Hypercalcemia is observed in >80% of ATL. Serum MIP-1␣ levels were elevated in all 24 ATL with hypercalcemia but undetectable in all 10 patients with humoral hypercalcemia of malignancy with solid tumors and in 34 of 37 ATL without hypercalcemia. We propose that serum MIP-1␣ is a clinical hallmark for hypercalcemia in ATL.Introduction: High serum cytokines levels are not always associated with hypercalcemia in patients with adult T-cell leukemia (ATL), suggesting that other factors are involved in the pathogenesis of ATL patients with hypercalcemia. This study was designed to determine the role of macrophage inflammatory protein-1␣ (MIP-1␣), a chemokine recently described as an osteoclast stimulatory factor, in ATL-associated hypercalcemia. Materials and Methods: We measured serum interleukin (IL)-1␤, IL-6, TNF-␣, parathyroid hormone-related protein (PTHrP), and MIP-1␣ levels in ATL patients by enzyme-linked immunosorbent assays. FACScan was used to measure the expression of RANKL on ATL cells. Osteoclast formation in cocultures of ATL cells and peripheral blood mononuclear cells (PBMCs) was evaluated by TRACP staining. Results: High serum MIP-1␣ levels were noted in all 24 ATL patients with hypercalcemia and in 3 of 37 ATL patients without hypercalcemia. The elevated levels of MIP-1␣ and calcium in ATL patients decreased after effective chemotherapy, emphasizing the role of MIP-1␣ in ATL hypercalcemia. ATL cells spontaneously produced MIP-1␣. MIP-1␣ significantly enhanced human monocyte (precursor cells of osteoclasts) migration and induced RANKL expression on ATL cells. ATL cell-induced osteoclast formation from PBMCs was inhibited by anti-MIP-1␣ antibody and osteoprotegerin. Conclusion: Our results suggest that MIP-1␣ can induce RANKL on ATL cells in autocrine fashion and that RANKL seems to mediate the hypercalcemic effect of MIP-1␣ in ATL. We propose that MIP-1␣ is the clinical hallmark of hypercalcemia in ATL and could be a potentially useful therapeutic target.

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Cyclin C, a putative G 1 cyclin, was originally isolated through its ability to complement a Saccharomyces cerevisiae strain lacking the G 1 cyclin gene CLN1-3. Unlike cyclins D1 and E, the other two G 1 cyclins obtained by the same approach and subsequently shown to play important roles during the G 1 /S transition, there is thus far no evidence to support the hypothesis that cyclin C is indeed critical for the promotion of cell cycle progression. In BAF-B03 cells, an interleukin 3 (IL-3)-dependent murine pro-B-cell line, cyclin C gene mRNA was induced at the G 1 /S phase upon IL-3 stimulation and reached a maximal level in the S phase. Enforced expression of exogenous cyclin C in this cell line failed to alter its growth properties. In the present study, we examined whether cyclin C is capable of cooperating with the cytokine-responsive immediate-early gene products c-Myc and c-Fos in the promotion of cell proliferation. We found that cyclin C is able to cooperate functionally with c-Myc, but not c-Fos, to induce both BAF-B03 cell proliferation in a cytokine-independent fashion and the formation of cell clusters. Furthermore, cyclin C was primarily responsible for the induction of cdc2 gene expression. Our data define a novel role for cyclin C in the regulation of both the G 1 /S and G 2 /M phases of the cell cycle, and this effect appears to be independent of the activity of CDK8 in the control of transcription.

Abstract. Accumulation of hyaluronan (HA) around smooth muscle cells in lesions of atherosclerosis in diabetic patients suggests that this protein plays an important role in diabetic angiopathy. The aim of this study was to determine the correlation between serum HA concentrations and diabetic angiopathy. Diabetic patients treated with or without an oral hypoglycemic agent and/or insulin for at least 1 year were recruited (n = 95). We also included 20 non-diabetic control subjects. We measured serum levels of HA, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, total cholesterol, triglyceride, glycated albumin (GA), high sensitivity CRP (hs-CRP), monocyte chemoattractant protein (MCP)-1 and evaluated diabetes mellitus history, drug use and presence of related complications. Serum HA levels were significantly (P<0.05) higher in diabetic patients (83.6 ± 5.6 ng/ml, mean ± SEM) than in normal subjects (41.7 ± 12 ng/ ml). In diabetic patients, serum HA concentration significantly correlated with FPG, HbA1c, GA, triglyceride and also significantly correlated with BMI, hs-CRP and MCP-1 and tended to be higher in diabetic patients with complications than in those without such complications. Our data suggest that serum HA level correlates with poor blood glucose control and diabetic angiopathy and that it could be used as a marker of diabetic angiopathy. HYALURONAN (HA), the principal CD44 ligand, is synthesized by resident cells of the arterial wall, including endothelial cells, smooth muscle cells, and adventitial fibroblasts and is also abundantly present in the intima and adventitia of all blood vessels. Physiologically, hyaluronan is a multifunctional protein, composed of repeating disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine, and it involved in water and protein homeostasis, cell proliferation, cell locomotion and migration through interactions with its receptor, CD44 [1,2]. Recently, we and others have reported that stimulation of CD44 with mAbs or HA transmits the signal into the cells, which leads to activation of T cells and cytokine or chemokine of release from monocytes/macrophages and synoviocytes [3][4][5]. Recent studies have reported HA production in diabetes-related arterial sclerosis and diabetic nephropathy [6][7][8]. It has been suggested that HA is possibly related to diabetic microangiopathy as well as macroangiopathy. However, there is little information on the correlation between serum HA and diabetes-related vascular disorders.The present study was designed to determine the correlation between serum HA concentrations and some of the components in the metabolic disorders of diabetes and examine the role of HA in predicting the presence of diabetes-related vasculopathies. Methods Study participantsWe studied patients who visited our hospital be-

Background : Hypoxia can induce tissue injury, including apoptosis of endothelial cells. However, little is known about the effects of hypoxia on endothelial cell function. We assessed the effects of hypoxia inducible factor (HIF)-1 α α α α on the functional charac-