Impact of vitamin D metabolism on clinical epigenetics

The bioactive vitamin D (VD) metabolite, 1,25-dihydroxyvitamin D3 regulates essential pathways of cellular metabolism and differentiation via its nuclear receptor (VDR). Molecular mechanisms which are known to play key roles in aging and cancer are mediated by complex processes involving epigenetic mechanisms contributing to efficiency of VD-activating CYP27A1 and CYP27B1 or inactivating CYP24 enzymes as well as VDR which binds to specific genomic sequences (VD response elements or VDREs). Activity of VDR can be modulated epigenetically by histone acetylation. It co-operates with other nuclear receptors which are influenced by histone acetyl transferases (HATs) as well as several types of histone deacetylases (HDACs). HDAC inhibitors (HDACi) and/or demethylating drugs may contribute to normalization of VD metabolism. Studies link VD signaling through the VDR directly to distinct molecular mechanisms of both HAT activity and the sirtuin class of HDACs (SIRT1) as well as the forkhead transcription factors thus contributing to elucidate complex epigenetic mechanisms for cancer preventive actions of VD

Molecular cloning of infectious viral DNA from ecotropic neurotropic wild mouse retrovirus.

Among a mixture of amphotropic and ecotropic murine leukemia viruses (MuLVs) isolated from paralyzed wild mice, only N-tropic ecotropic MuLV, cloned by cell culture techniques, has been shown to induce paralysis after reinjection into susceptible mice (M. B. Gardner, Curr. Top. Microbiol. Immunol. 79:215-239, 1978). The viral DNA genome of one of these neurotropic MuLVs (Cas-Br-E) has been cloned in Charon 21A at the SalI site. One clone, designated NE-8, was studied in more detail. A restriction endonuclease map of this cloned DNA was derived. Cloned viral DNA microinjected into NIH 3T3 cells produced infectious MuLV which was characterized as XC+, ecotropic, and N-tropic. The virus that was recovered after the microinjection of NE-8 DNA was also injected into susceptible SIM.S and NIH Swiss mice and was found to induce lower limb paralysis in these animals. These results make it highly unlikely that other agents (which might have escaped detection and separation from ecotropic MuLV by the techniques previously used) play a role in the etiology of this disease and clearly indicate that the ecotropic MuLV genome harbors sequences responsible for this paralysis. The availability of this clone DNA would now allow us to map these sequences on the genome

Abnormal capacity to induce cholesterol efflux and a new LpA-I pre-beta particle in type 2 diabetic patients.

A

Combination of polymorphisms from genes related to estrogen metabolism and risk of prostate cancers: the hidden face of estrogens.

PURPOSE: The association between common functional polymorphisms from the CYP17, CYP19, CYP1B1, and COMT genes involved in the estrogen metabolism and the risk of prostate carcinoma was evaluated. PATIENTS AND METHODS: The study investigated 1,983 white French men (1,101 patients with prostate cancer and 882 healthy controls) aged between 40 and 98 years. The different alleles and genotypes were analyzed according to case-control status, aggressiveness pattern of the tumors, age at onset, and family history of cancers. RESULTS: The VV (high activity) genotype of the V432L polymorphism from CYP1B1 (odds ratio [OR] = 1.36; 95% CI, 1.03 to 1.79; P = .031), and the long allele (> 175 bp) of the TTTA repeat from CYP19 (OR, 1.26; 95% CI, 1.08 to 1.47; P = .003) were significantly associated with the risk of prostate cancer. An additive effect was observed when we combined the two at-risk alleles (OR = 1.63; 95% CI, 1.24 to 2.13; P < .001). The association was stronger for the CYP1B1 VV genotype (OR = 1.55; 95% CI, 1.13 to 2.13; P = .007) among the group of patients with highly aggressive disease. Stratification by age at onset showed that the associations of CYP1B1 and CYP19 variants were largely confined to the younger prostate cancer patients. CONCLUSION: This association between polymorphisms from genes related to estrogen metabolism and prostate cancer risk suggest new clinical considerations in the management of prostate cancer: the development of new prevention trials based on genetic profiling and the evaluation of specific inhibitors involving the estrogen pathways