BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibito...BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.展开更多
BACKGROUND: Triggering receptor expressed on myeloid cells-1(TREM-1) is a cell surface receptor expressed on neutrophils and monocytes. TREM-1 acts to amplify infl ammation and serves as a critical mediator of infl am...BACKGROUND: Triggering receptor expressed on myeloid cells-1(TREM-1) is a cell surface receptor expressed on neutrophils and monocytes. TREM-1 acts to amplify infl ammation and serves as a critical mediator of infl ammatory response in the context of sepsis. To date, the predisposition of TREM-1 gene polymorphisms to septic shock has not been reported. This study was designed to investigate whether TREM-1 genomic variations are associated with the development of septic shock.METHODS: We genotyped two TREM-1 single nucleotide polymorphisms(SNPs, rs2234237 and rs2234246) and evaluated the relationships between these SNPs and septic shock on susceptibility and prognosis.RESULTS: TREM-1 rs2234246 A allele in the promoter region was signifi cantly associated with the susceptibility of septic shock in recessive model(AA, OR=3.10, 95%CI 1.15 to 8.32, P=0.02), and in codominant model(AG, OR=0.72, 95%CI 0.43–1.19, P=0.02; AA, OR=2.71, 95%CI 1.00–7.42; P=0.03). However, in three inherited models(dominant model, recessive model, and codominant model), none of the assayed loci was signif icantly associated with the prognosis of septic shock. The nonsurvivor group demonstrated higher plasma IL-6 levels(99.7±34.7 pg/mL vs. 61.2±26.5 pg/mL, P<0.01) than the survivor group. Plasma concentrations of IL-6 among the three genotypes of rs2234246 were AA 99.4±48.9 pg/m L, AG 85.4±43 pg/m L, and GG 65.3±30.7 pg/m L(P<0.01). The plasma concentrations of IL-6 in patients with AA genotypes were signifi cantly higher than those in patients with GG genotypes(P<0.01).CONCLUSION: TREM-1 genetic polymorphisms rs2234246 may be significantly correlated only with susceptibility to septic shock in the Chinese Han population.展开更多
目的探讨血清高迁移率族蛋白B1(high mobility group protein B1,HMGB1)、可溶性髓系细胞触发受体1(soluble myeloid cell trigger receptor-1,sTREM-1)联合检测对脓毒症并发急性肾损伤(acute kidney injury,AKI)的诊断价值。方法回顾...目的探讨血清高迁移率族蛋白B1(high mobility group protein B1,HMGB1)、可溶性髓系细胞触发受体1(soluble myeloid cell trigger receptor-1,sTREM-1)联合检测对脓毒症并发急性肾损伤(acute kidney injury,AKI)的诊断价值。方法回顾性选择徐州市中心医院2020年1月1日至2022年1月31日收治的156例脓毒症患者,另选取同期68例体检健康者为对照组。对比两组受试者血清HMGB1、sTREM-1水平,多因素Logistic回归分析脓毒症并发AKI的影响因素,受试者工作特征曲线分析血清HMGB1、sTREM-1水平对脓毒症并发AKI的诊断价值。结果脓毒症组患者血清HMGB1[172530(133870,204010)ng/L比83720(63480,99870)ng/L]、sTREM-1[(49.56±8.03)ng/L比(24.96±5.24)ng/L]水平明显高于对照组(P<0.05);多因素Logistic分析显示,血肌酐(OR=1.079,95%CI:1.037~1.122)、HMGB1(OR=1.933,95%CI:1.376~2.714)、sTREM-1(OR=1.201,95%CI:1.101~1.309)为脓毒症并发AKI的独立危险因素(P<0.05);受试者工作特征曲线显示,HMGB1联合sTREM-1[曲线下面积(area under the curve,AUC)=0.928,95%CI:0.876~0.963]诊断脓毒症并发AKI的敏感度、特异度、准确度高于HMGB1(AUC=0.790,95%CI:0.718~0.851)、sTREM-1(AUC=0.778,95%CI:0.705~0.840)诊断。结论脓毒症患者血清HMGB1、sTREM-1水平明显增高,是脓毒症并发AKI的独立危险因素。展开更多
Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we...Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.展开更多
BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accu...BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality.Soluble triggering receptor expressed on myeloid cells-1(sTREM-1)is released from activated innate immune cells and correlated with various inflammatory processes.AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort(n=309)and validation cohort(n=133).Demographic and clinical data were collected,and serum sTREM-1 was measured at admission.All enrolled patients were followed-up for at least 1 year.RESULTS In patients with AD and cirrhosis,serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver,coagulation,cerebral and kidney failure.A new prognostic model of AD(P-AD)incorporating sTREM-1,blood urea nitrogen(BUN),total bilirubin(TBil),international normalized ratio(INR)and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease(MELD),MELD-sodium(MELD-Na),chronic liver failure-consortium(CLIF-C)ACLF and CLIF-C AD scores.Additionally,sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up.The ACLF risk score incorporating serum sTREM-1,BUN,INR,TBil and aspartate aminotransferase levels was established and significantly superior to MELD,MELD-Na,CLIF-C ACLF,CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.展开更多
基金Supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,No.2021-I2M-1-061 and 2021-I2M-1-003Chinese Society of Clinical Oncology-Hengrui Cancer Research Fund,No.Y-HR2019-0239+1 种基金Chinese Society of Clinical Oncology-MSD Cancer Research Fund,No.Y-MSDZD2021-0213National Ten-thousand Talent Program.
文摘BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.
基金supported by Science&Technology Pillar Program of Guangdong Province(2009BAI86B03)
文摘BACKGROUND: Triggering receptor expressed on myeloid cells-1(TREM-1) is a cell surface receptor expressed on neutrophils and monocytes. TREM-1 acts to amplify infl ammation and serves as a critical mediator of infl ammatory response in the context of sepsis. To date, the predisposition of TREM-1 gene polymorphisms to septic shock has not been reported. This study was designed to investigate whether TREM-1 genomic variations are associated with the development of septic shock.METHODS: We genotyped two TREM-1 single nucleotide polymorphisms(SNPs, rs2234237 and rs2234246) and evaluated the relationships between these SNPs and septic shock on susceptibility and prognosis.RESULTS: TREM-1 rs2234246 A allele in the promoter region was signifi cantly associated with the susceptibility of septic shock in recessive model(AA, OR=3.10, 95%CI 1.15 to 8.32, P=0.02), and in codominant model(AG, OR=0.72, 95%CI 0.43–1.19, P=0.02; AA, OR=2.71, 95%CI 1.00–7.42; P=0.03). However, in three inherited models(dominant model, recessive model, and codominant model), none of the assayed loci was signif icantly associated with the prognosis of septic shock. The nonsurvivor group demonstrated higher plasma IL-6 levels(99.7±34.7 pg/mL vs. 61.2±26.5 pg/mL, P<0.01) than the survivor group. Plasma concentrations of IL-6 among the three genotypes of rs2234246 were AA 99.4±48.9 pg/m L, AG 85.4±43 pg/m L, and GG 65.3±30.7 pg/m L(P<0.01). The plasma concentrations of IL-6 in patients with AA genotypes were signifi cantly higher than those in patients with GG genotypes(P<0.01).CONCLUSION: TREM-1 genetic polymorphisms rs2234246 may be significantly correlated only with susceptibility to septic shock in the Chinese Han population.
文摘目的探讨血清高迁移率族蛋白B1(high mobility group protein B1,HMGB1)、可溶性髓系细胞触发受体1(soluble myeloid cell trigger receptor-1,sTREM-1)联合检测对脓毒症并发急性肾损伤(acute kidney injury,AKI)的诊断价值。方法回顾性选择徐州市中心医院2020年1月1日至2022年1月31日收治的156例脓毒症患者,另选取同期68例体检健康者为对照组。对比两组受试者血清HMGB1、sTREM-1水平,多因素Logistic回归分析脓毒症并发AKI的影响因素,受试者工作特征曲线分析血清HMGB1、sTREM-1水平对脓毒症并发AKI的诊断价值。结果脓毒症组患者血清HMGB1[172530(133870,204010)ng/L比83720(63480,99870)ng/L]、sTREM-1[(49.56±8.03)ng/L比(24.96±5.24)ng/L]水平明显高于对照组(P<0.05);多因素Logistic分析显示,血肌酐(OR=1.079,95%CI:1.037~1.122)、HMGB1(OR=1.933,95%CI:1.376~2.714)、sTREM-1(OR=1.201,95%CI:1.101~1.309)为脓毒症并发AKI的独立危险因素(P<0.05);受试者工作特征曲线显示,HMGB1联合sTREM-1[曲线下面积(area under the curve,AUC)=0.928,95%CI:0.876~0.963]诊断脓毒症并发AKI的敏感度、特异度、准确度高于HMGB1(AUC=0.790,95%CI:0.718~0.851)、sTREM-1(AUC=0.778,95%CI:0.705~0.840)诊断。结论脓毒症患者血清HMGB1、sTREM-1水平明显增高,是脓毒症并发AKI的独立危险因素。
基金supported by the Key Project of the National Natural Science Foundation of China,No.81930070(to SF)the National Natural Science Foundation of China,No.81972074(to XY)the Key Program of Natural Science Foundation of Tianjin,No.19JCZDJC34900(to XY)。
文摘Argatroban is a synthetic thrombin inhibitor approved by U.S.Food and Drug Administration for the treatment of thrombosis.However,whether it plays a role in the repair of spinal cord injury is unknown.In this study,we established a rat model of T10 moderate spinal cord injury using an NYU Impactor ModerⅢand performed intraperitoneal injection of argatroban for 3 consecutive days.Our results showed that argatroban effectively promoted neurological function recovery after spinal cord injury and decreased thrombin expression and activity in the local injured spinal cord.RNA sequencing transcriptomic analysis revealed that the differentially expressed genes in the argatroban-treated group were enriched in the JAK2/STAT3 pathway,which is involved in astrogliosis and glial scar formation.Western blotting and immunofluorescence results showed that argatroban downregulated the expression of the thrombin receptor PAR1 in the injured spinal cord and the JAK2/STAT3 signal pathway.Argatroban also inhibited the activation and proliferation of astrocytes and reduced glial scar formation in the spinal cord.Taken together,these findings suggest that argatroban may inhibit astrogliosis by inhibiting the thrombin-mediated PAR1/JAK2/STAT3 signal pathway,thereby promoting the recovery of neurological function after spinal cord injury.
基金National Natural Science Foundation of China,No.81970550,No.82070613 and No.82370638Natural Science Foundation of Hunan Province,China,No.2021JJ31067 and No.2021JJ41048+1 种基金Hunan innovative province construction project,No.2023JJ10095Innovative Talented Project of Hunan province,China,No.2022RC1212.
文摘BACKGROUND Acute decompensation(AD)of cirrhosis is associated with high short-term mortality,mainly due to the development of acute-on-chronic liver failure(ACLF).Thus,there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality.Soluble triggering receptor expressed on myeloid cells-1(sTREM-1)is released from activated innate immune cells and correlated with various inflammatory processes.AIM To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort(n=309)and validation cohort(n=133).Demographic and clinical data were collected,and serum sTREM-1 was measured at admission.All enrolled patients were followed-up for at least 1 year.RESULTS In patients with AD and cirrhosis,serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver,coagulation,cerebral and kidney failure.A new prognostic model of AD(P-AD)incorporating sTREM-1,blood urea nitrogen(BUN),total bilirubin(TBil),international normalized ratio(INR)and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease(MELD),MELD-sodium(MELD-Na),chronic liver failure-consortium(CLIF-C)ACLF and CLIF-C AD scores.Additionally,sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up.The ACLF risk score incorporating serum sTREM-1,BUN,INR,TBil and aspartate aminotransferase levels was established and significantly superior to MELD,MELD-Na,CLIF-C ACLF,CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.
