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  • Vorrink, Sabine U.; Ullah, Shahid; Schmidt, Staffan; Nandania, Jatin; Velagapudi, Vidya; Beck, Olof; Ingelman-Sundberg, Magnus; Lauschke, Volker M. (2017)
    Adverse reactions or lack of response to medications are important concerns for drug development programs. However, faithful predictions of drug metabolism and toxicity are difficult because animal models show only limited translatability to humans. Furthermore, current in vitro systems, such as hepatic cell lines or primary human hepatocyte (PHH) 2-dimensional (2D) monolayer cultures, can be used only for acute toxicity tests because of their immature phenotypes and inherent instability. Therefore, the migration to novel phenotypically stable models is of prime importance for the pharmaceutical industry. Novel 3-dimensional (3D) culture systems have been shown to accurately mimic in vivo hepatic phenotypes on transcriptomic and proteomic level, but information about their metabolic stability is lacking. Using a combination of targeted and untargeted high-resolution mass spectrometry, we found that PHHs in 3D spheroid cultures remained metabolically stable for multiple weeks, whereas metabolic patterns of PHHs from the same donors cultured as conventional 2D monolayers rapidly deteriorated. Furthermore, pharmacokinetic differences between donors were maintained in 3D spheroid cultures, enabling studies of interindividual variability in drug metabolism and toxicity. We conclude that the 3D spheroid system is metabolically stable and constitutes a suitable model for in vitro studies of long-term drug metabolism and pharmacokinetics.
  • Khulan, B.; Manning, J. R.; Dunbar, D. R.; Seckl, J. R.; Raikkonen, K.; Eriksson, J. G.; Drake, A. J. (2014)
  • Majumder, Muntasir Mamun; Silvennoinen, Raija; Anttila, Pekka; Tamborero, David; Eldfors, Samuli; Yadav, Bhagwan; Karjalainen, Riikka; Kuusanmaki, Heikki; Lievonen, Juha; Parsons, Alun; Suvela, Minna; Jantunen, Esa; Porkka, Kimmo; Heckman, Caroline A. (2017)
    Novel agents have increased survival of multiple myeloma (MM) patients, however high-risk and relapsed/refractory patients remain challenging to treat and their outcome is poor. To identify novel therapies and aid treatment selection for MM, we assessed the ex vivo sensitivity of 50 MM patient samples to 308 approved and investigational drugs. With the results we i) classified patients based on their ex vivo drug response profile; ii) identified and matched potential drug candidates to recurrent cytogenetic alterations; and iii) correlated ex vivo drug sensitivity to patient outcome. Based on their drug sensitivity profiles, MM patients were stratified into four distinct subgroups with varied survival outcomes. Patients with progressive disease and poor survival clustered in a drug response group exhibiting high sensitivity to signal transduction inhibitors. Del(17p) positive samples were resistant to most drugs tested with the exception of histone deacetylase and BCL2 inhibitors. Samples positive for t(4; 14) were highly sensitive to immunomodulatory drugs, proteasome inhibitors and several targeted drugs. Three patients treated based on the ex vivo results showed good response to the selected treatments. Our results demonstrate that ex vivo drug testing may potentially be applied to optimize treatment selection and achieve therapeutic benefit for relapsed/refractory MM.
  • Mohammad, H.; Marchisella, F.; Ortega-Martinez, S.; Hollos, P.; Eerola, K.; Komulainen, E.; Kulesskaya, N.; Freemantle, E.; Fagerholm, V.; Savontous, E.; Rauvala, H.; Peterson, B. D.; van Praag, H.; Coffey, E. T. (2018)
    Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.
  • Kulesskaya, Natalia; Karpova, Nina N.; Ma, Li; Tian, Li; Voikar, Vootele (2014)
  • Rodriguez-Martinez, Alejandra; Vuorinen, Elisa M.; Shcherban, Anastasia; Uusi-Mäkelä, Joonas; Rajala, Nina K. M.; Nykter, Matti; Kallioniemi, Anne (2022)
    Transcription factor binding to DNA is a central mechanism regulating gene expression. Thus, thorough characterization of this process is essential for understanding cellular biology in both health and disease. We combined data from three sequencing-based methods to unravel the DNA binding function of the novel ZNF414 protein in cells representing two tumor types. ChIP-exo served to map protein binding sites, ATAC-seq allowed identification of open chromatin, and RNA-seq examined the transcriptome. We show that ZNF414 is a DNAbinding protein that both induces and represses gene expression. This transcriptional response has an impact on cellular processes related to proliferation and other malignancy-associated functions, such as cell migration and DNA repair. Approximately 20% of the differentially expressed genes harbored ZNF414 binding sites in their promoters in accessible chromatin, likely representing direct targets of ZNF414. De novo motif discovery revealed several putative ZNF414 binding sequences, one of which was validated using EMSA. In conclusion, this study illustrates a highly efficient integrative approach for the characterization of the DNA binding and transcriptional activity of transcription factors.
  • 23me Res Team (2018)
    Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency