This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation fro...This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed, leading to an arginine （CGA） to stop codon （TGA） change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.展开更多
Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challeng...Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.展开更多
The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hype...The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region,and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome.We demonstrate that MrgprF forced expression inhibits tumor cell proliferation,migration,xenograft tumor growth,and metastasis.On the contrary,MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells,supporting the inhibitory role of MrgprF during tumor progression.Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase(PI3K)complex formation between p101 and p110γsubunits,the critical step for phosphatidylinositol-(3,4)-P2(PIP2)conversion to phosphatidylinositol-(3,4,5)-P3(PIP3),and then reduces the activation of PI3K/Akt signaling.This effect can be reversed by Akt specific agonist SC79.In addition,AMG 706,a previously documented inhibitor for endothelial cell proliferation,is identified as a potential agonist for MrgprF,and can impede tumor growth both in vitro and in vivo.Taken together,our findings suggest that MrgprF,a novel tumor suppressor in cutaneous melanoma,may be useful as a therapeutic target in the future.展开更多
基金the National Natural Science Foundation of China, No. 81041019the National High-Technology Research and Development Program of China (863 Program), No.2006AA02Z436
文摘This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed, leading to an arginine （CGA） to stop codon （TGA） change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.
基金supported by the National Natural Science Foundation of China(Nos.81920108001 and 81870007)Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.
文摘Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.
基金This study was supported by National Key Research and Development Program of China(2021YFF1000602)National Nature Science Foundation of China(U2102206,U1902216,81772996,82173110,82002439,81972181,82060515)+6 种基金Yunnan Applied Basic Research Projects(2019FJ009,202001AS070037,2019HB076,202001AY070001-068,2019FE001-042)C.P.Y was supported by Youth Innovation Promotion Association,CASY.B.C was supported by grant from the Strategic Priority Research Program of the Chinese Academy of Sciences XDPB17,and YJKYYQ20190048Science&Technology Department of Sichuan Province Research Program(2020YFSY0009)Q.S.S was also supported by China Postdoctoral Science Foundation(2019M662547)the Fellowship of China National Postdoctoral Program for Innovative Talents(BX20190299)S.Z was also supported by Key Scientific Research Projects of Colleges and Universities in Henan Province(21A320024).
文摘The incidence of cutaneous melanoma(CM)has been increasing annually worldwide.In this study,we identify that MrgprF,a MAS related GPR family member,is decreased in cutaneous melanoma tissues and cell lines due to hypermethylation of its promoter region,and show that patients with CM expressing high levels of MrgprF exhibit an improved clinical outcome.We demonstrate that MrgprF forced expression inhibits tumor cell proliferation,migration,xenograft tumor growth,and metastasis.On the contrary,MrgprF knockdown promotes tumor cell proliferation and transformation of immortalized human keratinocyte-HaCaT cells,supporting the inhibitory role of MrgprF during tumor progression.Mechanistic studies reveal that MrgprF reduces the phosphoinositol‑3‑kinase(PI3K)complex formation between p101 and p110γsubunits,the critical step for phosphatidylinositol-(3,4)-P2(PIP2)conversion to phosphatidylinositol-(3,4,5)-P3(PIP3),and then reduces the activation of PI3K/Akt signaling.This effect can be reversed by Akt specific agonist SC79.In addition,AMG 706,a previously documented inhibitor for endothelial cell proliferation,is identified as a potential agonist for MrgprF,and can impede tumor growth both in vitro and in vivo.Taken together,our findings suggest that MrgprF,a novel tumor suppressor in cutaneous melanoma,may be useful as a therapeutic target in the future.
