Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral th...Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.展开更多
Objective:To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer(mCRC) patients.Methods:From June 2001 to November 2006,after they had achieved clinical response from...Objective:To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer(mCRC) patients.Methods:From June 2001 to November 2006,after they had achieved clinical response from first-line chemotherapy,patients with mCRC in our hospital received two different treatment strategies.Thirty-three patients in maintenance group were treated with capecitabine 1000 mg/m2 po bid d1-14,q21d.Fifty-two patients in non-maintenance group did not receive any further chemotherapy.Results:Patients in maintenance group and non-maintenance group both received FOLFOX,FOLFIRI and XELOX as first-line therapy.The median chemotherapy cycles the two groups received were the same(6 vs 6).The response rates of first-line chemotherapy were 33.3% in maintenance group and 32.7% in non-maintenance group.Patients in maintenance group received 3-9 cycles of capecitabine therapy(median cycle 4).29/33(87.9%) patients in maintenance group and 47/52(90.4%) in non-maintenance group received following second-line chemotherapy,and no patients underwent targeted therapy.The median survival time and TTP were 40.4 months(95%CI:24.2-56.6) and 9.0 months(95%CI:6.7-11.3) in maintenance group,as compared with 21.5 months(95%CI:14.9-28.0,P=0.015) and 6.5 months(95%CI:4.4-8.5,P=0.007) in non-maintenance group.No severe adverse event was observed in the capecitabine maintenance group.Conclusion:mCRC patients could benefit from capecitabine maintenance therapy by prolonging survival time and TTP.展开更多
CD4+CD25+ Regulatory T cells (Treg) have been found to down-regulate immune activation in HIV-1 infection. However,whether the depletion of Treg benefits to the disease status of HIV infection remains undefined. To ad...CD4+CD25+ Regulatory T cells (Treg) have been found to down-regulate immune activation in HIV-1 infection. However,whether the depletion of Treg benefits to the disease status of HIV infection remains undefined. To address this issue,we enumerated the Treg absolute counts and frequency in 75 antiviral-nave HIV-1-infected individuals in this study. It was found that HIV-infected patients displayed a significant decline in Treg absolute counts but a significant increase in Treg frequency. In addition,with disease progression indicated by CD4 T-cell absolute counts,circulating Treg frequency gradually increased; while Treg absolute counts were gradually decreased,suggesting that the alteration of Treg number closely correlated with disease progression in HIV infection. Functional analysis further showed that Treg efficiently inhibit both CD4 and CD8 T cell proliferation in vitro. Thus,our findings indicates that Treg actively participate in pathogenesis of chronic HIV infection,influencing the disease progression.展开更多
The novel contagious primary atypical pneumonia epidemic,which broke out in Wuhan,China,in December 2019,is now formally called Coronavirus Disease 2019(COVID-19),with the causative virus named as Severe Acute Respira...The novel contagious primary atypical pneumonia epidemic,which broke out in Wuhan,China,in December 2019,is now formally called Coronavirus Disease 2019(COVID-19),with the causative virus named as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2).1,2 Recent studies have shown that in addition to dyspnea,hypoxemia,and acute respiratory distress,lymphopenia,and cytokine release syndrome are also important clinical features in patients with severe SARS-CoV-2 infection.3 This suggests that homeostasis of the immune system plays an important role in the development of COVID-19 pneumonia.展开更多
Background: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China.Both HIV and HBV can be treated with tenofovir disoproxil fumara...Background: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China.Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV.Methods: One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen ofTDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed.Results: Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%).Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min-1· 1.73 m-2) to week 12 (104 ml·min-1· 1.73 m-2) but was almost back to baseline at week 48 (1 1 1 ml·min-1· 1.73 m-2).Conclusion: This combination ART regimen is safe and effective for patients with HIV/HBV co-infection.Trial Registration: ClinicalTrials.gov, NCT01751555;https://clinicaltrials.gov/ct2/show/NCT01751555.展开更多
Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcr...Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell(PBMC)samples from 18 patients with coronavirus disease 2019(COVID-19)during their treatment,convalescence,and rehabilitation.After analyzing the regulatory networks of differentially expressed messenger RNAs(mRNAs),microRNAs(miRNAs)and long non-coding RNAs(lncRNAs)between the different clinical stages,we found that humoral immunity and type I interferon response were significantly downregulated,while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19.The formation of this T cell immune response might be driven by the activation of activating protein-1(AP-1)related signaling pathway and was weakly affected by other clinical features.These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.展开更多
Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcr...Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell(PBMC)samples from 18 patients with coronavirus disease 2019(COVID-19)during their treatment,convalescence,and rehabilitation.After analyzing the regulatory networks of differentially expressed messenger RNAs(mRNAs),microRNAs(miRNAs)and long non-coding RNAs(lncRNAs)between the different clinical stages,we found that humoral immunity and type I interferon response were significantly downregulated,while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19.The formation of this T cell immune response might be driven by the activation of activating protein-1(AP-1)related signaling pathway and was weakly affected by other clinical features.These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.展开更多
基金supported by the Peking University Clinical Scientist Program Special(BMU2019LCKXJ013)the National Natural Science Foundation Innovation Research Group Project(81721002)+2 种基金the Sanming Project of Medicine Project in Shenzhen(SZSM201612014)the Yunnan Applied Basic Research Projects-Union Foundation by Yunnan Provincial Department of Science and Technology and Kunming Medical University(202001AY070001-154)the Scientific Research Fund of Education Department of Yunnan Province(2021J0297)。
文摘Background: Mucosal-associated invariant T(MAIT) cells are systemically depleted in human immunodeficiency virus type 1(HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy(cART).This study aimed to identify the mechanism underlying MAIT cell depletion.Methods: In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.Results: Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D(GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12(IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro.Conclusions: Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients,which could potentiate disease progression and poor immune reconstitution.
文摘Objective:To evaluate the efficacy and toxicity of capecitabine maintenance therapy in metastatic colorectal cancer(mCRC) patients.Methods:From June 2001 to November 2006,after they had achieved clinical response from first-line chemotherapy,patients with mCRC in our hospital received two different treatment strategies.Thirty-three patients in maintenance group were treated with capecitabine 1000 mg/m2 po bid d1-14,q21d.Fifty-two patients in non-maintenance group did not receive any further chemotherapy.Results:Patients in maintenance group and non-maintenance group both received FOLFOX,FOLFIRI and XELOX as first-line therapy.The median chemotherapy cycles the two groups received were the same(6 vs 6).The response rates of first-line chemotherapy were 33.3% in maintenance group and 32.7% in non-maintenance group.Patients in maintenance group received 3-9 cycles of capecitabine therapy(median cycle 4).29/33(87.9%) patients in maintenance group and 47/52(90.4%) in non-maintenance group received following second-line chemotherapy,and no patients underwent targeted therapy.The median survival time and TTP were 40.4 months(95%CI:24.2-56.6) and 9.0 months(95%CI:6.7-11.3) in maintenance group,as compared with 21.5 months(95%CI:14.9-28.0,P=0.015) and 6.5 months(95%CI:4.4-8.5,P=0.007) in non-maintenance group.No severe adverse event was observed in the capecitabine maintenance group.Conclusion:mCRC patients could benefit from capecitabine maintenance therapy by prolonging survival time and TTP.
基金The National Outstanding Youth Foundation of China (30525042)National 973 project of China (2006CB504201,2006CB504205)
文摘CD4+CD25+ Regulatory T cells (Treg) have been found to down-regulate immune activation in HIV-1 infection. However,whether the depletion of Treg benefits to the disease status of HIV infection remains undefined. To address this issue,we enumerated the Treg absolute counts and frequency in 75 antiviral-nave HIV-1-infected individuals in this study. It was found that HIV-infected patients displayed a significant decline in Treg absolute counts but a significant increase in Treg frequency. In addition,with disease progression indicated by CD4 T-cell absolute counts,circulating Treg frequency gradually increased; while Treg absolute counts were gradually decreased,suggesting that the alteration of Treg number closely correlated with disease progression in HIV infection. Functional analysis further showed that Treg efficiently inhibit both CD4 and CD8 T cell proliferation in vitro. Thus,our findings indicates that Treg actively participate in pathogenesis of chronic HIV infection,influencing the disease progression.
文摘The novel contagious primary atypical pneumonia epidemic,which broke out in Wuhan,China,in December 2019,is now formally called Coronavirus Disease 2019(COVID-19),with the causative virus named as Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2).1,2 Recent studies have shown that in addition to dyspnea,hypoxemia,and acute respiratory distress,lymphopenia,and cytokine release syndrome are also important clinical features in patients with severe SARS-CoV-2 infection.3 This suggests that homeostasis of the immune system plays an important role in the development of COVID-19 pneumonia.
文摘Background: The prevalence of hepatitis B virus (HBV) infection is high among individuals infected with human immunodeficiency virus (HIV) in China.Both HIV and HBV can be treated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC), so we evaluated the safety and efficacy of combination antiretroviral therapy (ART) that included TDF, 3TC, and efavirenz (EFV) among ART-naive individuals who were co-infected with HIV and HBV.Methods: One hundred HIV/HBV co-infected ARV-naive individuals were started on the regimen ofTDF, 3TC, and EFV, and the levels of plasma HBV DNA, HIV RNA, and biochemical evaluation related to the function of liver and kidney were analyzed.Results: Concerning efficacy, this study found that by week 48, the vast majority co-infected participants receiving this ART regimen had undetectable HBV DNA levels (71%) and/or HIV RNA levels (90%).Concerning safety, this study found that the median estimated glomerular filtration rate of participants decreased from baseline (109 ml·min-1· 1.73 m-2) to week 12 (104 ml·min-1· 1.73 m-2) but was almost back to baseline at week 48 (1 1 1 ml·min-1· 1.73 m-2).Conclusion: This combination ART regimen is safe and effective for patients with HIV/HBV co-infection.Trial Registration: ClinicalTrials.gov, NCT01751555;https://clinicaltrials.gov/ct2/show/NCT01751555.
基金supported by the National Key Research and Development Program of China(2020YFC0842000 to Y.T.Z.)the Yunnan Provincial major science and technology special project(202003AC100007 to X.Q.D.).
文摘Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell(PBMC)samples from 18 patients with coronavirus disease 2019(COVID-19)during their treatment,convalescence,and rehabilitation.After analyzing the regulatory networks of differentially expressed messenger RNAs(mRNAs),microRNAs(miRNAs)and long non-coding RNAs(lncRNAs)between the different clinical stages,we found that humoral immunity and type I interferon response were significantly downregulated,while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19.The formation of this T cell immune response might be driven by the activation of activating protein-1(AP-1)related signaling pathway and was weakly affected by other clinical features.These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.
基金This work was supported by the National Key Research and Development Program of China(2020YFC0842000 to Y.T.Z.)the Yunnan Provincial major science and technology special project(202003AC100007 to X.Q.D.).
文摘Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is crucial for improving treatment.Here,we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell(PBMC)samples from 18 patients with coronavirus disease 2019(COVID-19)during their treatment,convalescence,and rehabilitation.After analyzing the regulatory networks of differentially expressed messenger RNAs(mRNAs),microRNAs(miRNAs)and long non-coding RNAs(lncRNAs)between the different clinical stages,we found that humoral immunity and type I interferon response were significantly downregulated,while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19.The formation of this T cell immune response might be driven by the activation of activating protein-1(AP-1)related signaling pathway and was weakly affected by other clinical features.These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.