Institute for Molecular Medicine Finland FIMM

Helsinki, Finland

Institute for Molecular Medicine Finland FIMM

Helsinki, Finland

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Edgren H.,Institute for Molecular Medicine Finland FIMM | Murumagi A.,Institute for Molecular Medicine Finland FIMM | Kangaspeska S.,Institute for Molecular Medicine Finland FIMM | Nicorici D.,Institute for Molecular Medicine Finland FIMM | And 9 more authors.
Genome Biology | Year: 2011

Background: Until recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements.Results: We applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival.Conclusions: In summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB-IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells. © 2011 Edgren et al.; licensee BioMed Central Ltd.

Lampe J.,University of Tübingen | Lampe J.,Institute for Molecular Medicine Finland FIMM | Bossow S.,Max Planck Institute of Biochemistry | Bossow S.,National Center for Tumor Diseases | And 5 more authors.
Gene Therapy | Year: 2013

Due to late diagnosis and a pronounced chemoresistance, most patients with hepatocellular carcinoma (HCC) have an overall poor prognosis. Measles vaccine viruses (MeV) have been shown to possess anti-tumor properties and their efficacy has been enhanced by arming with suicide genes. To test armed MeV for the treatment of HCC, we equipped it with the suicide gene Super-cytosine deaminase (SCD) and tested the efficacy in cell culture and in a mouse xenograft model of human HCC. Prodrug conversion was investigated in cell culture and quantified by high-performance liquid chromatography. We observed a strong oncolytic activity of MeV-SCD against human HCC in vitro and in vivo. The prodrug was efficiently converted in infected cells leading to a significant enhancement of the cytotoxic effect. Treatment of HCC xenografts with MeV caused long-term virus replication in tumor tissue. We show that the suicide gene therapy induces an apoptosis-like cell death but is not dependent on intact apoptosis pathways. These results demonstrate that MeV-based suicide gene therapy is a promising novel therapy regimen for HCC overcoming resistance towards conventional therapy. The independence from apoptosis raises hopes for the treatment of patients whose tumor cells exert defects in this cell death mechanism. Copy; 2013 Macmillan Publishers Limited. © 2013 Macmillan Publishers Limited.

Zareba-Koziol M.,Polish Academy of Sciences | Szwajda A.,Institute for Molecular Medicine Finland FIMM | Dadlez M.,Polish Academy of Sciences | Wyslouch-Cieszynska A.,Polish Academy of Sciences | And 2 more authors.
Molecular and Cellular Proteomics | Year: 2014

Alzheimer's disease (AD) is characterized by an early synaptic loss, which strongly correlates with the severity of dementia. The pathogenesis and causes of characteristic AD symptoms are not fully understood. Defects in various cellular cascades were suggested, including the imbalance in production of reactive oxygen and nitrogen species. Alterations in S-nitrosylation of several proteins were previously demonstrated in various AD animal models and patients. In this work, using combined biotinswitch affinity/nano-LC-MS/MS and bioinformatic approaches we profiled endogenous S-nitrosylation of brain synaptosomal proteins from wild type and transgenic mice overexpressing mutated human Amyloid Precursor Protein (hAPP). Our data suggest involvement of S-nitrosylation in the regulation of 138 synaptic proteins, including MAGUK, CamkII, or synaptotagmins. Thirty-eight proteins were differentially S-nitrosylated in hAPP mice only. Ninety-five S-nitrosylated peptides were identified for the first time (40% of total, including 33 peptides exclusively in hAPP synaptosomes). We verified differential S-nitrosylation of 10 (26% of all identified) synaptosomal proteins from hAPP mice, by Western blotting with specific antibodies. Functional enrichment analysis linked S-nitrosylated proteins to various cellular pathways, including: glycolysis, gluconeogenesis, calcium homeostasis, ion, and vesicle transport, suggesting a basic role of this post-translational modification in the regulation of synapses. The linkage of SNO-proteins to axonal guidance and other processes related to APP metabolism exclusively in the hAPP brain, implicates S-nitrosylation in the pathogenesis of Alzheimer's disease. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Yetukuri L.,VTT Technical Research Center of Finland | Soderlund S.,University of Helsinki | Koivuniemi A.,Tampere University of Technology | Seppanen-Laakso T.,VTT Technical Research Center of Finland | And 10 more authors.
Journal of Lipid Research | Year: 2010

A low level of high density lipoprotein cholesterol (HDL-C) is a powerful risk factor for cardiovascular disease. However, despite the reported key role of apolipoproteins, specifically, apoA-I, in HDL metabolism, lipid molecular composition of HDL particles in subjects with high and low HDL-C levels is currently unknown. Here lipidomics was used to study HDL derived from well-characterized high and low HDL-C subjects. Low HDL-C subjects had elevated triacylglycerols and diminished lysophosphatidyl-cholines and sphingomyelins. Using information about the lipid composition of HDL particles in these two groups, we reconstituted HDL particles in silico by performing large-scale molecular dynamics simulations. In addition to confirming the measured change in particle size, we found that the changes in lipid composition also induced specific spatial distributions of lipids within the HDL particles, including a higher amount of triacylglycerols at the surface of HDL particles in low HDL-C subjects. Our findings have important implications for understanding HDL metabolism and function. For the first time we demonstrate the power of combining molecular profiling of lipoproteins with dynamic modeling of lipoprotein structure. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.

Broms U.,University of Helsinki | Broms U.,Finnish National Institute for Health and Welfare | Kaprio J.,University of Helsinki | Kaprio J.,Finnish National Institute for Health and Welfare | And 6 more authors.
Addiction | Year: 2011

Aims To examine the association between diurnal type and smoking status and nicotine dependence (ND).Design A cohort study using random-effects model regressions for repeated longitudinal panel data was used to analyse smoking status by diurnal type. Regression analyses examined the association between diurnal type and ND.Participants A total of 23289 same-sex adult twin individuals from Finnish Twin Cohort. Nicotine dependence was studied in a subsample of 676 twin individuals.Measurements Subjects were classified by self-report into four categories: morning type, somewhat morning type, somewhat evening type, evening type (in 1981). Smoking status was defined as current and ever smoking (in 1975, 1981 and 1990). ND was measured by DSM-IV and Fagerström Test for Nicotine Dependence (FTND) (during 2001-05).Findings Evening types of both genders were much more likely to be current (OR=2.91, 95% CI 2.50, 3.38) and life-time smokers (OR=2.67, 95% CI 2.96, 4.07) compared to morning types. Evening types were less likely to stop smoking. The risk of nicotine dependence assessed by DSM-IV criteria was higher among evening types (OR=2.78, 95% CI 1.64, 4.72). Evening types scored 0.59 (95% CI 0.01, 1.17) points higher than morning types on the FTND. Adjustment for potential confounders did not change these associations.Conclusions Being an evening type is associated independently with a higher risk of being a current smoker, being more highly dependent upon cigarettes and a lower likelihood of stopping smoking. Understanding the cause of these associations could elucidate the causes of tobacco addiction. © 2010 The Authors, Addiction © 2010 Society for the Study of Addiction.

Hartkopf A.D.,University of Tübingen | Bossow S.,National Center for Tumor Diseases Heidelberg | Lampe J.,Institute for Molecular Medicine Finland FIMM | Zimmermann M.,University Hospital of Tuebingen | And 5 more authors.
Gynecologic Oncology | Year: 2013

Objective To preclinical assess the feasibility of combining oncolytic measles vaccine virus (MeV) with suicide gene therapy for ovarian cancer treatment. Methods We genetically engineered a recombinant MeV armed with a yeast-derived bifunctional suicide gene that encodes for cytosine deaminase and uracil phosphoribosyltransferase (MeV-SCD). From this suicide gene, a chimeric protein is produced that converts the non-toxic prodrug 5-fluorocytosine (5-FC) into highly cytotoxic 5-fluorouracil (5-FU) and directly into 5-fluorouridine monophosphate (5-FUMP) thereby bypassing an important mechanism of chemoresistance to 5-FU. Results MeV-SCD was demonstrated to infect, replicate in and effectively lyse not only human ovarian cancer cell lines, but also primary tumor cells (albeit at lower efficiencies) that were derived from malignant ascites of ovarian cancer patients. Addition of the prodrug 5-FC significantly enhanced cell killing. Importantly, precision-cut tumor slices of human ovarian cancer patient specimens were efficiently infected with MeV-SCD. The prodrug-converting enzyme SCD was expressed by all infected tumor slices, thereby ensuring provision of the suicide gene arming function in patient-derived materials. Conclusions With respect to safety and therapeutic impact, arming of oncolytic measles vaccine virus warrants further clinical investigation for ovarian cancer treatment. © 2013 Elsevier Inc. All rights reserved.

Larne O.,Lund University | Ostling P.,Institute for Molecular Medicine Finland FIMM | Ostling P.,Åbo Akademi University | Haflidadottir B.S.,Lund University | And 14 more authors.
European Urology | Year: 2015

Background Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood. Objective To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA. Design, setting, and participants Reporter assays with PSA and KLK2 3′ untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts. Outcome measurements and statistical analysis RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis. Results and limitations Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3′ UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression. Conclusions The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings. Patient summary These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer. © 2014 European Association of Urology.

Neme A.,Valle Private University | Neme A.,Institute for Molecular Medicine Finland FIMM | Miramontes P.,National Autonomous University of Mexico
Neural Processing Letters | Year: 2014

Decreasing neighborhood with distance has been identified as one of a few conditions to achieve final states in the self-organizing map (SOM) that resemble the distribution of high-dimensional input data. In the classic SOM model, best matching units (BMU) decrease their influence area as a function of distance. We introduce a modification to the SOM algorithm in which neighborhood is contemplated from the point of view of affected units, not from the view of BMUs. In our proposal, neighborhood for BMUs is not reduced, instead the rest of the units exclude some BMUs from affecting them. Each neuron identifies, from the set of BMUs that influenced it in previous epochs, those to whom it becomes refractory to for the rest of the process. Despite that the condition of decreasing neighborhood over distance is not maintained, self-organization still persists, as shown by several experiments. The maps achieved by the proposed modification have, in many cases, a lower error measure than the maps formed by SOM. Also, the model is able to remove discontinuities (kinks) from the map in a very small number of epochs, which contrasts with the original SOM model. © 2013 Springer Science+Business Media New York.

Heikkila J.,University of Oulu | Rahtu E.,University of Oulu | Ojansivu V.,Institute for Molecular Medicine Finland FIMM
Studies in Computational Intelligence | Year: 2014

Blur is one of the most common sources of image quality degradations, and it appears very often in practical photography. Most often blur is a result of misfocused optics, changes in the camera pose, and movements in the scene. Beyond the impaired visual quality, blurring may cause severe complications to computer vision algorithms, particularly in texture analysis. These problems have been tackled using deblurring approaches, which ultimately leads to much harder intermediate problem versus the original task of texture characterization. In this chapter, we present a simple yet powerful texture descriptor that is, by design, tolerant to most common types of image blurs. The proposed approach is based on quantizing the phase information of the local Fourier transform, which leads to computationally efficient and compact feature representation. We show how to construct several variants of our descriptor including rotation invariance and dynamic texture representation. Moreover, we present texture classification experiments, which illustrate the behavior under several different blur configurations. Surprisingly, the descriptor also achieves state-of-the-art performance with sharp textures, although the main design criteria was tolerance to blur. © 2014 Springer-Verlag Berlin Heidelberg.

Kangaspeska S.,Institute for Molecular Medicine Finland FIMM | Hultsch S.,Institute for Molecular Medicine Finland FIMM | Edgren H.,Institute for Molecular Medicine Finland FIMM | Nicorici D.,Institute for Molecular Medicine Finland FIMM | And 2 more authors.
PLoS ONE | Year: 2012

RNA-sequencing and tailored bioinformatic methodologies have paved the way for identification of expressed fusion genes from the chaotic genomes of solid tumors. We have recently successfully exploited RNA-sequencing for the discovery of 24 novel fusion genes in breast cancer. Here, we demonstrate the importance of continuous optimization of the bioinformatic methodology for this purpose, and report the discovery and experimental validation of 13 additional fusion genes from the same samples. Integration of copy number profiling with the RNA-sequencing results revealed that the majority of the gene fusions were promoter-donating events that occurred at copy number transition points or involved high-level DNA-amplifications. Sequencing of genomic fusion break points confirmed that DNA-level rearrangements underlie selected fusion transcripts. Furthermore, a significant portion (>60%) of the fusion genes were alternatively spliced. This illustrates the importance of reanalyzing sequencing data as gene definitions change and bioinformatic methods improve, and highlights the previously unforeseen isoform diversity among fusion transcripts. © 2012 Kangaspeska et al.

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