Search

1 Figure and 4 Tables

The American Women's Health Initiative study published in July 2002 caused considerable concern among hormone replacement therapy (HRT) users and prescribers in many countries. This study is an exploratory research comparing the genome-wide expression profile in whole-blood samples according to HRT use. Within the Norwegian Women and Cancer study, 100 postmenopausal women (50 HRT users and 50 non-HRT users) born between 1943 and 1949 with normal to high body mass index and no other medication use were selected. After total RNA extraction, amplification, and labeling, the samples were hybridized together with a common reference (Universal human reference RNA, Stratagen) to Agilent Human 1A oligoarrays (G4110b, Agilent Technologies) containing 20,173 unique genes. Differentially expressed genes were used to build a classifier using the nearest shrunken centroid method (PAM). Then, we tested the significant changes in single genes by different methods like t test, Significance Analysis of Microarrays, and Bayesian ANOVA analysis. Results did not reveal any distinct gene list which predicted accurately HRT exposure (error rate, 0.40). Classifier performance slightly improved (error rate, 0.26) including only women who were using continuous combined HRT treatment. According to the small amplitude of expression alterations observed in whole blood, more quantitative technique and larger sample sizes will be needed to be able to investigate whether significant single genes are differentially expressed in HRT versus non-HRT users. Taken cautiously, significant enrichments in biological process of genes with small changes after HRT use were observed (e.g., receptor and transporter activities, immune response, frizzled signaling pathway, actin filament organization, and glycogen metabolism). [Mol Cancer Ther 2006;5(4):868–76]

Alkylating drugs are among the most often used chemotherapeutics. While cancer cells frequently develop resistance to alkylation treatments, detailed understanding of mechanisms that lead to the resistance is limited. Here, by using genome-wide CRISPR–Cas9 based screen, we identify transcriptional Mediator complex subunit 13 (MED13) as a novel modulator of alkylation response. The alkylation exposure causes significant MED13 downregulation, while complete loss of MED13 results in reduced apoptosis and resistance to alkylating agents. Transcriptome analysis identified cyclin D1 (CCND1) as one of the highly overexpressed genes in MED13 knock-out (KO) cells, characterized by shorter G1 phase. MED13 is able to bind to CCND1 regulatory elements thus influencing the expression. The resistance of MED13 KO cells is directly dependent on the cyclin D1 overexpression, and its down-regulation is sufficient to re-sensitize the cells to alkylating agents. We further demonstrate the therapeutic potential of MED13-mediated response, by applying combinatory treatment with CDK8/19 inhibitor Senexin A. Importantly, the treatment with Senexin A stabilizes MED13, and in combination with alkylating agents significantly reduces viability of cancer cells. In summary, our findings identify novel alkylation stress response mechanism dependent on MED13 and cyclin D1 that can serve as basis for development of innovative therapeutic strategies., Graphical Abstract Graphical AbstractModel of MED13 regulated response to alkylation. Created with BioRender.com.

Mikronett er små elektriske distribusjonsnett på et begrenset geografisk område som består av laster, energiproduksjon og energilagring som kan være helt uavhengig av det statlige distribusjonsnettet. Det blir spådd som en mulig løsning for å forbedre fremtidens kraftnettverk. Denne oppgaven tar for seg hvordan et isolert mikronett kan dimensjoneres og driftes optimalt. Mer spesifikt fokuserer oppgaven på følgende: • Gjennomfør et litteraturstudie om ulike energikilder som kan brukes i mikronett og hvordan de er implementert i eksisterende mikronett. • Undersøke energiforbruket og potensialet for fornybar energiproduksjon på Froan. Det blir gjort ved å ta utgangspunkt i data fra ROME-prosjektet til SINTEF. • Dimensjonere komponentene i et mikronett på Froan ved å bruke numerisk optimering og resultatene fra forrige punkt. Det vurderes også hvordan endringer i forbruk, produksjon og kostnader vil påvirke dimensjoneringen. • Undersøke om det er mulig å predikere effektforbruk og effektproduksjon på Froan ved å bruke værdata. Forbruket og produksjonen blir først modellert etter faktiske målinger fra Froan. Deretter brukes værmeldingen for Froan for å predikere forbruket og produksjonen. • Bruke numerisk optimering for å planlegge bruken av batteri og dieselgenerator basert på predikeringene av forbruk og produksjon. Det vurderes også hvordan resultatene kan brukes i praksis på mikronettet på Froan. Resultatene fra denne oppgaven virker lovende og viser at dimensjonen og driften av mikronettet på Froan kan optimeres ved å bruke metodikken som er presentert. På grunn av noe usikkerhet knyttet til datagrunnlaget bør det vurderes hvor store sikkerhetsmarginer som er nødvendig når mikronettet dimensjoneres. Det må også vurderes hvordan optimering av driften skal implementeres i praksis. Microgrids are small electrical distribution grids in a limited geographical area that consist of loads, energy production and energy storage that can be completely independent of the main distribution grid. It is predicted as a possible solution to improve the power grid of the future. This thesis deals with how an isolated microgrid can be dimensioned and operated optimally. More specifically, the thesis focuses on the following: • Conduct a literature study on different energy sources that can be used in microgrids and how they are implemented in existing microgrids. • Investigate energy consumption and the potential for renewable energy production at Froan. This is done based on data from the ROME-project of SINTEF. • Dimension the components of a microgrid at Froan using numerical optimization and the results from the previous item. It is also considered how changes in consumption, production and costs will affect the dimensioning. • Investigate whether it is possible to predict power consumption and power production at Froan using weather data. Consumption and production are modeled after actual measurements from Froan first. Then the weather forecast for Froan is used to predict consumption and production. • Use numerical optimization to plan the use of battery and diesel generator based on the predictions of consumption and production. It is also considered how the results can be used in practice on the microgrid at Froan. The results from this thesis seem promising and show that the dimension and operation of the microgrid on Froan can be optimized by using the methods presented. Due to some uncertainty related to the data basis, it should be considered how large safety margins are needed when dimensioning the microgrid. It must also be considered how operation optimization is to be implemented in practice.

Background: Lynch‐like syndrome (LLS) represents around 50% of the patients fulfilling the Amsterdam Criteria II/revised Bethesda Guidelines, characterized by a strong family history of Lynch Syndrome (LS) associated cancer, where a causative variant was not identified during genetic testing for LS.Methods: Using data extracted from a larger gene panel, we have analyzed next‐generation sequencing data from 22 mismatch repair (MMR) genes (MSH3, PMS1, MLH3, EXO1, POLD1, POLD3 RFC1, RFC2, RFC3, RFC4, RFC5, PCNA, LIG1, RPA1, RPA2, RPA3, POLD2, POLD4, MLH1, MSH2, MSH6, and PMS2) in 274 LLS patients. Detected variants were annotated and filtered using ANNOVAR and FILTUS software.Results: Thirteen variants were revealed in MLH1, MSH2, and MSH6, all genes previously linked to LS. Five additional genes (EXO1, POLD1, RFC1, RPA1, and MLH3) were found to harbor 11 variants of unknown significance in our sample cohort, two of them being frameshift variants.Conclusion: We have shown that other genes associated with the process of DNA MMR have a high probability of being associated with LLS families. These findings indicate that the spectrum of genes that should be tested when considering an entity like Lynch‐like syndrome should be expanded so that a more inclusive definition of this entity can be developed. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. DOI: 10.1002/mgg3.850

Sertoli cells have dual roles during the cells’ lifetime. In the juvenile mammal, Sertoli cells proliferate and create the structure of the testis, and during puberty they cease to proliferate and take on the adult role of supporting germ cells through spermatogenesis. Accordingly, many genes expressed in Sertoli cells during testis formation are repressed during spermatogenesis. 5-Hydroxymethylcytosine (5hmC) is a DNA modification enzymatically generated from 5mC and present in all investigated mammalian tissues at varying levels. Using mass spectrometry and immunofluorescence staining we identified a substantial Sertoli cell-specific global 5hmC increase during rat puberty. Chemical labeling, pull-down and sequencing of 5hmC-containing genomic DNA from juvenile and adult rat Sertoli cells revealed that genes that lose or gain 5hmC belong to different functional pathways and mirror the functions of the cells in the two different states. Loss of 5hmC is associated with genes involved in development and cell structure, whereas gain of 5hmC is associated with genes involved in cellular pathways pertaining to the function of the adult Sertoli cells. This redistribution during maturation shows that 5hmC is a dynamic nucleotide modification, correlated to gene expression. © The Author(s) 2017. This work is licensed under a Creative Commons Attribution 4.0 International License.

Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme NEIL3 was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 after MI in mice, especially in a fibroblast-enriched cell fraction. Neil3−/− mice show increased mortality after MI caused by myocardial rupture. Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) reveals changes in the cardiac epigenome, including in genes related to the post-MI transcriptional response. Differentially methylated genes are enriched in pathways related to proliferation and myofibroblast differentiation. Accordingly, Neil3−/− ruptured hearts show increased proliferation of fibroblasts and myofibroblasts. We propose that NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after MI. © 2017 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Background Many families with a high burden of colorectal cancer fulfil the clinical criteria for Lynch Syndrome. However, in about half of these families, no germline mutation in the mismatch repair genes known to be associated with this disease can be identified. The aim of this study was to find the genetic cause for the increased colorectal cancer risk in these unsolved cases. Materials and methods To reach the aim, we designed a gene panel targeting 112 previously known or candidate colorectal cancer susceptibility genes to screen 274 patient samples for mutations. Mutations were validated by Sanger sequencing and, where possible, segregation analysis was performed. Results We identified 73 interesting variants, of whom 17 were pathogenic and 19 were variants of unknown clinical significance in well-established cancer susceptibility genes. In addition, 37 potentially pathogenic variants in candidate colorectal cancer susceptibility genes were detected. Conclusion In conclusion, we found a promising DNA variant in more than 25 % of the patients, which shows that gene panel testing is a more effective method to identify germline variants in CRC patients compared to a single gene approach. © 2017 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.