Purpose: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies. Colorectal and endometrial cancers are most frequently observed. The syndrome results mainly from germ-line mutations in DNA mismatch repair genes. A common G-to-C polymorphism at codon 72 in the p53 gene has been associated with increased risk for lung, nasopharyngeal, oral, prostate, and breast cancers and may be a marker for genetic susceptibility to colorectal cancer. We studied the influence of this p53 polymorphism on HNPCC age of onset.Experimental Design: We determined the p53 genotype of 92 Caucasian mismatch repair mutation carriers, of which, 47 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism analysis. We tested the association between age of onset and the p53 genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon's test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors.Results: The HNPCC patients who were heterozygous developed their colorectal cancer 13 years earlier than HNPCC patients who were homozygous for the wild-type allele.Conclusions: Combining knowledge of an individual's p53 genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Insulin-like growth factor-I (IGF-I) is involved in colorectal carcinogenesis, and elevated plasma IGF-I levels are associated with sporadic colorectal cancer (CRC) risk. We investigated the relationship between IGF1 promoter cytosine-adenine (CA) dinucleotide-repeat polymorphism length and CRC risk in 121 MMR gene mutation carriers using Cox regression and Kaplan-Meier analysis. All statistical tests were two-sided. Time to onset for CRC increased for each decrease in CA-repeat number (median = 19 repeats, range = 12-22 repeats; hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.05 to 1.31; P = .006). Patients carrying a CA(< or = 17) repeat allele had a statistically significantly higher CRC risk (HR = 2.36; 95% CI = 1.28 to 4.36; P = .006) than all others and were younger at onset (44 years versus 56.5 years; P = .023). These findings indicate a statistically significant association between shorter IGF1 CA-repeat lengths and increased risk for CRC in HNPCC. This is the first report, to our knowledge, to show that IGF1 variant genotypes modify risk of a hereditary form of cancer.

Aurora kinases are cell cycle regulated serine/threonine kinases that have been linked to cancer. Compound 1 was identified as a potent Aurora inhibitor but lacked oral bioavailability. Optimization of 1 led to the discovery of a series of fluoroamine and deuterated analogues, exemplified by compound 25, with an improved pharmacokinetic profile. We found that blocking oxidative metabolism at the benzylic position and decreasing the basicity of the amine are important to obtaining compounds with good biological profiles and oral bioavailability.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, À149 bp from the transcription start site, is reported to greatly increase promoter activity and is associated with increased risk for lung cancer and decreased postsurgical survival in patients with small cell carcinoma of the head and neck. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 146 mismatch repair mutation carriers from 72 families. Of these, 74 participants had colorectal cancer. The participants were genotyped by single-strand conformational polymorphism analysis and DNA sequencing. We tested the association between age of onset and DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test, Wilcoxon's test, and Fleming-Harrington test and estimating the strength and direction of the association using the Cox proportional hazards regression model adjusting for potential demographic and genetic confounding factors. HNPCC patients carrying one or two copies of the DNMT3b variant T allele developed their colorectal cancer significantly earlier than HNPCC patients who were homozygous for the wild-type DNMT3b allele.

Aurora-A kinase is considered a potential cancer susceptibility gene that encodes a centrosome-associated, cell cycle-regulated serine/threonine kinase. We studied two single nucleotide polymorphisms (SNP) in the coding region of Aurora-A, 91T-to-A (F31I) and 169G-to-A (V57I). We studied the influence of these two polymorphisms on age of onset of hereditary nonpolyposis colorectal cancer (HNPCC). Genotyping of the Aurora-A polymorphisms was carried out on 125 Caucasian with mismatch repair (MMR) gene mutations with real-time pyrophosphate DNA sequencing. For the 91T-to-A polymorphism, we found that patients with HNPCC who were homozygous for the wild-type allele developed colorectal cancer (CRC) 7 years earlier than patients who were homozygous or heterozygous for the mutant allele. The169G-to-A polymorphism did not have a significant influence on risk for HNPCC. However, when we did haplotype analysis for these two polymorphisms, the 91A-169G haplotype was associated with protection from HNPCC at an earlier age.

The imidazo-[1,2-a]-pyrazine (1) is a dual inhibitor of Aurora kinases A and B with modest cell potency (IC 50 = 250 nM) and low solubility (5 μM). Lead optimization guided by the binding mode led to the acyclic amino alcohol 12k (SCH 1473759), which is a picomolar inhibitor of Aurora kinases (TdF K d Aur A = 0.02 nM and Aur B = 0.03 nM) with improved cell potency (phos-HH3 inhibition IC 50 = 25 nM) and intrinsic aqueous solubility (11.4 mM). It also demonstrated efficacy and target engagement in human tumor xenograft mouse models.

Crop protection active ingredients and formulated products are essential tools for modern agriculture that serve to prevent yield loss related to insect, weed, or fungal pest pressure. Prior to commercialization, crop protection products must be authorized or registered across various regulatory jurisdictions globally. Registration decisions are based on the results of comprehensive testing requirements across multiple scientific disciplines. Full characterization of physical/chemical properties must be conducted, and specifications must be put in place for active ingredient purity and impurity levels. Additionally, studies to assess fate, behavior, and transformation in relevant environmental matrices are conducted. Hazard properties are identified by conducting multiple toxicology studies utilizing in vitro test systems as well as relevant invertebrate and vertebrate species. Hazard end points derived from these studies are then assessed relative to the exposure potential of the chemical obtained through empirical measurements or use of well-validated models. Taken together, the hazard and exposure profiles are used ultimately to assess risk to nontarget organisms as well as humans. If necessary, exposure assessments can be refined in several ways, for example, by conducting more comprehensive OECD test guideline studies to provide more refined end points, using sophisticated modeling approaches (e.g., probabilistic models), and implementing mitigation measures to reduce the potential for exposure. Looking forward, new crop protection technologies, including purified stereoisomer products, provide the opportunity to increase specificity against target pests and reduce potential off-target interactions. The rigorous process in place for assessment and registration of crop protection products provides a strong basis to ensure that under appropriate use conditions the benefits of the product can be realized without unacceptable risk to the environment or human health.

ALTHOUGH there is a great deal of information about the pathology ofcarcinoma of the rectum, no adequate data are available for the colon using Dukes' Classification. This paper reports a survey of 656 consecutive large bowel specimens received in the Bland-Sutton Institute over a 10-year period. The pathological features have been studied with particular emphasis on differences between the right and left colon and the rectum. The results of survival studies are presented and the differences between the coloii and rectum are discussed. MATERIALS AND METHODSThe specimens are from all bowel resections carried out at the Middlesex Hospital on ward patients between the years 1951 and 1961. The methods used follow those of Dukes (1940) and were introduced by Dr. B. C. Morson in 1951, and one histopathologist in rotation has been responsible for the preparation, dissection and histological reporting of all cases of carcinoma of the large bowel.All specimens were received in the fresh unfixed state and after opening the bowel along the anti-mesenteric border the blood vessels and lymph nodes were dissected out and their exact relation to each other noted on a diagram. The specimen was then pinned out on cork and fixed in 10 % formol saline. The glands * Present address: Wessex Regional Radiotherapy Centre, Southampton.