Cycloadditions in mixed aqueous solvents: the role of the water concentration

We examined the kinetics of a series of cycloaddition reactions in mixtures of water with methanol, acetonitrile and poly(ethylene glycol) (MW 1000). The reactions include the Diels–Alder (DA) reaction between cyclopentadiene and N-n-butylmaleimide or acridizinium bromide, the retro-Diels-Alder (RDA) reaction of 1,4,4a,9a-tetrahydro-4a-methyl-(1α,4α,4aα,9aα)-1,4-methaneanthracene-9,10-dione and the 1,3-dipolar cycloaddition of benzonitrile oxide with N-n-butylmaleimide. Plots of logk vs the molar concentration or volume fraction of water are approximately linear, but with a characteristic break around 40 M water. This break, absent for the RDA reaction, is ascribed to hydrophobic effects. Comparison with aqueous mixtures of the more hydrophobic 1-propanol shows that these mixtures induce qualitatively similar effects on the rate, but that preferential solvation effects cause the mixtures of 1-propanol to exhibit a more complex behavior of logk on composition. The results are analyzed using the Abraham–Kamlett–Taft model. The solvent effects in aqueous mixtures are not satisfactorily described by this model. For some cycloadditions, small maxima in rate are observed in highly aqueous mixtures of alcohols. The origin of these maxima and the aforementioned breaks is most likely the same.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Prostate cancer is part of the hereditary non-polyposis colorectal cancer (HNPCC) tumor spectrum

The recognized urologic tumor spectrum in hereditary non-polyposis colon cancer includes ureteral and renal pelvis malignancies. Here, we report a family in which the proband, who had three metachronous adenocarcinomas of the colon and rectum (at ages 54, 57, and 60), presented with an adenocarcinoma of the prostate at age 61. Immunohistochemical (IHC) staining of colonic, rectal, and prostatic tumor tissues demonstrated lack of expression of both MSH2 and MSH6. Accordingly, microsatellite instability (MSI) was found in the rectal, colonic, and prostatic tumors. The kindred complies with the Amsterdam criteria for HNPCC, as five members over three generations had colorectal cancer. Molecular investigations were initiated when the proband's son presented with an adenocarcinoma of the colon at age 35. Southern blotting analysis of genomic DNA led to identification of a novel genomic deletion encompassing exon 5 of the MSH2 gene. Although prostate cancer has occasionally been described in HNPCC families, to the best of our knowledge, this is the first report where the MSI and IHC analysis of the prostatic adenomcarcinoma clearly link its aetiology to the germline mismatch repair mutation. Hence, prostate cancer should be included in the HNPCC tumor spectrum