Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induct...Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.展开更多
Objectives:To explore the prognostic relevance of the number and ratio of metastatic lymph nodes in resected Carcinoma of the ampulla of Vater(CAV).Methods:The clinical data of 155 patients who underwent pancreaticodu...Objectives:To explore the prognostic relevance of the number and ratio of metastatic lymph nodes in resected Carcinoma of the ampulla of Vater(CAV).Methods:The clinical data of 155 patients who underwent pancreaticoduodenectomy(PD)for cancer of the ampulla of Vater between January 1990 and December 2010 were retrospectively analyzed.KaplanMeier method was used in survival analysis and Log rank method in comparison.Multivariate analysis was performed using Cox proportional hazards model.Results:Among these 155 patients,the in-hospital mortality rate was 4.5%,lymph node positive disease was21.3%,and the 5-year survival rate was 51.6%.Patients with a lymph node ratio(LNR)>20%were more likely to have tumor differentiation,depth of duodenal involvement,depth of pancreatic invasion,T-stage and TNM-Stage.The number of the metastatic lymph nodes is important prognostic factors of the CAV.Univariate analysis showed that the factors associated with the prognosis included tumor size(P=0.036),tumor differentiation(P=0.019),LNR(P=0.032),number of metastatic lymph nodes(P=0.024),lymph node metastasis(P=0.03),depth of pancreatic invasion(P=0.001),T-stage(P=0.002),TNM stage(P=0.001),elevated CA 19-9(P=0.000),and jaundice(P=0.021).Multivariate analysis showed that the factors associated with the prognosis were the number of metastatic lymph nodes(P=0.032;RR:1.283;95%CI:1.022-1.611),tumor size(P=0.043;RR:1.736;95%CI:1.017-2.963),and elevated CA 19-9(P=0.003;RR:3.247;95%CI:1.504-7.010).Conclusions:LNR is a useful factor for predicting the prognosis of the radical treatment for CAV,whereas the number of metastatic lymph nodes is the most important factor.Further research on the locations,number,and LNR will be clinically meaningful to improve survival in patients with CAV.展开更多
The utilization of cyclobutanones as the synthon in transition metal catalysis has been made great success.Because C(carbonyl)−C bond of cyclobutanones can be cleaved through strain release.Despite those advancements,...The utilization of cyclobutanones as the synthon in transition metal catalysis has been made great success.Because C(carbonyl)−C bond of cyclobutanones can be cleaved through strain release.Despite those advancements,the main catalysts in literature are Rh catalysts or Ni catalysts and the reaction with C—H bond is still underdeveloped.Herein,we realized the first palladium-catalyzed skeletal reorganization of cyclobutanones involving successive cleavage of C(carbonyl)−C bonds and C—H bond cleavage,which constitutes an rapid access to diverse indanones.In contrast to the previous Rh-catalytic system,the Pd-catalytic system herein involves different mechanism and features several advantages:1)no need of directing group to facilitate the C(carbonyl)−C bond cleavage;2)much milder reaction condition and 3)simplified work-up.展开更多
Formal cross-dimerization of two different strained rings represents an innovative strategy toward specific ring systems that are otherwise inaccessible.Yet,formidable challenges remain in controlling the reactivity a...Formal cross-dimerization of two different strained rings represents an innovative strategy toward specific ring systems that are otherwise inaccessible.Yet,formidable challenges remain in controlling the reactivity and site-selectivity.Herein,we realized the reversal of site-selectivity in formal crossdimerization of benzocyclobutenones(BCBs)and silacyclobutanes(SCBs)by development of a nickel/magnesium synergistic catalytic system,in which the C(sp3)−C(carbonyl)bond of BCBs was exclusively cleaved,providing previously inaccessible eight-membered benzosilacycles.The catalytic cycle,the origin of this unconventional site-selectivity,and the role of MgCl2 have explicitly been elucidated by density functional theory calculations.Combined experimental and computational studies have clearly illustrated that the C1-C8 cleavage selectivity of BCBs in our reaction are mainly attributed to both the steric hindrance by introduction of substituents at the C3-and the proper choice of the Ni/Mg synergistic catalytic system.展开更多
Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit t...Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.展开更多
Continuous success has been achieved for solution-processed inorganic-organic hybrid perovskite solar cells(PVSCs) in the past several years, in which organic charge transporting materials play an important role. At p...Continuous success has been achieved for solution-processed inorganic-organic hybrid perovskite solar cells(PVSCs) in the past several years, in which organic charge transporting materials play an important role. At present, most of the commonly used hole-transporting materials(HTMs) such as spiro-OMeTAD derivatives for PVSCs require additional chemical doping process to ensure sufficient conductivity and shift the Fermi level towards the HOMO level for efficient hole transport and collection. However, this doping process not only increases the complexity and cost of device fabrication, but also decreases the device stability. Thus development of efficient dopant-free HTMs for PVSCs is highly desirable and remains as a major challenge in this field. In this review, we will summarize the recent advances in the molecular design of dopant-free HTMs for PVSCs.展开更多
It is our great honor to dedicate this special issue of Science China Materials to Nankai University(NKU)in celebration of its 100th anniversary.Established by two famous patriotic educators Xiu Yan and Boling Zhang i...It is our great honor to dedicate this special issue of Science China Materials to Nankai University(NKU)in celebration of its 100th anniversary.Established by two famous patriotic educators Xiu Yan and Boling Zhang in1919,NKU is one of China’s top universities with a long tradition in education.It has been playing essential roles as a pioneer in the course of China’s modernization with the aim of“Knowing China and Serving China”.Chemistry at NKU has a rich history.展开更多
文摘Background: New therapeutic targets are needed to improve the outcomes for gastric cancer(GC) patients with advanced disease. Evasion of programmed cell death(apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions. Method: Here we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR(ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using(CellTiter-Glo) CTG assay in vitro. Western Blot(WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Coimmunoprecipitation(Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR(RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity. Results: The functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time-and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.Conclusion: We identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations(CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.
文摘Objectives:To explore the prognostic relevance of the number and ratio of metastatic lymph nodes in resected Carcinoma of the ampulla of Vater(CAV).Methods:The clinical data of 155 patients who underwent pancreaticoduodenectomy(PD)for cancer of the ampulla of Vater between January 1990 and December 2010 were retrospectively analyzed.KaplanMeier method was used in survival analysis and Log rank method in comparison.Multivariate analysis was performed using Cox proportional hazards model.Results:Among these 155 patients,the in-hospital mortality rate was 4.5%,lymph node positive disease was21.3%,and the 5-year survival rate was 51.6%.Patients with a lymph node ratio(LNR)>20%were more likely to have tumor differentiation,depth of duodenal involvement,depth of pancreatic invasion,T-stage and TNM-Stage.The number of the metastatic lymph nodes is important prognostic factors of the CAV.Univariate analysis showed that the factors associated with the prognosis included tumor size(P=0.036),tumor differentiation(P=0.019),LNR(P=0.032),number of metastatic lymph nodes(P=0.024),lymph node metastasis(P=0.03),depth of pancreatic invasion(P=0.001),T-stage(P=0.002),TNM stage(P=0.001),elevated CA 19-9(P=0.000),and jaundice(P=0.021).Multivariate analysis showed that the factors associated with the prognosis were the number of metastatic lymph nodes(P=0.032;RR:1.283;95%CI:1.022-1.611),tumor size(P=0.043;RR:1.736;95%CI:1.017-2.963),and elevated CA 19-9(P=0.003;RR:3.247;95%CI:1.504-7.010).Conclusions:LNR is a useful factor for predicting the prognosis of the radical treatment for CAV,whereas the number of metastatic lymph nodes is the most important factor.Further research on the locations,number,and LNR will be clinically meaningful to improve survival in patients with CAV.
基金the National Natural Science Foundation of China(22071114,22022103,and 21871146)the Haihe Laboratory of Sustainable Chemical Transformations,the National Key Research and Development Program of China(2019YFA0210500 and 2020YFA0711504)+5 种基金"Frontiers Science Center for New Organic Matter,"Nankai University(63181206)for their financial supportthe National Natural Science Foundation of China(52103221 and 52172048)the Shandong Provincial Natural Science Foundation(ZR2021QB179 and ZR2021ZD06)the National Key Research and Development Program of China(2022YFB4200400)funded by M0ST and the Fundamental Research Funds of Shandong UniversityYingguo Yang thanks the National Natural Science Foundation of China(12175298).
文摘The utilization of cyclobutanones as the synthon in transition metal catalysis has been made great success.Because C(carbonyl)−C bond of cyclobutanones can be cleaved through strain release.Despite those advancements,the main catalysts in literature are Rh catalysts or Ni catalysts and the reaction with C—H bond is still underdeveloped.Herein,we realized the first palladium-catalyzed skeletal reorganization of cyclobutanones involving successive cleavage of C(carbonyl)−C bonds and C—H bond cleavage,which constitutes an rapid access to diverse indanones.In contrast to the previous Rh-catalytic system,the Pd-catalytic system herein involves different mechanism and features several advantages:1)no need of directing group to facilitate the C(carbonyl)−C bond cleavage;2)much milder reaction condition and 3)simplified work-up.
基金grateful for financial support from the National Natural Science Foundation of China(grant nos.22071114,22022103,21871146,22122104,22193012,22188101,and 21933004)the National Key Research and Development Program of China(grant nos.2019YFA0210500 and 2021YFF0701700)+1 种基金the Frontiers Science Center for New Organic Matter,Nankai University(grant no.63181206)the Fundamental Research Funds for the Central Universities and Nankai University.
文摘Formal cross-dimerization of two different strained rings represents an innovative strategy toward specific ring systems that are otherwise inaccessible.Yet,formidable challenges remain in controlling the reactivity and site-selectivity.Herein,we realized the reversal of site-selectivity in formal crossdimerization of benzocyclobutenones(BCBs)and silacyclobutanes(SCBs)by development of a nickel/magnesium synergistic catalytic system,in which the C(sp3)−C(carbonyl)bond of BCBs was exclusively cleaved,providing previously inaccessible eight-membered benzosilacycles.The catalytic cycle,the origin of this unconventional site-selectivity,and the role of MgCl2 have explicitly been elucidated by density functional theory calculations.Combined experimental and computational studies have clearly illustrated that the C1-C8 cleavage selectivity of BCBs in our reaction are mainly attributed to both the steric hindrance by introduction of substituents at the C3-and the proper choice of the Ni/Mg synergistic catalytic system.
基金supported by the National Natural Science Foundation of China(Grant number,82141127).
文摘Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.
基金supported by grants from the National Natural Science Foundation of China(Nos. 21704030, 21602115)the financial support from the National 1000 Young Talents Program hosted by Chinathe independent innovation research funding from HUST
文摘Continuous success has been achieved for solution-processed inorganic-organic hybrid perovskite solar cells(PVSCs) in the past several years, in which organic charge transporting materials play an important role. At present, most of the commonly used hole-transporting materials(HTMs) such as spiro-OMeTAD derivatives for PVSCs require additional chemical doping process to ensure sufficient conductivity and shift the Fermi level towards the HOMO level for efficient hole transport and collection. However, this doping process not only increases the complexity and cost of device fabrication, but also decreases the device stability. Thus development of efficient dopant-free HTMs for PVSCs is highly desirable and remains as a major challenge in this field. In this review, we will summarize the recent advances in the molecular design of dopant-free HTMs for PVSCs.
文摘It is our great honor to dedicate this special issue of Science China Materials to Nankai University(NKU)in celebration of its 100th anniversary.Established by two famous patriotic educators Xiu Yan and Boling Zhang in1919,NKU is one of China’s top universities with a long tradition in education.It has been playing essential roles as a pioneer in the course of China’s modernization with the aim of“Knowing China and Serving China”.Chemistry at NKU has a rich history.
