Ewing sarcoma is an aggressive bone cancer of children and young adults defined by the presence of a chromosomal translocation t(11;22)(q24;q12). The encoded protein, EWS/FLI, fuses the amino-terminal domain of EWS to the carboxyl-terminus of FLI. The EWS portion is an intrinsically disordered transcriptional regulatory domain, while the FLI portion contains an ETS DNA-binding domain and two flanking regions of unknown function. Early studies using non-Ewing sarcoma models provided conflicting information on the roles of each domain of FLI in EWS/FLI oncogenic function. We therefore sought to define the specific contributions of each FLI domain to EWS/FLI activity in a well-validated Ewing sarcoma model and, in doing so, to better understand Ewing sarcoma development mediated by the fusion protein. We analyzed a series of engineered EWS/FLI mutants with alterations in the FLI portion using a variety of assays. Fluorescence anisotropy, CUT&RUN, and ATAC-sequencing experiments revealed that the isolated ETS domain is sufficient to maintain the normal DNA-binding and chromatin accessibility function of EWS/FLI. In contrast, RNA-sequencing and soft agar colony formation assays revealed that the ETS domain alone was insufficient for transcriptional regulatory and oncogenic transformation functions of the fusion protein. We found that an additional alpha-helix immediately downstream of the ETS domain is required for full transcriptional regulation and EWS/FLI-mediated oncogenesis. These data demonstrate a previously unknown role for FLI in transcriptional regulation that is distinct from its DNA-binding activity. This activity is critical for the cancer-causing function of EWS/FLI and may lead to novel therapeutic approaches.Single measurements of waist circumference (WC) can predict the incident hypertension, while dynamic change patterns of WC during young adulthood and their association with the incidence of hypertension are poorly demonstrated. This study aimed to identify the longitudinal WC trajectories during young adulthood and explore their association with the risk of incident hypertension. We utilized the data from the China Health and Nutrition Survey (1993-2015) and included 6604 participants aged 18-50 years with repeated WC measurements of 3-8 times and information on incident hypertension. The group-based trajectory model was used to identify WC trajectories. Cox proportional hazard model was conducted to evaluate the association of WC trajectories with the risk of incident hypertension. We identified four distinct WC trajectories during young adulthood. Participants with the low-increasing and the moderate-increasing trajectories had increasing but normal WC, while those with the high-increasing and the sharp-increasing trajectories developed from non-abdominal obesity to abdominal obesity. Compared with the low-increasing trajectory, the adjusted hazard ratios (95% confidence intervals) were 1.48 (1.16-1.89), 2.50 (1.84-3.40), and 3.86 (2.40-6.21) for the moderate-increasing, the high-increasing, and the sharp-increasing trajectories, respectively. After further excluding participants with obesity at baseline, this association did not alter substantially. The gender-specific trajectory analyses yielded similar results. Floxuridine WC trajectories during young adulthood were significantly associated with the risk of incident hypertension in Chinese. Moreover, even the increasing WC trajectory within the normal range during young adulthood might increase the risk of hypertension.

Much of the heredity of melanoma remains unexplained. We sought predisposing germline copy-number variants using a rare disease approach.

Whole-genome copy-number findings in patients with melanoma predisposition syndrome congenital melanocytic nevus were extrapolated to a sporadic melanoma cohort. Functional effects of duplications in PPP2R3B were investigated using immunohistochemistry, transcriptomics, and stable inducible cellular models, themselves characterized using RNAseq, quantitative real-time polymerase chain reaction (qRT-PCR), reverse phase protein arrays, immunoblotting, RNA interference, immunocytochemistry, proliferation, and migration assays.

We identify here a previously unreported genetic susceptibility to melanoma and melanocytic nevi, familial duplications of gene PPP2R3B. This encodes PR70, a regulatory unit of critical phosphatase PP2A. Duplications increase expression of PR70 in human nevus, and increased expression in melanoma tissue correlates with survival via a nonimmunological mechanism. PPP2R3B overexpression induces pigment cell switching toward proliferation and away from migration. Importantly, this is independent of the known microphthalmia-associated transcription factor (MITF)-controlled switch, instead driven by C21orf91. Finally, C21orf91 is demonstrated to be downstream of MITF as well as PR70.

This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.

This work confirms the power of a rare disease approach, identifying a previously unreported copy-number change predisposing to melanocytic neoplasia, and discovers C21orf91 as a potentially targetable hub in the control of phenotype switching.The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016-0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18-0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p  less then  0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs.