Animals ; Gene Expression ; Hypoxia ; metabolism ; Prefrontal Cortex ; metabolism ; Rats ; Somatomedins ; metabolism

Objective:To explore the clinical characteristics of autosomal dominant polycystic kidney disease (ADPKD).Methods:Clinical data of 103 patients with ADPKD first admitted to Renmin Hospital of Wuhan University from July 2017 to April 2021 were retrospectively analyzed. The clinical characteristics of patients in different renal function stages were analyzed, and multiple linear regression analysis was used to analyze the factors reflecting the severity of the disease.Results:Among the 103 patients with ADPKD, there were 49 males (47.6%), aged (51.23±10.99) years old. The extrarenal manifestation was mainly polycystic liver (64/71). The main clinical symptoms were gross hematuria (25 cases, 24.3%), lumbar distend and pain (37 cases, 35.9%) and hypertension (69 cases, 67.0%), appearing in the whole course of the disease. Early treatment was mainly drug conservative treatments (58 cases, 56.3%), followed by renal cyst aspiration (34 cases, 33.0%), and surgical treatments (11 cases, 10.7%). Patients in chronic kidney disease (CKD) stage 5 were mainly treated with conservative treatments (28/34). Laboratory examination results showed that hemoglobin, platelet, lymphocyte percentage and albumin in CKD stage 4-5 were lower than those in CKD stage 1-3 (all P<0.05) ; prothrombin time (PT), PT-international standardized ratio and plasma osmotic concentration in CKD stage 4-5 were higher than those in CKD stage 1-3 (all P<0.05). Multiple linear regression analysis showed that hemoglobin ( β=0.249, P=0.005), platelet ( β=0.207, P=0.005), lymphocyte percentage ( β=0.305, P<0.001) and plasma osmotic concentration ( β=-0.362, P<0.001) were correlated with estimated glomerular filtration rate. Conclusions:The clinical manifestations of ADPKD patients are hypertension, lumbar distend and pain, and gross hematuria, which can run through the whole stage of CKD. Polycystic liver is more common in extrarenal system. Hemoglobin, platelets, lymphocyte percentage and concentration osmotic concentration may be related to the disease progression of ADPKD.

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*