No abstract

No abstract

To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with alltrans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RAR␣ at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n ‫؍‬ 89) or observation (n ‫؍‬ 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P ‫؍‬ .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P ‫؍‬ .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RAR␣ fusion transcript after 3 courses of intensive consolidation therapy. (Blood. 2007;110:59-66)

Despite the progress in the therapeutic treatment of diabetes mellitus, diabetic nephropathy is one of the major complications of diabetes and the single largest cause of endstage renal diseases. Histologically, early diabetic nephropathy is characterized by glomerular hypertrophy and the inappropriate dilatation of afferent arterioles, which are believed to be associated with hyperfiltration and are followed by thickening of the glomerular basement membrane and accumulation of mesangial matrix [1,2]. The pathogenesis of glomerular hypertrophy and afferent arteriolar dilatation due to diabetes is, however, still not clear.Nitric oxide (NO) has been identified as a pleiotropic intercellular messenger that regulates a variety of cellular functions [3] and an endothelium-derived relaxing factor that inhibits contraction of vascular smooth muscles, as well as the adhesion or aggregation of platelets [4]. Three isoforms of this enzyme have Diabetologia (1998) Summary The overproduction of nitric oxide (NO) is reported in the diabetic kidney and considered to be involved in glomerular hyperfiltration. The precise mechanism of NO production in the diabetic kidney is, however, not known. In this report, we compare the localization of endothelial cell nitric oxide synthase (ecNOS) isoform expression in the kidney tissue of streptozotocin (STZ)-induced diabetic rats and 5/6 nephrectomized rats and clarify the pivotal role of ecNOS for the glomerular hyperfiltration in the early stages of diabetic nephropathy. In diabetic rats, the diameters of afferent arterioles, the glomerular volume, creatinine clearance, and urinary NO 2 / NO 3 were increased after the induction of diabetes. Efferent arterioles were, however, not altered. Insulin or L-NAME treatment returned the diameters of afferent arterioles, glomerular volume, creatinine clearance, and urinary NO 2 /NO 3 to normal. The expression of ecNOS in afferent arterioles and glomeruli of diabetic rats increased during the early stages of the disease, but was not altered in efferent arterioles. Treatment with either insulin or L-NAME decreased ecNOS expression in afferent arterioles and in glomeruli. In contrast, the ecNOS expression was upregulated in both afferent and efferent arterioles and in the glomeruli of 5/6 nephrectomized rats, where the dilatation of afferent and efferent arterioles and glomerular enlargement were observed. Treatment with L-NAME ameliorated the ecNOS expression and dilatation of arterioles. We conclude that enhanced NO synthesis by ecNOS in afferent arterioles and glomerular endothelial cells in response to the hyperglycaemic state could cause preferential dilatation of afferent arterioles, which ultimately induces glomerular enlargement and glomerular hyperfiltration. [Diabetologia (1998 Keywords Nitric oxide (NO), endothelial cell nitric oxide synthase (ecNOS), diabetic nephropathy, afferent arterioles, glomerular hyperfiltration Received: 5 January 1998 and in revised form: 27 April 1998Corresponding author: H. Sugimoto MD., Department of Med...

Intermittent fasting is one of the most effective dietary restriction regimens that extend life span in C. elegans and mammals. Fasting-stimulus responses are key to the longevity response; however, the mechanisms that sense and transduce the fasting stimulus remain largely unknown. Through a comprehensive transcriptome analysis in C. elegans, we find that along with the FOXO transcription factor DAF-16, AP-1 (JUN-1/FOS-1) plays a central role in fasting-induced transcriptional changes. KGB-1, one of the C. elegans JNKs, acts as an activator of AP-1 and is activated in response to fasting. KGB-1 and AP-1 are involved in intermittent fasting-induced longevity. Fasting-induced upregulation of the components of the SCF E3 ubiquitin ligase complex via AP-1 and DAF-16 enhances protein ubiquitination and reduces protein carbonylation. Our results thus identify a fasting-responsive KGB-1/AP-1 signaling pathway, which, together with DAF-16, causes transcriptional changes that mediate longevity, partly through regulating proteostasis.

Posttranslational modifications of clock proteins are crucial to generating proper circadian rhythms of the correct length and amplitude. Here, we show that the protein kinase CK2 (casein kinase 2) plays a role in regulating the mammalian circadian clock. We found that inhibiting CK2 activity resulted in a decrease in the amplitude and an increase in the period of oscillations in circadian gene expression. CK2 specifically bound and phosphorylated PERIOD2 (PER2) and collaborated with the protein kinase CKIepsilon to promote PER2 degradation. We also identified a CK2 phosphorylation site (serine-53) in PER2, whose phosphorylation played a role in fine-tuning circadian rhythms and regulating PER2 stability but was dispensable for the cooperative effect of CK2 and CKIepsilon. Thus, our study identifies CK2 as a regulatory element of mammalian circadian rhythms and uncovers a role for CK2 in PER2 degradation.

Mononuclear cells, including monocytes/macrophages and T-cells, are considered to be involved in the progression of diabetic nephropathy, although the mechanism of their recruitment into diabetic glomeruli is unclear. The intercellular adhesion molecule-1 (ICAM-1) promotes the infiltration of leukocytes into atherosclerotic lesions as well as inflammatory tissues. In the present study, we investigated the expression of ICAM-1 in the glomeruli of streptozotocin-induced diabetic rats. The expression of ICAM-1 was increased significantly during the early stage of diabetes. The number of mononuclear cells, primarily monocytes/macrophages and lymphocytes, was significantly increased in diabetic glomeruli. Mononuclear cell infiltration into diabetic glomeruli was prevented by anti-ICAM-1 monoclonal antibody. Insulin treatment decreased ICAM-1 expression and mononuclear cell infiltration. The ICAM-1 expression on cultured human umbilical vein endothelial cells was not induced under high glucose culture conditions. Glomerular hyperfiltration is a characteristic change in the early stage of diabetic nephropathy. Treatment with aldose reductase inhibitor, which prevented glomerular hyperfiltration without changes in blood glucose levels, decreased ICAM-1 expression and mononuclear cell infiltration. Moreover, we examined the ICAM-1 expression in the glomeruli of the 5/6 nephrectomized rat, which is a model for glomerular hyperfiltration without hyperglycemia. The ICAM-1 expression and infiltration of mononuclear cells was significantly increased in the glomeruli of 5/6 nephrectomized rats. We conclude that ICAM-1 is upregulated and promotes the recruitment of mononuclear cells in diabetic glomeruli. Moreover, glomerular hyperfiltration that occurs in the early stage of diabetic glomeruli may be one of the potential mechanisms of ICAM-1 upregulation in diabetic nephropathy.

No abstract