The imprinted gene PEG3 confers parenting and sexual behaviors, alters growth and development, and regulates apoptosis. However, a molecular mechanism that can account for the diverse functions of Peg3/Pw1 is not known. To elucidate Peg3-regulated pathways, we performed a functional screen in zebrafish. Enforced overexpression of PEG3 mRNA during zebrafish embryogenesis decreased β-catenin protein expression and inhibited Wnt-dependent tail development. Peg3/Pw1 also inhibited Wnt signaling in human cells by binding to β-catenin and promoting its degradation via a p53/Siah1-dependent, GSK3β-independent proteasomal pathway. The inhibition of the Wnt pathway by Peg3/Pw1 suggested a role in tumor suppression. Hypermethylation of the PEG3 promoter in primary human gliomas led to a loss of imprinting and decreased PEG3 mRNA expression that correlated with tumor grade. The decrease in Peg3/Pw1 protein expression increased β-catenin, promoted proliferation, and inhibited p53-dependent apoptosis in human CD133+ glioma stem cells. Thus, mammalian imprinting utilizes Peg3/Pw1 to co-opt the Wnt pathway, thereby regulating development and glioma growth.
BackgroundApproximately 15–20% of ulcerative colitis patients and 20–40% of those with Crohn’s disease experience extraintestinal manifestations (EIMs) of their inflammatory bowel disease (IBD). Clinicians who treat IBD must manage EIMs affecting multiple organs that variably correlate with intestinal disease activity. Vedolizumab is a monoclonal antibody for the treatment of IBD with a gut-selective mechanism of action.AimsThis report evaluates whether vedolizumab is an effective treatment of EIMs, given its gut-specific mechanism of action.MethodsWe report 8 case studies of patients with various EIMs, including pyoderma gangrenosum, peripheral arthralgia/arthritis, axial arthropathies, erythema nodosum, and uveitis, who received vedolizumab therapy.ResultsVedolizumab therapy was effective for pyoderma gangrenosum in ulcerative colitis, uveitis, erythema nodosum, polyarticular arthropathy, and ankylosing spondylitis/sacroiliitis but did not provide sustained benefit for the treatment of pyoderma gangrenosum in a patient with Crohn’s disease.ConclusionsThese cases demonstrate the potential of vedolizumab as a treatment of EIMs in patients with IBD.
Background Ten percent of pancreatic ductal adenocarcinoma (PDAC) is due to genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection and development of effective screening and surveillance programs. We aimed to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. Methods Patients in a high-risk PDAC prevention and genetics program or with a personal history of PDAC referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. Results 37 patients without PDAC underwent BRCA1/2 testing at our institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six carried Ashkenazi Jewish founder mutations (3 BRCA1, 3 BRCA2), and 1 had a BRCA2 mutation on comprehensive testing. 32 patients with PDAC underwent BRCA1/2 genetic testing. Five had Ashkenazi Jewish founder mutations (two BRCA1, three BRCA2), and 2 had BRCA2 mutations on comprehensive testing. The diagnostic yield was 7/32 (21.8%). Conclusions BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent, with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.
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