Number Of Molecular Defects Research Articles

Targeted therapy of hepatocellular carcinoma: Present and future

Following the encouraging results of sorafenib in advanced hepatocellular carcinoma (HCC), targeted therapy has become a new direction of research in the treatment of HCC. Emerging data provide evidence that the pathogenesis and progression of HCC are mediated by a number of molecular defects and dysregulated pathways. Novel targeted therapies are designed to inhibit the aberrant pathways at a molecular level with an aim to improve the clinical outcome. For the past few years, an increasing number of targeted agents have been tested in HCC in the clinical setting. This review aims to summarize the current status of clinical development of targeted therapy in HCC, with focus on novel agents targeting angiogenesis, signal transduction and epigenetic dysregulation of tumors. The review also discusses the lessons learned from outcomes of completed clinical trials and provides perspectives on future clinical trials in HCC.

The Development of Chronic Obstructive Pulmonary Diseases Correlates with Microsatellite DNA Instability

Allele distribution at a highly polymorphic minisatellite adjacent to the c-Hras1 gene as well as deletions of microsatellite markers, D3S966, D3S1298, D9S171, and a microsatellite within p53 gene, were examined in bronchial epithelium specimens obtained from 53 chronic obstructive pulmonary disease (COPD) patients and healthy donors. A higher frequency of rare Hras1minisatellite alleles in COPD patients than in the individuals without pulmonary pathology (6.6% versus 2.2%; P < 0.05) was shown. This difference was most pronounced in the group of ten COPD patients with idiopathic pulmonary fibrosis. Three of these patients had rare Hras1 minisatellite allele (P < 0.02 in comparison with healthy controls). Alterations in at least one of the microsatellite markers (deletions or microsatellite instability) were detected in bronchial epithelium samples obtained from: 4 of 10 COPD patients with pneumofibrosis (40%); 15 of 43 COPD patients (34.9%) without pneumofibrosis; and 8 of 20 tobacco smokers (40%) without pulmonary pathology. These defects were not observed in the analogous samples obtained from healthy nonsmoking individuals. No statistically significant differences were revealed between COPD patients and healthy smokers upon comparison of both the total number of molecular defects and the number of defects in the individual chromosomal loci. The total number of molecular defects revealed in bronchial epithelium samples from the individuals of two groups examined correlated with the intensity of exposure to tobacco smoke carcinogens (r = 0.28; P < 0.05). These findings suggest that rare alleles at theHras1 locus may be associated with hereditary predisposition to COPD and the development of pneumofibrosis, while mutations in microsatellite markers result from exposure to tobacco smoke carcinogens and are not associated with the appearance of these pathologies.

Molecular biological basis and diagnosis of hereditary defect of antithrombin III, protein c and protein S

Recent progress in molecular biology enabled the elucidation of the nucleotide sequences of the genes for antithrombin III (AT III), protein C (PROC) and protein S (PROS). Furthermore numerous mutations were identified causing genetic defects of the important inhibitors of blood coagulation. As the genes for AT III (13.8 kb) and PROC (11.2 kb) are small and easy to analyze a great number of molecular defects already are described in extensive databases (50, 73): 79 different mutations for AT III and 160 for PROC are included. The identification of mutations leading to AT III and PROC deficiency has given important information on the structure-function relationships of the proteins. In case of protein C deficiency the clinical relevance of DNA analyses is most important because the diagnosis at the protein level is often uncertain. The gene for PROS is not so easy to analyze like the other two genes. The PROS gene is large and also a PROS pseudogene exists. Although a number of mutations have been identified, there has not been published a database until now. The clinical relevance to identify gene defects in PROS deficiency is as important as for PROC deficiency. Presumably the elucidation of PROS gene defects will advance in the near future.

Four new haplotypes observed in Algerian beta-thalassemia patients.

beta-Thalassemia, a heterogeneous group of human anemias affecting the expression of beta-globin, is caused by a number of molecular defects. Restriction endonuclease mapping of ethnic populations has revealed many polymorphisms within and around the beta-like globin genes, combinations of which are assigned as haplotypes. Several haplotypes appear to be strongly linked with the molecular defects causing thalassemia in Greek and Italian patients (Orkin et al. 1982). We describe here haplotypes from 40 Algerian beta-thalassemic patients and eight normals determined by restriction endonuclease mapping at seven polymorphic sites. Four haplotypes previously unreported were observed in these thalassemic patients; this argues the existence in this population of undescribed beta-thalassemia alleles. The knowledge of the haplotypes in thalassemic families could be used for prenatal diagnosis of homozygote forms.