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This thesis work a looks into business-to-business (B2B) supplier’s product development processes through the concept of product-service systems with the aim to discover the most essential elements in the case company’s product process contributing to product-service system creation. Conducted literature review opens the current development of product-service system theory The case company internal study was carried out by nine semi-structured expert interviews. The interviewees were from different organizational levels, ranging from innovation specialists to the head of product management and development. The interview data were then analyzed using qualitative data analysis methods. Data analysis resulted in six categories and three sub categories, all which have specific traits and inputs for PSS development. The findings from the interview data was supported by a workshop were selected topics were discussed and ideated further. Outcomes of the interviews and the supportive workshop were utilized in a case study in case company The case study adopted one proposed PSS methodology and made use of recommended tools. The design outcomes went through an initial evaluation by expert user. The main contribution of this thesis work is firstly to shed light on the most essential elements of a B2B supplier’s product-service system development. Secondly it presents an approach on how to evaluate a B2B suppliers product process on systematic manner in connection to PSS theory and thirdly provides an example of adopting a PSS methodology through a case study.Tämä lopputyö tutkii B2B toimittajan tuotekehitysprosesseja tuotepalvelujärjestelmä -käsitteen (PSS) näkökulmasta. Pyrkimyksenä on selvittää tuotekehitysprosessin olennaisimmat tekijät, jotka myötävaikuttavat tuote-palvelujärjestelmien luomiseen. Tehty kirjallisuuskatsaus avaa tuotepalvelujärjestelmien teorioiden kehitystä. Yrityksen sisäinen tutkimus toteutettiin yhdeksällä puolistrukturoidulla asiantuntijahaastattelulla. Haastateltavien taustat kattoivat eri organisaatiotasot innovaatioasiantuntijasta tuote-ja palvelukehityksen johtajaan. Haastatteluista kertynyt materiaali analysoitiin laadullisen tutkimuksen menetelmin. Työ esittää analyysin lopputuloksena kuusi kategoriaa ja kolme alakategoriaa, joista jokaisella on omat ominaispiirteensä ja myötävaikutuksensa tuotepalvelujärjestelmien kehitykseen. Haastattelulöydöksiä tuettiin työpajalla, jossa kategorioista koostettuja aiheita käsiteltiin ja edelleen kehitettiin. Haastattelujen ja työpajan lopputuloksia käytetään hyväksi yrityksen sisäisessä tapaustutkimuksessa. Tapaustutkimus omaksuu yhden tuotepalvelujärjestelmien kehitykseen esitetyn metodologian ja hyödyntää sen esittämiä työkaluja. Alustava arviointi lopputuloksesta suoritettiin asiantuntijakäyttäjän avulla. Lopputyön keskeisin tulos valottaa olennaisimpia tekijöitä, jotka vaikuttavat B2B toimittajan tuotepalvelujärjestelmien kehitykseen. Toiseksi lopputyö esittää, kuinka B2B toimittajan tuoteprosesseja pystytään arvioimaan systemaattisin keinoin tuotepalvelujärjestelmiin liittyen ja lopulta lopputyö antaa esimerkin, kuinka valittu tuotepalvelujärjestelmien kehitykseen esitetty metodologia voidaan ottaa käyttöön.
Tämä opinnäytetyö on vertaileva tapaustutkimus, joka analysoi kansainvälisen tilinpäätöskäytännön harmonisointia pörssiyhtiöiden osalta Suomessa ja Britanniassa IFRS-standardien vaikutuksesta. Tutkimuksen päämääränä on selvittää, onko maiden tilinpäätöskäytännöissä edelleen eroavaisuuksia siitä huolimatta, että Euroopan Unionissa on siirrytty IFRS-raportointiin pörssiyhtiöiden osalta. Tutkimus rajoittuu valittuihin IFRS-standardeihin. Tämä opinnäytetyö on toteutettu hankkeistettuna projektina tilintarkastusyritykselle. Kolmen yrityksen vuosiraportteja molemmista maista vertaillaan tutkittaessa, onko raportoinnissa edelleen eroavaisuuksia. Tutkielma keskittyy tutkimaan mahdollisia eroavaisuuksia varallisuustyyppien arvostuksessa sekä raportoinnin avoimmuudessa tutkimalla valittuja laskentaperiaatteita. Kyseisillä alueilla odotetaan ilmenevän eroavaisuuksia kirjallisuuden sekä aiempien tutkimusten perusteella. Kansainvälistä tilinpäätöskäytäntöä sekä historiallisia syitä kansallisten tilinpäätöskäytäntöjen eroavaisuuksiin käsitellään. Kirjallisuuden perusteella Britannian tilinpäätöskäytäntö on optimistisempaa ja läpinäkyvämpää kuin Manner-Euroopassa. Manner-Euroopassa laskenta on ollut varovaisempaa ja salailevampaa erilaisista omistusrakenteista johtuen. Tutkimus analysoi ja vertailee kvalitatiivisesti laskentaperiaatteita ja sitä, miten niistä on raportoitu. Eroavaisuudet laskentaperiaatteissa arvostuksen ja avoimuuden suhteen havainnollistetaan sijoittamalla vertailuyritykset Grayn (1988) kehittämään laskentakäytäntöjen vertailumalliin. Suomalaiset vertailuyritykset ovat Nokia, Cargotec sekä Huhtamäki. Britanniasta vertailuyrityksiksi on valittu Vodafone, Tomkins sekä Rexam. Kirjallisuudessa esitettyjen väitteiden vastaisesti, tutkimuksen löydösten perusteella optimismi ei ole tärkeä tekijä Britannian tilinpäätöskäytännössä. Tutkittujen varallisuustyyppien osalta arvostusperiaatteissa ei ollut eroavaisuuksia suomalaisten ja brittiläisten yritysten välillä. Toisaalta, tutkimustulosten valossa brittiläisten yritysten raportointi on avoimempaa kuin suomalaisten.
Abstract We propose an effective machine learning approach to identify group of interacting single nucleotide polymorphisms (SNPs), which contribute most to the breast cancer (BC) risk by assuming dependencies among BCAC iCOGS SNPs. We adopt a gradient tree boosting method followed by an adaptive iterative SNP search to capture complex non-linear SNP-SNP interactions and consequently, obtain group of interacting SNPs with high BC risk-predictive potential. We also propose a support vector machine formed by the identified SNPs to classify BC cases and controls. Our approach achieves mean average precision (mAP) of 72.66, 67.24 and 69.25 in discriminating BC cases and controls in KBCP, OBCS and merged KBCP-OBCS sample sets, respectively. These results are better than the mAP of 70.08, 63.61 and 66.41 obtained by using a polygenic risk score model derived from 51 known BC-associated SNPs, respectively, in KBCP, OBCS and merged KBCP-OBCS sample sets. BC subtype analysis further reveals that the 200 identified KBCP SNPs from the proposed method performs favorably in classifying estrogen receptor positive (ER+) and negative (ER−) BC cases both in KBCP and OBCS data. Further, a biological analysis of the identified SNPs reveals genes related to important BC-related mechanisms, estrogen metabolism and apoptosis.
Abstract Several known breast cancer susceptibility genes with moderate‐to‐high risk alleles encode proteins involved in DNA damage response (DDR). As these explain less than half of the hereditary breast cancer cases, additional predisposing alleles are likely to be discovered. Many of the previous studies utilizing massive parallel sequencing have focused on the protein‐truncating variants, and the role of rare missense mutations has remained poorly addressed. To identify novel susceptibility factors, we have systematically analyzed the data from our parallel sequencing of 796 DDR genes in 189 Northern Finnish hereditary breast cancer patients for rare missense variants, predicted as deleterious. Thirty‐five variants were studied here for the disease association using Finnish breast cancer case (n = 492–2,035) and control (n = 277–1,539) cohorts. As a result, two missense variants in genes involved in DNA replication, RECQL p.I156M and POLG p.L392V, the former involving genomic and the latter mitochondrial DNA replication, showed significant association with risk of breast cancer. Rare RECQL p.I156M allele was observed in breast cancer cases only (6/1,946, 0.3%, p = 0.043), whereas POLG p.L392V was two times more frequent in breast cancer cases (53/2,238, 2.4%) compared to controls (18/1,539, 1.2%, OR = 2.1, 95% CI 1.2–3.5, p = 0.010). Based on the current genetic data, both RECQL p.I156M and POLG p.L392V represent novel breast cancer predisposing alleles.
Abstract The growing importance of product data management and master data necessitate companies to have practices for deriving product master data from their corporate strategy. Business drivers need to be understood from the perspective of corporate strategy to capture product master data in relevant systems in a straightforward manner. Ideally master data is created only once and used through the life-cycle of the product. This study clarifies the foundations for determining one product data from corporate strategy. Data definitions are analysed to understand its linkages to business drivers, whereas main business processes are used to support categorisation. The practices of three companies are analysed to understand how business drivers for new products impact product data requirements. The results highlight the importance of business drivers in defining one product data based on the product master data, business-process related product data and IT systems over the product life-cycle.
Purpose In HER2-positive (HER2 +) breast cancer, tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) may influence the efficacy of the HER2-antibody trastuzumab and the patient’s outcome. In this HER2 + patient cohort, our aim was to study the numbers of FoxP3 + regulatory TILs and CD8 + cytotoxic TILs, their correlations with CD68 + and CD163 + TAMs, and the prognostic and predictive value of the studied factors. Methods We evaluated 139 non-metastatic HER2 + breast cancer patients operated between 2001 and 2008. The FoxP3+TIL count (FoxP3+TILs) was assessed using the hotspot method, and the CD8 + TIL count (CD8+mTILs) utilizing a digital image analysis from invasive margin areas. The ratios between CD8+mTILs and FoxP3+TILs as well as CD8+mTILs and TAMs were calculated. Results FoxP3 + TILs and CD8 + mTILs correlated positively with each other (p<0.001). FoxP3+TILs had a positive correlation with CD68+and CD163+TAMs (p≤0.038), while CD8 + mTILs correlated only with CD68+TAMs (p<0.001). In the HER2 + and hormone receptor-positive Luminal B subgroup, high numbers of FoxP3+TILs were associated with shorter disease-free survival (DFS) (54% vs. 79%, p = 0.040). The benefit from adjuvant trastuzumab was extremely significant among patients with a high CD8 + mTILs/CD68 + TAMs ratio, with overall survival (OS) 84% vs. 33% (p = 0.003) and breast cancer-specific survival (BCSS) 88% vs. 48% (p = 0.009) among patients treated with or without trastuzumab, respectively. Conclusion In the HER2 + Luminal B subgroup, high FoxP3 + TILs were associated with shorter DFS. A high CD8 + mTILs/CD68 + TAMs ratio seems to associate with impressive efficacy of trastuzumab.
Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
Abstract Although the spliceogenic nature of the BRCA2 c.68‐7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real‐time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case‐control analysis in 83,636 individuals. Co‐occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5‐fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68‐7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10−115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86–1.24) nor for a deleterious effect of the variant when co‐occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68‐7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Abstract Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
Abstract Purpose: The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. Methods: We genotyped the FANCM c.5791C>mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. Results: The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87–4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65–16.0, P = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32–2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77–5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. Conclusions: These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.
Abstract Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89–1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.
Abstract In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
Abstract A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).