Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clin...Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.展开更多
Objective:To investigate the urodynamic study(UDS)patterns,obstruction status,continence status,and their correlations among neurologically intact women with lower urinary tract symptoms(LUTS)through an epidemiologica...Objective:To investigate the urodynamic study(UDS)patterns,obstruction status,continence status,and their correlations among neurologically intact women with lower urinary tract symptoms(LUTS)through an epidemiological and logistic regression analyses.Methods:We retrospectively analyzed the UDS data of 3265 neurologically intact women with LUTS(2002e2014).Five UDS patterns were identified:normo-active detrusor/sphincter(NA,or DSI,detrusor/sphincter intact),idiopathic detrusor overactivity(IDO),idiopathic sphincter overactivity(ISO),IDO+ISO,and detrusor underactivity(DUA).Analyses of UDS pattern distribution and stratification were performed(based on a modification of the European Urological Association-Madersbacher classification system),and their correlations with bladder outlet obstruction(BOO)and stress urinary incontinence(SUI)status were evaluated via logistic regression analysis.Results:NA,IDO,IDO+ISO,ISO,and DUA were noted in 927(28.4%),678(20.8%),320(9.8%),689(21.1%),and 651(19.9%)cases,respectively.Moreover,storage,storage+voiding,and voiding symptoms were noted in 62.4%,21.1%,and 16.5% cases,respectively,whereas BOO and SUI were observed in 12.1%and 29.0%cases,respectively.The risk factors for BOO included NA,IDO,ISO,and IDO+ISO,whereas the protective factors against BOO included storage symptoms,SUI,storage+voiding symptoms,and complaint duration within 1e12 months.NA was the only risk factor for SUI,whereas BOO,storage+voiding symptoms,IDO,and storage symptoms were protective factors for SUI.Conclusion:Five UDS patterns were identified among neurologically intact women with LUTS.Functional abnormalities of the detrusor and/or sphincter were the main causes of LUTS,and were correlated with the BOO or SUI status.Thus,the UDS pattern can provide additional information regarding the risk factors for BOO or SUI status,as compared to symptomatic typing.展开更多
Dear editor,Patients with clear-cell renal cell carcinoma(ccRCC)potentially have a high recurrence rate of more than 40%[1].Patients receive radical or partial nephrectomy,sometimes assisted by targeted therapies or/a...Dear editor,Patients with clear-cell renal cell carcinoma(ccRCC)potentially have a high recurrence rate of more than 40%[1].Patients receive radical or partial nephrectomy,sometimes assisted by targeted therapies or/and immune checkpoint inhibitors(ICIs),to improve overall survival(OS)[2].Large-cohort studies and large-scale human tissue sequencing have provided a series of molecular subtyping methods for precision medicine-based ccRCC risk stratification and therapeutic regimens,such as ClearCode34,the prognostic risk predictor[3],and seven subsets for ICI and angiogenesis blockade outcomes[4].However,these subtyping results are all based on human genomes without including the host microbiota,which may be non-negligible genome components.展开更多
Primary hyperoxaluria type 1(PH1)is a severe hereditary disease,leading to the accumulation of oxalate in multiple organs,particularly the kidney.Hydroxyacid oxidase 1(HAO1),a pivotal gene involved in oxalate producti...Primary hyperoxaluria type 1(PH1)is a severe hereditary disease,leading to the accumulation of oxalate in multiple organs,particularly the kidney.Hydroxyacid oxidase 1(HAO1),a pivotal gene involved in oxalate production,is an approved target for the treatment of PH1.In this study,we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1c.290-2 A in vivo with lipid nanoparticles(LNP)delivered adenine base editing(ABE)mRNA.A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver,leading to the sustainable normalization of urinary oxalate(for at least 6 months)and complete rescue of the pathophysiology in PH1 rats.Additionally,a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60%Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats.These findings suggest that the LNP-mediated base-editing of Hao1c.290-2 A is an efficient and safe approach to PH1 therapy,highlighting its potential utility in clinical settings.展开更多
The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting peo...The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic.This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future.Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment.In this review,we introduce the biologic principles and advancements of mRNA technology,and chemistry fundamentals of intriguing mRNA delivery nanoformulations.We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells,such as dendritic cells(DCs)at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy,and DCs,natural killer(NK)cells,cytotoxic T cells,or multiple immunosuppressive immune cells at tumor microenvironment(TME)for reversing immune evasion.We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.展开更多
Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(...Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.展开更多
基金supported by the Top-Level Clinical Discipline Project of Shanghai Pudong (PWYgf2018-03)National Natural Science Foundation of China (Nos.81773154,81902565,81772747,81974391)+4 种基金Shanghai Natural Science Foundation (No.20ZR1449600)Pudong New Area Science and Technology Development Fund Special Fund for People’s Livelihood Research (Medical and Health) (PKJ2019-Y19)Young Scientists Foundation of Changzhou No.2 People’s Hospital (2019K008)Changzhou Sci&Tech Program (CJ20190100)the Program of Shanghai Academic/Technology Research Leader (No.19XD1405100).
文摘Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.
文摘Objective:To investigate the urodynamic study(UDS)patterns,obstruction status,continence status,and their correlations among neurologically intact women with lower urinary tract symptoms(LUTS)through an epidemiological and logistic regression analyses.Methods:We retrospectively analyzed the UDS data of 3265 neurologically intact women with LUTS(2002e2014).Five UDS patterns were identified:normo-active detrusor/sphincter(NA,or DSI,detrusor/sphincter intact),idiopathic detrusor overactivity(IDO),idiopathic sphincter overactivity(ISO),IDO+ISO,and detrusor underactivity(DUA).Analyses of UDS pattern distribution and stratification were performed(based on a modification of the European Urological Association-Madersbacher classification system),and their correlations with bladder outlet obstruction(BOO)and stress urinary incontinence(SUI)status were evaluated via logistic regression analysis.Results:NA,IDO,IDO+ISO,ISO,and DUA were noted in 927(28.4%),678(20.8%),320(9.8%),689(21.1%),and 651(19.9%)cases,respectively.Moreover,storage,storage+voiding,and voiding symptoms were noted in 62.4%,21.1%,and 16.5% cases,respectively,whereas BOO and SUI were observed in 12.1%and 29.0%cases,respectively.The risk factors for BOO included NA,IDO,ISO,and IDO+ISO,whereas the protective factors against BOO included storage symptoms,SUI,storage+voiding symptoms,and complaint duration within 1e12 months.NA was the only risk factor for SUI,whereas BOO,storage+voiding symptoms,IDO,and storage symptoms were protective factors for SUI.Conclusion:Five UDS patterns were identified among neurologically intact women with LUTS.Functional abnormalities of the detrusor and/or sphincter were the main causes of LUTS,and were correlated with the BOO or SUI status.Thus,the UDS pattern can provide additional information regarding the risk factors for BOO or SUI status,as compared to symptomatic typing.
基金sponsored by the National Natural Science Foundation of China(Nos.81974391,82072806,and 82173265)the National Natural Science Foundation of China for Youths(No.8200100057)+6 种基金Program of Shanghai Academic/Technology Research Leader(No.19XD1405100)Clinical Research Plan of SHDC(No.SHDC2020CR4025)Shanghai“Rising Stars of Medical Talent”Youth Development Program:Youth Medical Talents-Specialist Program(Xiuwu Pan)Shanghai Municipal Commission of Health and Family Planning(No.20204Y0042)Technology Project of Jiading District Health System(No.2019-QN-03)Natural Science Foundation of Shanghai(No.20ZR1470500)Hospital Funded Clinical Research,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine(No.21XHDB06).
文摘Dear editor,Patients with clear-cell renal cell carcinoma(ccRCC)potentially have a high recurrence rate of more than 40%[1].Patients receive radical or partial nephrectomy,sometimes assisted by targeted therapies or/and immune checkpoint inhibitors(ICIs),to improve overall survival(OS)[2].Large-cohort studies and large-scale human tissue sequencing have provided a series of molecular subtyping methods for precision medicine-based ccRCC risk stratification and therapeutic regimens,such as ClearCode34,the prognostic risk predictor[3],and seven subsets for ICI and angiogenesis blockade outcomes[4].However,these subtyping results are all based on human genomes without including the host microbiota,which may be non-negligible genome components.
基金partially supported by the National Natural Science Foundation of China (82470794,32025023 and 32230064)the National Key Research and Development Program of China (2023YFC3403400 to Li,D)a grant from the Science and Technology Commission of Shanghai Municipality (22YF1426900)。
文摘Primary hyperoxaluria type 1(PH1)is a severe hereditary disease,leading to the accumulation of oxalate in multiple organs,particularly the kidney.Hydroxyacid oxidase 1(HAO1),a pivotal gene involved in oxalate production,is an approved target for the treatment of PH1.In this study,we demonstrated the discovery of several novel therapeutic sites of the Hao1 gene and the efficient editing of Hao1c.290-2 A in vivo with lipid nanoparticles(LNP)delivered adenine base editing(ABE)mRNA.A single infusion of LNP-ABE resulted in a near-complete knockout of Hao1 in the liver,leading to the sustainable normalization of urinary oxalate(for at least 6 months)and complete rescue of the pathophysiology in PH1 rats.Additionally,a significant correlation between Hao1 editing efficiency and urinary oxalate levels was observed and over 60%Hao1 editing efficiency was required to achieve the normalization of urinary oxalate in PH1 rats.These findings suggest that the LNP-mediated base-editing of Hao1c.290-2 A is an efficient and safe approach to PH1 therapy,highlighting its potential utility in clinical settings.
基金This work was supported by the National Natural Science Foundation of China[32101146,81974391,82072806,82173265]Shanghai Science and Technology Program[21010500100,22140901700]+5 种基金Basic Research Program of Shanghai Municipal Government[21JC1406002]Shanghai Pujiang Program[21PJ1404500]Shanghai Excellent Overseas Young Scientiststhe Clinical Research Plan of SHDC[SHDC2020CR4025]the Natural Science Foundation of Shanghai[20ZR1470500]Hospital Funded Clinical Research,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine[21XHDB06].
文摘The approved worldwide use of two messenger RNA(mRNA)vaccines(BNT162b2 and mRNA-1273)in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic.This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future.Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment.In this review,we introduce the biologic principles and advancements of mRNA technology,and chemistry fundamentals of intriguing mRNA delivery nanoformulations.We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells,such as dendritic cells(DCs)at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy,and DCs,natural killer(NK)cells,cytotoxic T cells,or multiple immunosuppressive immune cells at tumor microenvironment(TME)for reversing immune evasion.We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.
基金supported by the National Natural Ascience Foundation of China(No.31821003 to HX)the China Ministry of Science and Technology(No.2018AAA0100300 to HX).
文摘Objective:Although the neurological and olfactory symptoms of coronavirus disease 2019 have been identified,the neurotropic properties of the causative virus,severe acute respiratory syndrome-associated coronavirus 2(SARS-CoV-2),remain unknown.We sought to identify the susceptible cell types and potential routes of SARS-CoV-2 entry into the central nervous system,olfactory system,and respiratory system.Methods:We collected single-cell RNA data from normal brain and nasal epithelium specimens,along with bronchial,tracheal,and lung specimens in public datasets.The susceptible cell types that express SARS-CoV-2 entry genes were identified using single-cell RNA sequencing and the expression of the key genes at protein levels was verified by immunohistochemistry.We compared the coexpression patterns of the entry receptor angiotensin-converting enzyme 2(ACE2)and the spike protein priming enzyme transmembrane serine protease(TMPRSS)/cathepsin L among the specimens.Results:The SARS-CoV-2 entry receptor ACE2 and the spike protein priming enzyme TMPRSS/cathepsin L were coexpressed by pericytes in brain tissue;this coexpression was confirmed by immunohistochemistry.In the nasal epithelium,ciliated cells and sustentacular cells exhibited strong coexpression of ACE2 and TMPRSS.Neurons and glia in the brain and nasal epithelium did not exhibit coexpression of ACE2 and TMPRSS.However,coexpression was present in ciliated cells,vascular smooth muscle cells,and fibroblasts in tracheal tissue;ciliated cells and goblet cells in bronchial tissue;and alveolar epithelium type 1 cells,AT2 cells,and ciliated cells in lung tissue.Conclusion:Neurological symptoms in patients with coronavirus disease 2019 could be associated with SARS-CoV-2 invasion across the blood-brain barrier via pericytes.Additionally,SARS-CoV-2-induced olfactory disorders could be the result of localized cell damage in the nasal epithelium.
