The molecular mechanisms underlying the development of pancreatic neuroendocrine tumors (PanNETs) have not been well defined. We report here that the genomic region of the PHLDA3 gene undergoes loss of heterozygosity (LOH) at a remarkably high frequency in human PanNETs, and this genetic change is correlated with disease progression and poor prognosis. We also show that the PHLDA3 locus undergoes methylation in addition to LOH, suggesting that a two-hit inactivation of the PHLDA3 gene is required for PanNET development. We demonstrate that PHLDA3 represses Akt activity and Akt-regulated biological processes in pancreatic endocrine tissues, and that PHLDA3-deficient mice develop islet hyperplasia. In addition, we show that the tumor-suppressing pathway mediated by MEN1, a well-known tumor suppressor of PanNETs, is dependent on the pathway mediated by PHLDA3, and inactivation of PHLDA3 and MEN1 cooperatively contribute to PanNET development. Collectively, these results indicate the existence of a novel PHLDA3-mediated pathway of tumor suppression that is important in the development of PanNETs.p53 | PH domain | everolimus | p53 target gene | mTOR N euroendocrine tumors (NETs) arise from cells of the endocrine and nervous systems, and are found in tissues such as lung, pancreas and pituitary (1-3). NETs often produce, store and release biogenic amines and polypeptide hormones, and secretary granules containing these products provide a diagnostic marker for NETs. The mechanisms underlying the development of NETs remain unclear to date, due to the low incidence of these tumors and due to the lack of suitable experimental model systems, including genetically engineered mouse models. Pancreatic NET (PanNET), which is probably the best-studied NET, is the second-most common pancreatic tumor, having an incidence of ∼1 per 100,000 individuals. Patients having late-stage PanNET often harbor tumors that are unresectable or metastatic and face limited treatment options. Accordingly, the prognosis of patients having metastatic PanNET is the worst among the NET subtypes, with a 5-y survival rate of 27-43% (1). Recently, the drug Everolimus has shown promise in the treatment of PanNETs (4), providing a significant improvement in progression-free survival. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a downstream mediator of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. The striking efficacy of Everolimus demonstrates the importance of the PI3K/Akt pathway in the pathology of PanNETs.In agreement with these clinical results, studies on pancreatic endocrine cell lines have identified the PI3K/Akt signaling pathway as a major proliferation and survival pathway in these cells (5). Activated Akt phosphorylates substrates such as mTOR and controls various biological processes, including protein synthesis, proliferation, cell growth, and survival. Regulation of pancreatic islet β-cell proliferation, cell size, and apoptosis by Akt has been demonstrated using various mouse models. For examp...
We newly developed a sheet-type macroencapsulation device entrapping rat islets from 3% polyvinyl alcohol (PVA) dissolved in Euro-Collins solution containing 10% fetal bovine serum and 5% dimethyl sulfoxide (PVA + EC) using a freezing/thawing technique. The same encapsulation technique but with 3% PVA dissolved only in double-distilled water (PVA) and a culture of free islets were served as controls. After 14-day culture in the CMRL-1066 medium, the islet recovery rate, morphological changes, insulin content, and insulin secretion were evaluated in vitro to prove the feasibility of this method of encapsulation. We also xenotransplanted the device into the peritoneal cavity of diabetic C57BL/6 mice to check its function in vivo. After 1-day culture, the islet recovery rate and insulin content in the PVA group were significantly lower than that in the PVA + EC and free islet groups. After 14-day culture, only the islets in the PVA+EC group maintained a normal morphology and effective insulin secretory response to high glucose while the response was not observed in the PVA group after 1-day culture and no longer observed in the free islets after 7-day culture. After transplantation of rat islets encapsulated in the PVA + EC device to diabetic C57BL/6 mice, nonfasting blood glucose levels showed a rapid decrease from high glucose levels of pre-transplantation, maintaining significantly lower glucose levels during the whole course of study in comparison with the sham-operated group. Our results indicated that this freezing/thawing macroencapsulation technique using 3% PVA + EC was effective for xenotransplantation of islet cells.
Broad-spectrum autism, referred to as pervasive developmental disorder (PDD), may be associated with genetic factors. We examined 241 siblings in 269 Japanese families with affected children. The sibling incidence of PDD was 10.0% whereas the prevalence of PDD in the general population in the same geographic region was 2.1%. Both of these rates are higher than those reported previously, probably because of the expanded clinical criteria applied. The prevalence in males of the general population was 3.3% and that in females was 0.82%. The sibling incidences were 7.7 and 20.0% for families in which the probands were male and female, respectively. Because the reversed sex ratios correspond to the general rule for a multifactorial threshold model, we suggest that most PDD cases result from the cumulative effects of multiple factors (mostly genetic). The sibling incidences were 0 and 10.9% for families in which the proband had low and normal birth-weight, respectively, suggesting the risk is lower in families with lowbirth-weight probands.
An investigation of genetic structures underlying autistic traits was performed with samples from twins for which at least one proband had been ascertained as having autism spectrum disorders (ASDs) in our catchment area. In order to adjust for recent concepts of autism, we employed criteria for the broad spectrum of disease and the childhood autism rating scale (CARS) for quantitative assessment. The CARS test was performed on 45 twin pairs (19 monozygotic, 26 dizygotic) detected with a regional routine screening system. The obtained CARS scores were subjected to structural equation modeling (SEM), incorporating sex differences for each causal influence ascertainment correction, using the Mx software. A best fitting model of causal influences on autistic traits measured continuously, incorporating additive genetic (A) and non-shared environmental influences (E), was generated. With this AE model, the estimated heritability was 0.73 for males and 0.87 for females, based on the continuous CARS scores. There was no evidence for the existence of sex-specific genetic influences. Autistic traits were highly heritable in twins with even broad spectrum of autism, corresponding to the results of early studies based on classical autism. Additive genetic factors were more influential in females than males.
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