Solid-state nanopores with controllable pore size and morphology have huge application potential.However,it has been very challenging to process sub-10 nm silicon nanopore arrays with high efficiency and high quality ...Solid-state nanopores with controllable pore size and morphology have huge application potential.However,it has been very challenging to process sub-10 nm silicon nanopore arrays with high efficiency and high quality at low cost.In this study,a method combining metal-assisted chemical etching and machine learning is proposed to fabricate sub-10 nm nanopore arrays on silicon wafers with various dopant types and concentrations.Through a SVM algorithm,the relationship between the nanopore structures and the fabrication conditions,including the etching solution,etching time,dopant type,and concentration,was modeled and experimentally verified.Based on this,a processing parameter window for generating regular nanopore arrays on silicon wafers with variable doping types and concentrations was obtained.The proposed machine-learning-assisted etching method will provide a feasible and economical way to process high-quality silicon nanopores,nanostructures,and devices.展开更多
Background:A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab(LEP)has demonstrated a relatively high antitumor response in several solid tumors;however,the efficacy and safety of LE...Background:A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab(LEP)has demonstrated a relatively high antitumor response in several solid tumors;however,the efficacy and safety of LEP in patients with refractory bile tract carcinoma(BTC)remains unknown.Methods:This is a single-arm study for a preliminary assessment of the efficacy and tolerability of LEP in patients who experienced progression from prior systemic treatments.Pre-treatment tumor tissues were collected to retrospectively evaluate the expression status of PDL1.Results:Thirty-two patients received second-line and above treatment with LEP.Overall,the objective response rate(ORR)was 25%,the disease control rate(DCR)was 78.1%,and the clinical benefit rate(CBR)was 40.5%.The median progression-free survival(PFS)was 4.9 months(95%CI:4.7–5.2 months),and the median overall survival(OS)was 11.0 months(95%CI:9.6–12.3 months).For tolerability,no grade 5 serious adverse events(AEs)were reported.All patients had any-grade AEs,and 59.3%of the patients experienced grade 3 AEs,while only 1 patient experienced a grade 4 AE of stomach bleeding.Fatigue was the most common AE,followed by hypertension and elevated aminotransferase levels.Retrospective analysis for PDL1 expression revealed that PDL1 positive tumor cells were associated with improved clinical benefits and survival outcomes.Conclusions:LEP is a promising alternative as a non-first-line therapeutic regimen for patients with refractory BTC.Furthermore,well-designed prospective clinical trials with a control arm are still needed to obtain more evidences to confirm the efficacy and safety of this particular regimen as well as the role of PDL1 expression.展开更多
Background:A combination of tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies with local regional therapy has elicited yield substantial clinical benefits in patients who have hepatocellular carcinoma(HCC)with ...Background:A combination of tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies with local regional therapy has elicited yield substantial clinical benefits in patients who have hepatocellular carcinoma(HCC)with extrahepatic metastases.Using this treatment strategy to convert HCC patients with extrahepatic metastases from unresectable to resectable has not yet been reported.Methods:Consecutive hepatocellular carcinoma patients with extrahepatic metastases who received first-line therapy with a combination of TKIs and anti-PD-1 antibodies and at least one local regional therapy were analysed.Results:Nine patients with localized disease who received first-line systemic therapy were enrolled.At baseline,all of them had oligometastatic disease,namely,Barcelona Clinic Liver Cancer stage C(or Chinese Liver Cancer stage IIIB).The most common treatment administered was lenvatinib plus anti-PD-1 antibody and transarterial chemoembolization,and the median time span from systemic therapy to surgery was 3.2(IQR,2.8-6.2)months.Three patients achieved a pathological complete response.Six patients underwent laparoscopic surgery,and the other 3 patients underwent open surgery.After a median follow-up of 10.2(IQR,8.6-20.0)months,7 patients survived without disease recurrence,and 2 experienced tumour recurrence.All patients had any-grade AEs,and 55.6%of the patients experienced grade 3 AEs.Fatigue was the most common AE,followed by elevated aminotransferase levels and hypertension.Conclusions:Stereotactic therapy is a feasible conversion therapy for HCC patients with extrahepatic metastases to become resectable.This is the first study to analyse therapeutic outcomes of patients receiving these therapies for HCC with extrahepatic metastases.展开更多
Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinom...Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA.Methods:We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC.Results:We observed two molecular subtypes of H-ChC at the whole-transcriptome level(CHP and CIP),where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property.To define the heterogeneity of tumours and their associated microenvironments,we observe greater tumour diversity in H-ChC than HCC and iCCA.H-ChC exhibits weaker immune cell infiltration and greater CD8+exhausted T cell(Tex)dysfunction than HCC and iCCA.Then we defined two broad cell states of 6,852 CD8+Tex cells:GZMK+CD8+Tex cells and terminal CD8+Tex cells.GZMK+CD8+Tex cells exhibited higher infiltration of after treatment in H-ChC,the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy,which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy.Conclusions:In this paper,H-ChC was explored,hoping to contribute to the study of mixed tumours in other cancers.展开更多
基金supported by the National Natural Science Foundation of China[Grant Nos.51975127,U20A6004]the Guangdong-Hong Kong Technology Coopeartion[Grant No.GHP/112/19GD]from Hong Kong Innovation and Technology Commission+1 种基金Research and Development Program of Guangdong Province[Grant No.2020A0505140008]the Fund of Key-Area Research and Development Program of Guangdong Province[Grant No.2018B090906002]。
文摘Solid-state nanopores with controllable pore size and morphology have huge application potential.However,it has been very challenging to process sub-10 nm silicon nanopore arrays with high efficiency and high quality at low cost.In this study,a method combining metal-assisted chemical etching and machine learning is proposed to fabricate sub-10 nm nanopore arrays on silicon wafers with various dopant types and concentrations.Through a SVM algorithm,the relationship between the nanopore structures and the fabrication conditions,including the etching solution,etching time,dopant type,and concentration,was modeled and experimentally verified.Based on this,a processing parameter window for generating regular nanopore arrays on silicon wafers with variable doping types and concentrations was obtained.The proposed machine-learning-assisted etching method will provide a feasible and economical way to process high-quality silicon nanopores,nanostructures,and devices.
基金This work was supported by grants from the International Science and Technology Cooperation Projects(2016YFE0107100 and 2015DFA30650)CAMS Innovation Fund for Medical Science(CIFMS)(2017-I2M-4-003)+1 种基金Beijing Natural Science Foundation(L172055)National Ten-thousand Talent Program,Beijing Science and Technology Cooperation Special Award Subsidy Project and CAMS Initiative for Innovative Medicine(CAMS-2018-I2M-3-001)
文摘Background:A therapeutic strategy involving combined treatment with lenvatinib plus pembrolizumab(LEP)has demonstrated a relatively high antitumor response in several solid tumors;however,the efficacy and safety of LEP in patients with refractory bile tract carcinoma(BTC)remains unknown.Methods:This is a single-arm study for a preliminary assessment of the efficacy and tolerability of LEP in patients who experienced progression from prior systemic treatments.Pre-treatment tumor tissues were collected to retrospectively evaluate the expression status of PDL1.Results:Thirty-two patients received second-line and above treatment with LEP.Overall,the objective response rate(ORR)was 25%,the disease control rate(DCR)was 78.1%,and the clinical benefit rate(CBR)was 40.5%.The median progression-free survival(PFS)was 4.9 months(95%CI:4.7–5.2 months),and the median overall survival(OS)was 11.0 months(95%CI:9.6–12.3 months).For tolerability,no grade 5 serious adverse events(AEs)were reported.All patients had any-grade AEs,and 59.3%of the patients experienced grade 3 AEs,while only 1 patient experienced a grade 4 AE of stomach bleeding.Fatigue was the most common AE,followed by hypertension and elevated aminotransferase levels.Retrospective analysis for PDL1 expression revealed that PDL1 positive tumor cells were associated with improved clinical benefits and survival outcomes.Conclusions:LEP is a promising alternative as a non-first-line therapeutic regimen for patients with refractory BTC.Furthermore,well-designed prospective clinical trials with a control arm are still needed to obtain more evidences to confirm the efficacy and safety of this particular regimen as well as the role of PDL1 expression.
基金This work was supported by International Science and Technology Cooperation Projects(2016YFE0107100)CAMS Clinical and Translational Medicine Research Funds(2019XK320006)+3 种基金CAMS Innovation Fund for Medical Science(CIFMS)(2017-I2M-4-003 and 2018-I2M-3-001)Beijing Natural Science Foundation(L172055 and 7192158)the Fundamental Research Funds for the Central Universities(3332018032)CSCO-Hengrui Cancer Research Fund(Y-HR2019-0239)and National Ten-thousand Talent Program.
文摘Background:A combination of tyrosine kinase inhibitors(TKIs)and anti-PD-1 antibodies with local regional therapy has elicited yield substantial clinical benefits in patients who have hepatocellular carcinoma(HCC)with extrahepatic metastases.Using this treatment strategy to convert HCC patients with extrahepatic metastases from unresectable to resectable has not yet been reported.Methods:Consecutive hepatocellular carcinoma patients with extrahepatic metastases who received first-line therapy with a combination of TKIs and anti-PD-1 antibodies and at least one local regional therapy were analysed.Results:Nine patients with localized disease who received first-line systemic therapy were enrolled.At baseline,all of them had oligometastatic disease,namely,Barcelona Clinic Liver Cancer stage C(or Chinese Liver Cancer stage IIIB).The most common treatment administered was lenvatinib plus anti-PD-1 antibody and transarterial chemoembolization,and the median time span from systemic therapy to surgery was 3.2(IQR,2.8-6.2)months.Three patients achieved a pathological complete response.Six patients underwent laparoscopic surgery,and the other 3 patients underwent open surgery.After a median follow-up of 10.2(IQR,8.6-20.0)months,7 patients survived without disease recurrence,and 2 experienced tumour recurrence.All patients had any-grade AEs,and 55.6%of the patients experienced grade 3 AEs.Fatigue was the most common AE,followed by elevated aminotransferase levels and hypertension.Conclusions:Stereotactic therapy is a feasible conversion therapy for HCC patients with extrahepatic metastases to become resectable.This is the first study to analyse therapeutic outcomes of patients receiving these therapies for HCC with extrahepatic metastases.
基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-061 and 2021-1-I2M-003)CSCO-hengrui Cancer Research Fund(Y-HR2019-0239)+4 种基金CSCO-MSD Cancer Research Fund(Y-MSDZD2021-0213)National Ten-thousand Talent Program(to J.L.)Young Scientists Fund of the National Natural Science Foundation of China(82303720)Beijing Natural Science Foundation(7234381)Fundamental Research Funds for the Central Universities(3332023011 to J.L.).
文摘Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA.Methods:We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC.Results:We observed two molecular subtypes of H-ChC at the whole-transcriptome level(CHP and CIP),where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property.To define the heterogeneity of tumours and their associated microenvironments,we observe greater tumour diversity in H-ChC than HCC and iCCA.H-ChC exhibits weaker immune cell infiltration and greater CD8+exhausted T cell(Tex)dysfunction than HCC and iCCA.Then we defined two broad cell states of 6,852 CD8+Tex cells:GZMK+CD8+Tex cells and terminal CD8+Tex cells.GZMK+CD8+Tex cells exhibited higher infiltration of after treatment in H-ChC,the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy,which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy.Conclusions:In this paper,H-ChC was explored,hoping to contribute to the study of mixed tumours in other cancers.
