Nationwide Study of Breast Cancer Risk Factors in Latinas

Breast cancer is the most common cancer among American women. Any woman can be affected by breast cancer, with risk for the disease increasing with age. Risk for breast cancer is also exacerbated in women who have certain genetic alterations. Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer, and are increasingly recognized in prostate and pancreatic cancers (1-3). In Caucasian and Asian ethnicities BRCA mutations are associated with basal-type/triple-negative disease. However this association between BRCA gene mutations and basal/triple-negative disease has been understudied in other ethnicities (4-6). The incidence and mortality of breast cancer of Hispanics and Native Americans are lower than other ethnicities; however they are underrepresented in epidemiological and clinical studies. Further, it is known that common recurrent mutations in BRCA1 and BRCA2 genes exist in Hispanic/Latino communities which account for 35-45% of mutation carriers (7, 8). The objective of our study is thus to investigate triple negative disease and BRCA gene mutations in Hispanic women

Nationwide Study of Breast Cancer Risk Factors in Latinas

Breast cancer is the most common cancer among American women. Any woman can be affected by breast cancer, with risk for the disease increasing with age. Risk for breast cancer is also exacerbated in women who have certain genetic alterations. Mutations in the BRCA1 and BRCA2 genes predispose women to breast and ovarian cancer, and are increasingly recognized in prostate and pancreatic cancers (1-3). In Caucasian and Asian ethnicities BRCA mutations are associated with basal-type/triple-negative disease. However this association between BRCA gene mutations and basal/triple-negative disease has been understudied in other ethnicities (4-6). The incidence and mortality of breast cancer of Hispanics and Native Americans are lower than other ethnicities; however they are underrepresented in epidemiological and clinical studies. Further, it is known that common recurrent mutations in BRCA1 and BRCA2 genes exist in Hispanic/Latino communities which account for 35-45% of mutation carriers (7, 8). The objective of our study is thus to investigate triple-negative disease and BRCA gene mutations in Hispanic women

Modified bases enable high-efficiency oligonucleotide-mediated allelic replacement via mismatch repair evasion

Genome engineering using single-stranded oligonucleotides is an efficient method for generating small chromosomal and episomal modifications in a variety of host organisms. The efficiency of this allelic replacement strategy is highly dependent on avoidance of the endogenous mismatch repair (MMR) machinery. However, global MMR inactivation generally results in significant accumulation of undesired background mutations. Here, we present a novel strategy using oligos containing chemically modified bases (2′-Fluoro-Uridine, 5-Methyl-deoxyCytidine, 2,6-Diaminopurine or Iso-deoxyGuanosine) in place of the standard T, C, A or G to avoid mismatch detection and repair, which we tested in Escherichia coli. This strategy increases transient allelic-replacement efficiencies by up to 20-fold, while maintaining a 100-fold lower background mutation level. We further show that the mismatched bases between the full length oligo and the chromosome are often not incorporated at the target site, probably due to nuclease activity at the 5′ and 3′ termini of the oligo. These results further elucidate the mechanism of oligo-mediated allelic replacement (OMAR) and enable improved methodologies for efficient, large-scale engineering of genomes.Synthetic Biology Engineering Research CenterNational Science Foundation (U.S.) (Grant #SA5283-11210)United States. Dept. of Energy (Genomes to Life Center) (Grant #DE-FG02-03ER6344)Wyss Institute for Biologically Inspired Engineerin

RNA chaperones buffer deleterious mutations in E. coli

International audienc

The other antioxidants: Bioflavonoids and carotenoids

Free radical damage has been associated with atherosclerosis, agerelated macular degeneration, and age-related cataracts. Free radicals cause damage to human tissues through oxidative stress. Protection against free radicals has been found with the use of antioxidants, such as vitamin C, vitamin E, and beta-carotene. Antioxidants neutralize the free radicals and prevent tissue damage; therefore antioxidants are increasingly becoming routine therapies for such diseases as atherosclerosis. Foods may contain other antioxidants such as bioflavonoids and carotenoids other than betacarotene. Research is showing how bioflavonoids and carotenoids inhibit lipid peroxidation and platelet aggregation and thus may be even more beneficial than current therapies for free radical damage

Enhanced multiplex genome engineering through co-operative oligonucleotide co-selection

Genome-scale engineering of living organisms requires precise and economical methods to efficiently modify many loci within chromosomes. One such example is the directed integration of chemically synthesized single-stranded deoxyribonucleic acid (oligonucleotides) into the chromosome of Escherichia coli during replication. Herein, we present a general co-selection strategy in multiplex genome engineering that yields highly modified cells. We demonstrate that disparate sites throughout the genome can be easily modified simultaneously by leveraging selectable markers within 500 kb of the target sites. We apply this technique to the modification of 80 sites in the E. coli genome.United States. Dept. of Energy. Genomes To Life (DE-FG02-03ER6344)National Science Foundation (U.S.). Genes and Genomes Systems Cluster (0719344)National Science Foundation (U.S.). Center for Bits and Atoms (0122419)National Science Foundation (U.S.). Synthetic Biology Engineering Research Center (0540879

MODEST: a web-based design tool for oligonucleotide-mediated genome engineering and recombineering

Recombineering and multiplex automated genome engineering (MAGE) offer the possibility to rapidly modify multiple genomic or plasmid sites at high efficiencies. This enables efficient creation of genetic variants including both single mutants with specifically targeted modifications as well as combinatorial cell libraries. Manual design of oligonucleotides for these approaches can be tedious, time-consuming, and may not be practical for larger projects targeting many genomic sites. At present, the change from a desired phenotype (e.g. altered expression of a specific protein) to a designed MAGE oligo, which confers the corresponding genetic change, is performed manually. To address these challenges, we have developed the MAGE Oligo Design Tool (MODEST). This web-based tool allows designing of MAGE oligos for (i) tuning translation rates by modifying the ribosomal binding site, (ii) generating translational gene knockouts and (iii) introducing other coding or non-coding mutations, including amino acid substitutions, insertions, deletions and point mutations. The tool automatically designs oligos based on desired genotypic or phenotypic changes defined by the user, which can be used for high efficiency recombineering and MAGE. MODEST is available for free and is open to all users at http://modest.biosustain.dtu.dk

The Prevalence and Clinical Correlates of an Auscultatory Gap in Systemic Sclerosis Patients

Introduction. Accurate blood pressure (BP) measurement is essential to the diagnosis and management of hypertension in patients with systemic sclerosis (SSc) to help prevent renal and cardiovascular complications. The presence of an auscultatory gap during manual BP measurement—the temporary disappearance of the Korotkoff sounds during cuff deflation—leads to a potentially important underestimate of systolic BP if undetected. Objectives. Since the presence of an auscultatory gap is frequently associated with increased vascular stiffness, we investigated its presence and correlates in 50 consecutive SSc patients. Methods. For each patient, BP was measured sequentially using three different approaches performed in the same order. Results. Sixteen of 50 patients (32%) had an auscultatory gap which if undetected would have resulted in clinically important underestimates of systolic BP in 4 patients. The presence of an auscultatory gap was statistically associated with the presence of antibodies to RNA polymerase III (P<0.0068) and SSc diagnosis type (P<0.01). Conclusions. Our study demonstrates that auscultatory gaps are relatively common in SSc and correlate with markers for SSc vasculopathy. If undetected auscultatory gaps may result in clinically important underestimation of BP. Thus, electronic oscillometric BP may be preferred in SSc patients

Evidence of association of APOE with age‐related macular degeneration ‐ a pooled analysis of 15 studies

Age‐related macular degeneration (AMD) is the most common cause of incurable visual impairment in high‐income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low‐density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis ( n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65–0.74; P = 4.41×10 −11 ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04–3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38–1.72; P = 2.8×10 −15 ) and atrophic (OR = 1.38; CI: 1.18–1.61; P = 3.37×10 −5 ) AMD but not early AMD (OR = 0.94; CI: 0.86–1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low‐density cholesterol specifically, in AMD disease etiology. 32:1407–1416, 2011. ©2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88045/1/humu_21577_sm_SuppInfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/88045/2/21577_ftp.pd

The Vascular Microenvironment and Systemic Sclerosis

The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc) is appreciated clinically as Raynaud's syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC) including multipotential mesenchymal stem cells (MSC), pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment