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  1. Article ; Online: Genome-wide siRNA screening reveals several host receptors for the binding of human gut commensal Bifidobacterium bifidum

    Veera Kainulainen / Carina von Schantz-Fant / Ruusu-Maria Kovanen / Swapnil Potdar / Karoliina Laamanen / Jani Saarela / Reetta Satokari

    npj Biofilms and Microbiomes, Vol 8, Iss 1, Pp 1-

    2022  Volume 9

    Abstract: Abstract Bifidobacterium spp. are abundant gut commensals, especially in breast-fed infants. Bifidobacteria are associated with many health-promoting effects including maintenance of epithelial barrier and integrity as well as immunomodulation. However, ... ...

    Abstract Abstract Bifidobacterium spp. are abundant gut commensals, especially in breast-fed infants. Bifidobacteria are associated with many health-promoting effects including maintenance of epithelial barrier and integrity as well as immunomodulation. However, the protective mechanisms of bifidobacteria on intestinal epithelium at molecular level are poorly understood. In this study, we developed a high-throughput in vitro screening assay to explore binding receptors of intestinal epithelial cells for Bifidobacterium bifidum. Short interfering RNAs (siRNA) were used to silence expression of each gene in the Caco-2 cell line one by one. The screen yielded four cell surface proteins, SERPINB3, LGICZ1, PKD1 and PAQR6, which were identified as potential receptors as the siRNA knock-down of their expression decreased adhesion of B. bifidum to the cell line repeatedly during the three rounds of siRNA screening. Furthermore, blocking of these host cell proteins by specific antibodies decreased the binding of B. bifidum significantly to Caco-2 and HT29 cell lines. All these molecules are located on the surface of epithelial cells and three out of four, SERPINB3, PKD1 and PAQR6, are involved in the regulation of cellular processes related to proliferation, differentiation and apoptosis as well as inflammation and immunity. Our results provide leads to the first steps in the mechanistic cascade of B. bifidum-host interactions leading to regulatory effects in the epithelium and may partly explain how this commensal bacterium is able to promote intestinal homeostasis.
    Keywords Microbial ecology ; QR100-130
    Subject code 570
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Corrigendum to ‘Combined gene essentiality scoring improves the prediction of cancer dependency maps’ [EBioMedicine 50 (2019) 66–79]

    Wenyu Wang / Alina Malyutina / Alberto Pessia / Jani Saarela / Caroline A. Heckman / Jing Tang

    EBioMedicine, Vol 51, Iss , Pp - (2020)

    2020  

    Keywords Medicine ; R ; Medicine (General) ; R5-920
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Combined gene essentiality scoring improves the prediction of cancer dependency mapsResearch in context

    Wenyu Wang / Alina Malyutina / Alberto Pessia / Jani Saarela / Caroline A. Heckman / Jing Tang

    EBioMedicine, Vol 50, Iss , Pp 67-

    2019  Volume 80

    Abstract: Background: Probing genetic dependencies of cancer cells can improve our understanding of tumour development and progression, as well as identify potential drug targets. CRISPR-Cas9-based and shRNA-based genetic screening are commonly utilized to ... ...

    Abstract Background: Probing genetic dependencies of cancer cells can improve our understanding of tumour development and progression, as well as identify potential drug targets. CRISPR-Cas9-based and shRNA-based genetic screening are commonly utilized to identify essential genes that affect cancer growth. However, systematic methods leveraging these genetic screening techniques to derive consensus cancer dependency maps for individual cancer cell lines are lacking. Finding: In this work, we first explored the CRISPR-Cas9 and shRNA gene essentiality profiles in 42 cancer cell lines representing 10 cancer types. We observed limited consistency between the essentiality profiles of these two screens at the genome scale. To improve consensus on the cancer dependence map, we developed a computational model called combined essentiality score (CES) to integrate the genetic essentiality profiles from CRISPR-Cas9 and shRNA screens, while accounting for the molecular features of the genes. We found that the CES method outperformed the existing gene essentiality scoring approaches in terms of ability to detect cancer essential genes. We further demonstrated the power of the CES method in adjusting for screen-specific biases and predicting genetic dependencies in individual cancer cell lines. Interpretation: Systematic comparison of the CRISPR-Cas9 and shRNA gene essentiality profiles showed the limitation of relying on a single technique to identify cancer essential genes. The CES method provides an integrated framework to leverage both genetic screening techniques as well as molecular feature data to determine gene essentiality more accurately for cancer cells. Keywords: Functional genetic screen, CRISPR, RNAi, Gene essentiality, Data integration
    Keywords Medicine ; R ; Medicine (General) ; R5-920
    Subject code 004
    Language English
    Publishing date 2019-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: High-throughput compound screening identifies navitoclax combined with irradiation as a candidate therapy for HPV-negative head and neck squamous cell carcinoma

    Katja Tuomainen / Aini Hyytiäinen / Ahmed Al-Samadi / Philipp Ianevski / Aleksandr Ianevski / Swapnil Potdar / Laura Turunen / Jani Saarela / Sergey Kuznetsov / Wafa Wahbi / Maija Risteli / Antti Mäkitie / Outi Monni / Tuula Salo

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Abstract Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. ... ...

    Abstract Abstract Conventional chemotherapeutic agents are nonselective, often resulting in severe side effects and the development of resistance. Therefore, new molecular-targeted therapies are urgently needed to be integrated into existing treatment regimens. Here, we performed a high-throughput compound screen to identify a synergistic interaction between ionizing radiation and 396 anticancer compounds. The assay was run using five human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) cell lines cultured on the human tumor-derived matrix Myogel. Our screen identified several compounds with strong synergistic and antagonistic effects, which we further investigated using multiple irradiation doses. Navitoclax, which emerged as the most promising radiosensitizer, exhibited synergy with irradiation regardless of the p53 mutation status in all 13 HNSCC cell lines. We performed a live cell apoptosis assay for two representative HNSCC cell lines to examine the effects of navitoclax and irradiation. As a single agent, navitoclax reduced proliferation and induced apoptosis in a dose-dependent manner, whereas the navitoclax–irradiation combination arrested cell cycle progression and resulted in substantially elevated apoptosis. Overall, we demonstrated that combining navitoclax with irradiation resulted in synergistic in vitro antitumor effects in HNSCC cell lines, possibly indicating the therapeutic potential for HNSCC patients.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer

    Jing Tang / Prson Gautam / Abhishekh Gupta / Liye He / Sanna Timonen / Yevhen Akimov / Wenyu Wang / Agnieszka Szwajda / Alok Jaiswal / Denes Turei / Bhagwan Yadav / Matti Kankainen / Jani Saarela / Julio Saez-Rodriguez / Krister Wennerberg / Tero Aittokallio

    npj Systems Biology and Applications, Vol 5, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Network pharmacology modeling reveals synergistic drug combinations Triple negative breast cancer (TNBC) is a heterogeneous disease that easily develops drug resistance. To achieve more effective clinical responses, synergistic drug combinations that ... ...

    Abstract Network pharmacology modeling reveals synergistic drug combinations Triple negative breast cancer (TNBC) is a heterogeneous disease that easily develops drug resistance. To achieve more effective clinical responses, synergistic drug combinations that inhibit multiple survival pathways of cancer are urgently needed. However, pinpointing these drug combinations is difficult, as the number of possible combinations grows exponentially. Tang and co-workers from the University of Helsinki, University of Copenhagen, and University of Heidelberg developed a network pharmacology modeling approach to predict synergistic drug combinations and their underlying target interactions. With dynamic simulation of signaling pathways, they identified a synergistic target interaction that involved Aurora B and ZAK that play a critical role in regulating the survival of TNBC cells. These new combinatorial drug targets warrant further exploration of clinical benefits in treating TNBC.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Impact of normalization methods on high-throughput screening data with high hit rates and drug testing with dose-response data.

    Mpindi, John-Patrick / Swapnil, Potdar / Dmitrii, Bychkov / Jani, Saarela / Saeed, Khalid / Wennerberg, Krister / Aittokallio, Tero / Östling, Päivi / Kallioniemi, Olli

    Bioinformatics (Oxford, England)

    2015  Volume 31, Issue 23, Page(s) 3815–3821

    Abstract: Motivation: Most data analysis tools for high-throughput screening (HTS) seek to uncover interesting hits for further analysis. They typically assume a low hit rate per plate. Hit rates can be dramatically higher in secondary screening, RNAi screening ... ...

    Abstract Motivation: Most data analysis tools for high-throughput screening (HTS) seek to uncover interesting hits for further analysis. They typically assume a low hit rate per plate. Hit rates can be dramatically higher in secondary screening, RNAi screening and in drug sensitivity testing using biologically active drugs. In particular, drug sensitivity testing on primary cells is often based on dose-response experiments, which pose a more stringent requirement for data quality and for intra- and inter-plate variation. Here, we compared common plate normalization and noise-reduction methods, including the B-score and the Loess a local polynomial fit method under high hit-rate scenarios of drug sensitivity testing. We generated simulated 384-well plate HTS datasets, each with 71 plates having a range of 20 (5%) to 160 (42%) hits per plate, with controls placed either at the edge of the plates or in a scattered configuration.
    Results: We identified 20% (77/384) as the critical hit-rate after which the normalizations started to perform poorly. Results from real drug testing experiments supported this estimation. In particular, the B-score resulted in incorrect normalization of high hit-rate plates, leading to poor data quality, which could be attributed to its dependency on the median polish algorithm. We conclude that a combination of a scattered layout of controls per plate and normalization using a polynomial least squares fit method, such as Loess helps to reduce column, row and edge effects in HTS experiments with high hit-rates and is optimal for generating accurate dose-response curves.
    Contact: john.mpindi@helsinki.fi.
    Availability and implementation: Supplementary information: R code and Supplementary data are available at Bioinformatics online.
    MeSH term(s) Algorithms ; Antineoplastic Agents/pharmacology ; Data Interpretation, Statistical ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; High-Throughput Screening Assays/methods ; Humans ; Male ; Normal Distribution ; Prostatic Neoplasms/drug therapy ; Tumor Cells, Cultured
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2015-12-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btv455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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