No abstract

To clarify the clinicopathologic findings of idiopathic multicentric Castleman disease among Japanese, 28 cases were studied. Two variants were delineated by the clinicopathologic findings (1) idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (n = 18) and (2) nonidiopathic plasmacytic lymphadenopathy type (n= 10). Clinicopathologically, idiopathic plasmacytic lymphadenopathy was defined by the prominent polyclonal hyperimmunoglobulinemia, normal germinal centers, and sheet-like infiltration of plasma cells in the interfollicular area of the lymph node. Histologically, the nonidiopathic plasmacytic lymphadenopathy type was characterized by hyaline-vascular germinal centers of the lymph node lesion. In comparison with idiopathic plasmacytic lymphadenopathy, patients with nonidiopathic plasmacytic lymphadenopathy showed infrequent prominent polyclonal hyperimmunoglobulinemia and frequent association with autoimmune disease. However, there was no difference in the overall 5-year survival between the 2 subtypes. Compared with idiopathic multicentric Castleman disease in Western countries, the chronic course of the disease of idiopathic multicentric Castleman disease in Japan appears to be related to negativity for human herpesvirus 8 infection.

Vascular endothelial growth factor (VEGF) and its receptors are key regulators of angiogenesis and are potential targets in cancer therapy. Here we report the down-regulation of activated VEGF receptor (VEGFR)-1/Flt-1 by endocytosis and proteolytic degradation. VEGF stimulation induced a ternary complex of Flt-1, c-Cbl, and CD2AP. Substitution of tyrosine 1333 in Flt-1 with phenylalanine (Y1333F) impaired its binding to c-Cbl. In a transient expression system, VEGF stimulated colocalization of Flt-1, CD2AP, and c-Cbl in endocytic vesicles. This colocalization was significantly impaired by an inhibitor of VEGFR kinase SU5416, the Y1333F mutation in Flt-1, or by a dominant negative form of CD2AP. In Flt-1-overexpressing NIH3T3 cells, expression of the wild-type CD2AP enhanced VEGF-stimulated internalization as well as ubiquitination of Flt-1 whereas that of a mutated form of either CD2AP or c-Cbl failed to do so. These results suggest that the c-Cbl/CD2AP complex binds to activated Flt-1 and plays a crucial role in its endocytosis and subsequent degradation.

We reported evidence that horseradish peroxidase (HRP) and chloroperoxidase (CPO) catalyze oxygen transfer from H2O2 to thioanisoles [Kobayashi, S., Nakano, M., Goto, T., Kimura, T., & Schaap, A. P. (1986) Biochem. Biophys. Res. Commun. 135, 166-171]. In the present paper, the reaction mechanism of this oxygen transfer is discussed. The oxidation of para-substituted thioanisoles by HRP compound II showed a large negative rho value of -1.46 vs. the sigma + parameter in a Hammett plot. These results are in accord with the formation of a cation radical intermediate in the rate-determining step. Hammett treatments for HRP- and CPO-dependent S-oxygenations did not provide unequivocal proofs to judge the reaction mechanism, because of the poor correlations for sigma + and sigma p parameters. Different behavior was found in kinetics and stereoselectivity between the two enzymes. Results in the present study and recent studies strongly suggested the formation of a cation radical intermediate. The oxygen atom would transfer by reaction of compound II and the cation radical intermediate. Although involvement of the cation radical was not confirmed in the CPO system, a similar mechanism was proposed for CPO.