Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immuno...Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.展开更多
DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromo...DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining （NHEJ） and homologous recombination （HR）, and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1（XRS2） complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit （DNA-PKcs）, and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.展开更多
Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men an...Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women.Almost all cervical cancers are HPV-associated,however,an increasing number of head and neck cancers(HNCs),especially oropharyngeal cancer,can be linked to HPV infection.Moreover,anogenital cancers,including vaginal,vulvar,penial,and anal cancers,represent a subset of HPVrelated cancers.Whereas testing and prevention of cervical cancer have significantly improved over past decades,anogenital cancers remain more difficult to confirm.Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments.The HPV viral oncoproteins,E6 and E7,lead to degradation of,respectively,p53 and pRb resulting in entering the S phase without G1 arrest.These high-risk HPV viral oncogenes alter numerous cellular processes,including DNA repair,angiogenesis,and/or apoptosis,which eventually result in carcinogenesis.Additionally,a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks(DSB)repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers.In this review,we discuss the current knowledge regarding HPV-related cancers,current screening,and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.展开更多
文摘Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.
文摘DNA double-strand breaks （DSBs） are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining （NHEJ） and homologous recombination （HR）, and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1（XRS2） complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit （DNA-PKcs）, and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM.
基金supported by the Pamela and Wayne Garrison Distinguished Chair in Cancer Research to J.C.J.C.also received support from the CPRIT awards(Grant Nos RP160667 and RP180813)NIH grants(Grant Nos P01CA193124,R01CA210929,R01CA216911,and R01CA216437)。
文摘Cancer-related diseases represent the second overall cause of death worldwide.Human papilloma virus(HPV)is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women.Almost all cervical cancers are HPV-associated,however,an increasing number of head and neck cancers(HNCs),especially oropharyngeal cancer,can be linked to HPV infection.Moreover,anogenital cancers,including vaginal,vulvar,penial,and anal cancers,represent a subset of HPVrelated cancers.Whereas testing and prevention of cervical cancer have significantly improved over past decades,anogenital cancers remain more difficult to confirm.Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments.The HPV viral oncoproteins,E6 and E7,lead to degradation of,respectively,p53 and pRb resulting in entering the S phase without G1 arrest.These high-risk HPV viral oncogenes alter numerous cellular processes,including DNA repair,angiogenesis,and/or apoptosis,which eventually result in carcinogenesis.Additionally,a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks(DSB)repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers.In this review,we discuss the current knowledge regarding HPV-related cancers,current screening,and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.
