Whole-Exome Sequencing Analysis of Idiopathic Hypogonadotropic Hypogonadism: Comparison of Varicocele and Nonobstructive Azoospermia.

As a rare disease leading to male infertility, idiopathic hypogonadotropic hypogonadism (IHH) has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease. This study is to explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with asthenospermia, oligospermia, or azoospermia, 5 patients with simple nonobstructive azoospermia, and 13 normal healthy adult males and carried out comparative analysis, channel analysis, etc. After preliminary sequencing screening, 309-431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients' analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. We found that the NEFH, CCDC177, and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest that the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.

Survivin knockdown alleviates pathological hydrostatic pressure-induced bladder smooth muscle cell dysfunction and BOO-induced bladder remodeling via autophagy.

Aim: Bladder outlet obstruction (BOO) leads to bladder wall remodeling accompanying the progression from inflammation to fibrosis where pathological hydrostatic pressure (HP)-induced alteration of bladder smooth muscle cells (BSMCs) hypertrophic and excessive extracellular matrix (ECM) deposition play a pivotal role. Recently, we have predicted survivin (BIRC5) as a potential hub gene that might be critical during bladder fibrosis by bioinformatics analyses from rat BOO bladder, but its function during BOO progression remains unknown. Here, we investigated the role of survivin protein on bladder dysfunction of BOO both in vitro and in vivo. Methods: Sprague-Dawley female rats were divided into three groups: control group, BOO group, and BOO followed by the treatment with YM155 group. Bladder morphology and function were evaluated by Masson staining and urodynamic testing. To elucidate the underlying mechanism, hBSMCs were subjected to pathological HP of 200 cm H2O and co-cultured with the presence or absence of survivin siRNA and/or autophagy inhibitor 3-MA. Autophagy was evaluated by the detection of Beclin1 and LC3B-II expression, proliferation was conducted by the EdU analysis and PCNA expression, and fibrosis was assessed by the examination of Col 1 and Fn expression. Results: BOO led to a gradual alteration of hypertrophy and fibrosis of the bladder, and subsequently induced bladder dysfunction accompanied by increased survivin expression, while these histological and function changes were attenuated by the treatment with YM155. HP significantly increased survivin expression, upregulated Col1 and Fn expression, enhanced proliferation, and downregulated autophagy markers, but these changes were partially abolished by survivin siRNA treatment, which was consistent with the results of the BOO rat experiment. In addition, the anti-fibrotic and anti-proliferative effects of the survivin siRNA treatment on hBSMCs were diminished after the inhibition of autophagy by the treatment with 3-MA. Conclusion: In summary, the upregulation of survivin increased cell proliferation and fibrotic protein expression of hBSMC and drove the onset of bladder remodeling through autophagy during BOO. Targeting survivin in pathological hBSMCs could be a promising way to anti-fibrotic therapeutic approach in bladder remodeling secondary to BOO.

The prognosis difference between elderly and younger patients with adrenocortical carcinoma.

Background and aim: Adrenocortical carcinoma (ACC) is uncommon in the elderly. This study aimed to compare the surgical prognosis and survival between senior and younger patients. We also explored the factors that were independently related to the survival of elderly patients. Methods: We identified ACC patients between 2010 and 2019 in the Surveillance, Epidemiology, and End Results (SEER) database and applied Kaplan-Meier curves to evaluate the overall survival (OS) and cancer-specific survival (CSS) with log-rank tests. We also used Cox regression analysis to estimate the OS and CSS. The Fine and Gray model with the Gray test was used to measure the cumulative incidence function (CIF) of CSS and other mortality causes of patients in a competing-risks setting. Results: Of 876 patients, 44.06% were elderly. A lower proportion of elderly patients underwent surgery, regional lymph node surgery, and chemotherapy than young patients. Elderly patients also had inferior OS and CSS than younger patients. The 1- and 5-year OS of elderly patients who underwent surgery were 68% [95% confidence interval (CI): 62%-74%] and 30% (95% CI: 24%-38%), and the 1- and 5-year CSS were 73% (95% CI: 67%-80%) and 40% (95% CI: 32%-47%). The factors independently related to worsened survival included age ≥60 [Hazard Ratio (HR): 1.47 (1.24-1.75)], metastatic disease [HR: 1.90 (1.49-2.51)], higher grade [HR: 1.94 (1.08-3.46)] and Network for the Study of Adrenal Tumors (ENSAT) stage [HR: 1.99 (1.48-2.66)]. Conclusion: Younger ACC patients had better survival than the elderly. Factors independently related to worsened survival in elderly patients included age ≥60, metastatic disease, higher grade, and European ENSAT stage.