Increased CDK4 protein expression predicts a poor prognosis in mucosal melanoma associated with the p16INK4a-CDK4-pRb pathway.

Mucosal melanoma (MM) occurs in non-cutaneous mucosal sites, e.g., the head and neck or the lower genital tract; it is a rare and aggressive neoplasm with a poor prognosis. To date, few prognostic markers of MM have been well-defined. The aim of this study is to clarify the prognostic value of the cell-cycle regulatory proteins (CDK4, pRb and CyclinD1, p16) which are associated with the p16INK4a-CDK4-pRb pathway in MM. A total of 54 MM samples were obtained from biopsy specimens, and the expressions of the cell-cycle regulatory proteins (CDK4, pRb and CyclinD1, p16) were assessed by immunohistochemistry. A Mantel-Cox regression analysis was performed to investigate the association of these proteins with the overall survival of MM patients. Increased CDK4 expression was significantly associated with reduced survival at three years (P = 0.022). Increased CDK4 protein expression may be a helpful prognostic indicator for the management of these patients who infiltrate into the p16INK4a-CDK4-pRb pathway. In addition, we found that those patients with low expression of CDK4 were significantly older (P < 0.05) compared to the patients with high expression of CDK4.

The arteriolar injury in hypertension.

In 1937, Drs. Moritz and Oldt described arteriolar injuries in the kidneys (and other viscera) in hypertension, across the age range, in both sexes, and, in different races. This hypothesis proposes that injuries to vasomotor nerves cause the arteriolar injury in the kidney in hypertension, (as well as that in the uterus in preeclampsia). Different patterns of perivascular hyalinisation in different viscera are clues to the varying causes and consequences of arteriolar injury. In the uterus there is a symmetrical, perivascular "halo of hyalinisation" that marks the lines of extension of regenerating, injured nerves to the placental bed, whereas in the kidney there is a disordered and asymmetrical "halo of hyalinisation" where persistent, and recurrent, increases in intravascular pressures interrupt development of regenerating nerves. Consequences of injuries to vasomotor nerves include releasing a "soup" of cytokines that cause regeneration of "new" nerves expressing primitive, pain and stretch receptors including TRPV-1 and P2X3 purinergic "stretch" receptors that may be significant in the afferent mechanism in preeclampsia. There is also concurrent, "background" hyperplasia of denervated tunica media and intima leading to narrowing of the arterioles and a further drive to hypertension through renal ischaemia (Goldblatt, 1942). These observations require support from animal studies and other investigations to establish causation. This hypothesis may provide a number of potential mechanisms that reinforce, or accelerate, the physiological processes that contribute to hypertension.