Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover.

The mitochondrial pathway of apoptosis is controlled by the ratio of anti- and pro-apoptotic members of the Bcl-2 family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger apoptosis remains unclear. We report here that human 17-ß-estradiol (E2) and its related steroid hormones induce apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers apoptosis. The SLFN12 protein and an apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related hormones are high, and dynamic cell turnover by apoptosis is critical for successful implantation and placenta development.

Overexpression of CHAF1A is associated with poor prognosis, tumor immunosuppressive microenvironment and treatment resistance.

Background: As distinct marker of proliferating cells, chromatin assembly factor-1 (CAF-1) was critical in DNA replication. However, there is paucity information about the clinical significance, functions and co-expressed gene network of CHAF1A, the major subunit in CAF-1, in cancer. Methods: Bioinformatic analysis of CHAF1A and its co-expression gene network were performed using various public databases. Functional validation of CHAF1A was applied in breast cancer. Results: Overexpression of CHAF1A was found in 20 types of cancer tissues. Elevated expression of CHAF1A was positively correlated with breast cancer progression and poor patients' outcome. The analysis of co-expression gene network demonstrated CHAF1A was associated with not only cell proliferation, DNA repair, apoptosis, but cancer metabolism, immune system, and drug resistance. More importantly, higher expression of CHAF1A was positively correlated with immunosuppressive microenvironment and resistance to endocrine therapy and chemotherapy. Elevated expression of CHAF1A was confirmed in breast cancer tissues. Silencing of CHAF1A can significantly inhibit cell proliferation in MDA-MB-231 cells. Conclusion: The current work suggested that overexpression of CHAF1A can be used as diagnostic and poor prognostic biomarker of breast cancer. Higher expression of CHAF1A induced fast resistance to endocrine therapy and chemotherapy, it may be a promising therapeutic target and a biomarker to predict the sensitivity of immunotherapy in breast cancer.

An uncommon perineal embryonal rhabdomyosarcoma in adult: A case report.

RATIONALE: Embryonal rhabdomyosarcoma (ERMS) is a major subtype of rhabdomyosarcoma, mainly affect children. There is seldom report for perineal ERMS in adults, since its rare location and the age. PATIENT CONCERNS: A 20-year old male adult was admitted due to the perineal mass. DIAGNOSES: Diagnosis by histopathological examination of the biopsy sample was ERMS. Magnetic resonance imaging showed the tumor was found in the perineal region, with metastasis to pelvic cavity, right testis, lymph nodes and bone. INTERVENTIONS: The patient received Isophosphamide and Epirubicin for 4 cycles, followed by Irinotecan and Vindesine Sulfate for 2 cycles, then cisplatin, Dacarbazine and Apatinib for 3 cycles. OUTCOME: The patient showed no response to chemotherapy. LESSONS: Perineal ERMS in adults is very rare. There is still no standard therapy for adult ERMS. Personalized therapy might be promising treatment for each individual.

Identification of a Nuclear Mitochondrial-Related Multi-Genes Signature to Predict the Prognosis of Bladder Cancer.

INTRODUCTION: Bladder cancer (BC) is one of the most prevalent urinary cancers, and its management is still a problem causing recurrence and progression, elevating mortality. MATERIALS AND METHODS: We aimed at the nuclear mitochondria-related genes (MTRGs), collected from the MITOMAP: A Human Mitochondrial Genome Database. Meanwhile, the expression profiles and clinical information of BC were downloaded from the Cancer Genome Atlas (TCGA) as a training group. The univariate, multivariate, and the least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to construct a nuclear mitochondrial-related multi-genes signature and the prognostic nomogram. RESULTS: A total of 17 nuclear MTRGs were identified to be correlated with the overall survival (OS) of BC patients, and a nuclear MTRGs signature based on 16 genes expression was further determined by the LASSO Cox regression analysis. Based on a nuclear MTRGs scoring system, BC patients from the TCGA cohort were divided into high- and low- nuclear MTRGs score groups. Patients with a high nuclear MTRGs score exhibited a significantly poorer outcome (median OS: 92.90 vs 20.20 months, p<0.0001). The nuclear MTRGs signature was further verified in three independent datasets, namely, GSE13507, GSE31684, and GSE32548, from the Gene Expression Omnibus (GEO). The BC patients with a high nuclear MTRGs score had significantly worse survival (median OS in GSE13507: 31.52 vs 98.00 months, p<0.05; GSE31684: 32.85 months vs unreached, p<0.05; GSE32548: unreached vs unreached, p<0.05). Furthermore, muscle-invasive bladder cancer (MIBC) patients had a significantly higher nuclear MTRGs score (p<0.05) than non-muscle-invasive bladder cancer (NMIBC) patients. The integrated signature outperformed each involved MTRG. In addition, a nuclear MTRGs-based nomogram was constructed as a novel prediction prognosis model, whose AUC values for OS at 1, 3, 5 years were 0.76, 0.75, and 0.75, respectively, showing the prognostic nomogram had good and stable predicting ability. Enrichment analyses of the hallmark gene set and KEGG pathway revealed that the E2F targets, G2M checkpoint pathways, and cell cycle had influences on the survival of BC patients. Furthermore, the analysis of tumor microenvironment indicated more CD8+ T cells and higher immune score in patients with high nuclear MTRGs score, which might confer sensitivity to immune checkpoint inhibitors. CONCLUSIONS: Not only could the signature and prognostic nomogram predict the prognosis of BC, but it also had potential therapeutic guidance.

A MUCINs expression signature impacts overall survival in patients with clear cell renal cell carcinoma.

BACKGROUND: Kidney cancer, especially clear cell renal cell carcinoma (ccRCC), is one of the most common cancers in the urinary system. Previous studies suggested that certain members of MUCINs could serve as independent predictors for the survival of ccRCC patients. None of them, however, is robust enough to predict prognosis accurately. OBJECTIVE: To analyze the correlation of MUCINs alterations and their expression levels with the prognosis of ccRCC patients and develop a prognosis-related predictor. METHODS: We applied whole-exome sequencing in samples from 22 Chinese ccRCC patients to identify genetic alterations in MUCIN genes and analyzed their genetic alterations, expression, and correlation with survival using the TCGA, GSE73731, and GSE29069 datasets. RESULT: Genetic alternations in MUCINs were identified in 91% and 51% of ccRCC patients in our cohort and the TCGA database, respectively. No correlation with survival was found for the genetic alterations. Using unsupervised clustering analysis of gene expression, we identified two major clusters of MUCIN expression patterns. Cluster 1 was characterized by a global overexpression of MUC1, MUC12, MUC13, MUC16, and OVGP1; and cluster 2 was characterized by a global overexpression of MUC4, MUC5B, MUC6, MUC20, EMCN, and MCAM. Patients with cluster 1 expression pattern had significantly shorter overall survival time and worse clinical features, including higher tumor grades and metastasis. Meanwhile, they had a higher level of mutation counts and more infiltrated immune cells, but lower enrichment in angiogenesis signature genes. A five-MUCINs expression signature was constructed from cluster 1, and notably, it was demonstrated to be associated with shorter overall survival. A similar worse clinical feature, lower angiogenesis but the more immune signature, was identified in samples presented with signature 1. In the validation data set GSE29069, patients with signature 1 were also associated with a trend of poor survival outcomes. CONCLUSION: We established a five-MUCINs expression signature as a new prognostic marker for ccRCC. The distinct tumor microenvironment feature between the two signatures may further affect ccRCC patients' clinical management.

Case report: two rare cases of mixed epithelial and stromal tumor of the kidney and a review of the literature.

Mixed epithelial and stromal tumor of the kidney (MESTK) is rare renal neoplasm, which usually behaves benignly, while very rarely malignancies have also been reported. Histologically, MESTK is composed of both mesenchymal and epithelial components, where the epithelial components are arranged in a tubular or tubule-cystic pattern against a background of ovarian-like stromal proliferation. MESTK is more commonly seen in perimenopausal women or in patients on long-term estrogen replacement therapy. Given the popularity of routine health screening, patients main present asymptomatically. We report one rare case of MESTK, which was diagnosed in a 30-year-old woman. A computed tomography (CT) scan revealed one well-defined, uneven mass in the left kidney. The tissue obtained by fine-needle aspiration showed relatively homogeneous cells. Renal cell carcinoma could not be excluded, and left complete nephrectomy was performed, according to the patient's wishes. Another case of MESTK we present here was diagnosed in an 18-year-old male adolescent, who did not have a history of estrogen treatment, with estrogen treatment seen rarely in the clinical setting. Renal cell carcinoma was suspected, and a left partial nephrectomy was performed. Based on histopathological examination, the diagnosis was MESTK for both cases. Both patients were periodically monitored for one year following surgery and showed no imaging findings of recurrence or metastases. MESTK is benign tumor, and hence preoperative diagnosis is crucial to avoid overtreatment. To improve the current understanding of this disease, comprehensive studies on their pathogenesis and preoperative diagnosis are needed.

Does preoperative urine culture still play a role in predicting post-PCNL SIRS? A retrospective cohort study.

There is controversy regarding the predicting value of preoperative urine culture for post-percutaneous nephrolithotripsy (PCNL) infection. The purpose of our study was to re-evaluate the importance of preoperative urine culture for developing post-PCNL systemic inflammatory response syndrome (SIRS) in China. A total of 303 patients undergone PCNL from March 2012 to January 2018 were recruited. Urine tests, urine cultures and the perioperative data were prospectively recorded and analyzed. 95 patients (31.4%) were identified with positive preoperative urine cultures. Female patients had significantly higher rate of urine cultures positivity than that in male patients (42.9% vs. 21.5%, p < 0.01). Escherichia coli was the most common organism (56 cases, 58.9%) in patients with positive urine cultures and 35.7% of E. coli-positive patients developed SIRS after PCNL. Even with intensive perioperative prophylaxis, patients with positive urine cultures had a higher rate of post-PCNL SIRS than those patients with negative urine cultures (p = 0.043). On multivariable analysis, preoperative positive urine cultures (OR 1.943, 95% CI 1.11-3.39, p = 0.019), preoperative neutrophils (OR 1.228, 95% CI 1.07-1.41, p = 0.003), intraoperative pyonephrosis (OR 3.37, 95% CI 1.44-9.71, p = 0.01) and postoperative hospitalization (OR 1.154, 95% CI 1.05-1.28, p = 0.005) were independent risk factors for postoperative SIRS. These results demonstrated that preoperative urine culture still played a role in predicting post-PCNL SIRS, but it was unable to prevent the occurrence of SIRS even with intensive perioperative prophylaxis based on urine culture results. Further studies are required to explore the predicting role of advanced preoperative bacterial detecting techniques in post-PCNL infectious complications.