Multiparametric MRI radiomics for the differentiation of brain glial cell hyperplasia from low-grade glioma.

BACKGROUND: Differentiating between low-grade glioma and brain glial cell hyperplasia is crucial for the customized clinical treatment of patients. OBJECTIVE: Based on multiparametric MRI imaging and clinical risk factors, a radiomics-clinical model and nomogram were constructed for the distinction of brain glial cell hyperplasia from low-grade glioma. METHODS: Patients with brain glial cell hyperplasia and low-grade glioma who underwent surgery at the First Affiliated Hospital of Soochow University from March 2016 to March 2022 were retrospectively included. In this study, A total of 41 patients of brain glial cell hyperplasia and 87 patients of low-grade glioma were divided into training group and validation group randomly at a ratio of 7:3. Radiomics features were extracted from T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), contrast-enhanced T1-weighted imaging (T1-enhanced). Then, LASSO, SVM, and RF models were created in order to choose a model with a greater level of efficiency for calculating each patient's Rad-score (radiomics score). The independent risk factors were identified via univariate and multivariate logistic regression analysis to filter the Rad-score and clinical risk variables in turn. A radiomics-clinical model was next built of which effectiveness was assessed. RESULTS: Brain glial cell hyperplasia and low-grade gliomas from the 128 cases were randomly divided into 10 groups, of which 7 served as training group and 3 as validation group. The mass effect and Rad-score were two independent risk variables used in the construction of the radiomics-clinical model, and their respective AUCs for the training group and validation group were 0.847 and 0.858. The diagnostic accuracy, sensitivity, and specificity of the validation group were 0.821, 0.750, and 0.852 respectively. CONCLUSION: Combining with radiomics constructed by multiparametric MRI images and clinical features, the radiomics-clinical model and nomogram that were developed to distinguish between brain glial cell hyperplasia and low-grade glioma had a good performance.

Multi-omics profiling of cholangiocytes reveals sex-specific chromatin state dynamics during hepatic cystogenesis in polycystic liver disease.

BACKGROUND & AIMS: Cholangiocytes transit from quiescence to hyperproliferation during cystogenesis in polycystic liver disease (PLD), the severity of which displays prominent sex differences. Epigenetic regulation plays important roles in cell state transition. We aimed to investigate the sex-specific epigenetic basis of hepatic cystogenesis and to develop therapeutic strategies targeting epigenetic modifications for PLD treatment. METHODS: Normal and cystic primary cholangiocytes were isolated from wild-type and PLD mice of both sexes. Chromatin states were characterized by analyzing chromatin accessibility (ATAC sequencing) and multiple histone modifications (chromatin immunoprecipitation sequencing). Differential gene expression was determined by transcriptomic analysis (RNA sequencing). Pharmacologic inhibition of epigenetic modifying enzymes was undertaken in PLD model mice. RESULTS: Through genome-wide profiling of chromatin dynamics, we revealed a profound increase of global chromatin accessibility during cystogenesis in both male and female PLD cholangiocytes. We identified a switch from H3K9me3 to H3K9ac on cis-regulatory DNA elements of cyst-associated genes and showed that inhibition of H3K9ac acetyltransferase or H3K9me3 demethylase slowed cyst growth in male, but not female, PLD mice. In contrast, we found that H3K27ac was specifically increased in female PLD mice and that genes associated with H3K27ac-gained regions were enriched for cyst-related pathways. In an integrated epigenomic and transcriptomic analysis, we identified an estrogen receptor alpha-centered transcription factor network associated with the H3K27ac-regulated cystogenic gene expression program in female PLD mice. CONCLUSIONS: Our findings highlight the multi-layered sex-specific epigenetic dynamics underlying cholangiocyte state transition and reveal a potential epigenetic therapeutic strategy for male PLD patients. IMPACT AND IMPLICATIONS: In the present study, we elucidate a sex-specific epigenetic mechanism underlying the cholangiocyte state transition during hepatic cystogenesis and identify epigenetic drugs that effectively slow cyst growth in male PLD mice. These findings underscore the importance of sex difference in the pathogenesis of PLD and may guide researchers and physicians to develop sex-specific personalized approaches for PLD treatment.

Benzodiazepine Derivatives as Potent Vasopressin V2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease.

Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V2 receptor (V2R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V2R. Among these derivatives, compound 25 exhibited potent binding affinity to the V2R (Ki = 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC50 = 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound 25 in a murine model of ADPKD demonstrated a significantly improved in vivo efficacy compared with the reference compound tolvaptan. Overall, compound 25 holds therapeutic potential for the treatment of ADPKD.