AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resis...AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.展开更多
AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fl...AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.展开更多
AIM:To evaluate the efficacy and safety of cetuxim-ab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS:In this open-label,phase Ⅱ study...AIM:To evaluate the efficacy and safety of cetuxim-ab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS:In this open-label,phase Ⅱ study,the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially,then 250 mg/m2 every week,with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regim-ens allowed). The prim-ary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS,and an assessment of the overall response rate (ORR),duration of response,time to treatment failure (TTF),overall survival and the safety profile. RESULTS:One hundred and twenty nine patients were enrolled from-25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI,41-59) and m-edian PFS tim-e was 12.1 wk (95% CI:9.7-17.7). The ORR was 13.8% (95% CI:8.3-21.2) and disease control rate was 49.6% (95% CI:40.5-58.8). Median duration of response was 31.1 wk (95% CI:18.0-42.6) and median overall survival was 9.5 mo (95% CI,7.5-11.7). The median TTF was 11.7 wk (95% CI:9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%),neutropenia (8.9%),rash (5.7%) and vomiting (5.7%).CONCLUSION:In patients from Asia and Australia,this study confirm-s the activity and safety of cetuxim-ab plus irinotecan observed in previous studies in Europe and South America.展开更多
AZ15nXT is a chemically-amplified negative-tone thick film photoresist.The resist has vertical profile and is widely used for redistribution layer(RDL)and through silicon vias(TSV)applications.For lift-off applicati...AZ15nXT is a chemically-amplified negative-tone thick film photoresist.The resist has vertical profile and is widely used for redistribution layer(RDL)and through silicon vias(TSV)applications.For lift-off applications,however,the inverted profile is needed.In this paper,we report the effects of process conditions on the resist profile and process window for lift off applications.展开更多
Dear Editor,This letter presents an organoid segmentation model based on multi-axis attention with convolution parallel block.MACPNet adeptly captures dynamic dependencies within bright-field microscopy images,improvi...Dear Editor,This letter presents an organoid segmentation model based on multi-axis attention with convolution parallel block.MACPNet adeptly captures dynamic dependencies within bright-field microscopy images,improving global modeling beyond conventional UNet.展开更多
SiBN ceramics are widely considered to be the most promising material for microwavetransparent applications in harsh environments owing to its excellent thermal stability and low dielectric constant.This work focuses ...SiBN ceramics are widely considered to be the most promising material for microwavetransparent applications in harsh environments owing to its excellent thermal stability and low dielectric constant.This work focuses on the synthesis and ceramization of single-source precursors for the preparation of SiBN ceramics as well as the investigation of the corresponding microstructural evolution at high temperatures including molecular dynamic simulations.Carbon-and chlorine-free perhydropolysilazanes were reacted with borane dimethyl sulfide complex at different molar ratios to synthesize single-source precursors,which were subsequently pyrolyzed and annealed under N2 atmosphere(without ammonolysis)to prepare SiBN ceramics at 1100,1200,and 1300℃with high ceramic yield in contrast to previously widely-used ammonolysis synthesis process.The obtained amorphous SiBN ceramics were shown to have remarkably improved thermal stability and oxidation resistance compared to amorphous silicon nitride.Particularly,the experimental results have been combined with molecular dynamics simulation to further study the amorphous structure of SiBN and the atomic-scale diffusion behavior of Si,B,and N at 1300℃.Incorporation of boron into the Si–N network is found to suppress the crystallization of the formed amorphous silicon nitride and hence improves its thermal stability in N2 atmosphere.展开更多
Glass transition temperature,Tg,is the key quantity for assessing morphological stability and molecular ordering of films of organic semiconductors.A reliable prediction of Tg from the chemical structure is,however,ch...Glass transition temperature,Tg,is the key quantity for assessing morphological stability and molecular ordering of films of organic semiconductors.A reliable prediction of Tg from the chemical structure is,however,challenging,as it is sensitive to both molecular interactions and analysis of the heating or cooling process.By combining a fitting protocol with an automated workflow for forcefield parameterization,we predict Tg with a mean absolute error of~20℃for a set of organic compounds with Tg in the 50–230℃range.Our study establishes a reliable and automated prescreening procedure for the design of amorphous organic semiconductors,essential for the optimization and development of organic light-emitting diodes.展开更多
基金Supported by Research grants from Merck KGaA,Darmstadt,Germany,to Schulze-Bergkamen H
文摘AIM:To analyze the effect of chemotherapeutic drugs and specific kinase inhibitors,in combination with the death receptor ligand tumor necrosis factor-related apoptosis inducing ligand(TRAIL),on overcoming TRAIL resistance in hepatocellular carcinoma(HCC)and to study the efficacy of agonistic TRAIL antibodies,as well as the commitment of antiapoptotic BCL-2 proteins, in TRAIL-induced apoptosis. METHODS:Surface expression of TRAIL receptors (TRAIL-R1-4)and expression levels of the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL were analyzed by flow cytometry and Western blotting,respectively. Knock-down of MCL-1 and BCL-xL was performed by transfecting specific small interfering RNAs.HCC cellswere treated with kinase inhibitors and chemotherapeutic drugs.Apoptosis induction and cell viability were analyzed via flow cytometry and 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS:TRAIL-R1 and-R2 were profoundly expressed on the HCC cell lines Huh7 and Hep-G2. However,treatment of Huh7 and Hep-G2 with TRAIL and agonistic antibodies only induced minor apoptosis rates.Apoptosis resistance towards TRAIL could be considerably reduced by adding the chemotherapeutic drugs 5-fluorouracil and doxorubicin as well as the kinase inhibitors LY294002[inhibition of phosphoinositol- 3-kinase(PI3K)],AG1478(epidermal growth factor receptor kinase),PD98059(MEK1),rapamycin(mam- malian target of rapamycin)and the multi-kinase inhibitor Sorafenib.Furthermore,the antiapoptotic BCL-2 proteins MCL-1 and BCL-xL play a major role in TRAIL resistance:knock-down by RNA interference increased TRAIL-induced apoptosis of HCC cells.Additionally, knock-down of MCL-1 and BCL-xL led to a significant sensitization of HCC cells towards inhibition of both c-Jun N-terminal kinase and PI3K.CONCLUSION:Our data identify the blockage of survival kinases,combination with chemotherapeutic drugs and targeting of antiapoptotic BCL-2 proteins as promising ways to overcome TRAIL resistance in HCC.
文摘AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B in the progression-free survival (PFS) rate at 9 mo, 45% vs 34%; median PFS, 8.6 mo vs 8.3 mo [hazard ratio (HR) = 1.06]; overall response rate (ORR) 43% vs 45% [odds ratio (OR) = 0.93] and median overall survival (OS), 17.4 mo vs 18.9 mo (HR = 0.98). Patients with KRAS wild-type tumors demonstrated improved PFS (HR = 0.55, P = 0.0051), OS, (HR = 0.62, P = 0.0296) and ORR (53% vs 36%) and in arm A, improved PFS (HR = 0.49, P = 0.0196), OS (HR = 0.48, P = 0.0201) and ORR (56%vs 30%), compared with patients with KRAS mutated tumors. In arm B no significant differences were found in efficacy by KRAS mutation status. Treatment in arms A and B was generally well tolerated. CONCLUSION: This study confirms that combinations of cetuximab with FOLFOX6 or FOLFIRI are effective and significantly improve clinical outcome in KRAS wild-type compared with KRAS mutated mCRC.
文摘AIM:To evaluate the efficacy and safety of cetuxim-ab plus irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients from South-East Asia and Australia. METHODS:In this open-label,phase Ⅱ study,the main eligibility criteria were epidermal growth factor receptor-positive mCRC with progressive disease within 3 mo of an irinotecan-based regimen as the most recent chemotherapy. Patients received cetuximab 400 mg/m2 initially,then 250 mg/m2 every week,with the same regimen of irinotecan on which the patients had progressed (4 pre-defined regim-ens allowed). The prim-ary objective was evaluation of progression-free survival (PFS) at 12 wk. Secondary objectives included a further investigation of PFS,and an assessment of the overall response rate (ORR),duration of response,time to treatment failure (TTF),overall survival and the safety profile. RESULTS:One hundred and twenty nine patients were enrolled from-25 centers in the Asia-Pacific region and of these 123 received cetuximab plus irinotecan. The most common recent irinotecan regimen used was 180 mg/m2 every 2 wk which had been used in 93 patients (75.6%). The PFS rate at 12 wk was 50% (95% confidence interval (CI,41-59) and m-edian PFS tim-e was 12.1 wk (95% CI:9.7-17.7). The ORR was 13.8% (95% CI:8.3-21.2) and disease control rate was 49.6% (95% CI:40.5-58.8). Median duration of response was 31.1 wk (95% CI:18.0-42.6) and median overall survival was 9.5 mo (95% CI,7.5-11.7). The median TTF was 11.7 wk (95% CI:9.1-17.4). Treatment was generally well tolerated. The most common grade 3/4 adverse events were diarrhea (13.8%),neutropenia (8.9%),rash (5.7%) and vomiting (5.7%).CONCLUSION:In patients from Asia and Australia,this study confirm-s the activity and safety of cetuxim-ab plus irinotecan observed in previous studies in Europe and South America.
文摘AZ15nXT is a chemically-amplified negative-tone thick film photoresist.The resist has vertical profile and is widely used for redistribution layer(RDL)and through silicon vias(TSV)applications.For lift-off applications,however,the inverted profile is needed.In this paper,we report the effects of process conditions on the resist profile and process window for lift off applications.
基金supported by the Xinjiang Tianchi Talents Program(E33B9401)the Natural Science Foundation of Xinjiang Uygur Autonomous Region(2023D01E15)+1 种基金the National Natural Science Foundation of China(62302495)the National Natural Science Foundation of China(62373348)。
文摘Dear Editor,This letter presents an organoid segmentation model based on multi-axis attention with convolution parallel block.MACPNet adeptly captures dynamic dependencies within bright-field microscopy images,improving global modeling beyond conventional UNet.
基金The authors would like to acknowledge Merck KGaA for the financial support of this research project.Wei Li acknowledges financial support from China Scholarship Council(No.201907040060)during his research at TU Darmstadt.Zhenghao Wu acknowledges the funding of Deutsche Forschungsgemeinschaft via the SFB-TRR 146“Multiscale Simulation Methods for Soft Matter Systems”,Project A8.
文摘SiBN ceramics are widely considered to be the most promising material for microwavetransparent applications in harsh environments owing to its excellent thermal stability and low dielectric constant.This work focuses on the synthesis and ceramization of single-source precursors for the preparation of SiBN ceramics as well as the investigation of the corresponding microstructural evolution at high temperatures including molecular dynamic simulations.Carbon-and chlorine-free perhydropolysilazanes were reacted with borane dimethyl sulfide complex at different molar ratios to synthesize single-source precursors,which were subsequently pyrolyzed and annealed under N2 atmosphere(without ammonolysis)to prepare SiBN ceramics at 1100,1200,and 1300℃with high ceramic yield in contrast to previously widely-used ammonolysis synthesis process.The obtained amorphous SiBN ceramics were shown to have remarkably improved thermal stability and oxidation resistance compared to amorphous silicon nitride.Particularly,the experimental results have been combined with molecular dynamics simulation to further study the amorphous structure of SiBN and the atomic-scale diffusion behavior of Si,B,and N at 1300℃.Incorporation of boron into the Si–N network is found to suppress the crystallization of the formed amorphous silicon nitride and hence improves its thermal stability in N2 atmosphere.
基金D.A.acknowledges the BMBF Grant InterPhase(No.FKZ13N13661)and the European Union Horizon 2020 Research and Innovation Program‘Widening Materials Models’under Grant Agreement No.646259(MOSTOPHOS)This research has been supported by the King Abdullah University of Science and Technology(KAUST),via the Competitive Research Grants(CRG)Program+1 种基金D.A.acknowledges KAUST for hosting his sabbatical.DFG is acknowledged for financial support through the collaborative research center TRR 146K.-H.L.acknowledges the financial support from the Swiss NSF Early Postdoc Mobility fellowship(grant no.P2ELP2_195156).
文摘Glass transition temperature,Tg,is the key quantity for assessing morphological stability and molecular ordering of films of organic semiconductors.A reliable prediction of Tg from the chemical structure is,however,challenging,as it is sensitive to both molecular interactions and analysis of the heating or cooling process.By combining a fitting protocol with an automated workflow for forcefield parameterization,we predict Tg with a mean absolute error of~20℃for a set of organic compounds with Tg in the 50–230℃range.Our study establishes a reliable and automated prescreening procedure for the design of amorphous organic semiconductors,essential for the optimization and development of organic light-emitting diodes.
