Mutation analysis of BRCA1 and BRCA2 genes in Iranian high risk breast cancer families

Background: Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalization. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any association between telomerase sub-units: hTERT and hTR and the prognostic indicators including tumour's size and grade, nodal status and patient's age. Methods: Tumour samples from 46 patients with primary invasive breast cancer and 3 patients with benign tumours were collected. RT-PCR analysis was used for the detection of hTR, hTERT, and PGM1 (as a housekeeping) genes expression. Results: The expression of hTR and hTERT was found in 31(67.4%) and 38 (82.6%) samples respectively. We observed a significant association between hTR gene expression and younger age at diagnosis (p = 0.019) when comparing patients ≤ 40 years with those who are older than 40 years. None of the benign tumours expressed hTR gene. However, the expression of hTERT gene was revealed in 2 samples. No significant association between hTR and hTERT expression and tumour's grade, stage and nodal status was seen. Conclusion: The expression of hTR and hTERT seems to be independent of tumour's stage. hTR expression probably plays a greater role in mammary tumourogenesis in younger women (≤ 40 years) and this may have therapeutic implications in the context of hTR targeting strategies

Is a picture always worth a thousand words? The impact of presentation formats in consumers' early evaluations of really new products (RNPs)

Really new products (RNPs) enable consumers to do things they have never been able to do before. However, research has shown that consumers have difficulties understanding the benefits of such novel products, and therefore, adoption intentions remain low. Mental simulations and analogies have been identified as effective framing strategies to convey the benefits of RNPs. However, existing research has focused solely on the use of mental simulations and analogies conveyed using words, whereas these can also be conveyed using pictures. Although the general consumer research literature points to a superiority effect of pictures, because the underlying mechanisms that individuals use to understand RNPs differ entirely from those used for traditional products, there is a need to study the impact of pictures for RNPs. Moreover, prior work has not examined differences in RNP type. The present research argues that RNPs can be utilitarian, hedonic, or hybrid and that the optimal presentation format (words versus pictures) is contingent upon the type of RNP considered. Consequently, failure to acknowledge this distinction could lead to negative consequences. The present study aims to identify the impact of alternative presentation formats (i.e., words versus pictures) presented using different framing strategies (i.e., analogies versus mental simulations) on individual responses (i.e., product comprehension and attitude to the product) to three types of RNPs (i.e., utilitarian versus hedonic versus hybrid). Hypotheses are tested by means of an experimental study. The results of the study show that the effectiveness of alternative combinations of framing strategies and presentation formats in enhancing comprehension and attitude for RNPs depends on product type (utilitarian versus hedonic versus hybrid). The empirical findings presented not only extend prior work on consumer responses to mental simulations and analogies for RNPs, but also establish connections between this literature and an underdeveloped stream of research on hybrid products, as well as a broader stream of research on utilitarian versus hedonic product benefits. The findings suggest that practitioners may not have been using optimal marketing communications strategies to convey the benefits of RNPs. Strategies that may help enhance consumer responses to RNPs by taking into consideration product type (utilitarian versus hedonic versus hybrid) are put forward

Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.

We evaluated homologous recombination deficient (HRD) phenotypes in epithelial ovarian cancer (EOC) considering BRCA1, BRCA2, and RAD51C in a large well-annotated patient set. We evaluated EOC patients for germline deleterious mutations (n = 899), somatic mutations (n = 279) and epigenetic alterations (n = 482) in these genes using NGS and genome-wide methylation arrays. Deleterious germline mutations were identified in 32 (3.6%) patients for BRCA1, in 28 (3.1%) for BRCA2 and in 26 (2.9%) for RAD51C. Ten somatically sequenced patients had deleterious alterations, six (2.1%) in BRCA1 and four (1.4%) in BRCA2. Fifty two patients (10.8%) had methylated BRCA1 or RAD51C. HRD patients with germline or somatic alterations in any gene were more likely to be high grade serous, have an earlier diagnosis age and have ovarian and/or breast cancer family history. The HRD phenotype was most common in high grade serous EOC. Identification of EOC patients with an HRD phenotype may help tailor specific therapies.This work was supported by National Institutes of Health grants R01-CA122443, P50-CA136393, P30-CA15083, and the Fred C. and Katherine B. Andersen Foundation. We thank Gary Kenney, M.D. for pathology review of tumor tissue. We thank Craig Luccarini, Caroline Baynes from University of Cambridge for assisting our sample sequencing

A common missense variant in BRCA2 predisposes to early onset breast cancer

INTRODUCTION: Mutations in the BRCA2 gene are one of the two major causes of hereditary breast cancer. Protein-truncating mutations of BRCA2 are usually deleterious and increase the risk of breast cancer up to 80% over a lifetime. A few missense mutations in BRCA2 are believed to have a similarly high penetrance, apart from more common neutral polymorphisms. It is often difficult to classify a particular sequence variant as a mutation or a polymorphism. For a deleterious variant, one would expect a greater allele frequency in breast cancer cases than in ethnic-matched controls. In contrast, neutral polymorphic variants should be equally frequent in the two groups. METHODS: We genotyped 3,241 cases of breast cancer diagnosed at under 51 years of age, unselected for family history, from 18 hospitals throughout Poland and 2,791 ethnic-matched controls for a single BRCA2 C5972T variant. RESULTS: The variant was present in approximately 6% of the Polish population. In the study, 13 women (11 cases and two controls (OR = 4.7; p = 0.02)) were homozygous for the variant allele. The overall odds ratio for breast cancer in women with a single copy of the BRCA2 C5972T variant was 1.1 (p = 0.7); however, the effect was significant for patients diagnosed at or before age 40 (OR = 1.4; p = 0.04). We reviewed the association between the BRCA2 variant in different histologic subgroups and found the effect most pronounced in women who had ductal carcinoma in situ (DCIS) with micro-invasion (OR = 2.8; p < 0.0001). CONCLUSION: The BRCA2 C5972T allele is a common variant in Poland that increases the risk of DCIS with micro-invasion. The homozygous state is rare but increases the risk of breast cancer five-fold

Healthy Living after Cancer: A dissemination and implementation study evaluating a telephone-delivered healthy lifestyle program for cancer survivors

© 2015 Eakin et al. Background: Given evidence shows physical activity, a healthful diet and weight management can improve cancer outcomes and reduce chronic disease risk, the major cancer organisations and health authorities have endorsed related guidelines for cancer survivors. Despite these, and a growing evidence base on effective lifestyle interventions, there is limited uptake into survivorship care. Methods/Design: Healthy Living after Cancer (HLaC) is a national dissemination and implementation study that will evaluate the integration of an evidence-based lifestyle intervention for cancer survivors into an existing telephone cancer information and support service delivered by Australian state-based Cancer Councils. Eligible participants (adults having completed cancer treatment with curative intent) will receive 12 health coaching calls over 6 months from Cancer Council nurses/allied health professionals targeting national guidelines for physical activity, healthy eating and weight control. Using the RE-AIM evaluation framework, primary outcomes are service-level indicators of program reach, adoption, implementation/costs and maintenance, with secondary (effectiveness) outcomes of patient-reported anthropometric, behavioural and psychosocial variables collected at pre- and post-program completion. The total participant accrual target across four participating Cancer Councils is 900 over 3 years. Discussion: The national scope of the project and broad inclusion of cancer survivors, alongside evaluation of service-level indicators, associated costs and patient-reported outcomes, will provide the necessary practice-based evidence needed to inform future allocation of resources to support healthy living among cancer survivors. Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12615000882527(registered on 24/08/2015

Dedicated JPSS VIIRS Ocean Color Calibration/Validation Cruise

The NOAA/STAR ocean color team is focused on “end-to-end” production of high quality satellite ocean color products. In situ validation of satellite data is essential to produce the high quality, “fit for purpose” remotely sensed ocean color products that are required and expected by all NOAA line offices, as well as by external (both applied and research) users. In addition to serving the needs of its diverse users within the U.S., NOAA has an ever increasing role in supporting the international ocean color community and is actively engaged in the International Ocean-Colour Coordinating Group (IOCCG). The IOCCG, along with the Committee on Earth Observation Satellites (CEOS) Ocean Colour Radiometry Virtual Constellation (OCR-VC), is developing the International Network for Sensor Inter-comparison and Uncertainty assessment for Ocean Color Radiometry (INSITU-OCR). The INSITU-OCR has identified, amongst other issues, the crucial need for sustained in situ observations for product validation, with longterm measurement programs established and maintained beyond any individual mission. Recently, the NOAA/STAR Ocean Color Team has been making in situ validation measurements continually since the launch in fall 2011 of the Visible Infrared Imaging Radiometer Suite (VIIRS) aboard the Suomi National Polar-orbiting Partnership (SNPP) platform, part of the U.S. Joint Polar Satellite System (JPSS) program. NOAA ship time for the purpose of ocean color validation, however, had never been allocated until the cruise described herein. As the institutional lead for this cruise, NOAA/STAR invited external collaborators based on scientific objectives and existing institutional collaborations. The invited collaborators are all acknowledged professionals in the ocean color remote sensing community. Most of the cruise principal investigators (PIs) are also PIs of the VIIRS Ocean Color Calibration and Validation (Cal/Val) team, including groups from Stennis Space Center/Naval Research Laboratory (SSC/NRL) and the University of Southern Mississippi (USM); City College of New York (CCNY); University of Massachusetts Boston (UMB); University of South Florida (USF); University of Miami (U. Miami); and, the National Institute of Standards and Technology (NIST). These Cal/Val PIs participated directly, sent qualified researchers from their labs/groups, or else contributed specific instruments or equipment. Some of the cruise PIs are not part of the NOAA VIIRS Ocean Color Cal/Val team but were chosen to complement and augment the strengths of the Cal/Val team participants. Outside investigator groups included NASA Goddard Space Flight Center (NASA/GSFC), Lamont-Doherty Earth Observatory at Columbia University (LDEO), and the Joint Research Centre of the European Commission (JRC). This report documents the November 2014 cruise off the U.S. East Coast aboard the NOAA Ship Nancy Foster. This cruise was the first dedicated ocean color validation cruise to be supported by the NOAA Office of Marine and Air Operations (OMAO). A second OMAO-supported cruise aboard the Nancy Foster is being planned for late 2015. We at NOAA/STAR are looking forward to continuing dedicated ocean color validation cruises, supported by OMAO on NOAA vessels, on an annual basis in support of JPSS VIIRS on SNPP, J-1, J-2 and other forthcoming satellite ocean color missions from the U.S as well as other countries. We also look forward to working with the U.S. and the international ocean community for improving our understanding of global ocean optical, biological, and biogeochemical properties.JRC.H.1-Water Resource

Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates?

Observational epidemiological studies often include prevalent cases recruited at various times past diagnosis. This left truncation can be dealt with in non-parametric (Kaplan–Meier) and semi-parametric (Cox) time-to-event analyses, theoretically generating an unbiased hazard ratio (HR) when the proportional hazards (PH) assumption holds. However, concern remains that inclusion of prevalent cases in survival analysis results inevitably in HR bias. We used data on three well-established breast cancer prognosticators – clinical stage, histopathological grade and oestrogen receptor (ER) status – from the SEARCH study, a population-based study including 4470 invasive breast cancer cases (incident and prevalent), to evaluate empirically the effectiveness of allowing for left truncation in limiting HR bias. We found that HRs of prognostic factors changed over time and used extended Cox models incorporating time-dependent covariates. When comparing Cox models restricted to subjects ascertained within six months of diagnosis (incident cases) to models based on the full data set allowing for left truncation, we found no difference in parameter estimates (P=0.90, 0.32 and 0.95, for stage, grade and ER status respectively). Our results show that use of prevalent cases in an observational epidemiological study of breast cancer does not bias the HR in a left truncation Cox survival analysis, provided the PH assumption holds true

Genetic polymorphisms of DNA double strand break gene Ku70 and gastric cancer in Taiwan

<p>Abstract</p> <p>Background and aim</p> <p>The DNA repair gene <it>Ku70</it>, an important member of non-homologous end-joining repair system, is thought to play an important role in the repairing of DNA double strand breaks. It is known that defects in double strand break repair capacity can lead to irreversible genomic instability. However, the polymorphic variants of <it>Ku70</it>, have never been reported about their association with gastric cancer susceptibility.</p> <p>Methods</p> <p>In this hospital-based case-control study, the associations of <it>Ku70 </it>promoter T-991C (rs5751129), promoter G-57C (rs2267437), promoter A-31G (rs132770), and intron 3 (rs132774) polymorphisms with gastric cancer risk in a Taiwanese population were investigated. In total, 136 patients with gastric cancer and 560 age- and gender-matched healthy controls recruited from the China Medical Hospital in Taiwan were genotyped.</p> <p>Results</p> <p>As for <it>Ku70 </it>promoter T-991C, the ORs after adjusted by age and gender of the people carrying TC and CC genotypes were 2.41 (95% CI = 1.53-3.88) and 3.21 (95% CI = 0.96-9.41) respectively, compared to those carrying TT wild-type genotype. The <it>P </it>for trend was significant (<it>P </it>< 0.0001). In the dominant model (TC plus CC versus TT), the association between <it>Ku70 </it>promoter T-991C polymorphism and the risk for gastric cancer was also significant (adjusted OR = 2.48, 95% CI = 1.74-3.92). When stratified by age and gender, the association was restricted to those at the age of 55 or elder of age (TC vs TT: adjusted OR = 2.52, 95% CI = 1.37-4.68, <it>P </it>= 0.0139) and male (TC vs TT: adjusted OR = 2.58, 95% CI = 1.33-4.47, <it>P </it>= 0.0085). As for the other three polymorphisms, there was no difference between both groups in the distributions of their genotype frequencies.</p> <p>Conclusion</p> <p>In conclusion, the <it>Ku70 </it>promoter T-991C (rs5751129), but not the <it>Ku70 </it>promoter C-57G (rs2267437), promoter A-31G (rs132770) or intron 3 (rs132774), is associated with gastric cancer susceptibility. This polymorphism may be a novel useful marker for gastric carcinogenesis.</p

Functional capacity of XRCC1 protein variants identified in DNA repair-deficient Chinese hamster ovary cell lines and the human population

XRCC1 operates as a scaffold protein in base excision repair, a pathway that copes with base and sugar damage in DNA. Studies using recombinant XRCC1 proteins revealed that: a C389Y substitution, responsible for the repair defects of the EM-C11 CHO cell line, caused protein instability; a V86R mutation abolished the interaction with POLβ, but did not disrupt the interactions with PARP-1, LIG3α and PCNA; and an E98K substitution, identified in EM-C12, reduced protein integrity, marginally destabilized the POLβ interaction, and slightly enhanced DNA binding. Two rare (P161L and Y576S) and two frequent (R194W and R399Q) amino acid population variants had little or no effect on XRCC1 protein stability or the interactions with POLβ, PARP-1, LIG3α, PCNA or DNA. One common population variant (R280H) had no pronounced effect on the interactions with POLβ, PARP-1, LIG3α and PCNA, but did reduce DNA-binding ability. When expressed in HeLa cells, the XRCC1 variants—excluding E98K, which was largely nucleolar, and C389Y, which exhibited reduced expression—exhibited normal nuclear distribution. Most of the protein variants, including the V86R POLβ-interaction mutant, displayed normal relocalization kinetics to/from sites of laser-induced DNA damage: except for E98K and C389Y, and the polymorphic variant R280H, which exhibited a slightly shorter retention time at DNA breaks