designed and synthesized a fused-aromatic-ring-constructed near-infrared(NIR)polymer acceptor(PA)PYT-Tz with fused-ring benzotriazole(BTz)-based A’-DAD-A’structure as electron-deficient-core,n-nonane as alkyl-side-chain and thiophene asπ-bridge,and achieved a power conversion efficiency(PCE)of 15.10%for the all-PSCs with PYT-Tz as acceptor and a wide-bandgap PBDB-T as donor.A control PA PYT reported by our lab recently was introduced for investigating the synergistic effect of the electron-deficient-core and alkyl-side-chain on the optoelectronic properties and photovoltaic performance of the n-type PAs.Compared with PYT,the designed PYT-Tz exhibits intense and red-shifted absorption,upshifted energy levels,high electron mobility and ordered molecular packing in the active layers,and,blended with PBDB-T,yields the efficient hole injection,ultrafast charge generation,and the decreased non-radiative recombination loss of 0.17 eV.Of note is that the PCE of 15.10%is one of the highest PCE values for an all-PSC reported to date.Our results indicate BTz-based fused-aromatic-ring-constructed PAs are promising NIR acceptors in the all-PSCs.
基金supported by the National Basic Science Center Project of China(82488101)the National Natural Science Foundation of China(82341027,82072715,62302336,32341008,62088101,and 82403435)+8 种基金National Ten-thousand Talent Program of China,Shanghai Municipal Science and Technology Major Project,the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project(2019CXJQ02)the Shanghai Sailing program(21YF1407300)Shanghai Rising-Star Program(23YF1450200)the Project of Shanghai Municipal Health Commission(2022LJ005)the projects from the Shanghai Science and Technology Commission(21140900300 and 22S31901800)the Eastern Talent Program(leading project)Shanghai Pilot Program for Basic Research,Shanghai Science and Technology Innovation Action Plan-Key Specialization in Computational Biology,China Postdoctoral Science Foundation(2022M722418 and 2023T160485)the project from Shanghai Hospital Development Center(SHDC2023CRD025)the Projects from Science Foundation of Zhongshan Hospital,Fudan university(2021ZSCX28,2020ZSLC31,and ZP2023-017).
文摘Circulating tumor cells(CTCs),arising from the spread of primary or metastatic tumors,are crucial in understanding tumor metastasis.Unlike traditional serum biomarkers,CTCs,being actual tumor cells,offer more direct insight into the specific tumor's biology[1].In the past decade,CTCs proved instrumental in the diagnosis of cancer,as well as for prognostic prediction,and monitoring the response to treatment[2].
基金National Natural Science Foundation of China(81972232,81830102,82150004)Clinical Research Plan of SHDC(SHDC‑2020CR1003A,SHDC-2020CR1022B)+3 种基金National Key Research and Development Program of China(2019YFC1316000,2019YFC1315800,and 2019YFC1315802)the Key Disease Joint Research Program of Xuhui District(XHLHGG202103),the Clinical Medicine Research Pilot Project of Shanghai Medical School of Fudan University(2020,21DGF501035/00)the Shanghai Municipal Natural Science Foundation(20JC1419103,21ZR1412200)Beijing Mutual Care Public Welfare Foundation(GDXZ-08-05)Sanming Project of Medicine in Shenzhen(SZSM202003009),and Shanghai Municipal Key Clinical Specialty Construction Project(shslczdzk02401).
文摘Advanced intrahepatic cholangiocarcinoma(ICC)has a dismal prognosis.Here,we report the efficacy and safety of combining toripalimab,lenvatinib,and gemcitabine plus oxaliplatin(GEMOX)as first-line therapy for advanced ICC.Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine(1 g/m2)on Days 1 and 8 and oxaliplatin(85 mg/m2)Q3W for six cycles along with intravenous toripalimab(240 mg)Q3W and oral lenvatinib(8 mg)once daily for one year.The expression of programmed death-ligand 1(PD-L1)and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing(WES)analysis.The primary endpoint was the objective response rate(ORR).Secondary outcomes included safety,overall survival(OS),progression-free survival(PFS),disease control rate(DCR)and duration of response(DoR).As of July 1,2022,the median follow-up time was 23.5 months,and the ORR was 80%.Twenty-three patients achieved partial response,and one achieved complete response.Patients(21/30)with DNA damage response(DDR)-related gene mutations showed a higher ORR,while patients(14/30)with tumor area positivity≥1(PD-L1 staining)showed a trend of high ORR,but without significant difference.The median OS,PFS,and DoR were 22.5,10.2,and 11.0 months,respectively.The DCR was 93.3%.Further,56.7%of patients experienced manageable grade≥3 adverse events(AEs),commonly neutropenia(40.0%)and leukocytopenia(23.3%).In conclusion,toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC.A phase-III,multicenter,double-blinded,randomized study to validate our findings was approved by the National Medical Products Administration(NMPA,No.2021LP01825).
基金supported by the National Key R&D Program of China(2019YFC1315800,2019YFC1315802)the National Key Research and Development Program(2016YFF0101405)+3 种基金National Natural Science Foundation of China(No.81830102,81772578,81802991,and 81830102),STCSM(18YF1403600)Shanghai Municipal Health Commission Collaborative Innovation Cluster Project(2019CXJQ02)Projects from the Shanghai Science and Technology Commission(19441905000)Shanghai Municipal Key Clinical Specialty.
文摘The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma(HCC).Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib.The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab,cabozantinib,and the most influential,immune checkpoint inhibitors(ICIs).Over the same period combination therapies,including anti-angiogenesis agents with ICIs,dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies,have been extensively investigated and have shown promise and provided the basis for exciting clinical trials.Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance,with the goal of improving the survival of patients with HCC.
基金This study was supported by grants from the National High Technology Research and Development Program （863 Program） of China （No. 2015AA020401）, National Key Research and Development Program of China （No. 2016YFC0904101）, State Key Program of National Natural Science Foundation of China （No. 81530077）, National Natural Science Foundation of China （No. 81372317, 81472676, and 81572823）, Projects from the Shanghai Science and Technology Commission （No. 14DZ1940300, 14411970200, 134119a1201, and 14140902301）, and Specialized Research Fund for the Doctoral Program of Higher Education and Research Grants Council Earmarked Research Grants Joint Research Scheme （No. 20130071140008）.
文摘Background： For Chinese patients with hepatocellular carcinoma （HCC）, surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system （Shanghai Score） for individualized prognosis estimation and adjuvant treatment evaluation. Methods： A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, y-glutamyltransferase, a-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell＇s concordance index （C-index） was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable＇s corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis.Results： Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index （confidence interval [CI]） was 0.74 for overall survival （OS） and 0.68 for recurrence-free survival （RFS） in derivation cohort （4166 patients）, and in the three independent validation cohorts, the CIs for OS ranged 0.70 0.72 and that for RFS ranged 0.63 0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices （transcatheter arterial chemoembolization or interferon-a）. The identified subset of patients at low risk could be ideal candidates for curative surgery, and subsets of patients at moderate or high risk could be recommended with possible adjuvant therapies after surgery. Finally, a web server with individualized outcome prediction and treatment recommendation was constructed. Conclusions： Based on the largest cohort up to date, we established Shanghai Score - an individualized outcome prediction system specifically designed for Chinese HCC patients after surgery. The Shanghai Score web server provides an easily accessible tool to stratify the prognosis of patients undergoing liver resection for HCC.
基金the National Natural Science Foundation of China(21788102,91853201)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX03)+9 种基金the International Cooperation Program of Shanghai Science and Technology Committee(17520750100)the Projects from the Shanghai Science and Techonology Commission(19441905000)the Fundamental Research Funds for the Central Universities(222201717003)the Programme of Introducing Talents of Discipline to Universities(B16017)for financial supportthe National Natural Science Foundation of China(22107028)National Postdoctoral Program for Innovative Talents(BX20190115)Shanghai Post-doctoral Excellence Program(2019044)China Postdoctoral Science Foundation(2020M681206)for financial supportthe Project funded by China Postdoctoral Science Foundation(2020M681196)the Royal Society for a Wolfson Research Merit Award and the Open Research Fund of the School of Chemistry and Chemical Engineering,Henan Normal University for support(2020ZD01)。
文摘Fluorescent probes have emerged as indispensable chemical tools to the field of chemical biology and medicine.The ability to detect intracellular species and monitor physiological processes has not only advanced our knowledge in biology but has provided new approaches towards disease diagnosis.In this review,we detail the design criteria and strategies for some recently reported fluorescent probes that can detect a wide range of biologically important species in cells and in vivo.In doing so,we highlight the importance of each biological species and their role in biological systems and for disease progression.We then discuss the current problems and challenges of existing technologies and provide our perspective on the future directions of the research area.Overall,we hope this review will provide inspiration for researchers and prove as useful guide for the development of the next generation of fluorescent probes.
基金This study was jointly supported by the National Key R&D Program of China(No.2019YFC1315800,2019YFC1315802,2018YFA0109400)the National Natural Science Foundation of China(No.81830102,No.81772578,No.82173260+4 种基金No.81972708,No.82073123,No.81773069,No.82072681,No.82003082)Shanghai Technical Standard Program(21DZ2201100)Shanghai Rising-Star Program(18QA1401200)Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai(2018YQ14)Original Scientific Personalized Support Project of Fudan University(IDF152064/015).
文摘Patients with hepatocellular carcinoma(HCC)have poor long-term survival following curative resection because of the high rate of tumor early recurrence.Little is known about the trajectory of genomic evolution from primary to early-recurrent HCC.In this study,we performed whole-genome sequencing(WGS)on 40 pairs of primary and early-recurrent hepatitis B virus(HBV)-related HCC tumors from patients who received curative resection,and from four patients whose primary and recurrent tumor were extensively sampled.We identified two recurrence patterns:de novo recurrence(18/40),which developed genetically independently of the primary tumor and carried different HCC drivers,and ancestral recurrence(22/40),which was clonally related to the primary tumor and progressed more rapidly than de novo recurrence.We found that the recurrence location was predictive of the recurrence pattern:distant recurrence tended to display the de novo pattern,whereas local recurrence tended to display the ancestral pattern.We then uncovered the evolutionary trajectories based on the subclonal architecture,driver-gene mutations,and mutational processes observed in the primary and recurrent tumors.Multi-region WGS demonstrated spatiotemporal heterogeneity and polyclonal,monophyletic dissemination in HCC ancestral recurrence.In addition,we identified recurrence-specific mutations and copy-number gains in BCL9,leading to WNT/β-catenin signaling activation and an immuneexcluded tumor microenvironment,which suggests that BCL9 might serve as a new therapeutic target for recurrent HCC.Collectively,our results allow us to view with unprecedented clarity the genomic evolution during HBV-related HCC early recurrence,providing an important molecular foundation for enhanced understanding of HCC with implications for personalized therapy to improve patient survival.
基金W.W. and R.Z. were partially supported by National Institutesof Health (NIH)/National Cancer Institute grants(R01 CA186662 and R01CA214019)W.W. and R.Z. were alsosupported by American Cancer Society (ACS) grant RSG-15-009-01-CDD. R.Z. was also supported by funds for Robert L.Boblitt Endowed Professor in Drug Discovery and researchfunds from College of Pharmacy and University of Houston.J.C., J.F., and X-R. Y. were supported by grants from theNational Natural Science Foundation of China (No.81272389, 81472674, 81502486). The content of this reportis solely the responsibility of the authors, and does notnecessarily represent the official views of the National Institutesof Health or other funding agencies.
文摘Overexpression of the MDM2 oncogene and mutations in the p53 tumor suppressor commonly occur in hepatocellular carcinoma(HCC)and are associated with increased mortality due to this disease.Inhibiting MDM2 has been demonstrated to be a valid approach for the treatment of HCC.However,most of the MDM2 inhibitors evaluated to date have been designed to block the MDM2 and p53 binding,and have limited efficacy against tumors with mutant or deficient p53.In the present study,we developed a novel MDM2 inhibitor(termed SP141)that has direct effects on MDM2 and exerts anti-HCC activity independent of the p53 status of the cancer cells.We demonstrate that SP141 inhibits cell growth and prevents cell migration and invasion,independent of p53.Mechanistically,SP141 directly binds the MDM2 protein and promotes MDM2 degradation.The inhibition of MDM2 by SP141 also increases the sensitivity of HCC cells to sorafenib.In addition,in orthotopic and patient-derived xenograft models,SP141 inhibits MDM2 expression and suppresses tumor growth and metastasis,without any host toxicity.Furthermore,the inhibition of MDM2 by SP141 is essential for its anti-HCC activities.These results provide support for the further development of SP141 as a lead candidate for the treatment of HCC.
基金supported by The Scientific Research Project under the National Natural Science Foundation of China(No.81872979 and 81603418)。
文摘Objective: This study was designed to develop a method for detecting differences in the chemical composition of Corydalis yanhusuo W. T. Wang using high-performance liquid chromatography with a diode array detector technology. Materials and Methods: We established a novel quantitative evaluation method for identifying multiple components in natural extracts using a single-marker method quantitative analysis of multi-components by single marker(QAMS). This method was then validated using eight alkaloid phytochemical markers designed to evaluate C. yanhusuo quality. Results: Our evaluations revealed good linearity(R^(2) ≥ 0.9991) within the range of tested concentrations for all eight alkaloids, with recovery ranging from 95.5% to 101.5%. The evaluations also returned stability results that fell within the acceptable range. Cluster analysis and Heatmap analyses were applied to classify and evaluate alkaloids across 21 different production areas. These results revealed a significant difference in the component profiles between samples from different origins. Conclusions: Thus, these data suggest that in the absence of a material reference, QAMS may help facilitate the stable production of C. yanhusuo. In addition, our data suggest that this method may have value as a promising alternative to common quality evaluations for controlling C. yanhusuo composition.
基金the National Key R&D Pro-gram of China(Nos.2019YFC1315800,2019YFC1315802)National Natural Science Foundation of China(Nos.81830102,81772578,81802991),STCSM(No.18YF1403600)Shanghai Municipal Key Clinical Specialty.
文摘Background and Aims:The overall survival(OS)of hepatocellular carcinoma(HCC)remains dismal.Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision.This study aimed to develop a prognostic gene model for HCC.Methods:GSE14520 was retrieved as a training set to identify differential expressed genes(DEGs)between tumor and adjacent liver tissues in HCC patients with different OS.A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model.The area under the receiver operating characteristic curve(AUC)and hazard ratio(HR)of the model for OS were calculated.A model-based nomogram was estab-lished and verified.Results:In the training set,differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation.After univariate Cox and LASSO regression,eight genes(LPCAT1,DHRS1,SORBS2,ALDH5A1,SULT1C2,SPP1,HEY1 and GOLM1)were selected to build the prognostic model.The AUC for 1-,3-and 5-year OS were 0.779,0.736,0.754 in training set and 0.693,0.689,0.693 in the TCGA-LIHC validation set,respectively.The AUC for 1-and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set.Multivariate analysis confirmed the model was an independent prognostic factor(training set:HR=4.422,p<0.001;TCGA-LIHC validation set:HR=2.561,p<0.001;ICGC-LIRI validation set:HR=3.931,p<0.001).Furthermore,a nomogram combining the model and AJCC stage was established and validated,showing increased OS predictive efficacy compared with the prognostic model(p=0.035)or AJCC stage(p<0.001).Conclusions:Our eight-gene prognostic model and the related nomogram represent as reliable prognostic tools for OS prediction in HCC patients.
文摘We regret that an error was made in“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”(Genes Dis 2019 Dec;694:419e430).In Fig.1C of the original manuscript,the right panel(showing the migration ability of the MHCCLM3 cells)was erroneously duplicated with the left panel(showing the migration ability of the Huh7 cells)when the figures were assembled.We have now checked the original data and request to replace the right panel with the correct data for MHCCLM3 cells.The corrected Fig.
基金supported by grants from the National Key Research and Development Program(2016YFF0101405 and 2016YFC0902400)the State Key Program of National Natural Science of China(81530077 and 81830102)+4 种基金the National Natural Science Foundation of China(81602543,81672839,81572823,81772578,81772551,and 81872355)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12020105 and XDA12020103)the Shanghai Municipal Health Commission Collaborative Innovation Cluster Project(2019CXJQ02)Projects from the Shanghai Science and Technology Commission(19441905000)Projects from Shanghai Municipal Key Clinical Specialty.
文摘Hepatocellular carcinoma(HCC)is one of the most common malignant tumors worldwide and is associated with poor clinical prognosis,which is mainly caused by tumor recurrence and metastasis.Circulating tumor cells(CTCs)are tumor cells shed into the bloodstream and regarded as the“seeds”of tumor recurrent or metastatic lesions.Over the past decade,the clinical value of CTC analysis has been extensively explored.CTC analysis is a representative form of liquid biopsy,offering a novel solution that can bypass the problems of invasive biopsy procedures,enabling comprehensive,non-invasive,and real-time disease monitoring.In HCC,CTC analysis has facilitated early detection and prognosis prediction,as well as treatment monitoring and therapeutic intervention guiding.In this review,we summarize available literature and provide an overview of CTC biology,detection technologies,and clinical applications in the diagnosis,prognosis prediction,and personalized treatment of HCC.
