Browsing by Subject "SCREEN"

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  • Malyutina, Alina; Majumder, Muntasir Mamun; Wang, Wenyu; Pessia, Alberto; Heckman, Caroline A.; Tang, Jing (2019)
    High-throughput drug screening has facilitated the discovery of drug combinations in cancer. Many existing studies adopted a full matrix design, aiming for the characterization of drug pair effects for cancer cells. However, the full matrix design may be suboptimal as it requires a drug pair to be combined at multiple concentrations in a full factorial manner. Furthermore, many of the computational tools assess only the synergy but not the sensitivity of drug combinations, which might lead to false positive discoveries. We proposed a novel cross design to enable a more cost-effective and simultaneous testing of drug combination sensitivity and synergy. We developed a drug combination sensitivity score (CSS) to determine the sensitivity of a drug pair, and showed that the CSS is highly reproducible between the replicates and thus supported its usage as a robust metric. We further showed that CSS can be predicted using machine learning approaches which determined the top pharmaco-features to cluster cancer cell lines based on their drug combination sensitivity profiles. To assess the degree of drug interactions using the cross design, we developed an S synergy score based on the difference between the drug combination and the single drug dose-response curves. We showed that the S score is able to detect true synergistic and antagonistic drug combinations at an accuracy level comparable to that using the full matrix design. Taken together, we showed that the cross design coupled with the CSS sensitivity and S synergy scoring methods may provide a robust and accurate characterization of both drug combination sensitivity and synergy levels, with minimal experimental materials required. Our experimental-computational approach could be utilized as an efficient pipeline for improving the discovery rate in high-throughput drug combination screening, particularly for primary patient samples which are difficult to obtain.
  • Brodin, Bertha A.; Wennerberg, Krister; Lidbrink, Elisabet; Brosjö, Otte; Potdar, Swapnil; Wilson, Jennifer N.; Ma, Limin; Moens, Lotte N.; Hesla, Asle; Porovic, Edvin; Bernhardsson, Edvin; Papakonstantinou, Antroula; Bauer, Henrik; Tsagkozis, Panagiotis; von Sivers, Karin; Wejde, Johan; Östling, Päivi; Kallioniemi, Olli; Stragliotto, Christina Linder (2019)
    BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
  • Zagidullin, Bulat; Aldahdooh, Jehad M. F.; Zheng, Shuyu; Wang, Wenyu; Wang, Yinyin; Saad, Joseph; Malyutina, Alina; Jafari, Mohieddin; Tanoli, Zia-ur-Rehman; Pessia, Alberto; Tang, Jing (2019)
    Drug combination therapy has the potential to enhance efficacy, reduce dose-dependent toxicity and prevent the emergence of drug resistance. However, discovery of synergistic and effective drug combinations has been a laborious and often serendipitous process. In recent years, identification of combination therapies has been accelerated due to the advances in high-throughput drug screening, but informatics approaches for systems-level data management and analysis are needed. To contribute toward this goal, we created an open-access data portal called DrugComb (https://drugcomb.fimm.fi) where the results of drug combination screening studies are accumulated, standardized and harmonized. Through the data portal, we provided a web server to analyze and visualize users’ own drug combination screening data. The users can also effectively participate a crowdsourcing data curation effect by depositing their data at DrugComb. To initiate the data repository, we collected 437 932 drug combinations tested on a variety of cancer cell lines. We showed that linear regression approaches, when considering chemical fingerprints as predictors, have the potential to achieve high accuracy of predicting the sensitivity of drug combinations. All the data and informatics tools are freely available in DrugComb to enable a more efficient utilization of data resources for future drug combination discovery.
  • Yohannes, Dawit A.; de Kauwe, Andrea; Kaukinen, Katri; Kurppa, Kalle; Mäki, Markku; Anderson, Robert P.; Linnarsson, Sten; Greco, Dario; Saavalainen, Päivi (2020)
    The pathological mechanisms that lead to the onset and reactivation of celiac disease (CD) remain largely unknown. While gluten free diet (GFD) improves the intestinal damage and associated clinical symptoms in majority of cases, it falls short of providing full recovery. Additionally, late or misdiagnosis is also common as CD presents with a wide range of symptoms. Clear understanding of CD pathogenesis is thus critical to address both diagnostic and treatment concerns. We aimed to study the molecular impact of short gluten exposure in GFD treated CD patients, as well as identify biological pathways that remain altered constitutively in CD regardless of treatment. Using RNAseq profiling of PBMC samples collected from treated CD patients and gluten challenged patient and healthy controls, we explored the peripheral transcriptome in CD patients following a short gluten exposure. Short gluten exposure of just three days was enough to alter the genome-wide PBMC transcriptome of patients. Pathway analysis revealed gluten-induced upregulation of mainly immune response related pathways, both innate and adaptive, in CD patients. We evaluated the perturbation of biological pathways in sample-specific manner. Compared to gluten exposed healthy controls, pathways related to tight junction, olfactory transduction, metabolism of unsaturated fatty acids (such as arachidonic acid), metabolism of amino acids (such as cysteine and glutamate), and microbial infection were constitutively altered in CD patients regardless of treatment, while GFD treatment appears to mostly normalize immune response pathways to "healthy" state. Upstream regulator prediction analysis using differentially expressed genes identified constitutively activated regulators relatively proximal to previously reported CD associated loci, particularly SMARCA4 on 19p13.2 and CSF2 on 5q31. We also found constitutively upregulated genes in CD that are in CD associated genetic loci such as MEF2BNB-MEF2B (BORCS8-MEF2B) on 19p13.11 and CSTB on 21q22.3. RNAseq revealed strong effects of short oral gluten challenge on whole PBMC fraction and constitutively altered pathways in CD PBMC suggesting important factors other than gluten in CD pathogenesis.
  • Kalle, Lind; Johanna, Järvinen-Tassopoulos (2019)
    Purpose The purpose of this paper is to explore the prevalence of potential problem gambling among Finnish prisoners; the associations between problem gambling and demographics, substance use and crime-related factors; and problem gamblers’ support preferences.Design/methodology/approach Prisoners (n=96) from two Finnish prisons were recruited between December 2017 and January 2018. The estimated response rate was 31 percent. Gambling problems were measured using the Brief Biosocial Gambling Screen. The participants were asked to report their gambling both for one year prior to their incarceration and for the past year. The independent variables were demographics (age, gender and marital status), substance use (alcohol, smoking and narcotics) and crime-related factors (crime type, prison type and previous sentence). Statistical significance (p) was determined using Fischer’s exact test.Findings Past-year pre-conviction problem gambling prevalence was 16.3 percent and past-year prevalence 15 percent. Age, gender, smoking, alcohol or illicit drug use were not associated with past-year problem gambling before sentencing. One-third of the prisoners (33.3 percent) who were sentenced for a property crime, financial crime or robbery were problem gamblers. One-quarter (24 percent) of all participants showed an interest in receiving support by identifying one or more support preferences. The most preferred type of support was group support in its all forms.Research limitations/implications It is recommended that correctional institutions undertake systematic screening for potential problem gambling, and implement tailored intervention programs for inmates with gambling problems.Originality/value This study provides a deeper understanding of problem gambling in prisons. Problem gambling is associated with crime and also seems to be linked with serving a previous sentence. Early detection and tailored interventions for problem gambling may help to reduce reoffending rates.
  • Bauer, Michael; Flatt, Justin W.; Seiler, Daria; Cardel, Bettina; Emmenlauer, Mario; Boucke, Karin; Suomalainen, Maarit; Hemmi, Silvio; Greber, Urs F. (2019)
    Adenoviruses (AdVs) cause respiratory, ocular, and gastrointestinal tract infection and inflammation in immunocompetent people and life-threatening disease upon immunosuppression. AdV vectors are widely used in gene therapy and vaccination. Incoming particles attach to nuclear pore complexes (NPCs) of post-mitotic cells, then rupture and deliver viral DNA (vDNA) to the nucleus or misdeliver to the cytosol. Our genome-wide RNAi screen in AdV-infected cells identified the RING-type E3 ubiquitin ligase Mind bomb 1 (Mib1) as a proviral host factor for AdV infection. Mib1 is implicated in Notch-Delta signaling, ciliary biogenesis, and RNA innate immunity. Mib1 depletion arrested incoming AdVs at NPCs. Induced expression of full-length but not ligase-defective Mib1 in knockout cells triggered vDNA uncoating from NPC-tethered virions, nuclear import, misdelivery of vDNA, and vDNA expression. Mib1 is an essential host factor for AdV uncoating in human cells, and it provides a new concept for licensing virion DNA delivery through the NPC.
  • Castrén, Sari; Heiskanen, Maria; Salonen, Anne H (2018)
    Objective The aim of this study is to evaluate trends in past-year gambling participation and gambling severity among Finnish men and women from 2007 to 2015. Design Cross-sectional population surveys from years 2007, 2011 and 2015. Setting Data were drawn from the population register and collected using computer-assisted telephone interviews. Participants Representative random samples of Finns aged 15-74 were drawn in the study in 2007 (n=5008), 2011 (n=4484) and 2015 (n=4515) with response rates of 58%, 40% and 62%, respectively. Outcome measures The outcome measures were gambling versatility, type of games, gambling intensity and gambling severity. Significance (p) between time points was determined using (2) tests. All temporal comparisons between 2007-2011, 2011-2015 and 2007-2015 were performed separately for all respondents aged 15-74 and for women and men. Results Gambling participation overall showed a rising trend (6.6 percentage points, 95%CI 4.9 to 8.3) from 2007 to 2015. In 2007-2011 women's gambling participation increased more (7.8 percentage points, 95%CI 5.5 to 10.4) than men's (5.4 percentage points, 95%CI 3.2 to 7.6). The most popular game types since 2007 have been lottery games, scratch cards and electronic gaming machines (EGMs). EGM gambling, on the other hand, has decreased since 2007. Online gambling has increased significantly from 2007 to 2015 in both genders. Men's at-risk gambling decreased from 2007 to 2011, while women's at-risk gambling and problem gambling increased from 2011 to 2015. Conclusions Women's increasing gambling participation is causing gender differences in gambling behaviour to narrow. The article concludes with a discussion of the need for gender-specific interventions aimed at preventing gambling-related harm and ultimately at protecting the most vulnerable groups.