| 1. |
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| 2. |
- Andersson, Claes R., et al.
(författare)
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In vitro drug sensitivity-gene expression correlations involve a tissue of origin dependency
- 2007
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Ingår i: Journal of chemical information and modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 47:1, s. 239-248
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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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| 3. |
- Björklund, Peyman, et al.
(författare)
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Stathmin as a Marker for Malignancy in Pheochromocytomas
- 2010
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Ingår i: Experimental and clinical endocrinology & diabetes. - : Georg Thieme Verlag KG. - 0947-7349 .- 1439-3646. ; 118:1, s. 27-30
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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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| 4. |
- Fryknäs, Mårten, 1974-
(författare)
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Molecular Screening for Target Discovery in Cancer
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is one of the major causes of death in the western world. Resistance to anti-cancer drugs and diagnostic difficulties are major obstacles to successful treatment. This thesis describes studies based on microarray expression analysis and high-throughput compound screening for identification of resistance mechanisms, drug targets and diagnostic markers. In paper I-IV, we applied global expression analysis and measurements of drug response in a human tumor cell line panel to identify drug targets and resistance mechanisms. In paper I, we identified gene transcript levels that correlate with drug resistance and sensitivity. Both well known and new potential markers and mechanisms were identified. In paper II, we showed that STAT1 activity is associated with cross-resistance to both doxorubicin and radiation in vitro and that fludarabine can counteract STAT1 activity and reduce resistance. In Paper III-IV, cell lines were exposed to a compound library consisting of more than thousand different substances in a high-throughput screening effort. These studies revealed that cell line models of squamous cell carcinoma (Paper III) and drug resistant myeloma (Paper IV) are sensitive to phosphodiesterase inhibitors and glucocorticoids respectively. The target molecules for these drugs were over-expressed at the mRNA level and constitute likely explanations for the observed drug potency. In paper V, we identified mRNA markers for the distinction between two types of thyroid tumors, thyroid follicular adenomas and thyroid follicular carcinomas, by means of microarray expression analysis. Our results indicated that distinction between the two tumor types is possible with a small number of markers.
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| 5. |
- Fryknäs, Mårten, et al.
(författare)
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Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model
- 2006
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Ingår i: Journal of Biomolecular Screening. - : Elsevier BV. - 1087-0571 .- 1552-454X. ; 11:5, s. 457-468
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Tidskriftsartikel (refereegranskat)abstract
- The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP-protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.
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| 6. |
- Fryknäs, Mårten, et al.
(författare)
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STAT1 signaling is associated with acquired crossresistance to doxorubicin and radiation in myeloma cell lines
- 2007
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 120:1, s. 189-195
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Tidskriftsartikel (refereegranskat)abstract
- The myeloma cell line RPMI 8226/S and its doxorubicin resistant subline 8226/Dox40 were used as models to explore the potential importance of the STAT1 signaling pathway in drug and radiation resistance. The 40-fold doxorubicin resistant subline 8226/Dox40 was found to be crossresistant to single doses of 4 and 8 Gy of radiation. A genome-wide mRNA expression study comparing the 8226/Dox40 cell line to its parental line was performed to identify the underlying molecular mechanisms. Seventeen of the top 50 overexpressed genes have previously been implicated in the STAT1 signaling pathway. STAT1 was over expressed both at the mRNA and protein level. Moreover, analyses of nuclear extracts showed higher abundance of phosphorylated STAT1 (Tyr 701) in the resistant subline. Preexposure of the crossresistant cells to the STAT1 inhibiting drug fludarabine reduced expression of overexpressed genes and enhanced the effects of both doxorubicin and radiation. These results show that resistance to doxorubicin and radiation is associated with increased STAT1 signaling and can be modulated by fludarabine. The data support further development of therapies combining fludarabine and radiation.
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| 7. |
- Gustafsson, Mats G., et al.
(författare)
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Improving Bayesian credibility intervals for classifier error rates using maximum entropy empirical priors
- 2010
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Ingår i: Artificial Intelligence in Medicine. - : Elsevier BV. - 0933-3657 .- 1873-2860. ; 49:2, s. 93-104
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Tidskriftsartikel (refereegranskat)abstract
- Objective:Successful use of classifiers that learn to make decisions from a set of patient examples require robust methods for performance estimation. Recently many promising approaches for determination of an upper bound for the error rate of a single classifier have been reported but the Bayesian credibility interval (Cl) obtained from a conventional holdout test still delivers one of the tightest bounds. The conventional Bayesian CI becomes unacceptably large in real world applications where the test set sizes are less than a few hundred. The source of this problem is that fact that the Cl is determined exclusively by the result on the test examples. In other words, there is no information at all provided by the uniform prior density distribution employed which reflects complete lack of prior knowledge about the unknown error rate. Therefore, the aim of the study reported here was to study a maximum entropy (ME) based approach to improved prior knowledge and Bayesian CIs, demonstrating its relevance for biomedical research and clinical practice.Method and material:It is demonstrated how a refined non-uniform prior density distribution can be obtained by means of the ME principle using empirical results from a few designs and tests using non-overlapping sets of examples.Results:Experimental results show that ME based priors improve the CIs when employed to four quite different simulated and two real world data sets.Conclusions:An empirically derived ME prior seems promising for improving the Bayesian Cl for the unknown error rate of a designed classifier.
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| 8. |
- Hassan, Saadia, et al.
(författare)
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Gene expression signature-based chemcial genomics and activity pattern in a panel of tumour cell lines propose linalyl acetate as a protein kinase/NF-κB inhibitor
- 2008
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Ingår i: Gene Therapy and Molecular Biology. - 1529-9120. ; 12:B, s. 359-370
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Tidskriftsartikel (refereegranskat)abstract
- The essential oil of Lebanese sage, Salvia libanotica, was reported to have anti-tumour activity; however, the mechanism of action has not been identified yet. In this study, 14- cancer cell lines including drug-sensitive and resistant lung, leukaemia, and colon, as well as primary human tumours of chronic lymphocytic leukaemia (CLL) and primary normal mononuclear cells (PBMCs) were used to characterize the anti-tumour activity and mechanism of action of linalyl acetate, a component of the Lebanese sage essential oil. Drug activity and gene expression data sets were utilized to identify drugs with similar activity patterns and genes involved in drug sensitivity/resistance. In addition, the Connectivity Map, a gene expression signature-based screening approach, assisted in predicting further the molecular action of linalyl acetate. Small cell lung carcinoma and colorectal cancer cell lines were the most sensitive to the drug and greater tumour selectivity was observed against chronic lymphocytic leukaemia cells compared to normal mononuclear cells. Only limited effect of some of the classical mechanisms of multi-drug resistance on the activity of Linalyl acetate was noted which makes it potentially interesting for drug-resistant patients. There was high similarity between the activity-pattern/gene expression profile of linalyl acetate and that of protein kinase/NF-kappa B inhibitors. Validating this, linalyl acetate was found to strongly inhibit Janus kinase, JAK3, and p38 alpha kinases in a cell-free assay as well as the NF-kappa B translocation in a dose-dependent manner. Taken together, our results show that the NF-kappa B inhibitor, linalyl acetate, may represent a new therapeutic compound in the management of inflammation and cancer.
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| 9. |
- Milani, Lili, et al.
(författare)
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Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells
- 2007
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 35:5, s. E34-
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Tidskriftsartikel (refereegranskat)abstract
- Using the relative expression levels of two SNIP 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 Al as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of All 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 Al 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 SNIP 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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| 10. |
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