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Search Results: 1 - 10 of 210708 matches for " Merja Per?l? "
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Identification of MicroRNAs Inhibiting TGF-β-Induced IL-11 Production in Bone Metastatic Breast Cancer Cells
Sirkku Pollari, Suvi-Katri Leivonen, Merja Perl, Vidal Fey, Sanna-Maria K?k?nen, Olli Kallioniemi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037361
Abstract: Development of bone metastases is dependent on the cancer cell-bone cell interactions in the bone microenvironment. Transforming growth factor β (TGF-β) is released from bone during osteoclastic bone resorption and induces production of osteolytic factors, such as interleukin 11 (IL-11), in breast cancer cells. IL-11 in turn increases osteolysis by stimulating osteoclast function, launching a vicious cycle of cancer growth and bone destruction. We aimed to identify and functionally characterize microRNAs (miRNAs) that mediate the bone metastatic process, focusing on miRNAs that regulate the TGF-β induction of IL-11. First, we profiled the expression of 455 miRNAs in a highly bone metastatic MDA-MB-231(SA) variant as compared to the parental MDA-MB-231 breast cancer cell line and found 16 miRNAs (3.5%) having a >3-fold expression difference between the two cell types. We then applied a cell-based overexpression screen with Pre-miRNA constructs to functionally identify miRNAs regulating TGF-β-induced IL-11 production. This analysis pinpointed miR-204, miR-211, and miR-379 as such key regulators. These miRNAs were shown to directly target IL11 by binding to its 3′ UTR. MiR-379 also inhibited Smad2/3/4-mediated transcriptional activity. Gene expression analysis of miR-204 and miR-379-transfected cells indicated that these miRNAs downregulated the expression of several genes involved in TGF-β signaling, including prostaglandin-endoperoxide synthase 2 (PTGS2). In addition, there was a significant correlation between the genes downregulated by miR-379 and a set of genes upregulated in basal subtype of breast cancer. Taken together, the functional evidence and clinical correlations imply novel mechanistic links between miRNAs and the key steps in the bone metastatic process in breast cancer, with potential clinical relevance.
Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase
Elina Mattila, Heidi Marttila, Niko Sahlberg, Pekka Kohonen, Siri T?htinen, Pasi Halonen, Merja Perl, Johanna Ivaska
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-7
Abstract: We developed a high-throughput compatible assay to analyse activity of recombinant TCPTP in vitro. Using this assay we have screened 64280 small molecules to identify novel agonists for TCPTP. Dose-dependent response to TCPTP agonist was performed using the in vitro assay. Inhibition effects and specificity of TCPTP agonists were evaluated using TCPTP expressing and null mouse embryonic fibroblasts. Western blot analysis was used to evaluate attenuation of PDGFRβ and EGFR phosphorylation. Inhibition of VEGF signalling was analysed with VEGF-induced endothelial cell sprouting assays.From the screen we identified six TCPTP agonists. Two compounds competed with α1-cytoplasmic domain for binding to TCPTP, suggesting that they activate TCPTP similar to α1-cyt by disrupting the intra-molecular bond in TCPTP. Importantly, one of the compounds (spermidine) displayed specificity towards TCPTP in cells, since TCPTP -/- cells were 43-fold more resistant to the compound than TCPTP expressing cells. This compound attenuates PDGFRβ and VEGFR2 signalling in cells in a TCPTP-dependent manner and functions as a negative regulator of EGFR phosphorylation in cancer cells.In this study we showed that small molecules mimicking TCPTP-α1 interaction can be used as TCPTP agonists. These data provide the first proof-of-concept description of the use of high-throughput screening to identify small molecule PTP activators that could function as RTK antagonists in cells.Cellular homeostasis is maintained by the coordinated actions of kinases and phosphatases. Aberrant activation of several kinases due to overexpression, amplification or activating mutations are the underlying causes of many human pathologies like inflammation and cancer [1]. Conversely, loss of the negative regulation exerted by phosphatases may lead to a similar outcome [2]. To date, many kinase inhibitors have been developed and several small molecule inhibitors and function blocking antibodies against receptor tyrosine kinas
High-Throughput 3D Screening Reveals Differences in Drug Sensitivities between Culture Models of JIMT1 Breast Cancer Cells
Vesa Hongisto, Sandra Jernstr?m, Vidal Fey, John-Patrick Mpindi, Kristine Kleivi Sahlberg, Olli Kallioniemi, Merja Perl
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077232
Abstract: The traditional method for studying cancer in vitro is to grow immortalized cancer cells in two-dimensional monolayers on plastic. However, many cellular features are impaired in these artificial conditions, and large changes in gene expression compared to tumors have been reported. Three-dimensional cell culture models have become increasingly popular and are suggested to be better models than two-dimensional monolayers due to improved cell-to-cell contact and structures that resemble in vivo architecture. The aim of this study was to develop a simple high-throughput three-dimensional drug screening method and to compare drug responses in JIMT1 breast cancer cells when grown in two dimensions, in poly(2-hydroxyethyl methacrylate) induced anchorage-independent three-dimensional models, and in Matrigel three-dimensional cell culture models. We screened 102 compounds with multiple concentrations and biological replicates for their effects on cell proliferation. The cells were either treated immediately upon plating, or they were allowed to grow in three-dimensional cultures for 4 days before the drug treatment. Large variations in drug responses were observed between the models indicating that comparisons of culture model-influenced drug sensitivities cannot be made based on the effects of a single drug. However, we show with the 63 most prominent drugs that, in general, JIMT1 cells grown on Matrigel were significantly more sensitive to drugs than cells grown in two-dimensional cultures, while the responses of cells grown in poly(2-hydroxyethyl methacrylate) resembled those of the two-dimensional cultures. Furthermore, comparing the gene expression profiles of the cell culture models to xenograft tumors indicated that cells cultured in Matrigel and as xenografts most closely resembled each other. In this study, we also suggest that three-dimensional cultures can provide a platform for systematic experimentation of larger compound collections in a high-throughput mode and be used as alternatives to traditional two-dimensional screens for better comparability to the in vivo state.
Functional Profiling of Precursor MicroRNAs Identifies MicroRNAs Essential for Glioma Proliferation
Saija Haapa-Paananen, Ping Chen, Kirsi Hellstr?m, Pekka Kohonen, Sampsa Hautaniemi, Olli Kallioniemi, Merja Perl
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060930
Abstract: Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.
High-Throughput Transcriptomic and RNAi Analysis Identifies AIM1, ERGIC1, TMED3 and TPX2 as Potential Drug Targets in Prostate Cancer
Paula Vainio, John-Patrick Mpindi, Pekka Kohonen, Vidal Fey, Tuomas Mirtti, Kalle A. Alanen, Merja Perl, Olli Kallioniemi, Kristiina Iljin
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039801
Abstract: Prostate cancer is a heterogeneous group of diseases and there is a need for more efficient and targeted methods of treatment. In this study, the potential of gene expression data and RNA interference technique were combined to advance future personalized prostate cancer therapeutics. To distinguish the most promising in vivo prevalidated prostate cancer drug targets, a bioinformatic analysis was carried out using genome-wide gene expression data from 9873 human tissue samples. In total, 295 genes were selected for further functional studies in cultured prostate cancer cells due to their high mRNA expression in prostate, prostate cancer or in metastatic prostate cancer samples. Second, RNAi based cell viability assay was performed in VCaP and LNCaP prostate cancer cells. Based on the siRNA results, gene expression patterns in human tissues and novelty, endoplasmic reticulum function associated targets AIM1, ERGIC1 and TMED3, as well as mitosis regulating TPX2 were selected for further validation. AIM1, ERGIC1, and TPX2 were shown to be highly expressed especially in prostate cancer tissues, and high mRNA expression of ERGIC1 and TMED3 associated with AR and ERG oncogene expression. ERGIC1 silencing specifically regulated the proliferation of ERG oncogene positive prostate cancer cells and inhibited ERG mRNA expression in these cells, indicating that it is a potent drug target in ERG positive subgroup of prostate cancers. TPX2 expression associated with PSA failure and TPX2 silencing reduced PSA expression, indicating that TPX2 regulates androgen receptor mediated signaling. In conclusion, the combinatorial usage of microarray and RNAi techniques yielded in a large number of potential novel biomarkers and therapeutic targets, for future development of targeted and personalized approaches for prostate cancer management.
miRNA-mRNA Integrated Analysis Reveals Roles for miRNAs in Primary Breast Tumors
Espen Enerly,Israel Steinfeld,Kristine Kleivi,Suvi-Katri Leivonen,Miriam R. Aure,Hege G. Russnes,Jo Anders R?nneberg,Hilde Johnsen,Roy Navon,Einar R?dland,Rami M?kel?,Bj?rn Naume,Merja Perl,Olli Kallioniemi,Vessela N. Kristensen,Zohar Yakhini,Anne-Lise B?rresen-Dale
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016915
Abstract: Few studies have performed expression profiling of both miRNA and mRNA from the same primary breast carcinomas. In this study we present and analyze data derived from expression profiling of 799 miRNAs in 101 primary human breast tumors, along with genome-wide mRNA profiles and extensive clinical information.
Contrast-Enhanced Ultrasonographic Detection and Dual-Phase Computed Tomographic Angiography in a 5-Year-Old Boxer with Pancreatic Insulinoma
—Case Report

Vilma Reunanen, Merja Laitinen
Open Journal of Veterinary Medicine (OJVM) , 2015, DOI: 10.4236/ojvm.2015.57024
Abstract: This case report describes the findings in a canine histopathologically confirmed pancreatic insulinoma using contrast-enhanced ultrasound (CEUS) and dual-phase computed tomographic angiography (CTA). The insulinoma was better demarcated in CEUS and CTA compared with conventional B-mode ultrasound. On the other hand, only one of two nodules visible in CTA was detected in CEUS. In this case, the insulinoma had an atypical non-contrast-enhancing appearance in both CEUS and CTA. Lack of enhancement in CEUS and CTA has previously been reported in human and canine studies, but this was the first report using both CEUS and CTA for detecting canine insulinoma.
Tailored targeted therapy for all: a realistic and worthwhile objective?
Per L?nning
Breast Cancer Research , 2009, DOI: 10.1186/bcr2426
Abstract: In theory, a similar discussion should be applied not only to "targeted" therapy but to anticancer strategies in general, including options like cytotoxic therapy as well. On the one hand, parameters such as the histological grade as well as gene expression profiles revealed by microarrays provide moderate statistical correlates to outcome [4] but do not define biological targets. In contrast, a parameter such as topoisomerase II may be considered borderline in this respect. The fact that this enzyme is a direct target of anthracyclines, and amplification of its gene has been related to improved sensitivity to anthracycline therapy [5,6], suggests anthracycline-based chemotherapy to be a tailormade therapy for topoisomerase-II-amplified tumours. On the other hand, topoisomerase II overexpression is not mandatory for anthracycline response, and evidence regarding its predictive role remains conflicting [7].In the present article we will briefly go through the potential for tailormade treatment in breast cancer. As may be seen, most breast cancer patients already receive some form of tailored therapy, and recent evidence suggests novel highly innovative tailored approaches to be on their way into the clinic.It is conventional wisdom that breast cancers may be separated into two categories - so-called oestrogen receptor (ER)-positive tumours versus ER-negative tumours. What remains more controversial is the exact definition of receptor positivity; should we consider 1% or 10% of cells expressing positive staining as the lower limit, and should staining intensity be taken into account [8]?Breast cancers have more recently been separated into five distinct classes based on gene expression profiles (Figure 1): the luminal A and luminal B classes, the HER2 and basal classes, and, finally, so-called normal breast-like tumours [9]. The different tumour categories express distinct gene expression profiles; in addition, the different classes reveal different prognoses [9,10].
Corpora and historical linguistics
Kyt?, Merja;
Revista Brasileira de Linguística Aplicada , 2011, DOI: 10.1590/S1984-63982011000200007
Abstract: the present article aims to survey and assess the current state of electronic historical corpora and corpus methodology, and attempts to look into possible future developments. it highlights the fact that within the wide spectrum of corpus linguistic methodology, historical corpus linguistics has emerged as a vibrant field that has significantly added to the appeal felt for the study of language history and change. in fact, according to a historical linguist with more than fifty years of experience, "[w]e could even go as far as to say that without the support and new impetus provided by corpora, evidence-based historical linguistics would have been close to the end of its life-span in these days of rapid-changing life and research, increasing competition on the academic career track and the methodological attractions offered to young scholars" (rissanen, forthcoming). historical corpora and other electronic resources have also made the study of language history attractive: working on them engages students in an individual and interactive way that they find appealing (curzan 2000, p. 81).
A new feature of importance for the TNF-alpha system in inflammation—Bilateral myositis that develops early in response to unilateral overuse shows a marked involvement of TNF-alpha not only in the exercised side but also contralaterally  [PDF]
Lina Renstr?m, Per St?l, Sture Forsgren
Modern Research in Inflammation (MRI) , 2013, DOI: 10.4236/mri.2013.24012

Using a rabbit model leading to myositis in response to exercise-induced muscle overuse, we have previously observed that TNF-alpha is involved in the exercised muscle in early developing myositis as well as both ipsiand contralaterally in the myositis which develops in response to a lengthened period of overuse. It is unknown if TNF-alpha can also be engaged contralaterally in early stages of myositis. The hypothesis was that this is the case. It was therefore evaluated whether the TNF-alpha system is early involved contralaterally. An experimental model of 1 week of overuse of the soleus muscle on one side leading to myositis was used, and in situ hybridization and immunohistochemistry were applied to study the expression patterns of TNF-alpha in the soleus muscle in the contralateral side. TNF-alpha was expressed in the myositis process which occurred contralaterally. There were thus TNF-alpha mRNA reactions in the cells of the inflammatory infiltrates, in blood vessel walls and in certain of the muscle fibers. Parts of the latter were necrotic fibers, whereas others were interpreted to be in a regenerative stage. TNF-alpha immunoreactions were seen for infiltrating white blood cells. The observations show that the TNF-alpha system is early involved in the cross-over effects that occur in response to unilateral muscle overuse leading to myositis bilaterally. TNF-alpha is likely to have pro-inflammatory and destructive effects but also to have effects in the muscle regenerative processes. The occurrence of an early involvement of the TNF-alpha system contralaterally to the injury side shows a new aspect of importance of this

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