The tumour suppressor gene RASSF1A is frequently silenced in lung cancer and other sporadic tumours as a result of hypermethylation of a CpG island in its promoter. However, the precise mechanism by which RASSF1A functions in cell cycle regulation and tumour suppression has remained unknown. Here we show that RASSF1A regulates the stability of mitotic cyclins and the timing of mitotic progression. RASSF1A localizes to microtubules during interphase and to centrosomes and the spindle during mitosis. The overexpression of RASSF1A induced stabilization of mitotic cyclins and mitotic arrest at prometaphase. RASSF1A interacts with Cdc20, an activator of the anaphase-promoting complex (APC), resulting in the inhibition of APC activity. Although RASSF1A does not contribute to either the Mad2-dependent spindle assembly checkpoint or the function of Emi1 (ref. 1), depletion of RASSF1A by RNA interference accelerated the mitotic cyclin degradation and mitotic progression as a result of premature APC activation. It also caused a cell division defect characterized by centrosome abnormalities and multipolar spindles. These findings implicate RASSF1A in the regulation of both APC-Cdc20 activity and mitotic progression.

Dynamic enhancement with multi-detector row CT shows high sensitivity and negative predictive values for diagnosis of malignant nodules but low specificity because of highly enhancing benign nodules. Extent of enhancement reflects underlying nodule angiogenesis.

No abstract

We investigated the distribution of pulmonary arteriopathy in chronic pulmonary hypertension (PH) in a quantitative histopathologic study, using computer-assisted image analysis. We also examined the histologic manifestations and cellular phenotypes of various obstructive intimal lesions in PH with an immunohistochemical method. A total of 53 lungs removed at autopsy or explantation were obtained for the study from 51 documented cases of moderate to severe PH (15 cases of primary pulmonary hypertension [PPH], eight cases of Eisenmenger's syndrome [EISEN], 22 cases of chronic major-vessel thromboembolic disease [CTED], and three cases of PH associated with other known causes), and two unused donor lungs served as normal controls. Intimal thickening in PPH was most prominent in small pulmonary arteries and arterioles less than 200 micrometer in diameter. Plexiform lesions in PPH were associated with significantly smaller arteries than in EISEN. Arteries larger than 400 micrometer showed a significant intimal thickening only in CTED. Obstructive intimal lesions in PH comprised a morphologic spectrum with frequent intermediate forms between plexiform and thrombotic lesions. Most cells within various intimal lesions showed an immunoprofile of myofibroblasts that were positive for vimentin and alpha-smooth muscle actin, but negative for desmin and endothelial markers including Factor VIII, clonal designator (CD)31, and CD34. Endothelial markers were positive only in the single layer of cells lining slitlike lumens, when the latter were present. In conclusion, major types of PH had characteristic distribution patterns of obstructive intimal lesions, showing mainly a myofibroblastic phenotype and variable endothelial/vascular differentiation.

No abstract