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  • 1.
    Bulanova, Daria
    et al.
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Ianevski, Aleksandr
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Bugai, Andrii
    Univ Helsinki, Dept Biochem & Dev Biol, FIN-00290 Helsinki, Finland..
    Akimov, Yevhen
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Kuivanen, Suvi
    Univ Helsinki, Dept Virol, Haartmaninkatu 3, FIN-00290 Helsinki, Finland..
    Paavilainen, Henrik
    Univ Turku, Dept Virol, FIN-20520 Turku, Finland..
    Kakkola, Laura
    Univ Turku, Dept Virol, FIN-20520 Turku, Finland..
    Nandania, Jatin
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Turunen, Laura
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Ohman, Tiina
    Univ Helsinki, Inst Biotechnol, Valimotie 7, Helsinki 00014, Finland..
    Ala-Hongisto, Hanna
    Biomed Funct Genom Unit FuGU, Helsinki 00290, Helsinki, Finland..
    Pesonen, Hanna M.
    Biomed Funct Genom Unit FuGU, Helsinki 00290, Helsinki, Finland..
    Kuisma, Marika S.
    Biomed Funct Genom Unit FuGU, Helsinki 00290, Helsinki, Finland..
    Honkimaa, Anni
    Univ Tampere, Dept Virol, Tampere 33520, Finland..
    Walton, Emma L.
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, N-7028 Trondheim, Norway..
    Oksenych, Valentyn
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, N-7028 Trondheim, Norway..
    Lorey, Martina B.
    Univ Helsinki, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Rheumatol, Helsinki 00290, Finland..
    Guschin, Dmitry
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Shim, Jungmin
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Kim, Jinhee
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Than, Thoa T.
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Chang, So Young
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Hukkanen, Veijo
    Univ Turku, Dept Virol, FIN-20520 Turku, Finland..
    Kulesskiy, Evgeny
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Marjomaki, Varpu S.
    Univ Jyvaskyla, Dept Biol & Environm Sci, Nanosci Ctr, Jyvaskyla 40500, Finland..
    Julkunen, Ilkka
    Univ Turku, Dept Virol, FIN-20520 Turku, Finland..
    Nyman, Tuula A.
    Univ Helsinki, Inst Biotechnol, Valimotie 7, Helsinki 00014, Finland.;Univ Oslo, Dept Immunol, N-0424 Oslo, Norway..
    Matikainen, Sampsa
    Univ Helsinki, FIN-00290 Helsinki, Finland.;Helsinki Univ Hosp, Rheumatol, Helsinki 00290, Finland..
    Saarela, Jani S.
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Sane, Famara
    Univ Lille, CHU Lille, Lab Virol, EA3610, F-59037 Lille, France..
    Hober, Didier
    Univ Lille, CHU Lille, Lab Virol, EA3610, F-59037 Lille, France..
    Gabriel, Guelsah
    Leibniz Inst Expt Virol, Heinrich Pette Inst, D-20251 Hamburg, Germany..
    De Brabander, Jef K.
    Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA..
    Martikainen, Miika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Windisch, Marc P.
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Min, Ji-Young
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea..
    Bruzzone, Roberto
    Inst Pasteur Korea, Gyeonggi Do 13488, South Korea.;Univ Hong Kong, Sch Publ Hlth, HKU Pasteur Res Pole, Hong Kong, Hong Kong, Peoples R China.;Inst Pasteur, Dept Cell Biol & Infect, F-75015 Paris, France..
    Aittokallio, Tero
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Vaha-Koskela, Markus
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Vapalahti, Olli
    Univ Helsinki, Dept Virol & Immunol, FIN-00014 Helsinki, Finland.;Helsinki Univ Hosp, Helsinki 00014, Finland.;Univ Helsinki, Dept Vet Biosci, FIN-00014 Helsinki, Finland..
    Pulk, Arto
    Univ Tartu, Inst Technol, EE-50090 Tartu, Estonia..
    Velagapudi, Vidya
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland..
    Kainov, Denis E.
    Univ Helsinki, FIMM, Inst Mol Med Finland, FIN-00290 Helsinki, Finland.;Norwegian Univ Sci & Technol, Dept Clin & Mol Med, N-7028 Trondheim, Norway.;Inst Pasteur Korea, Gyeonggi Do 13488, South Korea.;Univ Tartu, Inst Technol, EE-50090 Tartu, Estonia..
    Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins2017In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 10, article id 271Article in journal (Refereed)
    Abstract [en]

    Viral diseases remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral diseases, new treatments are urgently needed. Here we show that small-molecules, which inhibit cellular anti-apoptotic Bcl-2 proteins (Bcl-2i), induced the premature death of cells infected with different RNA or DNA viruses, whereas, at the same concentrations, no toxicity was observed in mock-infected cells. Moreover, these compounds limited viral replication and spread. Surprisingly, Bcl-2i also induced the premature apoptosis of cells transfected with viral RNA or plasmid DNA but not of mock-transfected cells. These results suggest that Bcl-2i sensitizes cells containing foreign RNA or DNA to apoptosis. A comparison of the toxicity, antiviral activity, and side effects of six Bcl-2i allowed us to select A-1155463 as an antiviral lead candidate. Thus, our results pave the way for the further development of Bcl-2i for the prevention and treatment of viral diseases.

  • 2.
    Martikainen, Miika
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Virus-Based Immunotherapy of Glioblastoma2019In: Cancers, ISSN 2072-6694, Vol. 11, no 2, article id 186Article, review/survey (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

  • 3.
    Martikainen, Miika
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland.
    Ruotsalainen, Janne
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland.;Univ Hosp Magdeburg, Dept Dermatol, D-39120 Magdeburg, Germany..
    Tuomela, Johanna
    Univ Turku, Inst Biomed, FIN-20520 Turku, Finland..
    Harkonen, Pirkko
    Univ Turku, Inst Biomed, FIN-20520 Turku, Finland..
    Essand, Magnus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heikkila, Jari
    Abo Akad Univ, Dept Biochem & Pharm, Turku 20500, Finland..
    Hinkkanen, Ari
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Dept Biotechnol & Mol Med, Kuopio 70211, Finland..
    Oncolytic alphavirus SFV-VA7 efficiently eradicates subcutaneous and orthotopic human prostate tumours in mice2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 117, no 1, p. 51-55Article in journal (Refereed)
    Abstract [en]

    Background: Despite recent therapeutic and diagnostic advances, prostate cancer remains the second leading cause of cancer-related deaths among men in the Western world. Oncolytic viruses that replicate selectively in tumour cells represent a novel treatment candidate for these malignancies.

    Methods: We analysed infectivity of avirulent Semliki Firest virus SFV-VA7 in human prostate cancer cell lines VCaP, LNCaP and 22Rv1 and in nonmalignant prostate epithelial cell line RWPE-1. Therapeutic potency of SFV-VA7 was evaluated in subcutaneous and orthotopic mouse LNCaP xenograft models.

    Results: SFV-VA7 infected and killed the tested human prostate cancer cell lines irrespective of their hormone response status, while the nonmalignant prostate epithelial cell line RWPE-1 proved highly virus resistant. Notably, a single peritoneal dose of SFV-VA7 was sufficient to eradicate all subcutaneous and orthotopic LNCaP tumours.

    Conclusions: Our results indicate that SFV-VA7 is a novel, promising therapeutic virus against prostate cancer warranting further testing in early clinical trials.

  • 4.
    Niittykoski, Minna
    et al.
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    zu Fraunberg, Mikael von und
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Martikainen, Miika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rauramaa, Tuomas
    Univ Eastern Finland, Inst Clin Med, Pathol, Kuopio, Finland.;Kuopio Univ Hosp, Dept Pathol, Kuopio, Finland..
    Immonen, Arto
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Koponen, Susanna
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland..
    Leinonen, Ville
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Vaha-Koskela, Markus
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Zhang, Qiwei
    Southern Med Univ, Guangzhou, Guangdong, Peoples R China..
    Kuhnel, Florian
    Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany..
    Mei, Ya-Fang
    Umea Univ, Dept Clin Microbiol, Umea, Sweden..
    Yla-Herttuala, Seppo
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    Jaaskelainen, Juha E.
    Kuopio Univ Hosp, NeuroCtr, Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Neurosurg, Kuopio, Finland..
    Hinkkanen, Ari
    Univ Eastern Finland, AI Virtanen Inst Mol Sci, Biotechnol & Mol Med, Kuopio, Finland..
    Immunohistochemical Characterization and Sensitivity to Human Adenovirus Serotypes 3, 5, and 11p of New Cell Lines Derived from Human Diffuse Grade II to IV Gliomas2017In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 10, no 5, p. 772-779Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Oncolytic adenoviruses show promise in targeting gliomas because they do not replicate in normal brain cells. However, clinical responses occur only in a subset of patients. One explanation could be the heterogenic expression level of virus receptors. Another contributing factor could be variable activity of tumor antiviral defenses in different glioma subtypes.

    METHODS:

    We established a collection of primary low-passage cell lines from different glioma subtypes (3 glioblastomas, 3 oligoastrocytomas, and 2 oligodendrogliomas) and assessed them for receptor expression and sensitivity to human adenovirus (HAd) serotypes 3, 5, and 11p. To gauge the impact of antiviral defenses, we also compared the infectivity of the oncolytic adenoviruses in interferon (IFN)-pretreated cells with IFN-sensitive Semliki Forest virus (SFV).

    RESULTS:

    Immunostaining revealed generally low expression of HAd5 receptor CAR in both primary tumors and derived cell lines. HAd11p receptor CD46 levels were maintained at moderate levels in both primary tumor samples and derived cell lines. HAd3 receptor DSG-2 was reduced in the cell lines compared to the tumors. Yet, at equal multiplicities of infection, the oncolytic potency of HAd5 in vitro in tumor-derived cells was comparable to HAd11p, whereas HAd3 lysed fewer cells than either of the other two HAd serotypes in 72 hours. IFN blocked replication of SFV, while HAds were rather unaffected.

    CONCLUSIONS:

    Adenovirus receptor levels on glioma-derived cell lines did not correlate with infection efficacy and may not be a relevant indicator of clinical oncolytic potency. Adenovirus receptor analysis should be preferentially performed on biopsies obtained perioperatively.

  • 5.
    Sarén, Tina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Martikainen, Miika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Insertion of the Type-I IFN Decoy Receptor B18R in a miRNA-Tagged Semliki Forest Virus Improves Oncolytic Capacity but Results in Neurotoxicity2017In: MOLECULAR THERAPY-ONCOLYTICS, ISSN 2372-7705, Vol. 7, p. 67-75Article in journal (Refereed)
    Abstract [en]

    Oncolytic Semliki Forest virus (SFV) has been suggested as a potential candidate for the treatment of glioblastoma and neuroblastoma. However, the oncolytic capacity of SFV is restricted by the anti-viral type-I interferon (IFN) response. The aim of this study was to increase the oncolytic capacity of a microRNA target tagged SFV against glioblastoma by arming it with the Vaccinia-virus-encoded type-I IFN decoy receptor B18R (SFV4B18RmiRT) to neutralize type-I IFN response. Expression of B18R by SFV4B18RmiRT aided neutralization of IFN-b, which was shown by reduced STAT-1 phosphorylation and improved virus spread in plaque assays. B18R expression by SFV4 increased its oncolytic capacity in vitro against murine glioblastoma (CT-2A), regardless of the presence of exogenous IFN-b. Both SFV4B18RmiRT and SFV4miRT treatments controlled tumor growth in mice with syngeneic orthotopic gliomablastoma (CT-2A). However, treatment with SFV4B18RmiRT induced severe neurological symptoms in some mice because of virus replication in the healthy brain. Neither neurotoxicity nor virus replication in the brain was observed when SFV4miRT was administered. In summary, our results indicate that the oncolytic capacity of SFV4 was improved in vitro and in vivo by incorporation of B18R, but neurotoxicity of the virus was increased, possibly due to loss of microRNA targets.

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