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Sökning: WFRF:(Fryknäs Mårten)

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1.
  • Aftab, Obaid, 1984-, et al. (författare)
  • Detection of cell aggregation and altered cell viability by automated label-free video microscopy : A promising alternative to endpoint viability assays in high throughput screening
  • 2014
  • Ingår i: Journal of Biomolecular Screening. - 1087-0571.
  • Tidskriftsartikel (refereegranskat)abstract
    • Automated phase-contrast video microscopy now makes it feasible to monitor a high-throughput (HT) screening experiment in a 384-well microtiter plate format by collecting one time-lapse video per well. Being a very cost-effective and label-free monitoring method, its potential as an alternative to cell viability assays was evaluated. Three simple morphology feature extraction and comparison algorithms were developed and implemented for analysis of differentially time-evolving morphologies (DTEMs) monitored in phase-contrast microscopy videos. The most promising layout, pixel histogram hierarchy comparison (PHHC), was able to detect several compounds that did not induce any significant change in cell viability, but made the cell population appear as spheroidal cell aggregates. According to recent reports, all these compounds seem to be involved in inhibition of platelet-derived growth factor receptor (PDGFR) signaling. Thus, automated quantification of DTEM (AQDTEM) holds strong promise as an alternative or complement to viability assays in HT in vitro screening of chemical compounds.
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2.
  • Aftab, Obaid, 1984-, et al. (författare)
  • Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing
  • 2014
  • Ingår i: Apoptosis (London). - 1360-8185. ; 19:9, s. 1411-1418
  • Tidskriftsartikel (refereegranskat)abstract
    • Label free time-lapse microscopy has opened a new avenue to the study of time evolving events in living cells. When combined with automated image analysis it provides a powerful tool that enables automated large-scale spatiotemporal quantification at the cell population level. Very few attempts, however, have been reported regarding the design of image analysis algorithms dedicated to the detection of apoptotic cells in such time-lapse microscopy images. In particular, none of the reported attempts is based on sufficiently fast signal processing algorithms to enable large-scale detection of apoptosis within hours/days without access to high-end computers. Here we show that it is indeed possible to successfully detect chemically induced apoptosis by applying a two-dimensional linear matched filter tailored to the detection of objects with the typical features of an apoptotic cell in phase-contrast images. First a set of recorded computational detections of apoptosis was validated by comparison with apoptosis specific caspase activity readouts obtained via a fluorescence based assay. Then a large screen encompassing 2,866 drug like compounds was performed using the human colorectal carcinoma cell line HCT116. In addition to many well known inducers (positive controls) the screening resulted in the detection of two compounds here reported for the first time to induce apoptosis.
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3.
  • Aftab, Obaid, 1984-, et al. (författare)
  • Label free quantification of time evolving morphologies using time-lapse video microscopy enables identity control of cell lines and discovery of chemically induced differential activity in iso-genic cell line pairs
  • 2014
  • Ingår i: Chemometrics and Intelligent Laboratory Systems. - Elsevier. - 0169-7439.
  • Tidskriftsartikel (refereegranskat)abstract
    • Label free time-lapse video microscopy based monitoring of time evolving cell population morphology has potential to offer a simple and cost effective method for identity control of cell lines. Such morphology monitoring also has potential to offer discovery of chemically induced differential changes between pairs of cell lines of interest, for example where one in a pair of cell lines is normal/sensitive and the other malignant/resistant. A new simple algorithm, pixel histogram hierarchy comparison (PHHC), for comparison of time evolving morphologies (TEM) in phase contrast time-lapse microscopy movies was applied to a set of 10 different cell lines and three different iso-genic colon cancer cell line pairs, each pair being genetically identical except for a single mutation. PHHC quantifies differences in morphology by comparing pixel histogram intensities at six different resolutions. Unsupervised clustering and machine learning based classification methods were found to accurately identify cell lines, including their respective iso-genic variants, through time-evolving morphology. Using this experimental setting, drugs with differential activity in iso-genic cell line pairs were likewise identified. Thus, this is a cost effective and expedient alternative to conventional molecular profiling techniques and might be useful as part of the quality control in research incorporating cell line models, e.g. in any cell/tumor biology or toxicology project involving drug/agent differential activity in pairs of cell line models.
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4.
  • Aftab, Obaid, 1984-, et al. (författare)
  • Label free quantification of time evolving morphologies using time-lapse video microscopy enables identity control of cell lines and discovery of chemically induced differential activity in iso-genic cell line pairs
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • Background: Label free time-lapse video microscopy based monitoring of time evolving cell population morphology has potential to offer a simple and cost effective method for identity control of cell lines. An identity control method of this kind would be useful in any cell biology lab to ensure that new batches of cell lines and clones are not contaminated or simply assigned the wrong label. Such morphology monitoring also has potential to offer discovery of chemically induced differential changes between pairs of cell lines of interest, for example where one of the two cell lines is normal/sensitive and the other is malignant/resistant. A discovery tool of this kind would be useful in cancer as well as toxicological research where a key question is to identify individual chemicals/drugs, or mixtures, having outstanding differential biochemical effects in carefully selected pairs of in vitro cell line models.Results: A new simple algorithm for comparison of time evolving morphologies (TEM) in phase contrast time-lapse microscopy movies was applied to a set of 11 different cell lines as well as to three different iso-genic colon cancer cell line pairs, each pair being genetically identical except for one single mutation. The new algorithm, here called pixel histogram hierarchy comparison (PHHC), quantifies differences in morphology by comparing pixel histogram intensities at six different resolutions. Unsupervised clustering as well as machine learning based classification methods were employed and found to quite accurately identify cell lines based on their recorded time-evolving morphology. In the same way, drugs with differential activity in iso-genic cell line pairs were identified.Conclusions: Automated analysis of TEMs enables simple control of cell line identity as well as the finding of differential drug activity in iso-genic cell line pairs. Thus, this is a cost effective and simple alternative to conventional molecular profiling techniques and might be useful as part of the quality control in research based on cell line models and in any anti-cancer or toxicology project with interest in finding drug differential activity in pairs of cell line models of interest.
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5.
  • Andersen, Malin, et al. (författare)
  • Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells
  • 2007
  • Ingår i: Nucleic Acids Research. - 0305-1048. ; 35:5, s. e34
  • Tidskriftsartikel (refereegranskat)abstract
    • Using the relative expression levels of two SNP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of AI as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of AI in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed AI were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions.
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6.
  • Andersson, Claes R., et al. (författare)
  • In vitro drug sensitivity-gene expression correlations involve a tissue of origin dependency
  • 2007
  • Ingår i: Journal of chemical information and modeling. - 1549-9596. ; 47:1, s. 239-248
  • Tidskriftsartikel (refereegranskat)abstract
    • A major concern of chemogenomics is to associate drug activity with biological variables. Several reports have clustered cell line drug activity profiles as well as drug activity-gene expression correlation profiles and noted that the resulting groupings differ but still reflect mechanism of action. The present paper shows that these discrepancies can be viewed as a weighting of drug-drug distances, the weights depending on which cell lines the two drugs differ in.
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7.
  • Arner, Elias, et al. (författare)
  • The 19S Deubiquitinase Inhibitor b-AP15 Is Enriched in Cells and Elicits Rapid Commitment to Cell Death
  • 2014
  • Ingår i: Molecular Pharmacology. - 0026-895X. ; 85:6, s. 932-945
  • Tidskriftsartikel (refereegranskat)abstract
    • b-AP15 [(3E, 5E)-3,5-bis[(4-nitrophenyl) methylidene]-1-(prop-2enoyl) piperidin-4-one] is a small molecule inhibitor of the ubiquitin specific peptidase (USP) 14/ubiquitin carboxyl-terminal hydrolase (UCH) L5 deubiquitinases of the 19S proteasome that shows antitumor activity in a number of tumor models, including multiple myeloma. b-AP15 contains an alpha,beta-unsaturated carbonyl unit that is likely to react with intracellular nucleophiles such as cysteine thiolates by Michael addition. We found that binding of b-AP15 to USP14 is partially reversible, and that inhibition of proteasome function is reversible in cells. Despite reversible binding, tumor cells are rapidly committed to apoptosis/cell death after exposure to b-AP15. We show that b-AP15 is rapidly taken up from the medium and enriched in cells. Enrichment provides an explanation of the stronger potency of the compound in cellular assays compared with in vitro biochemical assays. Cellular uptake was impaired by 30-minute pretreatment of cells with low concentrations of N-ethylmaleimide (10 mu M), suggesting that enrichment was thiol dependent. We report that in addition to inhibition of deubiquitinases, b-AP15 inhibits the selenoprotein thioredoxin reductase (TrxR). Whereas proteasome inhibition was closely associated with cell death induction, inhibition of TrxR was not. TrxR inhibition is, however, likely to contribute to triggering of oxidative stress observed with b-AP15. Furthermore, we present structure-activity, in vivo pharmacokinetic, and hepatocyte metabolism data for b-AP15. We conclude that the strong enrichment of b-AP15 in cells and a rapid commitment to apoptosis/cell death are factors that likely contribute to the strong antitumor activity of this compound.
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8.
  • Björklund, Peyman, et al. (författare)
  • Stathmin as a Marker for Malignancy in Pheochromocytomas
  • 2010
  • Ingår i: Experimental and clinical endocrinology & diabetes. - 0947-7349. ; 118:1, s. 27-30
  • Tidskriftsartikel (refereegranskat)abstract
    • Pheochromocytomas of the adrenal medulla may be life-threatening catecholamine-producing tumors which are malignant in about 10% of cases. Differential diagnosis between malignant and benign tumors is dependent on the development of metastasis or extensive local invasion. A number of genetic aberrations have been described in pheochromocytomas, but no marker associated to malignancy has been reported. We applied an expression microarray containing 7770 cDNA clones and analysed the expression profiles in eleven tumors compared to normal adrenal medulla. Stathmin (STMN1, Op18) was most conspiciously overexpressed among the differentially expressed genes. RT-PCR analysis further confirmed mRNA overexpression, 6 to 8-fold for benign and malignant tumors, and 16-fold for metastases. Stathmin protein overexpression was observed by immunohistochemistry, and distinct differential protein expression between benign and malignant/metastasis specimens was confirmed by Western blot analysis. The results introduce stathmin as a possible diagnostic marker for malignant pheochromocytomas, and further evaluations are warranted.
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9.
  • Brnjic, Slavica, et al. (författare)
  • Induction of Tumor Cell Apoptosis by a Proteasome Deubiquitinase Inhibitor Is Associated with Oxidative Stress
  • 2014
  • Ingår i: Antioxidants and Redox Signaling. - 1523-0864. ; 21:17, s. 2271-2285
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. Results: We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of alpha-subunit of eukaryotic initiation factor 2 phosphorylation. Innovation: The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Conclusion: Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15. Antioxid. Redox Signal. 21, 2271-2285.
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10.
  • D'Arcy, Padraig, et al. (författare)
  • Inhibition of proteasome deubiquitinating activity as a new cancer therapy
  • 2011
  • Ingår i: Nature Medicine. - 1078-8956. ; 17:12, s. 1636-1640
  • Tidskriftsartikel (refereegranskat)abstract
    • Ubiquitin-tagged substrates are degraded by the 26S proteasome, which is a multisubunit complex comprising a proteolytic 20S core particle capped by 19S regulatory particles. The approval of bortezomib for the treatment of multiple myeloma validated the 20S core particle as an anticancer drug target. Here we describe the small molecule b-AP15 as a previously unidentified class of proteasome inhibitor that abrogates the deubiquitinating activity of the 19S regulatory particle. b-AP15 inhibited the activity of two 19S regulatory-particle-associated deubiquitinases, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14), resulting in accumulation of polyubiquitin. b-AP15 induced tumor cell apoptosis that was insensitive to TP53 status and overexpression of the apoptosis inhibitor BCL2. We show that treatment with b-AP15 inhibited tumor progression in four different in vivo solid tumor models and inhibited organ infiltration in an acute myeloid leukemia model. Our results show that the deubiquitinating activity of the 19S regulatory particle is a new anticancer drug target.
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