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| 2. |
- 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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| 3. |
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| 4. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia-A comparative study of four differently designed, high resolution microarray platforms
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 93, s. 0536-0536
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Tidskriftsartikel (refereegranskat)abstract
- Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.
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| 5. |
- Göransson, Hanna, et al.
(författare)
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Quantification of normal cell fraction and copy number neutral LOH in clinical lung cancer samples using SNP array data
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e6057-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells. PRINCIPAL FINDING: Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection. CONCLUSION: Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes.
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| 6. |
- Hagberg, Anette, et al.
(författare)
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Gene expression analysis identifies a genetic signature potentially associated with response to alpha-IFN in chronic phase CML patients
- 2007
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Ingår i: Leukemia research. - : Elsevier BV. - 0145-2126 .- 1873-5835. ; 31:7, s. 931-938
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Tidskriftsartikel (refereegranskat)abstract
- Microarray-based gene expression analysis was performed on diagnostic chronic phase CML patient samples prior to interferon treatment. Fifteen patient samples corresponding to six cytogenetic responders and nine non-responders were included. Genes differentially expressed between responder and non-responder patients were listed and a subsequent leave-one-out cross validation (LOOV) procedure showed that the top 20 genes allowed the highest prediction accuracy. The relevant genes were quantified by real-time PCR that supported the microarray results. We conclude that it might be possible to use gene expression analysis to predict future response to interferon in CML diagnostic samples.
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| 7. |
- 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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| 8. |
- Isaksson, Anders, et al.
(författare)
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Cross-validation and bootstrapping are unreliable in small sample classification
- 2008
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Ingår i: Pattern Recognition Letters. - : Elsevier BV. - 0167-8655 .- 1872-7344. ; 29:14, s. 1960-1965
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Tidskriftsartikel (refereegranskat)abstract
- The interest in statistical classification for critical applications such as diagnoses of patient samples based on supervised learning is rapidly growing. To gain acceptance in applications where the subsequent decisions have serious consequences, e.g. choice of cancer therapy, any such decision support system must come with a reliable performance estimate. Tailored for small sample problems, cross-validation (CV) and bootstrapping (BTS) have been the most commonly used methods to determine such estimates in virtually all branches of science for the last 20 years. Here, we address the often overlooked fact that the uncertainty in a point estimate obtained with CV and BTS is unknown and quite large for small sample classification problems encountered in biomedical applications and elsewhere. To avoid this fundamental problem of employing CV and BTS, until improved alternatives have been established, we suggest that the final classification performance always should be reported in the form of a Bayesian confidence interval obtained from a simple holdout test or using some other method that yields conservative measures of the uncertainty.
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| 9. |
- Isaksson, Hanna, et al.
(författare)
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Effect of rye bread breakfasts on subjective hunger and satiety: a randomized controlled trial
- 2009
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Ingår i: Nutrition Journal. - : Springer Science and Business Media LLC. - 1475-2891. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies report that dietary fibre from different sources promotes the feeling of satiety and suppresses hunger. However, results for cereal fibre from rye are essentially lacking. The aim of the present study was to investigate subjective appetite during 8 h after intake of iso-caloric rye bread breakfasts varying in rye dietary fibre composition and content.Methods: The study was divided into two parts. The first part (n = 16) compared the satiating effect of iso-caloric bread breakfasts including different milling fractions of rye (bran, intermediate fraction (B4) and sifted flour). The second part (n = 16) investigated the dose-response effect of rye bran and intermediate rye fraction, each providing 5 or 8 g of dietary fibre per iso-caloric bread breakfast. Both study parts used a wheat bread breakfast as reference and a randomised, within-subject comparison design. Appetite (hunger, satiety and desire to eat) was rated regularly from just before breakfast at 08: 00 until 16:00. Amount, type and timing of food and drink intake were standardised during the study period.Results: The Milling fractions study showed that each of the rye breakfasts resulted in a suppressed appetite during the time period before lunch (08:3012:00) compared with the wheat reference bread breakfast. At a comparison between the rye bread breakfasts the one with rye bran induced the strongest effect on satiety. In the afternoon the effect from all three rye bread breakfasts could still be seen as a decreased hunger and desire to eat compared to the wheat reference bread breakfast.In the Dose-response study both levels of rye bran and the lower level of intermediate rye fraction resulted in an increased satiety before lunch compared with the wheat reference bread breakfast. Neither the variation in composition between the milling fractions nor the different doses resulted in significant differences in any of the appetite ratings when compared with one another.Conclusion: The results show that rye bread can be used to decrease hunger feelings both before and after lunch when included in a breakfast meal. Rye bran induces a stronger effect on satiety than the other two rye fractions used when served in iso-caloric portions.
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| 10. |
- Staaf, Johan, et al.
(författare)
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Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays
- 2008
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1465-6906 .- 1465-6914. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- We present a strategy for detection of loss-of-heterozygosity and allelic imbalance in cancer cells from whole genome single nucleotide polymorphism genotyping data. Using a dilution series of a tumor cell line mixed with its paired normal cell line and data generated on Affymetrix and Illumina platforms, including paired tumor-normal samples and tumors characterized by fluorescent in situ hybridization, we demonstrate a high sensitivity and specificity of the strategy for detecting both minute and gross allelic imbalances in heterogeneous tumor samples.
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