DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

The value of miRNA in diagnosing thyroid cancer: a systematic review.

Thyroid cancer is the most common endocrine neoplasm accounting for approximately 1,7% of total cancer diagnoses. The gold standard for evaluation of thyroid nodules is cytology from fine needle aspiration. In 30% of biopsies there is no conclusive diagnosis and patients undergo a diagnostic hemithyroidectomy. Somatic mutations occur frequently in thyroid cancer, the value of testing FNA biopsies on different mutation is analyzed, it improves accuracy, but their sensitivity is low. Another class of molecules with potential diagnostic value are miRNAs (miRNA, miR). MiRNAs function as gene regulators thereby controlling many cellular processes including cell growth, differentiation, proliferation, and apoptosis. Several studies have analyzed the expression of miRNAs in thyroid cancer, either by performing microarray analyses or validating a set of miRNAs. Recent reports focused on the diagnostic value of miRNAs in indeterminate FNA biopsies. In this systematic review we will provide an overview of all miRNAs found to be up- or downregulated in the different types of thyroid carcinomas, give an overview of the value of validated sets of microRNAs or single microRNAs in distinguishing malignant from benign lesions and conclude with a clinical view on future study strategies.

A molecular cage of nickel(II) and copper(I): a [{Ni(L)2}2(CuI)6] cluster resembling the active site of nickel-containing enzymes.

A new mononuclear low-spin nickel(II) dithiolato complex, [NiL(2)] (1), reacts with copper iodide to form the hetero-octanuclear cluster [{Ni(L)(2)}(2)(CuI)(6)] (2) with four trigonal-planar CuI(2)S and two tetrahedral CuI(2)S(2) sites; anagostic interactions between the nickel(II) ions and aromatic protons have been demonstrated by variable-temperature NMR studies to pertain in solution.

Effect of liver regeneration on the pharmacokinetics of immunosuppressive drugs.

In liver transplantation the graft has been known to undergo regeneration, which is associated with down-regulation of the cytochrome P450 system. The latter is involved in the metabolism of several immunosuppressive drugs. The aim of this study was to investigate the effect of liver regeneration on the pharmacokinetics (PK) of cyclosporine, rapamycin, and tacrolimus. Rats were subjected to either partial hepatectomy (PH) or sham operation (SH). Cyclosporine, rapamycin, and tacrolimus PK studies were performed at 0, 24, and 96 hours postoperatively. The areas under the curve (AUC), trough levels, and maximum concentrations (Cmax) for cyclosporine and tacrolimus were numerically higher in the animals subjected to PH. The PK studies of rapamycin were not affected by PH. These studies indicated that cyclosporine and tacrolimus metabolism may be inhibited during liver regeneration.