The discovery and evaluation of treatment stratification biomarkers in epithelial ovarian cancer

Background: Epithelial ovarian cancer (EOC) has the poorest survival outcomes for all gynaecological malignancies. Despite emerging knowledge on the heterogeneity of the disease the majority of patients are initially treated the same. Biomarkers which could predict treatment response would greatly enhance patient care. Results: Differential DNA methylation analysis of serous EOC tumours identified 180 loci significantly associated with residual disease status (n=297, p<0.05, FDR <5%), with 23 corresponding genes also significantly associated in gene expression array analysis (p<0.05, FDR <10%). Differential DNA methylation of 27 loci were significantly associated with overall survival in patients receiving optimal debulking (n=78, p<0.05). Patients optimally debulked but with poor prognosis markers were found to have the same survival as those suboptimally debulked suggesting that supraradical surgery is not beneficial in these patients. Hypomethylation at intragenic regions of the homeobox gene MSX1 was associated with primary platinum resistance significantly (n=61, p<0.05, FDR<5%) and these findings were validated in an independent dataset (n=252, p<0.05). DNA methylation was also significantly correlated to gene expression. Platinum resistant ovarian cancer cell lines demonstrated significantly lower gene expression of MSX1 compared to sensitive pairs. Proliferation and apoptosis cell-line assays demonstrated sensitisation to cisplatin when cisplatin resistant A2780/CP70 cells re-expressed MSX1 following gene transfection. An increase in p53 downstream transcripts, CDKN1A (p21) and BAX was also demonstrated in these MSX1 transfectants. The detection of disease at 5 distinct anatomical sites determined by preoperative computed tomography was significantly associated with surgical debulking outcomes in a test (n=111) and validation (n=70) cohort of patients with EOC (sensitivity 64.7-69.2%, specificity 67.9-71.4%, AUC 0.721-0.749). Conclusions: DNA methylation is a potential rich source of biomarkers predicting cytoreductive outcome and survival. The discovery and validation of a novel DNA methylation biomarker of chemotherapy resistance is demonstrated with exciting findings related to its biological function in cisplatin sensitive assays.Open Acces

Epigenetic Regulation of the Homeobox Gene MSX1 Associates with Platinum-Resistant Disease in High-Grade Serous Epithelial Ovarian Cancer.

Purpose: Although high-grade serous ovarian cancer (HGSOC) is frequently chemoresponsive, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival (PFS) of less than 6 months. Validated predictive biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of intrinsic resistance. Our aim was to identify DNA methylation biomarkers of poor response to chemotherapy and demonstrate involvement of the associated gene in platinum drug cell sensitivity. Experimental Design: DNA methylation was investigated in independent tumor cohorts using Illumina HumanMethylation arrays and gene expression by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction and siRNA knockdown of ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in independent cohorts ofHGSOC patients, which recur by 6 months compared with after 12 months (P < 0.05, q < 0.05, n = 78), have poor RECIST response (P < 0.05, q < 0.05, n = 61), and are associated with PFS in an independent cohort (n = 146). A decrease in methylation at these CpG sites correlates with decreased MSX1 gene expression. MSX1 expression is associated with PFS (HR, 0.92; 95% CI, 0.85-0.99; P = 0.029; n = 309). Cisplatin-resistant ovarian cancer cell lines have reduced MSX1 expression, and MSX1 overexpression leads to cisplatin sensitization, increased apoptosis, and increased cisplatin-induced p21 expression. Conclusions: Hypomethylation of CpG sites within the MSX1 gene is associated with resistant HGSOC disease at presentation and identifies expression of MSX1 as conferring platinum drug sensitivity. (C) 2016 AACR

Henkilöstön vaihtuvuus ja siihen liittyvät tekijät telemarkkinointialalla : case: Gainer Oy

Tämä opinnäytetyö toteutettiin toimeksiantosopimuksena Gainer Oy:lle, joka on toiminut telemarkkinoinnin alalla jo vuodesta 1984. Opinnäytetyön tutkimusstrategiaksi valittiin case study eli tapaustutkimus. Käytimme tutkimusmenetelmänä kvalitatiivista eli laadullista tutkimusta. Tavoitteenamme oli tutkia ja selvittää henkilöstön vaihtuvuutta ja siihen liittyviä tekijöitä alalla, jossa henkilöstön vaihtuvuus koetaan ongelmaksi. Teoriaosuudessa käsittelemme teoreettisen viitekehyksen liittyen työnantajan keinoihin vaikuttaa työntekijän sitouttamiseen. Tämä on jaettu kahteen osa-alueeseen, jotka ovat rekrytointi sekä työhyvinvointi ja osaamisen kehittäminen. Empiirisessä osiossa päädyimme käyttämään puolistrukturoitua teemahaastattelua, joka toteutettiin suurimmaksi osaksi puhelimitse sekä muutama haastattelu tehtiin kasvotusten. Teemahaastattelu valikoitui parhaimmaksi menetelmäksi johtuen aiheen moniulotteisuudesta. Avoimella haastattelulla emme olisi välttämättä saaneet merkittävää tietoa samassa mittakaavassa kuin puolistrukturoidulla mallilla. Opinnäytetyön tuloksena päädyimme esittämään toimeksiantajalle muutamia kehitysehdotuksia. Haastatteluista johdetuilla päätelmillä saatettaisiin parantaa rekrytoinnin onnistumista, joka osaltaan parantaa kannattavuutta niin tuloksellisesti, kuin henkilöstön resurssejakin säästäen. Kehitysehdotuksia muodostui myös muihin osa-alueisiin liittyen. Näillä on myös vaikutusta henkilöstön yleiseen työhyvinvointiin ja työssä jaksamiseen.This thesis was carried out as a commission agreement for Gainer Oy, which has operated in the field of telemarketing since 1984. Our study was carried out as a case study using qualitative approach as our research method. Our objective was to study personnel turnover and matters relating to it in a field where personnel turnover is seen as a problem. In the theoretical section of the study we deal with the theoretical frame of reference related to the employer's means to influence employee engagement. This is divided into two sections that are recruiting, and occupational health and development of skills. In the empirical part of our study, we ended up using half-structured theme interviews, which were mainly carried out by telephone. A few interviews were carried out face-to-face. Theme interview was selected to be the best method because of the multidimensionality of the subject. By using open interviews, we would not necessarily have received as much significant information as by using the half-structured model. As a result of our study, we presented a few development proposals for our client/commissioner. The conclusions drawn from the interviews may lead to more successful recruiting, which in turn improves viability both in terms of productivity and by saving the resources of the personnel. There were also other development proposals concerning other areas. The results of the study may also help to improve the general well-being at work and coping with one’s workload

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

International audienc