Analysis of polymorphic sites in the promoter of the nitric oxide synthase 2 gene

A point mutation (G -> C) in the gene promoter for the human nitric oxide synthase (NOS) 2 at position -954 is associated with protection against severe Plasmodium falciparum malaria in Gabon. Carriers of this mutation show higher basal levels of nitric oxide production than wild type individuals. To obtain information about the possible binding transcription factors, nucleic proteins from the lung carcinoma cell line were enriched by affinity chromatography using DEAE-Sepharose and immobilized oligonucleotides derived from the promoter sequence. A mutational analysis was performed on 30 samples to detect polymorphisms in the NOS2 promoter region that contains important NF-kappa B sites. Three point mutations were identified in this region. In vitro studies with promoter constructs showed an altered expression of the marker gene depending on the promoter variant used

Phase I study of KW-2478, a novel Hsp90 inhibitor, in patients with B-cell malignancies

BACKGROUND: KW-2478 is a novel, non-ansamycin, non-purine heat-shock protein 90 (Hsp90) inhibitor.METHODS: In this phase I, multicentre study, KW-2478 was administered intravenously over 1 h at doses ranging from 14 to 176 mg m(-2) once daily on days 1-5 of a 14-day cycle in a standard 3+3 design in 27 patients (22 with multiple myeloma and 5 with non-Hodgkin lymphoma). Patients enrolled had relapsed/refractory disease previously treated with ⩾2 regimens.RESULTS: There were no dose-limiting toxicities, thus the maximum-tolerated dose was not reached. KW-2478 was well tolerated and did not manifest significant retinal or ocular toxicity. The most common treatment-related adverse events were diarrhoea (33.3%), fatigue (29.6%), headache (25.9%), hypertension (22.2%), nausea (14.8%), vomiting (7.4%), and dizziness (7.4%). Plasma concentrations peaked at the end of infusion and decayed in a biphasic manner with a terminal half-life of ∼6 h. Target inhibition was inferred from the increase in Hsp70 levels in peripheral blood mononuclear cells at doses ⩾71 mg m(-2). Twenty-four of 25 (96%) evaluable patients showed stable disease, with five being free of disease progression for ⩾6 months.CONCLUSIONS: Preliminary clinical response data were encouraging and warrant further investigation of KW-2478 in combination regimens for relapsed/refractory B-cell malignancies.</p

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro–Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0·022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0·04) and to the control group (P = 0·011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0·023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment