108 results on '"Vainio, Paula"'
Search Results
2. Germline-specific RNA helicase DDX4 forms cytoplasmic granules in cancer cells and promotes tumor growth
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Olotu, Opeyemi, Koskenniemi, Anna-Riina, Ma, Lin, Paramonov, Valeriy, Laasanen, Sini, Louramo, Elina, Bourgery, Matthieu, Lehtiniemi, Tiina, Laasanen, Samuli, Rivero-Müller, Adolfo, Löyttyniemi, Eliisa, Sahlgren, Cecilia, Westermarck, Jukka, Ventelä, Sami, Visakorpi, Tapio, Poutanen, Matti, Vainio, Paula, Mäkelä, Juho-Antti, and Kotaja, Noora
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- 2024
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3. A three-feature prediction model for metastasis-free survival after surgery of localized clear cell renal cell carcinoma
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Mattila, Kalle E., Laajala, Teemu D., Tornberg, Sara V., Kilpeläinen, Tuomas P., Vainio, Paula, Ettala, Otto, Boström, Peter J., Nisen, Harry, Elo, Laura L., and Jaakkola, Panu M.
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- 2021
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4. Performance of Finnish biobanks in nationwide pulmonary carcinoid tumour research
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Vesterinen, Tiina, Salmenkivi, Kaisa, Mustonen, Harri, Kuopio, Teijo, Lappi-Blanco, Elisa, Paavonen, Timo, Vainio, Paula, Knuuttila, Aija, Carpén, Olli, Haglund, Caj, and Arola, Johanna
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- 2020
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5. Low nuclear expression of HIF‐hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence‐free survival in clear cell renal cell carcinoma.
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Luomala, Lassi, Mattila, Kalle, Vainio, Paula, Nisén, Harry, Pellinen, Teijo, Lohi, Jouni, Laajala, Teemu D., Järvinen, Petrus, Koskenniemi, Anna‐Riina, Jaakkola, Panu, and Mirtti, Tuomas
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RENAL cell carcinoma ,CELL survival ,IMMUNOSTAINING ,PROGNOSIS ,ELECTRONIC health records - Abstract
Background: Hypoxia inducible factors, HIF‐1α and HIF‐2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments. Patients and Methods: In this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence‐free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue‐microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow‐up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated. Results: Nuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT‐stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts. Conclusions: The absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Tumor‐to‐tumor metastasis to Warthin tumor presenting as an initial sign of breast carcinoma: A case report.
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Mansikka, Iisa, Kinnunen, Ilpo, Hirvonen, Jussi, Vainio, Paula, and Velhonoja, Jarno
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PAROTID gland tumors ,SALIVARY gland cancer ,METASTASIS ,PAROTID glands ,SALIVARY glands ,NEEDLE biopsy - Abstract
Metastases of distant primary tumors on the parotid gland are very rare. Tumor‐to‐tumor metastasis to salivary gland tumors is extremely rare. A case of a 69‐year‐old woman with a large left parotid gland mass with no previous salivary gland problems or cancer. Fine‐needle aspiration (FNA) showed evidence of a Warthin tumor. A total left parotidectomy was performed. The final pathology report showed a Warthin tumor containing two metastases of adenocarcinoma. The immunohistochemistry of the metastases led to the diagnosis of primary breast cancer. A negative FNA does not rule out the possibility of a malignant parotid tumor or metastasis, and a parotid lump should be presumed to be a secondary tumor until proven otherwise if the patient has a history of any distant primary cancer. Our patient case serves as a reminder that a new distant primary cancer might be the cause of a parotid lump. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Molekyylipatologia osana syöpäpotilaan hoitoa : patologin uusi rooli
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Orte, Katri, Vainio, Paula, Mirtti, Tuomas, Taimen, Pekka, Arola, Johanna, Kallajoki, Markku, Research Program in Systems Oncology, HUSLAB, Patologian osasto, Tutkimusohjelmayksikkö, HUS Diagnostiikkakeskus, and Helsingin yliopisto
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Pathologists ,Professional Competence ,3111 Biolääketieteet ,+therapy ,Neoplasms ,+diagnosis ,+genetics ,Precision Medicine ,Physician's Role - Abstract
Teema : geeniohjatun syövän hoidon työryhmä
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- 2021
8. Integrative Genomic, Transcriptomic, and RNAi Analysis Indicates a Potential Oncogenic Role for FAM110B in Castration-Resistant Prostate Cancer
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Vainio, Paula, Wolf, Maija, Edgren, Henrik, He, Tao, Kohonen, Pekka, Mpindi, John-Patrick, Smit, Frank, Verhaegh, Gerald, Schalken, Jack, Perälä, Merja, Iljin, Kristiina, and Kallioniemi, Olli
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- 2012
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9. 15-Hydroxyprostaglandin dehydrogenase associates with poor prognosis in breast cancer, induces epithelial–mesenchymal transition, and promotes cell migration in cultured breast cancer cells
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Lehtinen, Laura, Vainio, Paula, Wikman, Harriet, Reemts, Johannes, Hilvo, Mika, Issa, Rana, Pollari, Sirkku, Brandt, Burkhard, Oresic, Matej, Pantel, Klaus, Kallioniemi, Olli, and Iljin, Kristiina
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- 2012
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10. How to read biparametric MRI in men with a clinical suspicious of prostate cancer: Pictorial review for beginners with public access to imaging, clinical and histopathological database.
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Jambor, Ivan, Martini, Alberto, Falagario, Ugo G, Ettala, Otto, Taimen, Pekka, Knaapila, Juha, Syvänen, Kari T, Steiner, Aida, Verho, Janne, Perez, Ileana M, Merisaari, Harri, Vainio, Paula, Lamminen, Tarja, Saunavaara, Jani, Carrieri, Giuseppe, Boström, Peter J, and Aronen, Hannu J
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MAGNETIC resonance imaging ,HISTOPATHOLOGY ,PROSTATE cancer ,CONTRAST media ,RESIDENTS (Medicine) - Abstract
Prostate Magnetic Resonance Imaging (MRI) is increasingly being used in men with a clinical suspicion of prostate cancer (PCa). Performing prostate MRI without the use of an intravenous contrast (IV) agent in men with a clinical suspicion of PCa can lead to reduced MRI scan time. Enabling a large array of different medical providers (from mid-level to specialized radiologists) to evaluate and potentially report prostate MRI in men with a clinical suspicion of PCa with a high accuracy could be one way to enable wide adoption of prostate MRI in men with a clinical suspicion of PCa. The aim of this pictorial review is to provide an insight into acquisition, quality control and reporting of prostate MRI performed without IV contrast agent in men with a clinical suspicion of PCa, aimed specifically at radiologists starting reporting prostate MRI, urologists, urology/radiology residents and mid-level medical providers without experience in reporting prostate MRI. Free public access (http://petiv.utu.fi/improd/and http://petiv.utu.fi/multiimprod/) to complete datasets of 161 and 338 men is provided. The imaging datasets are accompanied by clinical, laboratory and histopathological findings. Several topics are simplified in order to provide a solid base for the development of skills needed for an unsupervised review and potential reporting of prostate MRI in men with a clinical suspicion of PCa. The current review represents the first step towards enabling a large array of different medical providers to review and report accurately prostate MRI performed without IV contrast agent in men with a clinical suspicion of PCa. [ABSTRACT FROM AUTHOR]
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- 2021
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11. PLA2G7 associates with hormone receptor negativity in clinical breast cancer samples and regulates epithelial-mesenchymal transition in cultured breast cancer cells
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Lehtinen, Laura, Vainio, Paula, Wikman, Harriet, Huhtala, Heini, Mueller, Volkmar, Kallioniemi, Anne, Pantel, Klaus, Kronqvist, Pauliina, Kallioniemi, Olli, Carpèn, Olli, Iljin, Kristiina, Yhteiskuntatieteiden tiedekunta - Faculty of Social Sciences, Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, University of Tampere, Olli-Pekka Kallioniemi / Principal Investigator, Institute for Molecular Medicine Finland, Precision Cancer Pathology, and Precision Systems Medicine
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epithelial‐mesenchymal transition ,3122 Cancers ,EMT ,Original Articles ,invasion ,PLA2G7 ,PLA2G7, epithelial-mesenchymal transition, EMT, vimentin, breast cancer, prognosis, metastasis, invasion ,vimentin ,breast cancer ,Syöpätaudit - Cancers ,Lääketieteen bioteknologia - Medical biotechnology ,metastasis ,Original Article ,3111 Biomedicine ,prognosis ,skin and connective tissue diseases - Abstract
Breast cancer is the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein-associated phospholipase A2 (PLA2G7) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome-wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome-wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT-PCR. The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial-mesenchymal transition (EMT)-related signalling pathways, vimentin and E-cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.
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- 2017
12. Prostate Cancer Risk Stratification in Men With a Clinical Suspicion of Prostate Cancer Using a Unique Biparametric MRI and Expression of 11 Genes in Apparently Benign Tissue: Evaluation Using Machine-Learning Techniques.
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Montoya Perez, Ileana, Jambor, Ivan, Pahikkala, Tapio, Airola, Antti, Merisaari, Harri, Saunavaara, Jani, Alinezhad, Saeid, Väänänen, Riina‐Minna, Tallgrén, Terhi, Verho, Janne, Kiviniemi, Aida, Ettala, Otto, Knaapila, Juha, Syvänen, Kari T., Kallajoki, Markku, Vainio, Paula, Aronen, Hannu J., Pettersson, Kim, Boström, Peter J., and Taimen, Pekka
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PROSTATE cancer ,BIOMARKERS ,GLEASON grading system ,GENE expression ,DIFFUSION magnetic resonance imaging - Abstract
Background: Accurate risk stratification of men with a clinical suspicion of prostate cancer (cSPCa) remains challenging despite the increasing use of MRI.Purpose: To evaluate the diagnostic accuracy of a unique biparametric MRI protocol (IMPROD bpMRI) combined with clinical and molecular markers in men with cSPCa.Study Type: Prospective single-institutional clinical trial (NCT01864135).Subjects: Eighty men with cSPCa.Field Strength/sequence: 3T, surface array coils. Two T2 -weighted and three diffusion-weighted imaging (DWI) acquisitions: 1) b-values 0, 100, 200, 300, 500 s/mm2 ; 2) b-values 0,1500 s/mm2 ; 3) b-values 0, 2000 s/mm2 .Assessment: IMPROD bpMRI examinations were qualitatively (IMPROD bpMRI Likert score) and quantitatively (DWI-based Gleason grade score) prospectively reported. Men with IMPROD bpMRI Likert 3-5 had two targeted biopsies followed by 12-core systematic biopsies (SB); those with IMPROD bpMRI Likert 1-2 had only SB. Additionally, 2-core from normal-appearing prostate areas were obtained for the mRNA expression of ACSM1, AMACR, CACNA1D, DLX1, PCA3, PLA2G7, RHOU, SPINK1, SPON2, TMPRSS2-ERG, and TDRD1 measured by quantitative reverse-transcription polymerase chain reaction.Statistical Tests: Univariate and multivariate analysis using regularized least-squares, feature selection and tournament leave-pair-out cross-validation (TLPOCV), as well as 10 random splits of the data in training-testing sets, were used to evaluate the mRNA, clinical and IMPROD bpMRI parameters in detecting clinically significant prostate cancer (SPCa) defined as Gleason score ≥ 3 + 4. The evaluation metric was the area under the curve (AUC).Results: IMPROD bpMRI Likert demonstrated the highest TLPOCV AUC of 0.92. The tested clinical variables had AUC 0.56-0.73, while the mRNA and additional IMPROD bpMRI parameters had AUC 0.50-0.67 and 0.65-0.89 respectively. The combination of clinical and mRNA biomarkers produced TLPOCV AUC of 0.87, the highest TLPOCV performance without including IMPROD bpMRI Likert.Data Conclusion: The qualitative IMPROD bpMRI Likert score demonstrated the highest accuracy for SPCa detection compared with the tested clinical variables and mRNA biomarkers.Level Of Evidence: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1540-1553. [ABSTRACT FROM AUTHOR]- Published
- 2020
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13. IMPROD biparametric MRI in men with a clinical suspicion of prostate cancer (IMPROD Trial): Sensitivity for prostate cancer detection in correlation with whole-mount prostatectomy sections and implications for focal therapy.
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Merisaari, Harri, Jambor, Ivan, Ettala, Otto, Boström, Peter J., Montoya Perez, Ileana, Verho, Janne, Kiviniemi, Aida, Syvänen, Kari, Kähkönen, Esa, Eklund, Lauri, Pahikkala, Tapio, Vainio, Paula, Saunavaara, Jani, Aronen, Hannu J., and Taimen, Pekka
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PROSTATE cancer ,ABLATION techniques ,SUSPICION ,DIFFUSION magnetic resonance imaging ,GLEASON grading system - Abstract
Background: Prostate MRI is increasingly being used in men with a clinical suspicion of prostate cancer (PCa). However, development and validation of methods for focal therapy planning are still lagging.Purpose: To evaluate the diagnostic accuracy on lesion, region-of-interest (ROI), and voxel level of IMPROD biparametric prostate MRI (bpMRI) for PCa detection in men with a clinical suspicion of PCa who subsequently underwent radical prostatectomy.Study Type: Prospective single-institution clinical trial (NCT01864135).Population: Sixty-four men who underwent radical prostatectomy after IMPROD bpMRI performed in prebiopsy settings.Field Strength/sequence: IMPROD bpMRI consisted of T2 -weighted imaging (T2 w) and three separate diffusion-weighted imaging acquisitions with an average acquisition time of 15 minutes.Assessment: The diagnostic accuracy of prospectively reported manual cancer delineations and regions increased with 3D dilation were evaluated on the voxel level (volume of 1.17 mm3 , 1 mm3 , 125 mm3 ) as well as the 36 ROI level. Only PCa lesions with a diameter ≥ 5 mm or any Gleason Grade 4 were analyzed. All data and protocols are freely available at: http://petiv.utu.fi/improd STATISTICAL TESTS: Sensitivity, specificity, accuracy.Results: In total, 99 PCa lesions were identified. Forty (40%, 40/99) had a Gleason score (GS) of >3 + 4. Twenty-eight PCa lesions (28%, 28/99) were missed by IMPROD bpMRI, three (7.5%, 3/40) with GS >3 + 4. 3D dilation of manual cancer delineations in all directions by ~10-12 mm (corresponding to the Hausdorff distance) was needed to achieve sensitivity approaching 100% on a voxel level.Data Conclusion: IMPROD bpMRI had a high sensitivity on lesion level for PCa with GS >3 + 4. Increasing 3D lesion delineations by ~10-12 mm (corresponding to the Hausdorff distance) was needed to achieve high sensitivity on the voxel level. Such information may help in planning ablation therapies.Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1641-1650. [ABSTRACT FROM AUTHOR]- Published
- 2019
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14. Somatostatin Receptor Expression Is Associated With Metastasis and Patient Outcome in Pulmonary Carcinoid Tumors.
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Vesterinen, Tiina, Leijon, Helena, Mustonen, Harri, Remes, Satu, Knuuttila, Aija, Salmenkivi, Kaisa, Vainio, Paula, Arola, Johanna, and Haglund, Caj
- Abstract
Pulmonary carcinoids (PCs) belong to neuroendocrine tumors that often overexpress somatostatin receptors (SSTRs). This overexpression provides a molecular basis for tumor imaging and treatment with somatostatin analogs.
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- 2019
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15. High-Throughput Screening for Novel Prostate Cancer Drug Targets:Getting Personal: Dissertation
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Vainio, Paula
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tehoseulonta ,Prostate cancer ,eturauhassyöpä ,lääkehoidon kohde ,drug ,high-throughput screening ,drug target ,RNA interference ,SDG 3 - Good Health and Well-being ,lääke ,gene expression ,biomarker ,geenin ilmentyminen ,merkkiaine ,RNA interferenssi - Abstract
Prostate cancers form a heterogeneous group of diseases and there is a need for novel biomarkers, and for more efficient and targeted methods of treatment. In this thesis, the potential of microarray data, RNA interference (RNAi) and compound screens were utilized in order to identify novel biomarkers, drug targets and drugs for future personalized prostate cancer therapeutics. First, a bioinformatic mRNA expression analysis covering 9873 human tissue and cell samples, including 349 prostate cancer and 147 normal prostate samples, was used to distinguish in silico prevalidated putative prostate cancer biomarkers and drug targets. Second, RNAi based high-throughput (HT) functional profiling of 295 prostate and prostate cancer tissue specific genes was performed in cultured prostate cancer cells. Third, a HT compound screen approach using a library of 4910 drugs and drug-like molecules was exploited to identify potential drugs inhibiting prostate cancer cell growth. Nine candidate drug targets, with biomarker potential, and one cancer selective compound were validated in vitro and in vivo. In addition to androgen receptor (AR) signaling, endoplasmic reticulum (ER) function, arachidonic acid (AA) pathway, redox homeostasis and mitosis were identified as vital processes in prostate cancer cells. ERG oncogene positive cancer cells exhibited sensitivity to induction of oxidative and ER stress, whereas advanced and castrate-resistant prostate cancer (CRPC) could be potentially targeted through AR signaling and mitosis. In conclusion, this thesis illustrates the power of systems biological data analysis in the discovery of potential vulnerabilities present in prostate cancer cells, as well as novel options for personalized cancer management.
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- 2011
16. Known drugs, disulfiram, monensin and salinomycin, induce oxidative stress in prostate cancer cells
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Ketola, Kirsi, Vainio, Paula, Halonen, Pasi, Kohonen, Pekka, Fey, Vidal, Grafström, Roland, Perälä, Merja, Kallioniemi, Olli, and Iljin, Kristiina
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SDG 3 - Good Health and Well-being - Published
- 2011
17. PLA2G7 associates with aggressive prostate cancer in vivo and regulates prostate cancer cell migration and adhesion in vitro
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Vainio, Paula, Hilvo, Mika, Vesterinen, T., Gupta, Santosh, Härmä, Ville, Nees, Matthias, Turunen, J. P., Lundin, J., Rannikko, A., Oresic, Matej, Kallioniemi, Olli, and Iljin, Kristiina
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SDG 3 - Good Health and Well-being - Published
- 2011
18. Identification of novel therapeutic strategies to target ERG oncogene positive prostate cancer
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Vainio, Paula, Ketola, Kirsi, Mirtti, T., Alanen, K., Perälä, Merja, Kallioniemi, Olli, and Iljin, Kristiina
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SDG 3 - Good Health and Well-being - Published
- 2011
19. High-throughput compound and siRNA screening to identify novel treatment options for ERG oncogene positive prostate cancers
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Iljin, Kristiina, Vainio, Paula, Ketola, Kirsi, Björkman, M., Kohonen, Pekka, Mpindi, John, Fey, Vidal, Mirtti, T., Alanen, K., Perälä, Merja, and Kallioniemi, Olli
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SDG 3 - Good Health and Well-being - Published
- 2010
20. Drugs with known pharmacological profiles, such as monensin, disulfiram and salinomycin, show cancer-selective inhibition of prostate cancer cell growth by increasing oxidative stress
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Ketola, Kirsi, Vainio, Paula, Halonen, Pasi, Kohonen, Pekka, Fey, Vidal, Grafström, Roland, Perälä, Merja, Kallioniemi, Olli, and Iljin, Kristiina
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SDG 3 - Good Health and Well-being - Published
- 2010
21. High-throughput screening for novel prostate cancer drug targets
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Vainio, Paula, Ketola, Kirsi, Mpindi, John, Kilpinen, Sami, Kohonen, Pekka, Fey, Vidal, Björkman, Mari, Perälä, Merja, Kallioniemi, Olli, and Iljin, Kristiina
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SDG 3 - Good Health and Well-being - Published
- 2009
22. A link between multiple high throughput technology datasets
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Bucher, Elmar, Kohonen, Pekka, Fey, Vidal, Mpindi, John, Sara, Henri, Pisto, Tommi, Edgren, Henrik, Kilpinen, Sami, Ojala, Kalle, Tiikkainen, Pekka, Vainio, Paula, Iljin, Kristiina, Sahlberg, Niko, Rantala, Juha K., Mäkelä, Rami, Saviranta, Petri, Perälä, Merja, Nees, Matthias, Haapa-Paananen, Saija, and Kallioniemi, Olli
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SDG 3 - Good Health and Well-being ,database management system ,database design ,MySQL ,high througput screening technology - Abstract
Our laboratory performs high-throughput screening (HTS) experiments using siRNA, miRNA and compound libraries on cancer-cell lines. We utilize three technologies: plate-based screens with different assays as endpoints, transfected cell arrays with up to four antibody endpoints, and protein lysate arrays allowing many immunostaining endpoints. In addition, we profile samples using at least three commercially available microarray technologies: gene expression using Affymetrix arrays, miRNA expression using Agilent arrays, and gene copy numbers (aCGH) using Agilent arrays. This enables us to study the same biological sample from multiple angles which provides a unique integrated opportunity to understand cancer. The database design presented here is based on the idea that different high-throughput technologies can be integrated at the gene level.
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- 2008
23. Nakkisormesta älypelaajaksi : kertomus lentopallon taktisen viitepeliympäristön kehittämisestä
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Tuomaala, Juuso and Vainio, Paula
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pelit ,oppiminen ,joukkuepelit ,toimintatutkimus ,lentopallo ,viitepelit ,opetus - Published
- 2006
24. Novel COL1A1 Mutation c.3290G>T Associated With Severe Form of Osteogenesis Imperfecta in a Fetus.
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Tanner, Laura, Vainio, Paula, Sandell, Minna, and Laine, Jukka
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OSTEOGENESIS imperfecta ,SKELETAL dysplasia ,GENETIC code ,PRENATAL diagnosis - Abstract
Osteogenesis imperfecta is a genetically and clinically heterogenous group of skeletal dysplasias characterized by bone fragility. Its severity ranges from nearly asymptomatic individuals to perinatal lethality. The majority of cases are caused by mutations in either the COL1A1 or the COL1A2 gene coding for alpha 1 and alpha 2 chains of collagen type 1, respectively, and a large number of pathogenic variants of these genes has been identified. We describe a novel COL1A1 mutation associated with prenatally diagnosed severe form of osteogenesis imperfecta. [ABSTRACT FROM AUTHOR]
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- 2017
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25. Patient-specific pharmacokinetic parameter estimation on dynamic contrast-enhanced MRI of prostate: Preliminary evaluation of a novel AIF-free estimation method.
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Ginsburg, Shoshana B., Taimen, Pekka, Merisaari, Harri, Vainio, Paula, Boström, Peter J., Aronen, Hannu J., Jambor, Ivan, Madabhushi, Anant, and Boström, Peter J
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ALGORITHMS ,BIOLOGICAL models ,BIOTRANSFORMATION (Metabolism) ,COMPUTER simulation ,DIFFERENTIAL diagnosis ,DIAGNOSTIC imaging ,MAGNETIC resonance imaging ,COMPUTERS in medicine ,ORGANOMETALLIC compounds ,PROSTATE tumors ,RESEARCH evaluation ,RESEARCH funding ,SORBITOL ,PILOT projects ,CONTRAST media ,RETROSPECTIVE studies - Abstract
Purpose: To develop and evaluate a prostate-based method (PBM) for estimating pharmacokinetic parameters on dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) by leveraging inherent differences in pharmacokinetic characteristics between the peripheral zone (PZ) and transition zone (TZ).Materials and Methods: This retrospective study, approved by the Institutional Review Board, included 40 patients who underwent a multiparametric 3T MRI examination and subsequent radical prostatectomy. A two-step PBM for estimating pharmacokinetic parameters exploited the inherent differences in pharmacokinetic characteristics associated with the TZ and PZ. First, the reference region model was implemented to estimate ratios of Ktrans between normal TZ and PZ. Subsequently, the reference region model was leveraged again to estimate values for Ktrans and ve for every prostate voxel. The parameters of PBM were compared with those estimated using an arterial input function (AIF) derived from the femoral arteries. The ability of the parameters to differentiate prostate cancer (PCa) from benign tissue was evaluated on a voxel and lesion level. Additionally, the effect of temporal downsampling of the DCE MRI data was assessed.Results: Significant differences (P < 0.05) in PBM Ktrans between PCa lesions and benign tissue were found in 26/27 patients with TZ lesions and in 33/38 patients with PZ lesions; significant differences in AIF-based Ktrans occurred in 26/27 and 30/38 patients, respectively. The 75th and 100th percentiles of Ktrans and ve estimated using PBM positively correlated with lesion size (P < 0.05).Conclusion: Pharmacokinetic parameters estimated via PBM outperformed AIF-based parameters in PCa detection. J. Magn. Reson. Imaging 2016;44:1405-1414. [ABSTRACT FROM AUTHOR]- Published
- 2016
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26. High-Throughput Transcriptomic and RNAi Analysis Identifies AIM1, ERGIC1, TMED3 and TPX2 as Potential Drug Targets in Prostate Cancer
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University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Vainio, Paula, Mpindi, John Patrick, Kohonen, Pekka, Fey, Vidal, Mirtti, Tuomas, Alanen, Kalle A., Perala, Merja, Kallioniemi, Olli, Iljin, Kristiina, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Vainio, Paula, Mpindi, John Patrick, Kohonen, Pekka, Fey, Vidal, Mirtti, Tuomas, Alanen, Kalle A., Perala, Merja, Kallioniemi, Olli, and Iljin, Kristiina
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- 2012
27. Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins
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Vainio, Paula, Lehtinen, Laura, Mirtti, Tuomas, Hilvo, Mika, Seppänen-Laakso, Tuulikki, Virtanen, Johannes, Sankila, Anna, Nordling, Stig, Lundin, Johan, Rannikko, Antti, Oresic, Matej, Kallioniemi, Olli, Iljin, Kristiina, Vainio, Paula, Lehtinen, Laura, Mirtti, Tuomas, Hilvo, Mika, Seppänen-Laakso, Tuulikki, Virtanen, Johannes, Sankila, Anna, Nordling, Stig, Lundin, Johan, Rannikko, Antti, Oresic, Matej, Kallioniemi, Olli, and Iljin, Kristiina
- Abstract
Prostate cancer is the second leading cause of cancer mortality in men in developed countries. Due to the heterogeneous nature of the disease, design of novel personalized treatments is required to achieve efficient therapeutic responses. We have recently identified phospholipase 2 group VII (PLA2G7) as a potential drug target especially in ERG oncogene positive prostate cancers. Here, the expression profile of PLA2G7 was studied in 1137 prostate cancer and 409 adjacent non-malignant prostate tissues using immunohistochemistry to validate its biomarker potential and putative association with disease progression. In order to reveal the molecular alterations induced by PLA2G7 impairment, lipidomic and gene expression profiling was performed in response to PLA2G7 silencing in cultured prostate cancer cells. Moreover, the antineoplastic effect of statins combined with PLA2G7 impairment was studied in prostate cancer cells to evaluate the potential of repositioning of in vivo compatible drugs developed for other indications towards anti-cancer purposes. The results indicated that PLA2G7 is a cancer-selective biomarker in 50 % of prostate cancers and associates with aggressive disease. The alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti-migratorial therapeutic approach in prostate cancer. Moreover, the anti-proliferative effect of PLA2G7 silencing was potentiated by lipid-lowering statins in prostate cancer cells. Taken together, our results support the potential of PLA2G7 as a biomarker and a drug target in prostate cancer and present a rationale for combining PLA2G7 inhibition with the use of statins in prostate cancer management.
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- 2011
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28. High-Throughput Transcriptomic and RNAi Analysis Identifies AIM1, ERGIC1, TMED3 and TPX2 as Potential Drug Targets in Prostate Cancer.
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Vainio, Paula, Mpindi, John-Patrick, Kohonen, Pekka, Fey, Vidal, Mirtti, Tuomas, Alanen, Kalle A., Perälä, Merja, Kallioniemi, Olli, and Iljin, Kristiina
- Subjects
- *
PROSTATE cancer , *DRUG target , *TARGET organs (Anatomy) , *CANCER treatment , *GENE expression , *GENETIC regulation - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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29. GTI: A Novel Algorithm for Identifying Outlier Gene Expression Profiles from Integrated Microarray Datasets.
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Mpindi, John Patrick, Sara, Henri, Haapa-Paananen, Saija, Kilpinen, Sami, Pisto, Tommi, Bucher, Elmar, Ojala, Kalle, Iljin, Kristiina, Vainio, Paula, jörkman, Mari, Gupta, Santosh, Kohonen, Pekka, Nees, Matthias, and Kallioniemi, Olli
- Subjects
META-analysis ,GENE expression ,DNA microarrays ,ONCOGENES ,ASTROCYTOMAS ,GLIOBLASTOMA multiforme ,CENTRAL nervous system abnormality genetics - Abstract
Background: Meta-analysis of gene expression microarray datasets presents significant challenges for statistical analysis. We developed and validated a new bioinformatic method for the identification of genes upregulated in subsets of samples of a given tumour type ('outlier genes'), a hallmark of potential oncogenes. Methodology: A new statistical method (the gene tissue index, GTI) was developed by modifying and adapting algorithms originally developed for statistical problems in economics. We compared the potential of the GTI to detect outlier genes in meta-datasets with four previously defined statistical methods, COPA, the OS statistic, the t-test and ORT, using simulated data. We demonstrated that the GTI performed equally well to existing methods in a single study simulation. Next, we evaluated the performance of the GTI in the analysis of combined Affymetrix gene expression data from several published studies covering 392 normal samples of tissue from the central nervous system, 74 astrocytomas, and 353 glioblastomas. According to the results, the GTI was better able than most of the previous methods to identify known oncogenic outlier genes. In addition, the GTI identified 29 novel outlier genes in glioblastomas, including TYMS and CDKN2A. The overexpression of these genes was validated in vivo by immunohistochemical staining data from clinical glioblastoma samples. Immunohistochemical data were available for 65% (19 of 29) of these genes, and 17 of these 19 genes (90%) showed a typical outlier staining pattern. Furthermore, raltitrexed, a specific inhibitor of TYMS used in the therapy of tumour types other than glioblastoma, also effectively blocked cell proliferation in glioblastoma cell lines, thus highlighting this outlier gene candidate as a potential therapeutic target. Conclusions/Significance: Taken together, these results support the GTI as a novel approach to identify potential oncogene outliers and drug targets. The algorithm is implemented in an R package (Text S1). [ABSTRACT FROM AUTHOR]
- Published
- 2011
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30. Prognostic Factors for Localized Clear Cell Renal Cell Carcinoma and Their Application in Adjuvant Therapy.
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Mattila, Kalle E., Vainio, Paula, and Jaakkola, Panu M.
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- *
RENAL cell carcinoma , *NEPHRECTOMY , *DNA , *CANCER relapse , *RISK assessment , *GENE expression , *COMBINED modality therapy , *PREDICTION models , *TUMOR markers , *DISEASE risk factors - Abstract
Simple Summary: Approximately one fifth of patients with newly diagnosed renal cell carcinoma (RCC) present with metastatic disease and over one third of the remaining patients with localized RCC will eventually have metastases spread to distant sites after complete resection of the primary tumor in the kidney. Usually, disease recurrence is observed within the first five years of follow-up, but late recurrences after five years are seen in up to 10% of patients. Despite novel biomarkers, simple histopathological factors, such as tumor size, tumor grade, and tumor extension into the blood vessels or beyond the kidney, are still valid features in predicting the risk of disease recurrence after surgery. The optimal set of prognostic factors remains unclear. The results from ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic features that help to define high-risk patients for disease recurrence. Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized surveillance programs, as well as for designing adjuvant therapy and trials. Several clinical and histopathological prognostic factors have been identified and adopted into prognostic algorithms to assess the individual risk for disease recurrence after radical or partial nephrectomy. However, the prediction accuracy of current prognostic models has been studied in retrospective patient cohorts and the optimal set of prognostic features remains unclear. In addition to traditional histopathological prognostic factors, novel biomarkers, such as gene expression profiles and circulating tumor DNA, are extensively studied to supplement existing prognostic algorithms to improve their prediction accuracy. Here, we aim to give an overview of existing prognostic features and prediction models for localized postoperative clear cell RCC and discuss their role in the adjuvant therapy trials. The results of ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic factors and biomarkers that help to define patients at high risk for disease recurrence. [ABSTRACT FROM AUTHOR]
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- 2022
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31. Arachidonic Acid Pathway Members PLA2G7, HPGD, EPHX2, and CYP4F8Identified as Putative Novel Therapeutic Targets in Prostate Cancer
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Vainio, Paula, Gupta, Santosh, Ketola, Kirsi, Mirtti, Tuomas, Mpindi, John-Patrick, Kohonen, Pekka, Fey, Vidal, Perälä, Merja, Smit, Frank, Verhaegh, Gerald, Schalken, Jack, Alanen, Kalle A., Kallioniemi, Olli, and Iljin, Kristiina
- Abstract
The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PLA2G7, HPGD, EPHX2, and CYP4F8genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERGoncogene-positive prostate cancers, and its silencing sensitized ERG-positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitroreduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress.
- Published
- 2011
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32. Molecular subtype diagnosis of endometrial carcinoma: comparison of the next-generation sequencing panel and Proactive Molecular Risk Classifier for Endometrial Cancer classifier.
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Huvila J, Orte K, Vainio P, Mettälä T, Joutsiniemi T, and Hietanen S
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- Adult, Aged, Aged, 80 and over, Female, Humans, Microsatellite Instability, Middle Aged, Mutation, Biomarkers, Tumor analysis, Biomarkers, Tumor genetics, Endometrial Neoplasms diagnosis, Endometrial Neoplasms genetics, High-Throughput Nucleotide Sequencing methods, Immunohistochemistry methods
- Abstract
The Cancer Genome Atlas-based molecular classification of endometrial carcinoma (EC) has the potential to better identify those patients whose disease is likely to behave differently than predicted when using traditional risk stratification; however, the optimal approach to molecular subtype assignment in routine practice remains undetermined. The aim of this study was to compare the results of two different widely available approaches to diagnosis the EC molecular subtype. EC specimens from 60 patients were molecularly subclassified using two different methods, by using the FoundationOne CDx next-generation sequencing (NGS) panel and using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classifier and performing immunostaining for mismatch repair proteins and p53. POLE mutation status was derived from FoundationOne results in both settings. Molecular classification based on ProMisE was successful for all 60 tumors. Microsatellite instability status could be determined based on the NGS panel results in 53 of 60 tumors, so ProMisE and NGS molecular subtype assignment could be directly compared for these 53 tumors. Molecular subtype diagnosis based on NGS and ProMisE was in agreement for 52 of 53 tumors. One tumor was microsatellite stable but showed loss of MLH1 and PMS2 expression. Molecular subtype diagnosis of EC based on the NGS panel of formalin-fixed paraffin-embedded ECs and based primarily on immunostaining (ProMisE) yields identical results in 98.1% (52/53, kappa = 0.97) of cases. Although results obtained using these two approaches are comparable, each has advantages and disadvantages that will influence the choice of the method to be used in clinical practice., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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33. PLA2G7 associates with hormone receptor negativity in clinical breast cancer samples and regulates epithelial-mesenchymal transition in cultured breast cancer cells.
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Lehtinen L, Vainio P, Wikman H, Huhtala H, Mueller V, Kallioniemi A, Pantel K, Kronqvist P, Kallioniemi O, Carpèn O, and Iljin K
- Abstract
Breast cancer is the leading cause of cancer-related deaths in women due to distinct cancer subtypes associated with early recurrence and aggressive metastatic progression. High lipoprotein-associated phospholipase A2 ( PLA2G7 ) expression has previously been associated with aggressive disease and metastasis in prostate cancer. Here, we explore the expression pattern and functional role of PLA2G7 in breast cancer. First, a bioinformatic analysis of genome-wide gene expression data from 970 breast samples was carried out to evaluate the expression pattern of PLA2G7 mRNA in breast cancer. Second, the expression profile of PLA2G7 was studied in 1042 breast cancer samples including 89 matched lymph node metastasis samples using immunohistochemistry. Third, the effect of PLA2G7 silencing on genome-wide gene expression profile was studied and validated in cultured breast cancer cells expressing PLA2G7 at high level. Last, the expression pattern of PLA2G7 mRNA was investigated in 24 nonmalignant tissue samples and 65 primary and 7 metastatic tumour samples derived from various organs using qRT-PCR. The results from clinical breast cancer samples indicated that PLA2G7 is overexpressed in a subset of breast cancer samples compared to its expression in benign breast tissue samples and that high PLA2G7 expression associated with hormone receptor negativity as well as with poor prognosis in a subset of breast cancer samples. In vitro functional studies highlighted the putative role of PLA2G7 in the regulation of epithelial-mesenchymal transition (EMT)-related signalling pathways, vimentin and E-cadherin protein expression as well as cell migration in cultured breast cancer cells. Furthermore, supporting the findings in breast and prostate cancer, high PLA2G7 mRNA expression was associated with metastatic cancer in four additional organs of origin. In conclusion, our results indicate that PLA2G7 is highly expressed in a subset of metastatic and aggressive breast cancers and in metastatic samples of various tissues of origin and promotes EMT and migration in cultured breast cancer cells.
- Published
- 2017
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34. Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins.
- Author
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Vainio P, Lehtinen L, Mirtti T, Hilvo M, Seppänen-Laakso T, Virtanen J, Sankila A, Nordling S, Lundin J, Rannikko A, Orešič M, Kallioniemi O, and Iljin K
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase, Aldehyde Dehydrogenase metabolism, Antineoplastic Agents pharmacology, Apoptosis genetics, Biomarkers, Tumor, Caspase 3 metabolism, Caspase 7 metabolism, Cell Adhesion genetics, Cell Line, Tumor, Cell Proliferation drug effects, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lysophosphatidylcholines metabolism, Male, Neoplasm Invasiveness genetics, Phospholipases A2 genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, RNA Interference, RNA, Small Interfering, Cell Movement, Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology, Phospholipases A2 metabolism, Prostatic Neoplasms enzymology
- Abstract
Prostate cancer is the second leading cause of cancer mortality in men in developed countries. Due to the heterogeneous nature of the disease, design of novel personalized treatments is required to achieve efficient therapeutic responses. We have recently identified phospholipase 2 group VII (PLA2G7) as a potential drug target especially in ERG oncogene positive prostate cancers. Here, the expression profile of PLA2G7 was studied in 1137 prostate cancer and 409 adjacent non-malignant prostate tissues using immunohistochemistry to validate its biomarker potential and putative association with disease progression. In order to reveal the molecular alterations induced by PLA2G7 impairment, lipidomic and gene expression profiling was performed in response to PLA2G7 silencing in cultured prostate cancer cells. Moreover, the antineoplastic effect of statins combined with PLA2G7 impairment was studied in prostate cancer cells to evaluate the potential of repositioning of in vivo compatible drugs developed for other indications towards anti-cancer purposes. The results indicated that PLA2G7 is a cancer-selective biomarker in 50 % of prostate cancers and associates with aggressive disease. The alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti-migratorial therapeutic approach in prostate cancer. Moreover, the anti-proliferative effect of PLA2G7 silencing was potentiated by lipid-lowering statins in prostate cancer cells. Taken together, our results support the potential of PLA2G7 as a biomarker and a drug target in prostate cancer and present a rationale for combining PLA2G7 inhibition with the use of statins in prostate cancer management.
- Published
- 2011
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35. Arachidonic acid pathway members PLA2G7, HPGD, EPHX2, and CYP4F8 identified as putative novel therapeutic targets in prostate cancer.
- Author
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Vainio P, Gupta S, Ketola K, Mirtti T, Mpindi JP, Kohonen P, Fey V, Perälä M, Smit F, Verhaegh G, Schalken J, Alanen KA, Kallioniemi O, and Iljin K
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Aged, 80 and over, Aryl Hydrocarbon Hydroxylases genetics, Aryl Hydrocarbon Hydroxylases metabolism, Cell Proliferation drug effects, Epoxide Hydrolases antagonists & inhibitors, Epoxide Hydrolases genetics, Epoxide Hydrolases metabolism, Flutamide pharmacology, Flutamide therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Gene Silencing drug effects, Humans, Hydroxyprostaglandin Dehydrogenases genetics, Hydroxyprostaglandin Dehydrogenases metabolism, Male, Middle Aged, Oxidative Stress drug effects, Oxidative Stress genetics, Phospholipase A2 Inhibitors, Phospholipases A2 genetics, Phospholipases A2 metabolism, Prostatic Neoplasms enzymology, Prostatic Neoplasms pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Androgen genetics, Receptors, Androgen metabolism, Reproducibility of Results, Signal Transduction drug effects, Arachidonic Acid metabolism, Molecular Targeted Therapy, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Signal Transduction genetics
- Abstract
The arachidonic acid and prostaglandin pathway has been implicated in prostate carcinogenesis, but comprehensive studies of the individual members in this key pathway are lacking. Here, we first conducted a systematic bioinformatic study of the expression of 36 arachidonic acid pathway genes across 9783 human tissue samples. The results showed that the PLA2G7, HPGD, EPHX2, and CYP4F8 genes are highly expressed in prostate cancer. Functional studies using RNA interference in prostate cancer cells indicated that all four genes are also essential for cell growth and survival. Clinical validation confirmed high PLA2G7 expression, especially in ERG oncogene-positive prostate cancers, and its silencing sensitized ERG-positive prostate cancer cells to oxidative stress. HPGD was highly expressed in androgen receptor (AR)-overexpressing advanced tumors, as well as in metastatic prostate cancers. EPHX2 mRNA correlated with AR in primary prostate cancers, and its inhibition in vitro reduced AR signaling and potentiated the effect of antiandrogen flutamide in cultured prostate cancer cells. In summary, we identified four novel putative therapeutic targets with biomarker potential for different subtypes of prostate cancer. In addition, our results indicate that inhibition of these enzymes may be particularly powerful when combined with other treatments, such as androgen deprivation or induction of oxidative stress., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
36. Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells.
- Author
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Ketola K, Vainio P, Fey V, Kallioniemi O, and Iljin K
- Subjects
- Aldehyde Dehydrogenase metabolism, Androgen Antagonists pharmacology, Animals, Ascorbic Acid pharmacology, Cattle, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cholesterol biosynthesis, Gene Expression Regulation, Neoplastic drug effects, Humans, Male, Monensin chemistry, Oxidative Stress genetics, Progesterone antagonists & inhibitors, Prostatic Neoplasms enzymology, Prostatic Neoplasms genetics, Protein Transport drug effects, Receptors, Androgen metabolism, Subcellular Fractions drug effects, Subcellular Fractions metabolism, Terfenadine agonists, Androgens metabolism, Apoptosis drug effects, Monensin pharmacology, Oxidative Stress drug effects, Prostatic Neoplasms pathology, Signal Transduction drug effects
- Abstract
Current treatment options for advanced and hormone refractory prostate cancer are limited and responses to commonly used androgen pathway inhibitors are often unsatisfactory. Our recent results indicated that sodium ionophore monensin is one of the most potent and cancer-specific inhibitors in a systematic sensitivity testing of most known drugs and drug-like molecules in a panel of prostate cancer cell models. Because monensin has been extensively used in veterinary applications to build muscle mass in cattle, the link to prostate cancer and androgen signaling was particularly interesting. Here, we showed that monensin effects at nanomolar concentrations are linked to induction of apoptosis and potent reduction of androgen receptor mRNA and protein in prostate cancer cells. Monensin also elevated intracellular oxidative stress in prostate cancer cells as evidenced by increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response. Importantly, the antiproliferative effects of monensin were potentiated by combinatorial treatment with the antiandrogens and antagonized by antioxidant vitamin C. Taken together, our results suggest monensin as a potential well-tolerated, in vivo compatible drug with strong proapoptotic effects in prostate cancer cells, and synergistic effects with antiandrogens. Moreover, our data suggest a general strategy by which the effects of antiandrogens could be enhanced by combinatorial administration with agents that increase oxidative stress in prostate cancer cells., (©2010 AACR.)
- Published
- 2010
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37. FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells.
- Author
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Gupta S, Iljin K, Sara H, Mpindi JP, Mirtti T, Vainio P, Rantala J, Alanen K, Nees M, and Kallioniemi O
- Subjects
- Cadherins biosynthesis, Cadherins genetics, Cell Adhesion genetics, Cell Line, Tumor, Epithelial Cells pathology, Frizzled Receptors metabolism, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Silencing, Humans, Integrin beta1 biosynthesis, Integrin beta1 genetics, Male, Mesoderm pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Receptors, G-Protein-Coupled metabolism, Signal Transduction genetics, Trans-Activators biosynthesis, Transcriptional Regulator ERG, Transfection, Up-Regulation, Frizzled Receptors genetics, Receptors, G-Protein-Coupled genetics, Trans-Activators genetics, Wnt Proteins metabolism
- Abstract
TMPRSS2-ERG and other gene fusions involving ETS factors and genes with strong promoter elements are common in prostate cancer. Although ERG activation has been linked to invasive properties of prostate cancers, the precise mechanisms and pathways of ERG-mediated oncogenesis remain poorly understood. Here, we show that ERG knockdown in VCaP prostate cancer cells causes an activation of cell adhesion, resulting in strongly induced active beta(1)-integrin and E-cadherin expression as well as changes in WNT signaling. These observations were corroborated by data from ERG-overexpressing nontransformed prostate epithelial cells as well as gene expression data from clinical prostate cancer samples, which both indicated a link between ERG and epithelial-to-mesenchymal transition (EMT). Upregulation of several WNT pathway members was seen in ERG-positive prostate cancers, with frizzled-4 (FZD4) showing the strongest overexpression as verified by both reverse transcription-PCR and immunostaining. Both ERG knockin and knockdown modulated the levels of FZD4 expression. FZD4 silencing could mimic the ERG knockdown phenotype by inducing active beta(1)-integrin and E-cadherin expression, whereas FZD4 overexpression reversed the phenotypic effects seen with ERG knockdown. Taken together, our results provide mechanistic insights to ERG oncogenesis in prostate cancer, involving activation of WNT signaling through FZD4, leading to cancer-promoting phenotypic effects, including EMT and loss of cell adhesion.
- Published
- 2010
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38. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth.
- Author
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Iljin K, Ketola K, Vainio P, Halonen P, Kohonen P, Fey V, Grafström RC, Perälä M, and Kallioniemi O
- Subjects
- Animals, Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Cells, Cultured, Disulfiram isolation & purification, Drug Screening Assays, Antitumor methods, High-Throughput Screening Assays methods, Humans, Male, Mice, Mice, Nude, Models, Biological, Small Molecule Libraries analysis, Xenograft Model Antitumor Assays, Carcinoma pathology, Cell Proliferation drug effects, Disulfiram pharmacology, Prostatic Neoplasms pathology
- Abstract
Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells., Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC(50) values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration., Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro., Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically well-known molecules can be readily translated to in vivo preclinical studies and clinical trials.
- Published
- 2009
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39. Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues.
- Author
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Kilpinen S, Autio R, Ojala K, Iljin K, Bucher E, Sara H, Pisto T, Saarela M, Skotheim RI, Björkman M, Mpindi JP, Haapa-Paananen S, Vainio P, Edgren H, Wolf M, Astola J, Nees M, Hautaniemi S, and Kallioniemi O
- Subjects
- Databases, Genetic, Disease genetics, Gene Expression Regulation, Humans, Organ Specificity, Gene Expression Profiling, Oligonucleotide Array Sequence Analysis methods
- Abstract
Our knowledge on tissue- and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.
- Published
- 2008
- Full Text
- View/download PDF
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