ABSTRACT
Nitropolychlorobutadienes are valuable precursors for highly functionalized acyclic or (hetero)cyclic compounds. In this 8th part of our synthetically oriented series we focus on the application of these versatile starting materials in the synthesis of analogs of the heterocyclic insecticides imidacloprid and thiacloprid, and the acyclic counterpart clothianidin. In addition to the main synthetic part, leading to imidazolidines or oxazolidines, further promising types of compounds derived by subsequent chemical modifications, are introduced. Most of the new compounds show high insecticidal activity.
Subject(s)
Butadienes/chemistry , Insecticides/chemistry , Butadienes/chemical synthesis , Guanidines/chemical synthesis , Guanidines/chemistry , Halogenation , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazolidines/chemistry , Insecticides/chemical synthesis , Neonicotinoids , Nitro Compounds/chemical synthesis , Nitro Compounds/chemistry , Oxazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Thiazines/chemical synthesis , Thiazines/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
DNA pooling in combination with high-throughput sequencing was done as a part of the Sequenom-Genefinder project. In the pilot study, we tested 83,715 single nucleotide polymorphisms (SNP), located primarily in gene-based regions, to identify polymorphic susceptibility variants for lung cancer. For this pilot study, 369 male cases and 287 controls of both sexes (white Europeans of Southern German origin) were analyzed. The study identified a candidate region in 22q12.2 that contained numerous SNPs showing significant case-control differences and that coincides with a region that was shown previously to be frequently deleted in lung cancer cell lines. The candidate region overlies the seizure 6-like (SEZ6L) gene. The pilot study identified a polymorphic Met430Ile substitution in the SEZ6L gene (SNP rs663048) as the top candidate for a variant modulating risk of lung cancer. Two replication studies were conducted to assess the association of SNP rs663048 with lung cancer risk. The M. D. Anderson Cancer Center study included 289 cases and 291 controls matched for gender, age, and smoking status. The Liverpool Lung Project (a United Kingdom study) included 248 cases and 233 controls. Both replication studies showed an association of the rs663048 with lung cancer risk. The homozygotes for the variant allele had more than a 3-fold risk compared with the wild-type homozygotes [combined odds ratio (OR), 3.32; 95% confidence interval (95% CI), 1.81-7.21]. Heterozygotes also had a significantly elevated risk of lung cancer from the combined replication studies with an OR of 1.15 (95% CI, 1.04-1.59). The effect remained significant after adjusting for age, gender, and pack-years of tobacco smoke. We also compared expression of SEZ6L in normal human bronchial epithelial cells (n = 7), non-small cell lung cancer (NSCLC; n = 52), and small cell lung cancer (SCLC; n = 22) cell lines by using Affymetrix HG-U133A and HG-U133B GeneChips. We found that the average expression level of SEZ6L in NSCLC cell lines was almost two times higher and in SCLC cell lines more than six times higher when compared with normal lung epithelial cell lines. Using the National Center for Biotechnology Information Gene Expression Omnibus database, we found a approximately 2-fold elevated and statistically significant (P = 0.004) level of SEZ6L expression in tumor samples compared with normal lung tissues. In conclusion, the results of these studies representing 906 cases compared with 811 controls indicate a role of the SEZ6L Met430Ile polymorphic variant in increasing lung cancer risk.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Small Cell/genetics , Lung Neoplasms/genetics , Membrane Proteins/genetics , Aged , Case-Control Studies , Cell Line, Tumor , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Pilot Projects , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
The outcome of infectious diseases in vertebrates is under genetic control at least to some extent. In swine, e.g., marked differences in resistance/susceptibility to Sarcocystis miescheriana have been shown between Chinese Meishan and European Pietrain pigs, and these differences are associated with high heritabilities. A first step toward the identification of genes and polymorphisms causal for these differences may be the mapping of quantitative trait loci (QTLs). Considering clinical, immunological, and parasitological traits in the above model system, this survey represents the first QTL study on parasite resistance in pigs. QTL mapping was performed in 139 F(2) pigs of a Meishan/Pietrain family infected with S. miescheriana. Fourteen genome-wide significant QTLs were mapped to several chromosomal areas. Among others, major QTLs were identified for bradyzoite numbers in skeletal muscles (F = 17.4; p < 0.001) and for S. miescheriana-specific plasma IgG(2) levels determined 42 days p.i. (F = 20.9; p < 0.001). The QTLs were mapped to different regions of chromosome 7, i.e., to the region of the major histocompatibility complex (bradyzoites) and to an immunoglobulin heavy chain cluster, respectively. These results provide evidence for a direct and causal role for gene variants within these gene clusters (cis-acting) in differences in resistance to S. miescheriana.
Subject(s)
Genetic Predisposition to Disease , Immunity, Innate/genetics , Quantitative Trait Loci , Sarcocystosis/veterinary , Swine Diseases/genetics , Animals , Chromosome Mapping , Disease Susceptibility , Genetic Markers/genetics , Host-Parasite Interactions/genetics , Sarcocystis/pathogenicity , Sarcocystosis/genetics , Swine , Swine Diseases/parasitologyABSTRACT
PURPOSE: Whole-genome scan association analysis was carried out to identify genetic variants predictive of lung cancer risk in smokers and to confirm the identified variants in an independent sample. PATIENTS AND METHODS: A case-control study was performed using two pools consisting of DNA from 322 German smoking lung cancer patients and 273 healthy smoking controls, respectively. A replication study was carried out using 254 Italian lung adenocarcinoma (ADCA) patients and 235 healthy controls. RESULTS: Patients with genotypes GG or CG for the rs1862214 single nucleotide polymorphism, 5' upstream of the programmed cell death 5 (PDCD5) gene, compared with those with the common genotype CC showed an increased risk of lung cancer (odds ratio, 1.6; 95% CI, 1.2 to 2.1) and a higher incidence of poor clinical stage disease (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.4; P = .023), nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.6; P = .033), and short-term survivorship (HR, 1.8; 95% CI, 1.2 to 2.6, P = .003). PDCD5 mRNA expression levels were approximately 2.4-fold lower in lung ADCA as compared to normal lung tissue. Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased colony-forming ability. CONCLUSION: These results suggest that the rs1862214 polymorphism in PDCD5 is predictive for lung cancer risk and prognosis, and that PDCD5 may represent a novel tumor suppressor gene influencing lung cancer.
