| 1. |
- Bulanova, Daria, et al.
(författare)
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Antiviral Properties of Chemical Inhibitors of Cellular Anti-Apoptotic Bcl-2 Proteins
- 2017
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Hansson, Karin, et al.
(författare)
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Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:562
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.
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| 3. |
- Saarela, Jan, et al.
(författare)
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Born to move? : Birth order and emigration
- 2024
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Ingår i: Social Science Research. - : Elsevier. - 0049-089X .- 1096-0317. ; 122
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Tidskriftsartikel (refereegranskat)abstract
- This paper studies the interrelation between birth order and emigration adopting a family fixed-effects approach. We use register data on all persons in full-siblings groups born 1970–2002 in the entire Finnish-born population, and observe their first move abroad since age 18 in the period 1987–2020. The total number of siblings is 1,352,908, the total number of sibling groups 549,842, and the total number of first moves abroad 31,192. By comparing siblings in the same family, we effectively adjust for all time-invariant confounding from unobserved or unmeasured time-invariant variables. Emigration is found to be positively associated with birth order. The hazard of emigration for second-born siblings is 1.05 that of first borns, that of third borns 1.07, and that of fourth borns 1.11. The pattern is particularly marked for emigration to countries where there is free mobility, and the association is similar for both genders. Potential explanations to the birth order pattern may be variation in personality traits, risk-taking behaviours and aspirations between siblings, or differential allocation of resources and opportunities within families. The results highlight the importance of considering birth order within the context of family dynamics and individual mobility patterns, and they need to be extended to broader settings.
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