Molecular and cellular effects of vitamin B12 in brain, myocardium and liver through its role as co-factor of methionine synthase.

Vitamin B12 (cobalamin, cbl) is a cofactor of methionine synthase (MTR) in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAM), which is involved in epigenomic regulatory mechanisms. We have established a neuronal cell model with stable expression of a transcobalamin-oleosin chimer and subsequent decreased cellular availability of vitamin B12, which produces reduced proliferation, increased apoptosis and accelerated differentiation through PP2A, NGF and TACE pathways. Anti-transcobalamin antibody or impaired transcobalamin receptor expression produce also impaired proliferation in other cells. Consistently, the transcription, protein expression and activity of MTR are increased in proliferating cells of skin and intestinal epitheliums, in rat intestine crypts and in proliferating CaCo2 cells, while MTR activity correlates with DNA methylation in rat intestine villi. Exposure to nitrous oxide in animal models identified impairment of MTR reaction as the most important metabolic cause of neurological manifestations of B12 deficiency. Early vitamin B12 and folate deprivation during gestation and lactation of a 'dam-progeny' rat model developed in our laboratory is associated with long-lasting disabilities of behavior and memory capacities, with persisting hallmarks related to increased apoptosis, impaired neurogenesis and altered plasticity. We found also an epigenomic deregulation of energy metabolism and fatty acids beta-oxidation in myocardium and liver, through imbalanced methylation/acetylation of PGC-1alpha and decreased expression of SIRT1. These nutrigenomic effects display similarities with the molecular mechanisms of fetal programming. Beside deficiency, B12 loading increases the expression of MTR through internal ribosome entry sites (IRES) and down-regulates MDR-1 gene expression. In conclusion, vitamin B12 influences cell proliferation, differentiation and apoptosis in brain. Vitamin B12 and folate combined deficiency impairs fatty acid oxidation and energy metabolism in liver and heart through epigenomic mechanisms related to imbalanced acetylation/methylation. Some but not all of these effects reflect the upstream role of vitamin B12 in SAM synthesis.

[Diagnostic approach for breast cancer classification]. / Démarche diagnostique dans cancer du sein, classification.

The pathologist is involved at various steps in the management of a patient with breast cancer and in the therapeutic decision. First, the pathologist confirms a diagnosis of malignancy on cytology specimens, microbiopsies and surgical specimens. During the surgery, through the frozen section, the pathologist specifies the surgical limits and collects specimens for research purposes. Then the pathologist evaluates the parameters needed to establish the final diagnosis, the prognosis and the identification of predictive factors, using ancillary techniques such as immunohistochemistry, in situ hybridization or molecular techniques. Mandatory elements to be included in the final pathological report are size, histological type, SBR grade modified by Elston and Ellis, the presence or absence of vascular or lymphatic peritumoral emboli (prognostic parameters), the status of resection margins (local relapse risk) and the status of hormonal receptor and HER2 (predictive parameters).