Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.Red Tematica de Investigacion Cooperative en Cancer RD06/0020/1054 Danish Cancer Society "Europe Against Cancer": European Prospective Investigation into Cancer and Nutrition (EPIC) deCODE Genetics/AMGE

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility

New basal cell carcinoma susceptibility loci.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.NCI\SAIC-Frederick, Inc. (SAIC-F) 10XS170 Roswell Park Cancer Institute 10XS171 Science Care Inc. X10S172 Laboratory, Data Analysis and Coordinating Center (LDACC) HHSN268201000029C SAIC-F 10ST1035 HHSN261200800001E Brain Bank DA006227 DA033684 N01MH000028 University of Geneva MH090941 MH101814 University of Chicago MH090951 MH090937 MH101820 MH101825 University of North Carolina-Chapel Hill MH090936 MH101819 Harvard University MH090948 Stanford University MH101782 Washington University St Louis MH101810 University of Pennsylvania MH10182

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10−17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10−20). rs78378222 is in the 3′ untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3′-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10−6), glioma (OR = 2.35, P = 1.0 × 10−5) and colorectal adenoma (OR = 1.39, P = 1.6 × 10−4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88–1.27)

Active truck seat for improved driverergonomics and health

The project concerns a predevelopment work for Scania AB, a leading manufacturer of heavytrucks, and was performed as a master thesis work for the program Design and ProductDevelopment at KTH. The purpose of this work was to examine how the work situation of truckdrivers, especially long-haulage drivers, can be improved with respect to prolonged sedentaryoccupation. Mental fatigue and under-stimulation due to low cognitive load during long drivescan be major risk factors for traffic accidents. Physical strain injuries to both the skeleton andmuscles are common for this working group and minimal opportunity for daily exercise alsoincreases the risk of developing blood clots in the legs, which can have serious consequences forthe driver's health.An extensive background study, both theoretical and exploratory, was performed to identify thedrivers' concerns and comfort needs. Various treatments such as massage and active sitting wereinvestigated and existing products within the area studied. The background study resulted in adefinition of the product that would be developed: an active seat that stimulates the muscles andspine during driving.From early on it was observed that the product development work would need to focus oncreating functional models to test various concepts. Theoretical analyses were not an option asthe underlying theory considers physical effects that could not be simulated. A matrix withheight-adjustable cells that change the seat contour in different patterns, and thus physicallyaffect the body, was defined. A pneumatic system with air bags that are filled and emptied indifferent ways proved to be the most applicable technology, both for constructing a model andfor future implementation in the truck. The model was developed from being manuallycontrolled to computer-controlled. Iterative testing was performed during the development andongoing changes of the airbag placement in the chair as well as the movement patterns weremade. A final concept was developed which was assessed by quantitative user tests in a test hall,with positive results. This consists of two airbag systems, one in the backrest and one in the seatpart, having five different movements that influence the body in different ways.As the developed concept was limited to only functional models, further development and testingare required for a fully developed and implementable system. The positive results of the usertests indicate that the concept is a good start to a further development work and the drivers'responses show that there is a market for the product.Projektet avser ett förutvecklingsarbete för Scania AB, en ledande tillverkare av tunga lastbilar,och utfördes som ett examensarbete för civilingenjörsutbildningen Design ochproduktframtagning vid KTH. Syftet med arbetet var att undersöka hur arbetssituationen förlastbilsförare, i synnerhet fjärrtransportförare, kan förbättras med avseende på långvarigtstillasittande. Mental trötthet och understimulering på grund av låg kognitiv belastning underlånga körningar kan utgöra stora riskfaktorer för olyckor i trafiken. Fysiska belastningsskador påbåde skelett och muskler är vanligt förekommande inom arbetsgruppen och minimerad möjlighettill vardagsmotion ökar även risken för uppkomst av blodproppar i benen som kan få allvarligakonsekvenser för förarens hälsa.En omfattande bakgrundsstudie, både teoretisk och undersökande, genomfördes för att kartläggaförares problemområden och komfortbehov. Olika behandlingsmetoder som massage och aktivtsittande undersöktes och befintliga produkter inom området studerades. Bakgrundsstudienresulterade i en definition av produkten som skulle tas fram: en aktiv förarstol som stimulerarmuskler och ryggrad under arbetstid i lastbilen.Från ett tidigt skede visade det sig att produktutvecklingsarbetet skulle behöva fokusera påskapande av funktionsmodeller för att testa olika koncept. Teoretiska analyser var inte aktuelladå bakomliggande teori behandlar fysisk påverkan som inte kunde simuleras. En matris med höjochsänkbara celler som förändrar stolens konturer i olika mönster, och därmed påverkarkroppen fysiskt, definierades. Pneumatiskt system med luftkuddar som fylls och töms på olikasätt visades vara den mest applicerbara tekniken, både för byggande av modell samt för framtidaimplementering i lastbil. Modellen utvecklades från manuell till datorstyrd och iterativa testeroch förändringar av luftkuddarnas placering i stolen samt rörelsernas mönster gjordes löpande.Ett slutkoncept togs fram vilket utvärderades med kvantitativa användartester i testhall, medpositiva resultat. Detta består av två blåssystem, ett i ryggstödet och ett i sätesdelen, med femolika rörelser som påverkar kroppen på olika sätt.Då det framtagna konceptet avgränsades till endast fungerande modeller krävs vidare utvecklingoch testning för ett fullt utvecklat och implementerbart system. Det positiva resultatet avanvändartesterna visar att konceptet är en bra start till ett fortsatt utvecklingsarbete och förarnasmottagande visar att det inte bara finns en marknad utan även intresse för produkten

Discharge door

Det finns ett stort sortiment av mjukglassmaskiner på marknaden idag och för att uppfylla de högt ställda hygienkraven kräver dessa såväl noggrann som ofta återkommande rengöring. I dagsläget är rengöringen en tidskrävande och komplicerad process, särskilt vad det gäller glassens slutstation i maskinen, den så kallade öppningsdörren. Med den bakgrunden utfördes detta kandidatarbete i samarbete med det kinesiska företaget Ocean Power med syftet att vidareutveckla öppningsdörren till deras mjukglassmaskiner. Huvudsaklig fokus har legat på att förenkla hanteringen vid daglig rengöring samt vid montering och demontering. Genom en analys av Ocean Powers öppningsdörr, som fanns tillgänglig under arbetets gång, identifierades en rad problem som uppstår vid normal användning. En undersökning av monteringsförloppet för öppningsdörren gav dels att själva monteringsprincipen, ett skruvförband, är svårhanterlig och dels att tätningen på öppningsdörrens baksida är bristfällig. Detta åtgärdades genom att modifiera både spår och packningar för optimala tätningsegenskaper mellan öppningsdörr och maskin samt genom att utforma en helt ny fästanordning. Denna består av två handtag som monteras på öppningsdörrens kortsidor och använder excentrar för att låsa fast dörren mot glassmaskinens yttre. En FEM-analys utfördes på utsatta delar i den nya konstruktionen för undersökning av hållfasthet vid tryck inifrån maskinen. Samtliga komponenter anses uppfylla uppsatta krav. Fortsatt undersökning av öppningsdörrens funktioner visade fler tätningsproblem då både placering och spår för kolvarnas packningar är felaktiga. Detta löstes genom att avlägsna en packning från varje kolv och omforma spåren enligt standard för dynamiska tätningar. Vid närmare undersökning uppmärksammades flera ergonomirelaterade problem, däribland utmatningshandtagens vinkel samt spritsarnas fästanordning. Handtagen omformades för att optimera handhavandet och spritsarnas fästen ersattes helt. Samtliga komponenter i den nya öppningsdörren tillverkas med samma metoder som för den ursprungliga dörren. Sammanfattningsvis reducerades antalet komponenter i konstruktionen och därmed monterings och demonteringssteg vid rengöringsprocessen. Även öppningsdörrens funktion förbättrades med optimerade tätningsegenskaper och ergonomi.There is a wide selection of soft serve ice-cream machines on the market today and in order to comply with the high hygiene standards these require thorough and frequent cleaning. In the present situation the cleaning process is both time-consuming and complicated, especially concerning the product’s final destination in the machine, the so called discharge door. That is the background of this project, which was carried out in cooperation with the Chinese company Ocean Power with the objective to improve the discharge door of their ice cream machines. The principal focus was on simplifying the process of cleaning as well as assembling and disassembling the door. By analyzing a copy of Ocean Power’s discharge door, which was available during the project, a series of problems that occur during normal use of the door was identified. A study of the assembly process revealed firstly that the assembling method itself, a screw joint, is difficult to handle and secondly that the sealing on the backside of the door is inadequate. These faults were corrected by modifying both gaskets and glands to optimize the sealing properties between doorand machine and by designing a new fastening mechanism. The new fixture consists of two levers mounted on the short sides of the door using excenters to attach the door against the outside of the machine. A finite element analysis was performed on exposed parts of the new construction to investigate the material strength against inside pressure from the machine. All the components are assumed to fulfill required specifications. A continued investigation of the discharge door showed more sealing problems as both the position and shaping of the piston seals were faulty. These problems were solved by removing one O-ring from each piston and by reshaping the glands according to standards for dynamic seals. Further inspection indicated a number of ergonomic-related problems, including the angle of the discharge handles and the fastener of the discharge spouts. The handles were reshaped to optimize the handling and the fasteners replaced completely. All components in the new discharge door are manufactured by using the same methods that are used for the original door. In conclusion, the number of components in the construction was reduced and consequently the number of steps in assembling and disassembling during the cleaning process. Also, the function of the discharge door was improved with optimal sealing properties and ergonomics

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadCutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI) United States Department of Health & Human Services National Institutes of Health (NIH) - USA Walther Cancer Foundation Damon Runyon Cancer Research Foundation Erasmus Medical Center and Erasmus University Rotterdam Netherlands Organization for Health Research and Development Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Ministry for Health, Welfare and Sports European Commission Joint Research Centre Municipality of Rotterda

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

To access publisher's full text version of this article click on the hyperlink belowMost pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.deCODE genetics/Amgen American Cancer Society National Institutes of Health National Cancer Institut

Two newly identified genetic determinants of pigmentation in Europeans.

Contains fulltext : 70561.pdf (publisher's version ) (Closed access)We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R