An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Common breast cancer susceptibility alleles are associated with tumor subtypes in BRCA1 and BRCA2 mutation carriers : results from the Consortium of Investigators of Modifiers of BRCA1/2.

Abstract Introduction Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. Methods We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. Results The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. Conclusions The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers

Tillsyn av fartyg i syfte att förhindra oljeutsläpp från fartyg

Varje år bedöms närmare tusen illegala oljeutsläpp ske då fartygen rengör tankar och maskiner rätt ner i Östersjön. Under flera årtionden har försök gjorts att få bukt med oljeutsläppen utan alltför stora positiva resultat. Oljetransporterna från Ryssland och andra baltiska stater har under de senaste åren ökat markant, vilket också medför större risker för olyckor. Höga krav ställs både på den objektiva och subjektiva sidan vilket leder till att utredningen måste läggas ned med motivering att brott ej kunnat styrkas. Under senare år har resurserna i stället inriktats på att genom förebyggande åtgärder komma tillrätta med oljeutsläppen i Östersjön. Uppsatsen behandlar den tillsyn som görs av fartyg men tittar också närmare på förebyggande lagstiftning såsom regler vad gäller fartygets konstruktion och utrustning samt regler för ilandlämning av oljeavfall. Allmänt om tillsyns effektivitet beskrivs och en inblick görs av hur de förebyggande reglerna efterlevs. Uppsatsen försöker dessutom svara på frågan om lagstiftaren lyckats med sina intentioner, att komma tillrätta med en undermålig sjöfart och förhindra fartygs oljeutsläpp till sjöss. En genomgång av både den internationella och den svenska lagstiftningen på området är nödvändigt för att kunna belysa problemen med oljeutsläpp från fartyg. Den omfattande rätten inom sjöfartsnäringen har dock gjort att långt ifrån alla regler på området har kunnat tas med. Tillsynen av fartyg har varit nödvändig för att öka efterlevnaden av reglerna inom sjöfarten. Den inspektionsverksamhet som utövas av Sjöfartsinspektionen skall se till att kraven på fartygs säkerhet och skydd mot förorening från fartyg, samt kraven på rederiers och fartygs säkerhetsorganisation uppfylls. Få undersökningar har gjorts beträffande tillsynens effektivitet på miljöområdet. Intervju med Sjöfartsinspektionen och rapporter från Sjöfartsverket har varit till stor hjälp för att kunna bedöma hur effektiv tillsynen av fartyg är

Including Student Case Projects in Integrated Product and Production Development Research – Methodology Description and Discussion

Within integrated product and production development research, casestudies needto be performed for data gathering purposes. Today, there are two commonly used ways to perform this research; observingindustry projects orhaving the researchers perform the projects themselves. The first option can pose data access and IPRissues, and the second optioncomes with biasing risks. Another approach is to work with studentcaseprojects, givingstudents interesting projects and findinga solution to mediate both data gathering opportunity and biasing risks. This approach has been tested at Linköping University, with students performing projects in the Vinnovafunded Production 2030 –Large Scale Production in Mixed Materials project. Two larger student case projects have been performed on the topic of material substitution and mixed material solutions within the automotive industry.In this paper, the method used to include student projects is presented along with identified benefits and drawbacks. Including student case projects in research have shown to be beneficial in research on processes, projects and methodology, but needs to be complemented by data fromindustry projects and the researcher ́s own work within integrated product and production development in order to create a more reliable analysis with high level of detail.Fulltexten i denna post har endast gjorts tillgänglig via DiVA.The full text of this entry has only been made available via DiVA.</p

An outlook on multi material body solutions in the automotive industry – possibilities and manufacturing challenges

In the automotive industry, mass reduction and lightweight design is a continuing trend that does not show signs of declining. When looking at where to reduce weight in a vehicle, the body is a preferential subsystem due to its large contribution to overall mass and the stability of body composition over a specific model range. The automotive industry of today moves toward a greater differentiation in materials that compose a car, which can be seen in the several different multi material vehicle bodies that have been introduced by manufacturers in recent years. But while mixing materials may contribute to a good compromise between weight reduction and vehicle cost, it also proposes a number of challenges that need to be addressed. Among other material factors, the different coefficients of thermal expansions might introduce new stresses during painting and curing. Joining processes and possible chemical reactions between materials also needs to be taken into account, the same with the question of whether to integrate or differentiate different functions in a system. If the manufacturing plant uses mixed model assembly lines, design of end effectors for gripping multiple different materials is another challenge not previously encountered in this context. In this paper, a number of production and manufacturing related challenges are discussed, and the authors highlight different areas where the requirements of design engineering tools needs to be evaluated for these new multi material concepts and design decisions in order for automotive manufacturers to ensure future market competitiveness.Produktion2030 - Storskalig tillverkning av produkter i flera materia

On Material Substitution in Automotive BIWs – From Steel to Aluminum Body Sides

Weight reduction and material substitution are increasing trends in the automotive industry. In this project, the task of substituting the steel body side in the monocoque of a large SUV towards an aluminum body side was investigated through a design engineering approach adopting a breadth-first analysis method. One conclusion based on the analysis is that the choice of joining technology would become arbitrary due to the breadth-first approach. In this paper, the authors present their findings from the aforementioned case, including the challenges with switching between materials with fundamentally different properties when performing material substitution projects. The possibility of having taken a depth-first analysis approach, and the possible effects on the project result, is discussed.Produktion 2030 - Storskalig tillverkning av produkter i flera materia

Integrated Product and Production Research on Introducing Internet of Things in Swedish Wood Industry Products

To enable transitioning the Swedish economy into a bioeconomy, Swedish wood industry need to increase added value and introduce new products to market by introducing new technology and improving the product and production development processes. Research in automotive industry have shown the need for integrating product and production development when introducing new technology in existing production systems, and have indicated a possibility of using specifically designed student case projects in order to generate qualitative data. In this paper, one student case project on product and production development in the Swedish wood industry, involving IoT wood products, is presented and evaluated

Product development in the Swedish Automotive industry: Can design tools be viewed as decision support systems?

Design engineers working in the automotive industry have to take many design decisions, based on numerous diverse criteria. This results in a high workload of complex decisions. One way to reduce decision complexity and improve decisions could be to improve design tools. Decision support systems (DSSs) have been used in a managerial context to improve decisions. In this article, the authors assess whether design tools generally can be viewed as DSSs. A combination of literature review, surveys and qualitative interviews with seven design engineers was used to assess whether current design tools function as decision supports in product development. Although the specific design context needs to be considered, this study’s results suggest that design tools can generally function as DSSs. In future work, the adaptability to different problem solving patterns needs further in-depth research in the form of individual studies for specific tools in specific contexts.Production 2030 - Large Scale Manufacturing in Mixed Material

Towards Applying The Boothroyd, Dewhurst and Knight Methodology for Cost Estimation on Fibre Composite Manufacturing - A Theoretical Approach

Increased usage of carbon fibre composite poses challenges for the automotive industry; one is to manage carbon fibre composites within the product development process. This paper combines knowledge in design engineering, material science and production technology, aiming to bridge these domains. The study indicates that mass production methods suitable for carbon fibre have several factors in common with traditional polymer production methods. Thus, it is possible that DfMA methods for traditional polymer production can be adjusted for carbon fibre composite production. The result is summarised in a table aiming to facilitate engineering decisions related to cost estimations for composite moulding