OBJECTIVE -In patients with clinical hemochromatosis, the frequency of diabetes ranges from 20 to 50%, and the heterozygosity for the C282Y mutation in the HFE gene might be associated with an increased risk for diabetes. There are also some reports that suggest that iron overload might cause diabetic nephropathy.RESEARCH DESIGN AND METHODS -We performed an association study to assess the role of the C282Y and H63D mutations in the HFE gene as a risk factor for type 2 diabetes and diabetic nephropathy. Altogether, 563 patients with type 2 diabetes were included in the study. In the analyzed group, 108 patients had overt proteinuria, 154 had microalbuminuria, and 301 had normoalbuminuria. Among the patients with normoalbuminuria, only those with known diabetes duration Ն10 years were considered normoalbuminuric (n ϭ 162). A total of 196 unrelated healthy subjects were used as a control group. All subjects were genotyped for C282Y and H63D using the polymerase chain reaction-based protocol.RESULTS -There was an increased frequency of 282Y allele carriers among patients with type 2 diabetes versus healthy control subjects (OR 5.3, 95% CI 1.6 -17.3). We observed an increased frequency of the 63D allele carriers among patients with diabetic nephropathy (1.8, 1.2-2.8).CONCLUSIONS -In conclusion, our study is the first to indicate that being a carrier of the H63D hemochromatosis mutation is a risk factor for nephropathy in type 2 diabetic patients. We also confirmed previous observations that the frequency of the 282Y mutation was higher in patients with type 2 diabetes than it was in the general population of healthy subjects.
The different gene expression pattern in peripheral blood mononuclear cells in patients with diabetic nephropathy might indicate an important pathway in the pathogenesis of this complication.
2373 Poster Board II-350 Background: CLL cells are not highly proliferative, but are resistant to apoptosis and thus exhibit prolonged survival and accumulation in vivo. Exogenous soluble BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand) bind to the TACI receptor and have been shown to protect CLL cells from apoptosis in vitro. Nurse-like cells derived in vitro from CLL patients express high levels of APRIL and BLyS and thereby support CLL cell survival. Inhibition of both APRIL and BLyS (but not BLyS alone) significantly reduces CLL viability in vitro, indicating an important role for APRIL in this setting. Atacicept is a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc (modified) portion of a human IgG. It binds and neutralizes both APRIL and BLyS. We present the final results of a phase I study of atacicept. Methods: This is an open-label, dose-escalation trial to assess the safety, pharmacokinetics and biological effects of atacicept dosed intravenously once weekly for 5 weeks to patients with refractory or relapsed CLL. Eligible patients have been enrolled in sequential cohorts of 3 to receive atacicept at doses of 1, 4, 10, 15, 20 or 27 mg/kg (max. dose proposed due to high protein load). Patients who demonstrated at least stable disease after the first cycle (5 weeks treatment, 3 weeks follow-up) were allowed to receive up to 4 additional treatment cycles depending on response. PK was assessed after the 1st, 2nd, 3rd, and 5th dose in cycle 1. The biological activity assessment comprised peripheral leukocyte counts, lymphocyte subpopulation counts (by flow cytometric analysis) and lymph node size (assessed by CT scan). Response has been assessed using NCI-WG criteria at the end of cycle 1 and at regular intervals thereafter. Results: Twenty-one CLL patients with an average number of 7 prior treatments have been treated with atacicept for at least one cycle. Before starting Atacicept treatment, most patients had rapidly increasing leukocyte counts. No dose-limiting toxicity has been reported and no SAE related to study drug has been observed. One case of mild nausea is the only drug-related toxicity reported to date. Five of nine patients treated with 10, 15 or 20 mg/kg experienced a stabilization of their disease during the treatment period. At the dose of 27 mg/kg, one of six patients experienced a partial response (PR), which has lasted for 12 months. Five of six patients treated with 27 mg/kg experienced a stabilization of their disease during the treatment period. At lower dose levels (1 and 4 mg/kg) all patients demonstrated progressive disease. Conclusions: Treatment with atacicept was well tolerated. The multiple cases of disease stabilization and one PR seen at higher dose levels in this heavily pre-treated patient population suggest that atacicept might interfere with CLL cell proliferation and survival in vivo. Disclosures: Off Label Use: Atacicept is a soluble receptor fusion protein comprised of the extracellular domain of TACI and the Fc (modified) portion of a human IgG. It binds and neutralizes the proteins APRIL and BLyS which are suspected to drive disease progression in CLL patients. Gianella-Borradori:Merck Serono: Employment.
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