Development of Diagnostic Technology for Monitoring Pyrethroid Resistance Mechanisms in the Tobacco Budworm, Heliothis Virescens (F.).

Metabolic resistance was studied in the tobacco budworm, Heliothis virescens (F.) using pyrethroid analogs, insecticide synergists, and an in vitro assay with \sp{14}C-cypermethrin. In initial studies, the phenoxybenzyl moiety of conventional pyrethroid, a major site of oxidative metabolism in resistant H. virescens, was replaced with P450 monooxygenase-inhibiting or oxidatively blocked groups. Isomers (1R/1S, cis/trans) of the resulting chrysanthemates were separated and tested as insecticides against pyrethroid-susceptible (LSU) and -resistant H. virescens (Pyr-R). A number of compounds with pentafluorophenyl (PFP), methylenedioxyphenyl (MDP), and propargyloxyphenyl (PP) groups were insecticidal and activity was dependent on both geometric and stereochemical configuration of the acid moiety. Both trans and cis isomers of 1R-fenfluthrin, which contains a PFP group, suppressed resistance to cypermethrin in Pyr-R insects, confirming that oxidative metabolism of the phenoxybenzyl moiety is a major mechanism of resistance in this strain. Of the MDP compounds, 1R, trans and cis isomers were toxic and partially suppressed resistance in Pyr-R larvae. Similarly, both trans and cis isomers of $\alpha S,1R$ PP-containing compounds were insecticidal. In a second approach, studies with pyrethroid synergists showed the importance of enhanced metabolism to pyrethroid-resistance in Pyr-R larvae. Among four P450 monooxygenase inhibitors tested, the propynyl ether, 1, 2, 4-trichloro-3(2-propynyloxy)benzene, was the most effective synergist for cypermethrin toxicity, whereas synergism with piperonyl butoxide (PBO) was moderate. An esterase inhibitor, S,S,S-tributylphosphorotrithioate, also was active as a synergist of cypermethrin toxicity. Non-toxic isomers of pyrethroid analogs were tested as synergists, and only $\alpha R,1R,cis$-MDP- and PP-containing compounds significantly enhanced cypermethrin toxicity. Finally, the enzymes involved in cypermethrin metabolism and resistance in Pyr-R insects were investigated using an in vitro assay. Studies with \sp{14}C-cypermethrin revealed that both P450 monooxygenases and esterases were associated with pyrethroid resistance in Pyr-R larvae. HO-cypermethrin, a monooxygenase product, and phenoxybenzoic acid, a product of esterase-mediated hydrolysis, were identified as the two major metabolites. Compared with the LSU strain, field-collected MRS-June and -August H. virescens showed very high levels of the hydrolytic metabolite as well as moderate levels of the oxidative product. Inhibition studies indicated that the monooxygenase inhibitor, PBO, also inhibits esterases

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.This work was conducted on behalf of the CHIPGECS and The PRACTICAL consortia (see Supplementary Consortia). We acknowledge the contribution of doctors, nurses and postgraduate research students at the CHIPGENCS sample collecting centers. We thank Orchid and Rosetrees for funding support. This work was also supported by National Natural Science foundation of China for funding support to H Zhang (Grant No: 30671793 and 81072377), N Feng (Grant No: 81272831), X Zhang (Grant No: 30572139, 30872924 and 81072095), S Zhao (Grant No: 81072092 and 81328017), Y Yu (Grant No: 81172448) and Program for New Century Excellent Talents in University from Department of Education of China (NCET-08-0223) and the National High Technology Research and Development Program of China (863 Program 2012AA021101) to X Zhang.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.725

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Insecticide choice for alfalfa may protect water quality

Some insecticides used for controlling Egyptian alfalfa weevil have been detected in California's surface waters and are of concern, due to their impact on water quality and toxicity to some aquatic life. To assess the impact of insecticide choice on water quality, we collected tail-water samples from on-farm alfalfa sites in the northern Sacramento Valley over a 3-year period. Samples were collected during irrigation after organophosphate and pyrethroid sprays were applied. We found significant differences between insecticide classes in the mortality of Ceriodaphnia dubia (water flea), a test organism used to detect pesticides in water. Nearly all sites where organophosphate insecticides were used resulted in 100% water flea mortality in a 24-hour test of tail-water samples; pyrethroid-treated sections of the same fields exhibited insignificant flea mortality. The pyrethroids we used provided significantly better control of Egyptian alfalfa weevil than the organophosphates, with no significant differences in beneficial insect counts. Although water runoff does not always occur in alfalfa fields, insecticide choice may be an important tool for protecting water quality. In addition, consideration should be given to the fact that pyrethroids, while they proved advantageous in these experiments, can affect beneficial species and do have high toxicity to fish at extremely low concentrations