| 2 | Subclinical proximal tubulopathy in hepatitis B:The roles of nucleot(s)ide analogue treatment and the hepatitis B virus显示文摘BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity,such as estimated glomerular filtration rate(eGFR)and phosphatemia,are late markers of proximal tubulopathy.Multiple early markers are available,but no consensus exists on their use.AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy(SPT),as defined with early biomarkers,in treated vs untreated hepatitis B virus(HBV)-monoinfected patients.METHODS A prospective,non-randomized,multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted.The patients were separated into three groups:Naïve,starting entecavir(ETV)treatment,or starting tenofovir disoproxil(TDF)treatment.Data on the early markers of SPT,the eGFR and phosphatemia,were collected quarterly.SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%.The prevalence and cumulative incidence of SPT at month 24(M24)were calculated.Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests,whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data.Multivariate analyses were used to adjust for any potential confounding factors.RESULTS Of the 196 patients analyzed,138(84 naïve,28 starting ETV,and 26 starting TDF)had no SPT at inclusion.At M24,the prevalence of SPT was not statistically different between naïve and either treated group(21.1%vs 30.7%,P<0.42 and 50.0%vs 30.7%,P=0.32 for ETV and TDF,respectively);no patient had an eGFR lower than 50 mL/min/1.73 m²or phosphatemia less than 0.48 mmoL/L.In the multivariate analysis,no explanatory variables were identified after adjustment.The cumulative incidence of SPT over 24 mo(25.5%,13.3%,and 52.9%in the naïve,ETV,and TDF groups,respectively)tended to be higher in the TDF group vs the naïve group(hazard ratio:2.283,P=0.05).SPT-free survival at M24 was 57.6%,68.8%,and 23.5%for the naïve,ETV,and TDF groups,respectively.The median survival time without SPT,evaluated only in the TDF group,was 5.9 mo.CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients.SPT in the naïve population suggests that HBV can induce renal tubular toxicity. | Anais Brayette Marie Essig Paul Carrier Marilyne Debette-Gratien Anais Labrunie Sophie Alain Marianne Maynard Nathalie Ganne-Carrie Eric Nguyen-Khac Pauline Pinet Victor De Ledinghen Christophe Renou Philippe Mathurin Claire Vanlemmens Vincent Di Martino Anne Gervais Juliette Foucher Fouchard-Hubert Isabelle Julien Vergniol Isabelle Hourmand-Ollivier Daniel Cohen Xavier Duval Thierry Poynard Marc Bardou Armand Abergel Manh-Thong Dao Thierry Thevenot Jean-Baptiste Hiriart Valerie Canva Guillaume Lassailly Christine Aurières Nathalie Boyer Dominique Thabut Pierre-Henri Bernard Matthieu Schnee Dominique Larrey Bertrand Hanslik Severine Hommel Jeremie Jacques Veronique Loustaud-Ratti | 2020 | World Journal of Hepatology2020，12，12： | 0 |
| 3 | Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma显示文摘Loss of function of the von Hippel-Lindau(VHL)tumor suppressor gene is a hallmark of clear cell renal cell carcinoma(ccRCC).The importance of heterogeneity in the loss of this tumor suppressor has been under reported.To study the impact of intratumoral VHL heterogeneity observed in human ccRCC,we engineered VHL gene deletion in four RCC models,including a new primary tumor cell line derived from an aggressive metastatic case.The VHL gene-deleted(VHL-KO)cells underwent epithelial-to-mesenchymal transition(EMT)and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing(VHL+)cells.Renal tumors with either VHL+or VHL-KO cells alone exhibit minimal metastatic potential.Combined tumors displayed rampant lung metastases,highlighting a novel cooperative metastatic mechanism.The poorly proliferative VHL-KO cells stimulated the proliferation,EMT,and motility of neighboring VHL+cells.Periostin(POSTN),a soluble protein overexpressed and secreted by VHL non-expressing(VHL−)cells,promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape.Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models.This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor. | Junhui Hu Ping Tan Moe Ishihara Nicholas ABayley Shiruyeh Schokrpur Jeremy GReynoso Yangjun Zhang Raymond JLim Camelia Dumitras Lu Yang Steven MDubinett Parmjit SJat Jacques Van Snick Jiaoti Huang Arnold IChin Robert MPrins Thomas GGraeber Hua Xu Lily Wu | 2023 | Signal Transduction and Targeted Therapy2023，8，5： | 0 |
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