Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangio...Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangiomas(RCHs). Thus we tried to summarize the features of RCHs and estimate their relationship with tumor response.Methods: This prospective observational study systematically enrolled 98 patients with advanced solid tumors from April 27th,2016 to June 8th, 2017 in the context of the phase I clinical study of SHR-1210. This report focused on the skin toxicities. Patients underwent entire skin inspection every two weeks while taking medication. The clinical course of RCHs was recorded and their association with tumor response was estimated. The data cut-off date was November 15th, 2017.Results: After a median follow-up of 242(range, 29–567) days, RCHs were observed in 85.7%(84/98) of patients on cutaneous/mucosal surfaces; 84.5%(71/84) of the RCHs were evaluated as grade 1 adverse events. No grade 3 or 4 RCHs were observed. The time of onset of RCHs was dose dependent and shortest in the 400 mg-dose cohort(P < 0.001). Spontaneous and complete regression of RCHs was observed both during and after treatment. The objective response rate of tumors for patients with RCHs was 28.9%(24/83). However, no responders were observed among the patients without RCHs.Conclusions: RCHs were prevalent but manageable during treatment with SHR-1210. It might add to the expanding literature regarding immune-related dermatologic adverse events.展开更多
Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant ...Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant hematological tumors.However,the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients.Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects.In this study,we explored the potential function in ACT of ginsenoside Rg1,the main pharmacologically active component of ginseng.We introduced Rg1 during the in vitro activation and expansion phase of T cells,and found that Rg1 treatment upregulated two T cell activation markers,CD69 and CD25,while promoting T cell differentiation towards a mature state.Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis.When co-cultured with tumor cells,Rg1-treated T cells showed stronger cytotoxicity than untreated cells.Moreover,adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy.This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.展开更多
To achieve GSH-responsive 5-Fluorouridine(5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly...To achieve GSH-responsive 5-Fluorouridine(5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly-α, β-polyasparthydrazide(PAHy) chains and 3,3′-dithiodipropionic acid(DTDPA) consisting of a redox-responsive chain network. This particle highlights recent efforts in introducing a disulfide bond to drug delivery nanogel by DTDPA,and the increased release properties of complex nanogels produced excellent glutathione(GSH)-sensitivity and significant anti-tumor therapeutic efficacy. The PAHy-based nanogels were characterized by Fourier transform infrared spectroscopy(FT-IR), dynamic light scattering(DLS)(nano-particle size ~200 nm), UV–vis spectrometry, X-ray diffraction(XRD) and differential scanning calorimetric(DSC). PAHy-based nanogels are promising controlledrelease carriers for the tumor-targeting delivery of the anticancer agent 5-Fluorouridine.展开更多
Metformin,a first-line drug for type 2 diabetes mellitus,has been recognized as a potential anti-tumor agent in recent years.Epigallocatechin-3-gallate(EGCG),as the dominant catechin in green tea,is another promising ...Metformin,a first-line drug for type 2 diabetes mellitus,has been recognized as a potential anti-tumor agent in recent years.Epigallocatechin-3-gallate(EGCG),as the dominant catechin in green tea,is another promising adjuvant agent for tumor prevention.In the present work,the potential effect of EGCG on the anti-tumor efficacy of metformin in a mouse melanoma cell line(B16F10)was investigated.Results indicated that EGCG and metformin exhibited a synergistic effect on cell viability,migration,and proliferation,as well as signal transducer and activator of transcription 3/nuclear factor-κB(STAT3/NF-κB)pathway signaling and the production of inflammation cytokines.Meanwhile,the combination showed an antagonistic effect on cell apoptosis and oxidative stress levels.The combination of EGCG and metformin also differentially affected the nucleus(synergism)and cytoplasm(antagonism)of B16F10 cells.Our findings provide new insight into the potential effects of EGCG on the anti-tumor efficacy of metformin in melanoma cells.展开更多
Considering the results of our previous research that conjugated linoleic acid mixture-paclitaxel （CLA-mixture-PTX） possesses anti-tumor activity against melanoma and brain glioma, the purpose of this study was to i...Considering the results of our previous research that conjugated linoleic acid mixture-paclitaxel （CLA-mixture-PTX） possesses anti-tumor activity against melanoma and brain glioma, the purpose of this study was to investigate the potential anti-tumor efficacy of cis-9, trans- 1 1-conjugated linoleic acid-paclitaxel （c9, tl 1-CLA-PTX） and trans- 1 O, cis- 12-conjugated linoleic acid-paclitaxel （tl0, c12-CLA-PTX） on MCF-7 breast cancer cell line in vitro and in vivo. The in vitro cytotoxicity, apoptosis induction effect and cell cycle arresting effect of c9, t1 1-CLA-PTX and t10, c12-CLA-PTX were investigated. The in vitro cellular uptake of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX in MCF-7 cells were also analyzed. Besides, the anti-tumor activity of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX was evaluated in MCF-7 tumor bearing nude mice in vivo. The in vitro cytotoxicity results showed that the value of ICs0 of the tl 0, c l2-CLA-PTX is （0.17±0.02） μM, compared with that of （1.08±0.15） μM in CLA-mixture-PTX and （6.50±1.20） μM in c9, tl 1-CLA-PTX treatment group （P〈0.01）. Both tl0, cl2-CLA-PTX and c9, t l 1-CLA-PTX increased the percentage of total apoptotic cells compared with that of control （P〈0.01）. And the rank of apoptosis induction efficacy was t 10, c 12-CLA-PTX〉CLA-mixture-PTX〉c9, t 11-CLA-PTX （P〈0.01）. Compared with untreated cells, the tl0, c12-CLA-PTX and c9, tl 1-CLA-PTX arrested cell cycle progression at the S and G2-M phase. The amount of cellular uptake of t 10, c 12-CLA-PTX was significantly higher than that of CLA-mixture-PTX （P〈0.01）, which was significantly higher than that of c9, t1 1-CLA-PTX （P〈0.01）. The rank of in vivo anti-tumor activity was tl0, c12-CLA-PTX〉CLA-mixture-PTX〉 c9, t1 1-CLA-PTX （P〈0.01）. In conclusion, our study demonstrated that both tl0, cl2-CLA-PTX and c9, tl 1-CLA-PTX has significant anti-tumor activity in MCF-7 cell line. And while c9, tl 1-CLA-PTX showed weaker inhibitory effect than CLA-mixture-PTX, str展开更多
基金supported by a grant from CAMS Initiative for Innovative Medicine (Grant No. CAMS-12M-1-010)
文摘Objective: SHR-1210 is a new and promising anti-PD-1 agent for solid tumors. During the phase I study of SHR-1210, we encountered a novel but prevalent immune-related dermatologic toxicity: reactive capillary hemangiomas(RCHs). Thus we tried to summarize the features of RCHs and estimate their relationship with tumor response.Methods: This prospective observational study systematically enrolled 98 patients with advanced solid tumors from April 27th,2016 to June 8th, 2017 in the context of the phase I clinical study of SHR-1210. This report focused on the skin toxicities. Patients underwent entire skin inspection every two weeks while taking medication. The clinical course of RCHs was recorded and their association with tumor response was estimated. The data cut-off date was November 15th, 2017.Results: After a median follow-up of 242(range, 29–567) days, RCHs were observed in 85.7%(84/98) of patients on cutaneous/mucosal surfaces; 84.5%(71/84) of the RCHs were evaluated as grade 1 adverse events. No grade 3 or 4 RCHs were observed. The time of onset of RCHs was dose dependent and shortest in the 400 mg-dose cohort(P < 0.001). Spontaneous and complete regression of RCHs was observed both during and after treatment. The objective response rate of tumors for patients with RCHs was 28.9%(24/83). However, no responders were observed among the patients without RCHs.Conclusions: RCHs were prevalent but manageable during treatment with SHR-1210. It might add to the expanding literature regarding immune-related dermatologic adverse events.
基金supported by the National Natural Science Foundation of China(No.82020108004 and 81873424)the Natural Science Foundation of Chongqing,China(No.CSTB2022NSCQ-MSX1287)+2 种基金Special Funding for the Frontiers of Military Medical Basics(No.2018YQYLY002)Key Technical Innovation Projects in Clinical Fields of Xinqiao Hospital(No.2018JSLC0020)the Young Doctor Talent Incubation Program of Xinqiao Hospital(No.2022YQB016).
文摘Adoptive cell therapy(ACT)has emerged with remarkable efficacies for tumor immunotherapy.Chimeric antigen receptor(CAR)T cell therapy,as one of most promising ACTs,has achieved prominent effects in treating malignant hematological tumors.However,the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients.Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects.In this study,we explored the potential function in ACT of ginsenoside Rg1,the main pharmacologically active component of ginseng.We introduced Rg1 during the in vitro activation and expansion phase of T cells,and found that Rg1 treatment upregulated two T cell activation markers,CD69 and CD25,while promoting T cell differentiation towards a mature state.Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis.When co-cultured with tumor cells,Rg1-treated T cells showed stronger cytotoxicity than untreated cells.Moreover,adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy.This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.
基金National Basic Research Program of China(973 Program)(No.2015CB932100)National Natural Science Foundation of China(No.81473165)+1 种基金Liaoning Provincial Key Laboratory of Drug Preparation Design&Evaluation of Liaoning Provincial Education Department(LZ2014045)Liaoning Provincial Key Laboratory of Studying the Modern Drug preparations.
文摘To achieve GSH-responsive 5-Fluorouridine(5-FU) delivery, a novel family of nanogel drug carriers has been successfully prepared. The new class of PAHy-based nanogels was prepared by the crossing-link reaction of poly-α, β-polyasparthydrazide(PAHy) chains and 3,3′-dithiodipropionic acid(DTDPA) consisting of a redox-responsive chain network. This particle highlights recent efforts in introducing a disulfide bond to drug delivery nanogel by DTDPA,and the increased release properties of complex nanogels produced excellent glutathione(GSH)-sensitivity and significant anti-tumor therapeutic efficacy. The PAHy-based nanogels were characterized by Fourier transform infrared spectroscopy(FT-IR), dynamic light scattering(DLS)(nano-particle size ~200 nm), UV–vis spectrometry, X-ray diffraction(XRD) and differential scanning calorimetric(DSC). PAHy-based nanogels are promising controlledrelease carriers for the tumor-targeting delivery of the anticancer agent 5-Fluorouridine.
基金the National Natural Science Foundation of China(No.U19A2034)。
文摘Metformin,a first-line drug for type 2 diabetes mellitus,has been recognized as a potential anti-tumor agent in recent years.Epigallocatechin-3-gallate(EGCG),as the dominant catechin in green tea,is another promising adjuvant agent for tumor prevention.In the present work,the potential effect of EGCG on the anti-tumor efficacy of metformin in a mouse melanoma cell line(B16F10)was investigated.Results indicated that EGCG and metformin exhibited a synergistic effect on cell viability,migration,and proliferation,as well as signal transducer and activator of transcription 3/nuclear factor-κB(STAT3/NF-κB)pathway signaling and the production of inflammation cytokines.Meanwhile,the combination showed an antagonistic effect on cell apoptosis and oxidative stress levels.The combination of EGCG and metformin also differentially affected the nucleus(synergism)and cytoplasm(antagonism)of B16F10 cells.Our findings provide new insight into the potential effects of EGCG on the anti-tumor efficacy of metformin in melanoma cells.
基金National Natural Science Foundation of China (Grant No.81172992)the National Basic Research Program of China (973 Program,Grant No.2013CB932501)Innovation Team of Ministry of Education (Grant No.BMU20110263)
文摘Considering the results of our previous research that conjugated linoleic acid mixture-paclitaxel （CLA-mixture-PTX） possesses anti-tumor activity against melanoma and brain glioma, the purpose of this study was to investigate the potential anti-tumor efficacy of cis-9, trans- 1 1-conjugated linoleic acid-paclitaxel （c9, tl 1-CLA-PTX） and trans- 1 O, cis- 12-conjugated linoleic acid-paclitaxel （tl0, c12-CLA-PTX） on MCF-7 breast cancer cell line in vitro and in vivo. The in vitro cytotoxicity, apoptosis induction effect and cell cycle arresting effect of c9, t1 1-CLA-PTX and t10, c12-CLA-PTX were investigated. The in vitro cellular uptake of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX in MCF-7 cells were also analyzed. Besides, the anti-tumor activity of c9, tl 1-CLA-PTX and tl0, cl2-CLA-PTX was evaluated in MCF-7 tumor bearing nude mice in vivo. The in vitro cytotoxicity results showed that the value of ICs0 of the tl 0, c l2-CLA-PTX is （0.17±0.02） μM, compared with that of （1.08±0.15） μM in CLA-mixture-PTX and （6.50±1.20） μM in c9, tl 1-CLA-PTX treatment group （P〈0.01）. Both tl0, cl2-CLA-PTX and c9, t l 1-CLA-PTX increased the percentage of total apoptotic cells compared with that of control （P〈0.01）. And the rank of apoptosis induction efficacy was t 10, c 12-CLA-PTX〉CLA-mixture-PTX〉c9, t 11-CLA-PTX （P〈0.01）. Compared with untreated cells, the tl0, c12-CLA-PTX and c9, tl 1-CLA-PTX arrested cell cycle progression at the S and G2-M phase. The amount of cellular uptake of t 10, c 12-CLA-PTX was significantly higher than that of CLA-mixture-PTX （P〈0.01）, which was significantly higher than that of c9, t1 1-CLA-PTX （P〈0.01）. The rank of in vivo anti-tumor activity was tl0, c12-CLA-PTX〉CLA-mixture-PTX〉 c9, t1 1-CLA-PTX （P〈0.01）. In conclusion, our study demonstrated that both tl0, cl2-CLA-PTX and c9, tl 1-CLA-PTX has significant anti-tumor activity in MCF-7 cell line. And while c9, tl 1-CLA-PTX showed weaker inhibitory effect than CLA-mixture-PTX, str
