Browsing by Subject "TARGET"

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  • Douglass Jr., Eugene F.; Allaway, Robert J.; Szalai, Bence; Wang, Wenyu; Tian, Tingzhong; Fernández-Torras, Adrià; Realubit, Ron; Karan, Charles; Zheng, Shuyu; Pessia, Alberto; Tanoli, Ziaurrehman; Jafari, Mohieddin; Wan, Fangping; Li, Shuya; Xiong, Yuanpeng; Duran-Frigola, Miquel; Bertoni, Martino; Badia-i-Mompel, Pau; Mateo, Lídia; Guitart-Pla, Oriol; Chung, Verena; Tang, Jing; Zeng, Jianyang; Aloy, Patrick; Saez-Rodriguez, Julio; Guinney, Justin; Gerhard, Daniela S.; Califano, Andrea (2022)
    The Columbia Cancer Target Discovery and Development (CTD2) Center is developing PANACEA, a resource comprising dose-responses and RNA sequencing (RNA-seq) profiles of 25 cell lines perturbed with similar to 400 clinical oncology drugs, to study a tumor-specific drug mechanism of action. Here, this resource serves as the basis for a DREAM Challenge assessing the accuracy and sensitivity of computational algorithms for de novo drug polypharmacology predictions. Dose-response and perturbational profiles for 32 kinase inhibitors are provided to 21 teams who are blind to the identity of the compounds. The teams are asked to predict high-affinity binding targets of each compound among similar to 1,300 targets cataloged in DrugBank. The best performing methods leverage gene expression profile similarity analysis as well as deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessments of drug mechanisms of action.
  • Okutachi, Sunday; Manoharan, Ganesh Babu; Kiriazis, Alexandros; Laurini, Christina; Catillon, Marie; McCormick, Frank; Yli-Kauhaluoma, Jari; Abankwa, Daniel (2021)
    Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. Here we identified a less toxic, functional analog of OphA that can efficiently inactivate CaM by covalent inhibition. We analyzed a small series of benzazulenones, which bear some structural similarity to OphA and can be synthesized in only six steps. We identified the formyl aminobenzazulenone 1, here named Calmirasone1, as a novel and potent covalent CaM inhibitor. Calmirasone1 has a 4-fold increased affinity for CaM as compared to OphA and was active against K-Ras in cells within minutes, as compared to hours required by OphA. Calmirasone1 displayed a 2.5-4.5-fold higher selectivity for KRAS over BRAF mutant 3D spheroid growth than OphA, suggesting improved relative on-target activity. Importantly, Calmirasone1 has a 40-260-fold lower unspecific toxic effect on HRAS mutant cells, while it reaches almost 50% of the activity of novel K-RasG12C specific inhibitors in 3D spheroid assays. Our results suggest that Calmirasone1 can serve as a new tool compound to further investigate the cancer cell biology of the K-Ras and CaM associated stemness activities.
  • Schnitzbauer, Andreas A.; Zuelke, Carl; Graeb, Christian; Rochon, Justine; Bilbao, Itxarone; Burra, Patrizia; de Jong, Koert P.; Duvoux, Christophe; Kneteman, Norman M.; Adam, Rene; Bechstein, Wolf O.; Becker, Thomas; Beckebaum, Susanne; Chazouilleres, Olivier; Cillo, Umberto; Colledan, Michele; Faendrich, Fred; Gugenheim, Jean; Hauss, Johann P.; Heise, Michael; Hidalgo, Ernest; Jamieson, Neville; Koenigsrainer, Alfred; Lamby, Philipp E.; Lerut, Jan P.; Mäkisalo, Heikki; Margreiter, Raimund; Mazzaferro, Vincenzo; Mutzbauer, Ingrid; Otto, Gerd; Pageaux, Georges-Philippe; Pinna, Antonio D.; Pirenne, Jacques; Rizell, Magnus; Rossi, Giorgio; Rostaing, Lionel; Roy, Andre; Sanchez Turrion, Victor; Schmidt, Jan; Troisi, Roberto I.; van Hoek, Bart; Valente, Umberto; Wolf, Philippe; Wolters, Heiner; Mirza, Darius F.; Scholz, Tim; Steininger, Rudolf; Soderdahl, Gunnar; Strasser, Simone I.; Jauch, Karl-Walter; Neuhaus, Peter; Schlitt, Hans J.; Geissler, Edward K. (2010)
  • Knuuttila, Matias; Mehmood, Arfa; Huhtaniemi, Riikka; Yatkin, Emrah; Häkkinen, Merja R.; Oksala, Riikka; Laajala, Teemu D.; Ryberg, Henrik; Handelsman, David J.; Aittokallio, Tero; Auriola, Seppo; Ohlsson, Claes; Laiho, Asta; Elo, Laura L.; Sipila, Petra; Makela, Sari I.; Poutanen, Matti (2018)
    The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P <0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P <0.05) and the AR splice variants 1 (threefold, P <0.05) and 7 (threefold, P <0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
  • Vilimova, Monika; Contrant, Maud; Randrianjafy, Ramy; Dumas, Philippe; Elbasani, Endrit; Ojala, Päivi M.; Pfeffer, Sebastien; Fender, Aurelie (2021)
    MicroRNAs (miRNAs) are small regulatory RNAs involved in virtually all biological processes. Although many of them are co-expressed from clusters, little is known regarding the impact of this organization on the regulation of their accumulation. In this study, we set to decipher a regulatory mechanism controlling the expression of the ten clustered pre-miRNAs from Kaposi's sarcoma associated herpesvirus (KSHV). We measured in vitro the efficiency of cleavage of each individual pre-miRNA by the Microprocessor and found that pre-miR-K1 and -K3 were the most efficiently cleaved pre-miRNAs. A mutational analysis showed that, in addition to producing mature miRNAs, they are also important for the optimal expression of the whole set of miRNAs. We showed that this feature depends on the presence of a canonical pre-miRNA at this location since we could functionally replace pre-miR-K1 by a heterologous pre-miRNA. Further in vitro processing analysis suggests that the two stem-loops act in cis and that the cluster is cleaved in a sequential manner. Finally, we exploited this characteristic of the cluster to inhibit the expression of the whole set of miRNAs by targeting the premiR-K1 with LNA-based antisense oligonucleotides in cells either expressing a synthetic construct or latently infected with KSHV.
  • Aidala, C.; Kim, D. J.; Krizek, F.; Novitzky, N.; Rak, J.; PHENIX Collaboration (2017)
    The cross section and transverse single-spin asymmetries of mu(-) and mu(+) from open heavy-flavor decays in polarized p + p collisions at pffisffiffi root s = 200 GeV were measured by the PHENIX experiment during 2012 at the Relativistic Heavy Ion Collider. Because heavy-flavor production is dominated by gluon-gluon interactions at ffiffiffi root s = 200 GeV, these measurements offer a unique opportunity to obtain information on the trigluon correlation functions. The measurements are performed at forward and backward rapidity (1.4 <vertical bar y vertical bar <2.0) over the transverse momentum range of 1.25 <p(T) <7 GeV/c for the cross section and 1.25 <p(T) <5 GeV/c for the asymmetry measurements. The obtained cross section is compared to a fixed-order-plus-next-to-leading-log perturbative-quantum-chromodynamics calculation. The asymmetry results are consistent with zero within uncertainties, and a model calculation based on twist-3 three-gluon correlations agrees with the data.
  • Apu, Ehsanul Hoque; Akram, Saad Ullah; Rissanen, Jouni; Wan, Hong; Salo, Tuula (2018)
    Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but its role in carcinoma cell migration and invasion is mostly unknown. Our aim was to quantitatively analyse the motion of Dsg3-modified carcinoma cells in 2D settings and in 3D within tumour microenvironment mimicking (TMEM) matrices. We tested mutant constructs of C-terminally truncated Dsg3 (Delta 238 and Delta 560), overexpressed full-length (FL) Dsg3, and empty vector control (Ct) of buccal mucosa squamous cell carcinoma (SqCC/Y1) cells. We captured live cell images and analysed migration velocities and accumulated and Euclidean distances. We compared rodent collagen and Matrigel. with human Myogel TMEM matrices for these parameters in 3D sandwich, in which we also tested the effects of monoclonal antibody AK23, which targets the EC1 domain of Dsg3. In monolayer culture, FL and both truncated constructs migrated faster and had higher accumulated distances than Ct cells. However, in the 3D assays, only the mutants invaded faster relative to Ct cells. Of the mutants, the shorter form (Delta 238) exhibited faster migration and invasion than Delta 560 cells. In the Transwell, all of the cells invaded faster through Myogel than Matrigel coated wells. In 3D sandwich, AK23 antibody inhibited only the invasion of FL cells. We conclude that different experimental 2D and 3D settings can markedly influence the movement of oral carcinoma cells with various Dsg3 modifications.
  • Bogacheva, Mariia S.; Khan, Sofia; Kanninen, Liisa K.; Yliperttula, Marjo; Leung, Alan W.; Lou, Yan-Ru (2018)
    Definitive endoderm (DE) is the first stage of human pluripotent stem cell (hPSC) differentiation into hepatocyte-like cells. Developing human liver cell models for pharmaceutical applications is highly demanding. Due to the vast number of existing protocols to generate DE cells from hPSCs, we aimed to compare the specificity and efficiency of selected published differentiation conditions. We differentiated two hPSC lines (induced PSC and embryonic stem cell) to DE cells on Matrigel matrix using growth factors (Activin A and Wnt-3a) and small molecules (sodium butyrate and IDE 1) in different combinations. By studying dynamic changes during 6 days in cell morphology and the expression of markers for pluripotency, DE, and other germ layer lineages, we found that Activin A is essential for DE differentiation, while Wnt-3a and sodium butyrate are dispensable. Although sodium butyrate exerted rapid DE differentiation kinetics, it caused massive cell death and could not generate sufficient cells for further differentiation and applications. We further discover that IDE 1 could not induce DE as reported previously. Hereby, we compared different conditions for DE induction and found an effective six day-protocol to obtain DE cells for the further differentiation and applications.
  • Johansson, Niklas G; Turku, Ainoleena; Vidilaseris, Keni; Dreano, Loic; Khattab, Ayman; Ayuso Perez, Daniel; Wilkinson, Aaron; Zhang, Yuezhou; Tamminen, Matti; Grazhdankin, Evgeni; Kiriazis, Alexandros; Fishwick, Colin W. G.; Meri, Seppo; Yli-Kauhaluoma, Jari; Goldman, Adrian; Boije af Gennäs, Gustav; Xhaard, Henri (2020)
    Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6-10 mu M IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.
  • Giri, Anil K.; Aittokallio, Tero (2019)
    DNA methyltransferase inhibitors (DNMTi) decitabine and azacytidine are approved therapies for myelodysplastic syndrome and acute myeloid leukemia, and their combinations with other anticancer agents are being tested as therapeutic options for multiple solid cancers such as colon, ovarian, and lung cancer. However, the current therapeutic challenges of DNMTis include development of resistance, severe side effects and no or partial treatment responses, as observed in more than half of the patients. Therefore, there is a critical need to better understand the mechanisms of action of these drugs. In order to discover molecular targets of DNMTi therapy, we identified 638 novel CpGs with an increased methylation in response to decitabine treatment in HCT116 cell lines and validated the findings in multiple cancer types (e.g., bladder, ovarian, breast, and lymphoma) cell lines, bone marrow mononuclear cells from primary leukemia patients, as well as peripheral blood mononuclear cells and ascites from platinum resistance epithelial ovarian cancer patients. Azacytidine treatment also increased methylation of these CpGs in colon, ovarian, breast, and lymphoma cancer cell lines. Methylation at 166 identified CpGs strongly correlated (vertical bar r vertical bar >= 0.80) with corresponding gene expression in HCT116 cell line. Differences in methylation at some of the identified CpGs and expression changes of the corresponding genes was observed in TCGA colon cancer tissue as compared to adjacent healthy tissue. Our analysis revealed that hypermethylated CpGs are involved in cancer cell proliferation and apoptosis by P53 and olfactory receptor pathways, hence influencing DNMTi responses. In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients.
  • Kuusanmäki, Heikki; Dufva, Olli; Parri, Elina; van Adrichem, Arjan J.; Rajala, Hanna; Majumder, Muntasir M.; Yadav, Bhagwan; Parsons, Alun; Chan, Wing C.; Wennerberg, Krister; Mustjoki, Satu; Heckman, Caroline A. (2017)
    Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of-function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3.
  • Unbiased Biomarkers Prediction Re; Jevnikar, Zala; Östling, Jörgen; Vaarala, Outi (2019)
    Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
  • Fedorets, Grigori; Micheli, Marco; Jedicke, Robert; Naidu, Shantanu P.; Farnocchia, Davide; Granvik, Mikael; Moskovitz, Nicholas; Schwamb, Megan E.; Weryk, Robert; Wierzchos, Kacper; Christensen, Eric; Pruyne, Theodore; Bottke, William F.; Ye, Quanzhi; Wainscoat, Richard; Devogele, Maxime; Buchanan, Laura E.; Djupvik, Anlaug Amanda; Faes, Daniel M.; Fohring, Dora; Roediger, Joel; Seccull, Tom; Smith, Adam B. (2020)
    We report on our detailed characterization of Earth's second known temporary natural satellite, or minimoon, asteroid 2020 CD3. An artificial origin can be ruled out based on its area-to-mass ratio and broadband photometry, which suggest that it is a silicate asteroid belonging to the S or V complex in asteroid taxonomy. The discovery of 2020 CD3 allows for the first time a comparison between known minimoons and theoretical models of their expected physical and dynamical properties. The estimated diameter of 1.2(-0.2)(+0.4) m and geocentric capture approximately a decade after the first known minimoon, 2006.RH120, are in agreement with theoretical predictions. The capture duration of 2020 CD3 of at least 2.7 yr is unexpectedly long compared to the simulation average, but it is in agreement with simulated minimoons that have close lunar encounters, providing additional support for the orbital models. 2020 CD3's atypical rotation period, significantly longer than theoretical predictions, suggests that our understanding of meter-scale asteroids needs revision. More discoveries and a detailed characterization of the population can be expected with the forthcoming Vera C. Rubin Observatory Legacy Survey of Space and Time.
  • Johansson, Niklas G; Dreano, Loic; Vidilaseris, Keni; Khattab, Ayman; Liu, Jianing; Lasbleiz, Arthur; de Castro Ribeiro, Orquidea Marilia; Kiriazis, Alexandros; Boije af Gennäs, Gustav; Meri, Seppo; Goldman, Adrian; Yli-Kauhaluoma, Jari; Xhaard, Henri (2021)
    Inhibition of membrane-bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure-activity relationships around a new scaffold having a pyrazolo[1,5-a]pyrimidine core. The most promising pyrazolo[1,5-a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
  • Ridolfo, Roxane; Tavakoli, Shirin; Junnuthula, Vijayabhaskarreddy; Williams, David S.; Urtti, Arto; van Hest, Jan C. M. (2021)
    Nanoparticle morphology (size, shape, and composition) and surface chemistry are the determining factors underpinning the efficacy of such materials in therapeutic applications. The size, shape, and surface chemistry of a nanoparticle can strongly influence key properties such as interactions with diverse biological fluids and interfaces and, in turn, impact the delivery of bioactive cargo, modulating therapeutic performance. This is exemplified in ocular drug delivery, where potential therapeutics must navigate complex biological media such as the gel-like vitreal fluid and the retina. Biodegradable block copolymer amphiphiles are a robust tool for the engineering of various types of self-assembled nanoparticles with diverse morphologies ranging from spherical and tubular polymersomes to spherical and worm-like micelles. Here, we explore the effect of morphological features such as shape and surface chemistry upon the interactions of a series of copolymer nanoparticles with retinal (ARPE-19) cells and the release of a low solubility drug (dexamethasone) that is currently used in ocular therapy and study their diffusion in vitreous using ex vivo eyes. We demonstrate that both aspect ratio and surface chemistry of nanoparticles will influence their performance in terms of cell uptake, drug release, and diffusion with high aspect ratio shapes demonstrating enhanced properties in relation to their spherical counterparts.
  • Wagner, Maximilian; Bracun, Sandra; Duenser, Anna; Sturmbauer, Christian; Gessl, Wolfgang; Ahi, Ehsan Pashay (2022)
    Background Elasmoid scales are one of the most common dermal appendages and can be found in almost all species of bony fish differing greatly in their shape. Whilst the genetic underpinnings behind elasmoid scale development have been investigated, not much is known about the mechanisms involved in moulding of scales. To investigate the links between gene expression differences and morphological divergence, we inferred shape variation of scales from two different areas of the body (anterior and posterior) stemming from ten haplochromine cichlid species from different origins (Lake Tanganyika, Lake Malawi, Lake Victoria and riverine). Additionally, we investigated transcriptional differences of a set of genes known to be involved in scale development and morphogenesis in fish. Results We found that scales from the anterior and posterior part of the body strongly differ in their overall shape, and a separate look on scales from each body part revealed similar trajectories of shape differences considering the lake origin of single investigated species. Above all, nine as well as 11 out of 16 target genes showed expression differences between the lakes for the anterior and posterior dataset, respectively. Whereas in posterior scales four genes (dlx5, eda, rankl and shh) revealed significant correlations between expression and morphological differentiation, in anterior scales only one gene (eda) showed such a correlation. Furthermore, eda displayed the most significant expression difference between species of Lake Tanganyika and species of the other two younger lakes. Finally, we found genetic differences in downstream regions of eda gene (e.g., in the eda-tnfsf13b inter-genic region) that are associated with observed expression differences. This is reminiscent of a genetic difference in the eda-tnfsf13b inter-genic region which leads to gain or loss of armour plates in stickleback. Conclusion These findings provide evidence for cross-species transcriptional differences of an important morphogenetic factor, eda, which is involved in formation of ectodermal appendages. These expression differences appeared to be associated with morphological differences observed in the scales of haplochromine cichlids indicating potential role of eda mediated signal in divergent scale morphogenesis in fish.
  • FinnGen; Leskelä, Jaakko; Toppila, Iiro; Härmä, Mari-Anne; Palviainen, Teemu; Salminen, Aino; Sandholm, Niina; Pietiäinen, Milla; Kopra, Elisa; Pais de Barros, Jean-Paul; Lassenius, Mariann I.; Kumar, Anmol; Harjutsalo, Valma; Roslund, Kajsa; Forsblom, Carol; Loukola, Anu; Havulinna, Aki S.; Lagrost, Laurent; Salomaa, Veikko; Groop, Per-Henrik; Perola, Markus; Kaprio, Jaakko; Lehto, Markku; Pussinen, Pirkko J. (2021)
    Background Translocation of lipopolysaccharide from gram-negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome-wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high-performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis-related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome-wide significant association with 741 single-nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included KNG1, KLKB1, F12, SLC34A1, YPEL4, CLP1, ZDHHC5, SERPING1, CBX5, and LIPC. The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.
  • FinnGen; Yin, Xianyong; Chan, Lap Sum; Bose, Debraj; Ripatti, Samuli; Palotie, Aarno; Boehnke, Michael (2022)
    The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.
  • Beaune, Gregory; Lam, Andy Y. W.; Dufour, Sylvie; Winnik, Francoise M.; Brochard-Wyart, Francoise (2017)
    We study the spreading of cell aggregates deposited on adhesive substrates decorated with microparticles (MPs). A cell monolayer expands around the aggregate. The cells on the periphery of the monolayer take up the MPs, clearing the substrate as they progress and forming an aureole of cells filled with MPs. We study the dynamics of spreading and determine the width of the aureole and the level of MP internalization in cells as a function of MP size, composition, and density. From the radius and width of the aureole, we quantify the volume fraction of MPs within the cell, which leads to an easy, fast, and inexpensive measurement of the cell - particle internalization.
  • Legehar, Ashenafi; Xhaard, Henri; Ghemtio, Leo (2016)
    Background: The disposition of a pharmaceutical compound within an organism, i.e. its Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties and adverse effects, critically affects late stage failure of drug candidates and has led to the withdrawal of approved drugs. Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and ADMET or adverse effects, but this is limited by the size, quality, and heterogeneity of the data available from individual sources. Thus, large, clean and integrated databases of approved drug data, associated with fast and efficient predictive tools are desirable early in the drug discovery process. Description: We have built a relational database (IDAAPM) to integrate available approved drug data such as drug approval information, ADMET and adverse effects, chemical structures and molecular descriptors, targets, bioactivity and related references. The database has been coupled with a searchable web interface and modern data analytics platform (KNIME) to allow data access, data transformation, initial analysis and further predictive modeling. Data were extracted from FDA resources and supplemented from other publicly available databases. Currently, the database contains information regarding about 19,226 FDA approval applications for 31,815 products (small molecules and bio-logics) with their approval history, 2505 active ingredients, together with as many ADMET properties, 1629 molecular structures, 2.5 million adverse effects and 36,963 experimental drug-target bioactivity data. Conclusion: IDAAPM is a unique resource that, in a single relational database, provides detailed information on FDA approved drugs including their ADMET properties and adverse effects, the corresponding targets with bioactivity data, coupled with a data analytics platform. It can be used to perform basic to complex drug-target ADMET or adverse effects analysis and predictive modeling. IDAAPM is freely accessible at http://idaapm.helsinki.fi and can be exploited through a KNIME workflow connected to the database.