Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introducti...Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.展开更多
Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, p...Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-ceU infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.展开更多
Objective:Previous reports have shown that the gene promoter region of retinoic acid receptor β(RARβ) was hypermethylated in cervical carcinoma,implying the inhibition of gene transcription.The aim of this study was...Objective:Previous reports have shown that the gene promoter region of retinoic acid receptor β(RARβ) was hypermethylated in cervical carcinoma,implying the inhibition of gene transcription.The aim of this study was to investigate the association of cervical cancer development with the RARβ gene expression at the mRNA and protein level to assess the impact of RARβ as a marker for early detection of the cancer.Methods:We collected 126 cases of formalin fixed and paraffin embedded cervical tissue specimens as well as 37 cases of fresh tissue samples from women with cervicitis,cervical intraepithelial neoplasia(CIN) and cervical squamous cell carcinoma(CSCC).The RARβ mRNA and protein expression was detected by quantitative RT-PCR and immunohistochemistry,respectively.Results:(1) The mRNA expression of RARβ in CIN and cervical cancer was markedly decreased compared to cervicitis with a statistically very significant difference,but no difference was found between CIN and cervical cancer.(2) RARβ protein was normally expressed in the epithelial cells of cervicitis and partially lost in a few cases,but with the development of cervical lesion pathogenesis and cancer,a significant loss of protein expression was detected in CIN(38%) and CSCC(57%) compared to cervicitis(P < 0.01).Conclusion:The downregulation of RARβ transcription or loss of protein expression is an important indicator of cervical cancer and its precursur lesions.The detection of RARβ expression coupled with aberrant methylation of the gene may become a biomarker for the early prognosis or diagnosis of the cancer.展开更多
Monoclonal antibodies (McAbs) 1A9 and 9F12 against Foot-and-mouth disease virus (FMDV) serotype O were produced by fusing SP2/0 myeloma cells with splenocyte from the mouse immunized with O/China99. Both McAbs reacted...Monoclonal antibodies (McAbs) 1A9 and 9F12 against Foot-and-mouth disease virus (FMDV) serotype O were produced by fusing SP2/0 myeloma cells with splenocyte from the mouse immunized with O/China99. Both McAbs reacted with O/China99 but not with Asia 1, as determined by immunohistochemistry assay. The microneutralization titer of the McAbs 1A9 and 9F12 were 640 and 1 280, respectively. Both McAbs contain kappa light chains, but the McAbs 1A9 and 9F12 were IgG1 and IgM, respectively. In order to define the McAbs binding epitopes, the reactivity of these McAbs against VP1, P20 and P14 were examined using indirect ELISA, the result showed that both McAbs reacted with VP1 and P20. McAbs may be used for further studies of vaccine, diagnostic methods, prophylaxis, etiological and immunological researches on FMDV.展开更多
Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients ...Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.展开更多
基金NIH grants 1K08CA160692-01A1,U54CA163125-01 and the generous philanthropic support of several families whose lives have been affected by melanoma
文摘Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy(BRAF and MEK inhibitors) and immune checkpoint blockade(anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with longterm responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.
基金supported by the Viragh Foundation(L.Z.)National Institutes of Health(NIH)(Grant No.K23 CA148964,L.Z.)the NCI SPORE in Gastrointestinal Cancers(Grant No.P50 CA062924,L.Z.)
文摘Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-ceU infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clinical trials to test the combination are currently ongoing.
基金Supported by a grant from the Natural Science Foundation of China (No. 30760279)
文摘Objective:Previous reports have shown that the gene promoter region of retinoic acid receptor β(RARβ) was hypermethylated in cervical carcinoma,implying the inhibition of gene transcription.The aim of this study was to investigate the association of cervical cancer development with the RARβ gene expression at the mRNA and protein level to assess the impact of RARβ as a marker for early detection of the cancer.Methods:We collected 126 cases of formalin fixed and paraffin embedded cervical tissue specimens as well as 37 cases of fresh tissue samples from women with cervicitis,cervical intraepithelial neoplasia(CIN) and cervical squamous cell carcinoma(CSCC).The RARβ mRNA and protein expression was detected by quantitative RT-PCR and immunohistochemistry,respectively.Results:(1) The mRNA expression of RARβ in CIN and cervical cancer was markedly decreased compared to cervicitis with a statistically very significant difference,but no difference was found between CIN and cervical cancer.(2) RARβ protein was normally expressed in the epithelial cells of cervicitis and partially lost in a few cases,but with the development of cervical lesion pathogenesis and cancer,a significant loss of protein expression was detected in CIN(38%) and CSCC(57%) compared to cervicitis(P < 0.01).Conclusion:The downregulation of RARβ transcription or loss of protein expression is an important indicator of cervical cancer and its precursur lesions.The detection of RARβ expression coupled with aberrant methylation of the gene may become a biomarker for the early prognosis or diagnosis of the cancer.
基金The national high technology research and development program of China 863 (2006AA10A204)The national science and technology pillar program (2006BAD06A17)
文摘Monoclonal antibodies (McAbs) 1A9 and 9F12 against Foot-and-mouth disease virus (FMDV) serotype O were produced by fusing SP2/0 myeloma cells with splenocyte from the mouse immunized with O/China99. Both McAbs reacted with O/China99 but not with Asia 1, as determined by immunohistochemistry assay. The microneutralization titer of the McAbs 1A9 and 9F12 were 640 and 1 280, respectively. Both McAbs contain kappa light chains, but the McAbs 1A9 and 9F12 were IgG1 and IgM, respectively. In order to define the McAbs binding epitopes, the reactivity of these McAbs against VP1, P20 and P14 were examined using indirect ELISA, the result showed that both McAbs reacted with VP1 and P20. McAbs may be used for further studies of vaccine, diagnostic methods, prophylaxis, etiological and immunological researches on FMDV.
基金supported by the National Natural Science Foundation of China (81000107,30670835,81071072,31171088)the National Basic Research Program of China (2011CB933500)grants from Key Laboratory of Medical Electrophysiology of Sichuan Province (MEPSCKL2011-01)
文摘Autoimmune activities have been implicated in the pathogenesis of hypertension.High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor(α1-AR autoantibody,α1-AA) are found in patients with hypertension,and α1-AA could exert a α1-AR agonist-like vasoconstrictive effect.However,whether the vasoconstrictive effect of α1-AA is enhanced in hypertension is unknown.Using aortic rings of spontaneously hypertensive rats(SHR) and normotensive Wistar-Kyoto(WKY) rats,we observed the vasoconstrictive responses to α1-AA with phenylephrine(α1-AR agonist) as a positive control drug.Aortic nitrotyrosine levels were also measured by ELISA and immunohistochemistry.The results showed that the aortic constrictive responses to α1-AA and phenylephrine(both 1 nmol L-1-10 μmol L-1) were greater in SHR than in WKY rats.Endothelial denudation or L-NAME(a non-selective NOS inhibitor)(100 μmol L-1) increased α1-AA- or phenylephrine-induced vasoconstrictions both in SHR and WKY.However,selective iNOS inhibitor 1400W(10 μmol L-1) enhanced the α1-AA-induced aortic constriction in WKY,but not in SHR.The aortic nitrotyrosine level was significantly higher in SHR than WKY,as shown by both ELISA and immunohistochemistry.These results indicate that the vasoconstrictive response to α1-AA is enhanced in SHR,and this altered responsiveness is due to endothelial dysfunction and decreased NO bioavailability.The study suggests an important role of α1-AR autoimmunity in the pathogenesis and management of hypertension especially in those harboring high α1-AA levels.