MGMT promoter methylation and correlation with protein expression in primary central nervous system lymphoma.

The O (6)-methylguanine-DNA-methyltransferase (MGMT) gene encodes for a DNA repairing enzyme of which silencing by promoter methylation is involved in brain tumorigenesis. MGMT promoter methylation represents a favorable prognostic factor and has been associated with a better response to alkylating agents in glioma and systemic lymphoma. Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal malignant lymphoma. The current standard of care, based on high-dose methotrexate chemotherapy, has improved prognosis but outcome remains poor for a majority of patients. Therapeutic progress in this field is conditioned by limited biological and molecular knowledge about the disease. Temozolomide has recently emerged as an alternative option for PCNSL treatment. We aimed to analyze the MGMT gene methylation status in a series of 24 PCNSLs, to investigate the relationship between methylation status of the gene and immunohistochemical expression of MGMT protein and to evaluate the possible prognostic significance of these biomarkers. Our results confirm that methylation of the MGMT gene and loss of MGMT protein are frequent events in these lymphomas (54 % of our cases) and suggest that they are gender and age related. MGMT methylation showed high correlation with loss of protein expression (concordance correlation coefficient = -0.49; Fisher exact test: p < 0.01), different from what has been observed in other brain tumors. In the subgroup of ten patients who received high dose chemotherapy, the presence of methylated MGMT promoter (n = 4), seems to be associated with a prolonged overall survival (>60 months in three of four patients). The prognostic significance of these molecular markers in PCNSL needs to be further studied in groups of patients treated in a homogeneous way.

Secretion of ions and pharmacological responsiveness in the mouse paw sweat gland.

1. Some of the basic functional features of the mouse paw eccrine sweat gland were delineated to allow comparison with those of transgenic mice in the future. 2. The mouse sweat secretory coil responds to methacholine, elaborating a K(+)-rich (> 120 mmol/l), Na(+)-poor (< 70 mmol/l) primary fluid as does the rat paw sweat gland, as previously reported. The methacholine-induced sweat rate increases with age in parallel with the growth of the sweat gland over the first 6 weeks of life. 3. The sweating response to cyclic AMP-elevating agents, such as isoprenaline or forskolin, is as much as 40% of the methacholine-induced sweat rate at 1 week of age, but falls to 10% by 6 weeks of age despite the fact that the agonist-induced tissue accumulation of cyclic AMP expressed on a per microgram of protein basis triples with age over the same period. 4. A marked K+ outflux was also noted in response to methacholine and a small K+ outflux was seen in response to cyclic AMP-elevating agonists in superfused adult mouse secretory coils in vitro. 5. Since sweat secretion is usually associated with activation of either K+ channels or Cl- channels or both, and since the sweating occurred in response to cyclic AMP-elevating agonists, we speculate that the cyclic AMP-activated Cl- channels (the mouse version of the cystic fibrosis transmembrane conductance regulator) may also occur in the mouse sweat gland, but that the degree of their expression may be influenced by the age of the mice.