Relation between smoking history and gene expression profiles in lung adenocarcinomas

Background: Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers' lung carcinomas remain to a large extent unclear. Methods: Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets. Results: Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking. Conclusions: Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history

Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function

Objective: Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function. Methods: A genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography. Results: We identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals. Conclusions: Our study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.publishedVersio

Experimental and numerical evaluation of heat transfer in the press hardening process

In recent decades, the use of high- and ultra high strength steels in modern car bodies has increased drastically. This is due to both severe legislation of passenger passive safety and the recent year's effort to reduce fuel consumption to decrease environmental harmful emissions. Many new materials and technologies have been developed to meet these new demands, where press hardening, or also called hot stamping, has been one of the most successful technologies to produce complex components with superior mechanical properties. In the product development process, thermo-mechanical coupled forming simulations are used to predict the final components properties. In order to obtain accurate results, correct models of the physics involved in the simultaneous forming and quenching is needed. The objective of current work is to investigate the heat transfer between the hot blank and the cold tools in the press hardening process. The transfer of heat is the key process that affects the products formability, final geometry, residual stresses and the development of mechanical properties. The two most important contact criteria are investigated in this thesis, heat transfer at a thin contact gap and heat transfer at mechanical contact under an applied contact pressure. An experimental setup to investigate these two contact criteria is developed. It consists of an upper and lower cylindrically shaped tool were the hot blank is quenched between cold tool surfaces. The results from experiments consist of measured temperature histories in the tools. A finite element model of the experiments in combination with an inverse simulation algorithm is used to predict the heat transfer at each contact condition. The inverse technique called improved advance retreat and golden section method is used to solve the ill conditioned inverse heat conduction problem that arise when solving for the heat transfer at the contact interface. The result from inverse simulations in combination with regression analysis is used to develop a general model of the heat transfer coefficient. The outcome is two regression models, one for each contact criterion, were the parameters affecting the heat transfer coefficient are identified. It is found, that a heat transfer coefficient depending on contact pressure or contact gap as well as contacting surface temperatures provide a good match between experimental and simulated temperature response in the tools. The regression model captures the main characteristics of the heat transfer coefficient and has been implemented as a subroutine in the finite element code LS-DYNA.Godkänd; 2009; 20091108 (persal); LICENTIATSEMINARIUM Ämnesområde: Hållfasthetslära/Solid Mechanics Examinator: Professor Mats Oldenburg, Luleå tekniska universitet Tid: Fredag den 11 december 2009 kl 10.00 Plats: E 243, Luleå tekniska universitet</p

Skapande av Interface-Controllers med hjälp av Model Driven Architecture

In this thesis we will examine a telecom industry case, where combining synchronous and asynchronous interfaces causes problems. A solution to the problem is being presented in form of an interface controller framework that is based on patterns of common functionality of interface controllers. The solution is implemented using four different implementation methods (Java, Erlang, XDE, Executable UML), and compared in lines of code, performance and throughput.I rapporten undersöks ett fall i telekominudstrin, där kombinerandet av synkrona och asynkrona interface orsakar problem. En lösning på problemet är presenterat i form av ett framework för interface controllers som är baserat på mönster som beskriver den gemensamma funktionaliten i interface controllers. Lösningen är implementerad med hjälp av fyra olika implementeringsmetoder (Java, Erlang, XDE och Executable UML), där rader kod och prestanda jämfö[email protected] [email protected]

Investigation of heat transfer in the press hardening process

The use of thin ultra high strength steel automotive passive safety components manufactured with the press hardening process has increased drastically the last two decades. The application and complexity in design has increased and thermo mechanical forming simulation is an important tool to optimize the final component properties early in the product development process. The transfer of heat is a key process that affects formability and the evolution of the mechanical properties in the product. Therefore it is essential that the thermal contact conditions between the blank and tool are properly described in the forming simulation code. In this study, an experimental setup and inverse simulation approach is used to predict the interfacial heat transfer coefficient (IHTC) in the press hardening process. Different process conditions such as contact pressure, air gaps in the contact and blank material (22MnB5 and Usibor 1500P) are investigated. In the inverse simulation approach, the improved-advance-retreat and golden section method is used to solve the ill-posed inverse heat conduction problem (IHCP). In the finite element analysis, a thermo-mechanical coupled simulation model is used including effects from changes in the microstructure during quenching. The results from simulations give the variations of the heat transfer coefficient in time for best match to experimental results. It is found that the heat transfer coefficient is dependent of the contact pressure and air gap and varies in time. The variation in time is assumed to be the temperature dependence. When heat transfer is under mechanical contact, the variation of the heat transfer coefficient is higher for higher contact pressures compared to lower. If there is heat transfer over a thin gap of air, the heat transfer coefficient also varies but tend to be close to constant for bigger air gaps. The present work will be used as a base in a future model of the heat transfer coefficient influence at different contact conditions in press hardening process.Godkänd; 2009; 20090622 (ysko

Sportmarknadsföring : En studie av SM-finalen i innebandy och AIK innebandy

Intresset för det undersökta fenomenet, uppmärksammades av en slump då vi tog del av publiksiffran från förra årets SM-final i innebandy. För oss med en uppväxt på ishockeyrinken tyckte vi det var helt otroligt att SM-finalen fyllde hela globen. Ishockeyn hade inte ens fyllt Globen på 4 år, hur kunde en ung sport som innebandy klara detta? Dessutom var det intressant att publikkontrasten mellan en seriematch och SM-finalen för innebandy var hela 14 gånger större. Ur detta skapades vår problemformulering; På vilket sätt skiljer sig marknadsföringen mellan SM-finalmatchen i innebandy och en seriematch i innebandy och vilka likheter kan urskiljas? Syftet var att beskriva vad AIK innebandy och arrangörerna för SM-finalen i innebandy gör för att locka publik till sina seriespelsmatcher respektive sitt finalevenemang. Samtidigt som eventuella likheter respektive skillnader mellan de två aktörernas marknadsföring belyses. För att göra fenomenet forskningsbart valdes att endast titta på AIK innebandy och deras marknadsföring. Vi valde att göra två intervjuer samt en fältstudie för att få svar på vårt problem. Vi valde att intervjua Erik Nilsson och Roland Pettersson som är ansvariga för SMfinalen samt Lars Ekholmer, marknadsansvarig för AIK innebandy. Fältstudien genomfördes under SM-finalmatchen, där cirka 400 respondenter fick svara på frågan; Hur fick du först reda på att SM-finalen ägde rum? De resultat som framgick ur undersökningen var att många avseenden i SM-finalens och AIK’s marknadsföring var densamma, dock var det ett fåtal skillnader. SM-finalens allmänna kännedom fungerar som en snöboll i rullning och lockar en stor del av publiken av sig själv. Genom vår fältstudie framgick det att endast 37% hade fått reda på att SM-finalen ägde rum via någon mediekanal. Det framgick även ur intervjuerna att AIK och SM-finalen använde sig av traditionell marknadsföring i form av de 5 P:na. Dessutom har de två aktörerna som mål att erbjuda publiken en upplevelse. SM-finalen vill även förmedla ett budskap om att innebandyn står för begrepp som; fart, fläkt och ungdomlighet. Både arrangörerna för SM-finalen och Lars Ekholmer ser gärna att innebandyn i framtiden växer som sport och får ett större erkännande hos det svenska folket

Skapande av Interface-Controllers med hjälp av Model Driven Architecture

In this thesis we will examine a telecom industry case, where combining synchronous and asynchronous interfaces causes problems. A solution to the problem is being presented in form of an interface controller framework that is based on patterns of common functionality of interface controllers. The solution is implemented using four different implementation methods (Java, Erlang, XDE, Executable UML), and compared in lines of code, performance and throughput.I rapporten undersöks ett fall i telekominudstrin, där kombinerandet av synkrona och asynkrona interface orsakar problem. En lösning på problemet är presenterat i form av ett framework för interface controllers som är baserat på mönster som beskriver den gemensamma funktionaliten i interface controllers. Lösningen är implementerad med hjälp av fyra olika implementeringsmetoder (Java, Erlang, XDE och Executable UML), där rader kod och prestanda jämfö[email protected] [email protected]