Association between mitral annular calcification and progression of mitral and aortic stenoses.

BACKGROUND: Mitral annular calcification (MAC) is a chronic degenerative process affecting the annular fibrosus of the mitral valve. We sought to examine the relationship between MAC and the progression of valve disease. METHODS: The echocardiography database was searched for patients with MAC who had undergone at least two studies more than 1 year apart. The degree of MAC was quantified according to both extent and thickness. The degree of aortic stenosis (AS) and mitral stenosis (MS) was classified according to valve area and mean gradient, respectively. RESULTS: Of 125 patients, moderate or greater AS was present in 8 of 86 (9.3%) patients with mild, 12 of 29 (41.4%) patients with moderate, and 4 of 10 (40%) patients with severe MAC extent, P = .0002. The rate of progression of AS was highest in those with greatest MAC extent (0.21 cm2 /y) or greatest MAC thickness (0.28 cm2 /y) compared with those with least MAC extent (0.09 cm2 /y) or thickness (0.07 cm2 /y), P = .04 and <.0001, respectively. The rate of progression of mean mitral gradient was highest in those with greatest MAC extent (0.71 mm Hg/y) or greatest MAC thickness (0.17 mm Hg/y) compared with those with least MAC extent (0.07 mm Hg/y) or thickness (0.07 mm Hg/y), P = .0003 and P < .0001, respectively. Patients with greatest MAC extent had lower survival than those with lower MAC extent, P = .03. However, there was no difference in survival between patients with different MAC thickness, P = .43. CONCLUSION: Both the degree of MAC extent and thickness are associated with the rate of progression of aortic and mitral stenosis and may serve as a risk marker for future progression.

Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen.

Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization.