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Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
For the understanding of the variable, transient and non-thermal universe, unbiased long-term monitoring is crucial. To constrain the emission mechanisms at the highest energies, it is important to characterize the very high energy emission and its correlation with observations at other wavelengths. At very high energies, only a limited number of instruments is available. This article reviews the current status of monitoring of the extra-galactic sky at TeV energies.
Background: Intestinal infections remain a major public health burden in developing countries. Due to social, ecological, environmental, and cultural conditions, Indigenous peoples in Colombia are at particularly high risk. Materials: 137 stool samples were analyzed by microscopy and real-time-Polymerase Chain Reaction (RT-PCR), targeting protozoan parasites (Giardia intestinalis, Entamoeba histolytica, Cryptosporidium spp., and Cyclospora cayetanensis), bacteria (Campylobacter jejuni, Salmonella spp., Shigella ssp./enteroinvasive E. coli (EIEC), Yersinia spp., enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), enterotoxin-producing E. coli (ETEC), enteroaggregative E. coli (EAEC), and Tropheryma whipplei), and helminths (Necator americanus, Strongyloides stercoralis, Ascaris lumbricoides, Ancylostoma spp., Trichuris. trichiura, Taenia spp., Hymenolepis nana, Enterobius vermicularis, and Schistosoma spp.). Microscopy found additional cases of helminth infections. Results: At least one pathogen was detected in 93% of the samples. The overall results revealed protozoa in 79%, helminths in 69%, and bacteria in 41%. G. intestinalis (48%), Necator/hookworm (27%), and EAEC (68%) were the most common in each group. Noteworthy, T. whipplei was positive in 7% and T. trichirua in 23% of the samples. A significant association of one infection promoting the other was determined for G. intestinalis and C. jejuni, helminth infections, and EIEC. Conclusions: The results illustrate the high burden of gastrointestinal pathogens among Indigenous peoples compared to other developing countries. Countermeasures are urgently required.
Knowledge about ransomware is important for protecting sensitive data and for participating in public debates about suitable regulation regarding its security. However, as of now, this topic has received little to no attention in most school curricula. As such, it is desirable to analyze what citizens can learn about this topic outside of formal education, e.g., from news articles. This analysis is both relevant to analyzing the public discourse about ransomware, as well as to identify what aspects of this topic should be included in the limited time available for this topic in formal education. Thus, this paper was motivated both by educational and media research. The central goal is to explore how the media reports on this topic and, additionally, to identify potential misconceptions that could stem from this reporting. To do so, we conducted an exploratory case study into the reporting of 109 media articles regarding a high-impact ransomware event: the shutdown of the Colonial Pipeline (located in the east of the USA). We analyzed how the articles introduced central terminology, what details were provided, what details were not, and what (mis-)conceptions readers might receive from them. Our results show that an introduction of the terminology and technical concepts of security is insufficient for a complete understanding of the incident. Most importantly, the articles may lead to four misconceptions about ransomware that are likely to lead to misleading conclusions about the responsibility for the incident and possible political and technical options to prevent such attacks in the future.