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Your search keyword '"Pietiäinen, V. (Vilja)"' showing total 3 results
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3 results on '"Pietiäinen, V. (Vilja)"'

1. Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer:real-time therapy tailoring for a patient with low-grade serous carcinoma

Author

Murumägi, A. (Astrid), Ungureanu, D. (Daniela), Khan, S. (Suleiman), Arjama, M. (Mariliina), Välimäki, K. (Katja), Ianevski, A. (Aleksandr), Ianevski, P. (Philipp), Bergström, R. (Rebecka), Dini, A. (Alice), Kanerva, A. (Anna), Koivisto-Korander, R. (Riitta), Tapper, J. (Johanna), Lassus, H. (Heini), Loukovaara, M. (Mikko), Mägi, A. (Andrus), Hirasawa, A. (Akira), Aoki, D. (Daisuke), Pietiäinen, V. (Vilja), Pellinen, T. (Teijo), Bützow, R. (Ralf), Aittokallio, T. (Tero), Kallioniemi, O. (Olli), Murumägi, A. (Astrid), Ungureanu, D. (Daniela), Khan, S. (Suleiman), Arjama, M. (Mariliina), Välimäki, K. (Katja), Ianevski, A. (Aleksandr), Ianevski, P. (Philipp), Bergström, R. (Rebecka), Dini, A. (Alice), Kanerva, A. (Anna), Koivisto-Korander, R. (Riitta), Tapper, J. (Johanna), Lassus, H. (Heini), Loukovaara, M. (Mikko), Mägi, A. (Andrus), Hirasawa, A. (Akira), Aoki, D. (Daisuke), Pietiäinen, V. (Vilja), Pellinen, T. (Teijo), Bützow, R. (Ralf), Aittokallio, T. (Tero), and Kallioniemi, O. (Olli)

Abstract

Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.

Published
2022

2. Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction

Author

Kaustio, M. (Meri), Nayebzadeh, N. (Naemeh), Hinttala, R. (Reetta), Tapiainen, T. (Terhi), Åström, P. (Pirjo), Mamia, K. (Katariina), Pernaa, N. (Nora), Lehtonen, J. (Johanna), Glumoff, V. (Virpi), Rahikkala, E. (Elisa), Honkila, M. (Minna), Olsén, P. (Päivi), Hassinen, A. (Antti), Polso, M. (Minttu), Al Sukaiti, N. (Nashat), Al Shekaili, J. (Jalila), Al Kindi, M. (Mahmood), Al Hashmi, N. (Nadia), Almusa, H. (Henrikki), Bulanova, D. (Daria), Haapaniemi, E. (Emma), Chen, P. (Pu), Suo-Palosaari, M. (Maria), Vieira, P. (Päivi), Tuominen, H. (Hannu), Kokkonen, H. (Hannaleena), Al Macki, N. (Nabil), Al Habsi, H. (Huda), Löppönen, T. (Tuija), Rantala, H. (Heikki), Pietiäinen, V. (Vilja), Zhang, S.-Y. (Shen-Ying), Renko, M. (Marjo), Hautala, T. (Timo), Al Farsi, T. (Tariq), Uusimaa, J. (Johanna), Saarela, J. (Janna), Kaustio, M. (Meri), Nayebzadeh, N. (Naemeh), Hinttala, R. (Reetta), Tapiainen, T. (Terhi), Åström, P. (Pirjo), Mamia, K. (Katariina), Pernaa, N. (Nora), Lehtonen, J. (Johanna), Glumoff, V. (Virpi), Rahikkala, E. (Elisa), Honkila, M. (Minna), Olsén, P. (Päivi), Hassinen, A. (Antti), Polso, M. (Minttu), Al Sukaiti, N. (Nashat), Al Shekaili, J. (Jalila), Al Kindi, M. (Mahmood), Al Hashmi, N. (Nadia), Almusa, H. (Henrikki), Bulanova, D. (Daria), Haapaniemi, E. (Emma), Chen, P. (Pu), Suo-Palosaari, M. (Maria), Vieira, P. (Päivi), Tuominen, H. (Hannu), Kokkonen, H. (Hannaleena), Al Macki, N. (Nabil), Al Habsi, H. (Huda), Löppönen, T. (Tuija), Rantala, H. (Heikki), Pietiäinen, V. (Vilja), Zhang, S.-Y. (Shen-Ying), Renko, M. (Marjo), Hautala, T. (Timo), Al Farsi, T. (Tariq), Uusimaa, J. (Johanna), and Saarela, J. (Janna)

Abstract

Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients’ immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in

Published
2021

3. The impact of low-frequency and rare variants on lipid levels

Author

Surakka, I. (Ida), Horikoshi, M. (Momoko), Mägi, R. (Reedik), Sarin, A.-P., Mahajan, A. (Anubha), Lagou, V. (Vasiliki), Marullo, L. (Letizia), Ferreira, T. (Teresa), Miraglio, B. (Benjamin), Timonen, S. (Sanna), Kettunen, J. (Johannes), Pirinen, M. (Matti), Karjalainen, J. (Juha), Thorleifsson, G. (Gudmar), Hägg, S. (Sara), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Ladenvall, C. (Claes), Beekman, M. (Marian), Esko, T. (Tõnu), Ried, J.S. (Janina), Nelson, C.P. (Christopher P.), Willenborg, C. (Christina), Gustafsson, S. (Stefan), Westra, H.J. (Harm-Jan), Blades, M. (Matthew), De Craen, A.J.M. (Anton J. M.), Geus, E.J.C. (Eco) de, Deelen, J. (Joris), Grallert, H. (Harald), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hengstenberg, C. (Christian), Houwing-Duistermaat, J.J. (Jeanine), Hypponen, E. (Elina), Karssen, L.C. (Lennart), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Magnusson, P.K. (Patrik), Mihailov, E. (Evelin), Müller-Nurasyid, M. (Martina), Mpindi, J.-P. (John-Patrick), Pedersen, N.L. (Nancy L.), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pers, T.H. (Tune), Peters, A. (Annette), Rung, J. (Johan), Smit, J.H. (Johannes), Steinthorsdottir, V. (Valgerdur), Tobin, M.D. (Martin), Tsernikova, N. (Natalia), Leeuwen, E.M. (Elisa) van, Viikari, J. (Jorma), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Kaprio, J. (Jaakko), Lind, L. (Lars), Gieger, C. (Christian), Metspalu, A. (Andres), Slagboom, P.E. (Eline), Groop, L. (Leif), Duijn, C.M. (Cornelia) van, Eriksson, J.G. (Johan G.), Jula, A. (Antti), Salomaa, V. (Veikko), Boomsma, D.I. (Dorret), Power, C. (Christopher), Raitakari, O.T. (Olli T.), Ingelsson, E. (Erik), Jarvelin, M.-R. (Marjo-Riitta), Thorsteinsdottir, U. (Unnur), Franke, L. (Lude), Ikonen, E. (Elina), Kallioniemi, O. (Olli), Pietiäinen, V. (Vilja), Lindgren, C.M. (Cecilia M.), Zwart, J-A. (John-Anker), Palotie, A. (Aarno), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Prokopenko, I. (Inga), Ripatti, S. (Samuli), Surakka, I. (Ida), Horikoshi, M. (Momoko), Mägi, R. (Reedik), Sarin, A.-P., Mahajan, A. (Anubha), Lagou, V. (Vasiliki), Marullo, L. (Letizia), Ferreira, T. (Teresa), Miraglio, B. (Benjamin), Timonen, S. (Sanna), Kettunen, J. (Johannes), Pirinen, M. (Matti), Karjalainen, J. (Juha), Thorleifsson, G. (Gudmar), Hägg, S. (Sara), Hottenga, J.J. (Jouke Jan), Isaacs, A.J. (Aaron), Ladenvall, C. (Claes), Beekman, M. (Marian), Esko, T. (Tõnu), Ried, J.S. (Janina), Nelson, C.P. (Christopher P.), Willenborg, C. (Christina), Gustafsson, S. (Stefan), Westra, H.J. (Harm-Jan), Blades, M. (Matthew), De Craen, A.J.M. (Anton J. M.), Geus, E.J.C. (Eco) de, Deelen, J. (Joris), Grallert, H. (Harald), Hamsten, A. (Anders), Havulinna, A.S. (Aki), Hengstenberg, C. (Christian), Houwing-Duistermaat, J.J. (Jeanine), Hypponen, E. (Elina), Karssen, L.C. (Lennart), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Magnusson, P.K. (Patrik), Mihailov, E. (Evelin), Müller-Nurasyid, M. (Martina), Mpindi, J.-P. (John-Patrick), Pedersen, N.L. (Nancy L.), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pers, T.H. (Tune), Peters, A. (Annette), Rung, J. (Johan), Smit, J.H. (Johannes), Steinthorsdottir, V. (Valgerdur), Tobin, M.D. (Martin), Tsernikova, N. (Natalia), Leeuwen, E.M. (Elisa) van, Viikari, J. (Jorma), Willems, S.M. (Sara), Willemsen, G.A.H.M. (Gonneke), Schunkert, H. (Heribert), Erdmann, J. (Jeanette), Samani, N.J. (Nilesh), Kaprio, J. (Jaakko), Lind, L. (Lars), Gieger, C. (Christian), Metspalu, A. (Andres), Slagboom, P.E. (Eline), Groop, L. (Leif), Duijn, C.M. (Cornelia) van, Eriksson, J.G. (Johan G.), Jula, A. (Antti), Salomaa, V. (Veikko), Boomsma, D.I. (Dorret), Power, C. (Christopher), Raitakari, O.T. (Olli T.), Ingelsson, E. (Erik), Jarvelin, M.-R. (Marjo-Riitta), Thorsteinsdottir, U. (Unnur), Franke, L. (Lude), Ikonen, E. (Elina), Kallioniemi, O. (Olli), Pietiäinen, V. (Vilja), Lindgren, C.M. (Cecilia M.), Zwart, J-A. (John-Anker), Palotie, A. (Aarno), McCarthy, M.I. (Mark), Morris, A.P. (Andrew), Prokopenko, I. (Inga), and Ripatti, S. (Samuli)

Abstract

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing.

Published
2015
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