Optimization of prediction methods for risk assessment of pathogenic germline variants in the Japanese population

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1, 995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction

Volatile Profiles of Members of the USDA Geneva Malus Core Collection: Utility in Evaluation of a Hypothesized Biosynthetic Pathway for Esters Derived from 2‑Methylbutanoate and 2‑Methylbutan-1-ol

The volatile ester and alcohol profiles of ripening apple fruit from 184 germplasm lines in the USDA Malus Germplasm Repository at the New York Agricultural Experiment Station in Geneva, NY, USA, were evaluated. Cluster analysis suggested biochemical relationships exist between several ester classes. A strong linkage was revealed between 2-methylbutanoate, propanoate, and butanoate esters, suggesting the influence of the recently proposed “citramalic acid pathway” in apple fruit. Those lines with a high content of esters formed from 2-methylbutan-1-ol and 2-methylbutanoate (2MB) relative to straight-chain (SC) esters (high 2MB/SC ratio) exhibited a marked increase in isoleucine and citramalic acid during ripening, but those lines with a low content did not. Thus, the data were consistent with the existence of the hypothesized citramalic acid pathway and suggest that the Geneva <i>Malus</i> Germplasm Repository, appropriately used, could be helpful in expanding our understanding of mechanisms for fruit volatile synthesis and other aspects of secondary metabolism

Volatile Profiles of Members of the USDA Geneva Malus Core Collection: Utility in Evaluation of a Hypothesized Biosynthetic Pathway for Esters Derived from 2‑Methylbutanoate and 2‑Methylbutan-1-ol

The volatile ester and alcohol profiles of ripening apple fruit from 184 germplasm lines in the USDA Malus Germplasm Repository at the New York Agricultural Experiment Station in Geneva, NY, USA, were evaluated. Cluster analysis suggested biochemical relationships exist between several ester classes. A strong linkage was revealed between 2-methylbutanoate, propanoate, and butanoate esters, suggesting the influence of the recently proposed “citramalic acid pathway” in apple fruit. Those lines with a high content of esters formed from 2-methylbutan-1-ol and 2-methylbutanoate (2MB) relative to straight-chain (SC) esters (high 2MB/SC ratio) exhibited a marked increase in isoleucine and citramalic acid during ripening, but those lines with a low content did not. Thus, the data were consistent with the existence of the hypothesized citramalic acid pathway and suggest that the Geneva <i>Malus</i> Germplasm Repository, appropriately used, could be helpful in expanding our understanding of mechanisms for fruit volatile synthesis and other aspects of secondary metabolism

Efficacy of liquid 1-methylcyclopropene to delay ripening of ‘Bartlett’ pears

1-Methylcyclopropene (1-MCP) has been a useful tool to extend the postharvest life of ‘Bartlett’ pears, but fruit response can be highly variable due to competition with ethylene. Application of liquid 1-MCP after harvest was tested to determine its efficacy as compared with gaseous 1-MCP. Fruit harvested from Sacramento and Lakeport, California at early-, mid- and late- commercial harvest maturity were treated with 0.6 μL L−1 gaseous 1-MCP at 0 °C for 24 h or dipped for 0, 15, 30, 45 or 60 s in 250, 500, 750 or 1000 μg L−1 1-MCP in four experiments across three years of study. After treatment, pears were exposed to ethylene or kept in cold storage at 1 °C for 5 weeks before ripening at 20 °C. Treatment with liquid 1-MCP delayed pear ripening as evidenced by delayed softening for a minimum of 6 d compared to the control fruit, delayed the increase in respiration and ethylene production rates, and reduced respiration and ethylene production rates. Treatment was effective in a concentration- and dip time-dependent manner. Overall, dipping in 1000 μg L−1 liquid 1-MCP for 60 s was the most consistent treatment among years and locations; however, the resulting time to ripen at 20 °C could be too long for some commercial applications. Treatment at 500 μg L−1 liquid 1-MCP is recommended for ‘Bartlett’ pears as this dose controls the ripening process, and provides consistent response for mid- and late-maturity fruit. A postharvest evaluation of a liquid formulation of 1-MCP provided a more consistently effective treatment for ‘Bartlett’ pears (Pyrus communis) than the current gaseous treatments

Efficacy of liquid 1-methylcyclopropene to delay ripening of ‘Bartlett’ pears

1-Methylcyclopropene (1-MCP) has been a useful tool to extend the postharvest life of ‘Bartlett’ pears, but fruit response can be highly variable due to competition with ethylene. Application of liquid 1-MCP after harvest was tested to determine its efficacy as compared with gaseous 1-MCP. Fruit harvested from Sacramento and Lakeport, California at early-, mid- and late- commercial harvest maturity were treated with 0.6 μL L−1 gaseous 1-MCP at 0 °C for 24 h or dipped for 0, 15, 30, 45 or 60 s in 250, 500, 750 or 1000 μg L−1 1-MCP in four experiments across three years of study. After treatment, pears were exposed to ethylene or kept in cold storage at 1 °C for 5 weeks before ripening at 20 °C. Treatment with liquid 1-MCP delayed pear ripening as evidenced by delayed softening for a minimum of 6 d compared to the control fruit, delayed the increase in respiration and ethylene production rates, and reduced respiration and ethylene production rates. Treatment was effective in a concentration- and dip time-dependent manner. Overall, dipping in 1000 μg L−1 liquid 1-MCP for 60 s was the most consistent treatment among years and locations; however, the resulting time to ripen at 20 °C could be too long for some commercial applications. Treatment at 500 μg L−1 liquid 1-MCP is recommended for ‘Bartlett’ pears as this dose controls the ripening process, and provides consistent response for mid- and late-maturity fruit. A postharvest evaluation of a liquid formulation of 1-MCP provided a more consistently effective treatment for ‘Bartlett’ pears (Pyrus communis) than the current gaseous treatments

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

KRAS遺伝子変異を持ったがんを標的とした新規のアルキル化剤の開発について. 京都大学プレスリリース. 2015-05-01.Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours