Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature

Objective: Up to 40% of multiple endocrine neoplasia type 1 (MEN1) patients may have adrenal cortical tumors. However, adrenocortical carcinoma (ACC) is rare. The clinical manifestations, prevalence, inheritance and prognosis of ACC associated with MEN1 remain unclear. Here we report the clinical manifestations and prevalence of ACC in patients with MEN1. Design and methods: A retrospective analysis of ACC associated with MEN1 patients at a single tertiary care center from December 2001 to June 2017. Genetic analysis of MEN1 and other ACC associated genes, loss of heterozygosity (LOH) of MEN1 locus, immunohistochemistry staining of menin, P53 and β-catenin in ACC tissue were performed. Results: Two related patients had ACC associated with MEN1. The father had ENSAT stage IV tumor with excessive production of cortisol; the daughter had nonfunctional ENSAT stage I tumor. Both patients carried novel germline heterozygous mutation (c.400_401insC) of MEN1. The wild-type MEN1 allele was lost in the resected ACC tissue from the daughter with no menin staining. The ACC tissue had nuclear β-catenin staining, with heterozygous CTNNB1 mutation of 357del24 and P53 staining in only 20% cells. Conclusions: ACC associated with MEN1 is rare and may occur in familial aggregates

Modular construction of mammalian gene circuits using TALE transcriptional repressors

An important goal of synthetic biology is the rational design and predictable implementation of synthetic gene circuits using standardized and interchangeable parts. However, engineering of complex circuits in mammalian cells is currently limited by the availability of well-characterized and orthogonal transcriptional repressors. Here, we introduce a library of 26 reversible transcription activator–like effector repressors (TALERs) that bind newly designed hybrid promoters and exert transcriptional repression through steric hindrance of key transcriptional initiation elements. We demonstrate that using the input-output transfer curves of our TALERs enables accurate prediction of the behavior of modularly assembled TALER cascade and switch circuits. We also show that TALER switches using feedback regulation exhibit improved accuracy for microRNA-based HeLa cancer cell classification versus HEK293 cells. Our TALER library is a valuable toolkit for modular engineering of synthetic circuits, enabling programmable manipulation of mammalian cells and helping elucidate design principles of coupled transcriptional and microRNA-mediated post-transcriptional regulation.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50GM098792)National Institutes of Health (U.S.) (Grant 1R01CA173712-01

Nomograms for Individualized Evaluation of Prognosis in Adrenocortical Carcinomas for the Elderly: A Population-Based Analysis

Background Adrenocortical carcinoma (ACC) is extremely rare in elderly patients. Thus, this study aimed to identify the incidence rate and develop nomogram models for predicting survival in elderly ACC patients. Methods Data of ACC patients aged >60 years from 1975 to 2016 were obtained from the Surveillance, Epidemiology, and End Results dataset. The national incidence rate was estimated, and survival was subjected to Kaplan–Meier analysis. A multivariate Cox regression model was used to identify predictors of survival. Nomograms were generated to predict survival, calibrated and internally validated. Results We identified 583 cases. Univariate analysis showed that patients with younger age (≤67 years), female sex, lower tumor grade, surgical treatment performed, and earlier European Network for the Study of Adrenal Tumors (ENSAT) stage had a better survival (P < 0.05). In the Cox regression analysis, no surgery performed (hazard ratio [HR]: 3.544, 95% CI: 1.142–10.995, P = 0.029 for overall survival [OS]; HR: 3.230, 95% CI: 1.040–10.034, P = 0.043 for disease-specific survival [DSS]) and advanced ENSAT stage (HR: 3.328, 95% CI: 1.628–6.801, P = 0.001 for OS; HR: 3.701, 95% CI: 1.682–8.141, P = 0.001 for DSS) were associated with worse outcomes. Age, sex, histologic grade, surgical resection, radiotherapy, and ENSAT stage were included in the nomograms, with a C-index of 0.692 for OS and 0.694 for DSS, demonstrating a good accuracy in predicting survival. Conclusions This study is the largest review of ACC in elderly patients. We present nomograms to predict survival in elderly ACC patients using clinicopathologic data, which could aid in accurate clinical decision-making