Chemo- and Regioselective Functionalization of Isotactic Polypropylene: A Mechanistic and Structure-Property Study.

Polyolefins represent a high-volume class of polymers prized for their attractive thermomechanical properties, but the lack of chemical functionality on polyolefins makes them inadequate for many high-performance engineering applications. We report a metal-free postpolymerization modification approach to impart functionality onto branched polyolefins without the deleterious chain-coupling or chain-scission side reactions inherent to previous methods. The identification of conditions for thermally initiated polyolefin C-H functionalization combined with the development of new reagents enabled the addition of xanthates, trithiocarbonates, and dithiocarbamates to a variety of commercially available branched polyolefins. Systematic experimental and kinetic studies led to a mechanistic hypothesis that facilitated the rational design of reagents and reaction conditions for the thermally initiated C-H xanthylation of isotactic polypropylene (iPP) within a twin-screw extruder. A structure-property study showed that the functionalized iPP adheres to polar surfaces twice as strongly as commercial iPP while demonstrating similar tensile properties. The fundamental understanding of the elementary steps in amidyl radical-mediated polyolefin functionalization provided herein reveals key structure-reactivity relationships for the design of improved reagents, while the demonstration of chemoselective and scalable iPP functionalization to realize a material with improved adhesion properties indicates the translational potential of this method.

CYP3A variation, premenopausal estrone levels, and breast cancer risk.

BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study.

BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

Replication timing profile reflects the distinct functional and genomic features of the MHC class II region.

The timing of DNA replication generally correlates with transcription, gene density and sequence composition. How is the timing affected if a genomic region has a combination of features that individually correlate with either early or late replication? The major histocompatibility complex (MHC) class II region is an AT-rich isochore that would be expected to replicate late, but it also contains coordinately regulated genes that are highly expressed in antigen-presenting cells and are strongly inducible in other cell types. Using cytological and biochemical assays, we find that the entire MHC replicates within the first half of S-phase, and that the class II region replicates slightly later than the adjacent regions irrespective of gene expression. These data suggest that despite AT-richness, an early-to-middle replication time in the class II region is defined by an open chromatin conformation that allows rapid transcriptional activation as a defence against pathogens.

Mutation cluster region, association between germline and somatic mutations and genotype-phenotype correlation in upper gastrointestinal familial adenomatous polyposis.

Studies of adenomatous polyposis coli (APC) mutations in familial adenomatous polyposis (FAP) have focused on large bowel disease. It has been found that: 1) germline APC mutations around codon 1300 are associated with severe colorectal polyposis; 2) somatic APC mutations in colorectal tumors tend to cluster approximately between codons 1250 and 1450; and 3) patients with germline mutations close to codon 1300 tend to acquire somatic mutations (second hits) in their colorectal polyps by allelic loss, whereas the tumors of other FAP patients have truncating second hits. Using new and published data, we have investigated how germline and somatic APC mutations influence the pathogenesis of upper gastrointestinal polyps in FAP. We have compared the results with those from colorectal disease. We found that somatic mutations in upper gastrointestinal polyps cluster approximately between codons 1400 and 1580. Patients with germline APC mutations after codon 1400 tend to show allelic loss in their upper gastrointestinal polyps; the tumors of other patients have truncating somatic mutations after codon 1400. Finally, patients with germline mutations after codon 1400 tend to have more severe duodenal polyposis (odds ratio, 5.72; 95% confidence interval, 1.13 to 28.89; P = 0.035). Thus, in both upper gastrointestinal and colorectal tumors, a specific region of the APC gene is associated with severe disease, clustering of somatic mutations, and loss of the wild-type allele. However, the region concerned is different in upper gastrointestinal and colorectal disease. The data suggest that loss of all APC SAMP repeats is probably necessary for duodenal and gastric tumorigenesis in FAP, as it is in colonic tumors. Compared with colonic tumors, however, retention of a greater number of beta-catenin binding/degradation repeats is optimal for tumorigenesis in upper gastrointestinal FAP.

Sex chromosome anomalies in pancreatic endocrine tumors.

We have investigated the status of sex chromosomes in 40 pancreatic endocrine tumors (PETs) using 2 complementary techniques: microsatellite and interphase FISH analysis. Twenty-five tumors were from female and 15 from male patients and included 31 nonfunctioning and 9 functioning PET (6 insulinomas, 2 glucagonomas and 1 VIPoma). Microsatellite and FISH analysis showed concordant results in all cases. PETs from females showed frequent loss of chromosome X (40%) whereas PETs from males showed relatively frequent loss of chromosome Y (36%) but never loss of the X chromosome. Statistical analysis showed significant association of sex chromosome loss with metastases (Spearman correlation test, r = 0.5, p < 0.001), local invasion (r = 0.33, p < 0.05) and high proliferation rate measured as Ki-67 index with a 5% cut-off (r = 0.42, p < 0.02). The analysis also showed that local invasion and metastases were highly correlated (r = 0.86). Multivariate survival analysis was therefore carried out including local invasion and loss of sex chromosomes. The presence of local invasion increased the risk of death almost 9 times whereas sex chromosome loss was an independent variable associated with a shorter survival period and an increased risk of death of approximately 4-fold.