Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients

BACKGROUND: Molecular markers and the rich biological information they contain have great potential for cancer diagnosis, prognostication and therapy prediction. So far, however, they have not superseded routine histopathology and staging criteria, partly because the few studies performed on molecular subtyping have had little validation and limited clinical characterization. METHODS: We obtained gene expression and clinical data for 412 breast cancers obtained from population-based cohorts of patients from Stockholm and Uppsala, Sweden. Using the intrinsic set of approximately 500 genes derived in the Norway/Stanford breast cancer data, we validated the existence of five molecular subtypes – basal-like, ERBB2, luminal A/B and normal-like – and characterized these subtypes extensively with the use of conventional clinical variables. RESULTS: We found an overall 77.5% concordance between the centroid prediction of the Swedish cohort by using the Norway/Stanford signature and the k-means clustering performed internally within the Swedish cohort. The highest rate of discordant assignments occurred between the luminal A and luminal B subtypes and between the luminal B and ERBB2 subtypes. The subtypes varied significantly in terms of grade (p < 0.001), p53 mutation (p < 0.001) and genomic instability (p = 0.01), but surprisingly there was little difference in lymph-node metastasis (p = 0.31). Furthermore, current users of hormone-replacement therapy were strikingly over-represented in the normal-like subgroup (p < 0.001). Separate analyses of the patients who received endocrine therapy and those who did not receive any adjuvant therapy supported the previous hypothesis that the basal-like subtype responded to adjuvant treatment, whereas the ERBB2 and luminal B subtypes were poor responders. CONCLUSION: We found that the intrinsic molecular subtypes of breast cancer are broadly present in a diverse collection of patients from a population-based cohort in Sweden. The intrinsic gene set, originally selected to reveal stable tumor characteristics, was shown to have a strong correlation with progression-related properties such as grade, p53 mutation and genomic instability

Hormone-replacement therapy influences gene expression profiles and is associated with breast-cancer prognosis: a cohort study

BACKGROUND: Postmenopausal hormone-replacement therapy (HRT) increases breast-cancer risk. The influence of HRT on the biology of the primary tumor, however, is not well understood. METHODS: We obtained breast-cancer gene expression profiles using Affymetrix human genome U133A arrays. We examined the relationship between HRT-regulated gene profiles, tumor characteristics, and recurrence-free survival in 72 postmenopausal women. RESULTS: HRT use in patients with estrogen receptor (ER) protein positive tumors (n = 72) was associated with an altered regulation of 276 genes. Expression profiles based on these genes clustered ER-positive tumors into two molecular subclasses, one of which was associated with HRT use and had significantly better recurrence free survival despite lower ER levels. A comparison with external data suggested that gene regulation in tumors associated with HRT was negatively correlated with gene regulation induced by short-term estrogen exposure, but positively correlated with the effect of tamoxifen. CONCLUSION: Our findings suggest that post-menopausal HRT use is associated with a distinct gene expression profile related to better recurrence-free survival and lower ER protein levels. Tentatively, HRT-associated gene expression in tumors resembles the effect of tamoxifen exposure on MCF-7 cells

Importprocessen för inrednings- och gåvoartiklar från USA till Finland : En handbok för företagaren

Det här examensarbetet handlar om import från USA med fokus på inrednings- och gåvoartiklar. I arbetet lyfter vi steg för steg fram de delar som utgör importprocessen hela vägen från hur man hittar en pålitlig leverantör till förtullningen av produkterna här i Finland. Syftet med arbetet är att det skall kunna fungera som en handbok för företag som vill starta en småskalig importverksamhet av inrednings- och gåvoartiklar. Vi tar även upp information om import och internationell handel i allmänhet eftersom det finns många faktorer utöver de delar som utgör själva importprocessen som påverkar hur väl importen fungerar, till exempel handelsavtal och kultur. Det som utgör själva importprocessen är kravspecifikation, leverantörsval, köpeavtal och beställning, transport och leveransvillkor, förtullning samt betalning.Tämä opinnäytetyö kertoo sisustus- ja lahjatuotteiden tuontiprosessista Yhdysvalloista Suomeen. Opinnäytetyössä käydään läpi tuontiprosessin kaikki vaiheet: miten aloittaa ja löytää luotettava tavarantoimittaja ja kaikki muut vaiheet ennen tullausta Suomessa. Tarkoituksena on, että opinnäytetyö voisi toimia käsikirjana yrittäjille, jotka haluavat aloittaa pientä tuontitoimintaa ja tuoda sisustus- ja lahjatuotteita Suomeen. Opinnäytetyö käsittelee myös yleistietoa tuonnista ja kansainvälisestä kaupankäynnistä. Koska onnistunut tuontiprosessi muodostuu monista tekijöistä, olemme kirjoittaneet myös esimerkiksi kauppasopimuksen teosta ja kulttuurieroista. Tuontiprosessi muodostuu vaatimuksien määrittelyistä, toimittaja- ja kauppasopimuksien teosta, tilauksista, kuljetuksista ja kuljetusvaatimuksista, tullauksista ja maksuista.This Bachelor’s thesis is about import from the US focusing on interior and gift items. In this thesis we discuss, step by step, the parts that form the import process, all the way from finding a reliable supplier to the customs clearance here in Finland. The purpose of this thesis is to create a manual for entrepreneurs who want to start a small scale import business of interior and gift items. We also bring up information about import and international business in general since there are many elements, in addition to the parts that form the import process, affecting the import functions, for example trade agreements and culture. What constitutes the import process is requirement specification, finding the right suppliers, purchase agreement and order, shipment and terms of delivery, customs clearance and payment

Role of the CDKN2A and related cell cycle regulatory genes in melanoma and other human cancers

The main objective of this thesis has been to investigate the involvement of the CDKN2A (p16INK4a and p14ARF) and related cell cycle regulatory genes in melanoma and other types of human cancer. The CDKN2A gene represents a unique locus in the entire human genome. It encodes two separate cell cycle regulators from distinctive exon 1 alpha and exon 1 beta, that splice with common exons 2 and 3 and are translated in different reading frames. By inhibition of the cyclin D-CDK4/6 complex, p16 INK4a prevents phosphorylation of the RB protein, in turn leading to block of cell cycle progression. The p14 A F protein participates in the p53 pathway and restrains cell growth by p53 stabilization by sequestering HDM2. The locus carrying the CDKN2A gene on chromosome 9p21 is commonly altered in a number of human cancer types. This study has assessed the status of the CDKN2A (p16INK4a and p14ARF) gene in malignant melanoma and squamous cell carcinoma of esophagus (ESCC). In addition, mutations were determined in the CDKN2B, CDKN2C, CDK4, p53 and p53R2 genes. The results showed alterations of the CDKN2A gene in both primary and metastatic melanomas. In the primary melanomas a high frequency of loss of heterozygosity was detected at chromosome 9p21, while the rates of mutations and homozygous deletions in the CDKN2A gene were relatively low. A significantly increased frequency of loss of heterozygosity was found at the marker D9S736, which is located telomeric to the CDKN2A gene, suggesting the presence of an additional tumour suppressor gene. An interesting correlation was found between the frequency of loss of heterozygosity on chromosome 9 and increased patient age at diagnosis. Analysis of metastatic melanoma likewise showed low frequencies of mutations and homozygous deletions of the CDKN2A gene. The results showed an association between polymorphisms in the 3´untranslated region of the CDKN2A gene and progression of disease. One of those polymorphisms was also significantly overrepresented in sporadic primary melanomas compared to healthy controls. No mutations were found in the CDKN2B, CDKN2C, CDK4 or p53R2 genes, suggesting a limited role in melanoma. Similarly no evidence was found for the involvement of the p53 gene in malignant melanoma. The study of esophageal squamous cell carcinomas showed a very high proportion of genetic and epigenetic alterations in the CDKN2A (p16INK4a and p14ARF) and p53 genes. Of 21 cases analysed, 86% were found to have at least one alteration in the CDKN2A gene. No major alterations were detected in the CDKN2B, CDKN2C, CDK4 or p53R2 genes. However, in the 5´untranslated region of the p53R2 gene a novel polymorphism was detected. Additionally another novel polymorphism, an 8 base pair insertion in the same region was detected in control population, which was subsequently genotyped for association with different cancers. Altogether, the cancer types studied showed a complex pattern of genetic alterations, indicating the contribution of various disrupted cell cycle regulatory mechanisms. Involvement of the CDKN2A gene was found in a subset of sporadic melanoma cases. The mutation rate of the CDKN2A gene was low, albeit allelic loss at 9p21 was frequent. A prevailing theory is the existence of other tumour suppressor genes within the locus. However, candidate genes remain to be identified. Alterations of the CDKN2A (p16INK4a and p14ARF) and p53 genes were found to be major events in esophageal squamous cell carcinomas

Varför följer inte alla vårdnadshavare det nationella vaccinationsprogrammet för barn och ungdomar? En kartläggande studie om rädslor i vaccinationsbeslutet

Detta examensarbete tillhör yrkeshögskolan Arcadas egna projekt ”säkerhetskultur”. Syftet med studien är att kartlägga vilken information som vårdnadshavare behöver för att göra ett evidensbaserat vaccinationsbeslut enligt det nationella vaccinationsprogrammet för barn och ungdomar. Med detta ökar vi även vår egen förståelse för vårdnadshavares vaccinationsbeslut. Metoden som används är en kvalitativ litteraturstudie och analysmetoden är induktiv innehållsanalys. I detta arbete har tre vetenskapliga artiklar, THL:s vaccinationsguide för småbarn, tre kommentarer från diskussionsforumen keskustelu.suomi24 och vauva.fi samt tre kommentarer från den finländska tidningen Vasabladet analyserats. Den teoretiska referensramen som använts är The health belief model. Resultatet svarar på forskningsfrågan, alltså vilken information vårdnadshavare behöver för att känna sig säkrare i vaccinationsbeslutet, vilket är information angående immunitet och vaccinsäkerhet. Vaccinationsbeslutet påverkas också mycket av medier och andra människors negativa upplevelser av vaccin, men fynden överlag är att de flesta vårdnadshavare har en stark tillit till hälsovården och till det nationella vaccinationsprogrammet. Många vårdnadshavare upplever att behovet av transparent, objektiv och evidensbaserad information där farmaceutbolagens inverkan utesluts är stor. Utgående från det vetenskapliga materialet och materialet från diskussionsforum och tidningen konstateras fynden vara mycket liknande. Resultatet kan kopplas till den teoretiska referensramen eftersom The health belief model förklarar människans hälsobeteenden