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Sökning: WFRF:(Brunnstrom Hans)

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1.
  • Biswas, Dhruva, et al. (författare)
  • A clonal expression biomarker associates with lung cancer mortality
  • 2019
  • Ingår i: Nature Medicine. - Nature Publishing Group. - 1078-8956. ; 25:10, s. 1540-1548
  • Tidskriftsartikel (refereegranskat)abstract
    • An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage1. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2–6. Here, we analyze multi-region whole-exome and RNA sequencing data for 156 tumor regions from 48 patients enrolled in the TRACERx study to explore and control for RNA-ITH in non-small cell lung cancer. We find that chromosomal instability is a major driver of RNA-ITH, and existing prognostic gene expression signatures are vulnerable to tumor sampling bias. To address this, we identify genes expressed homogeneously within individual tumors that encode expression modules of cancer cell proliferation and are often driven by DNA copy-number gains selected early in tumor evolution. Clonal transcriptomic biomarkers overcome tumor sampling bias, associate with survival independent of clinicopathological risk factors, and may provide a general strategy to refine biomarker design across cancer types.
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2.
  • Bossé, Yohan, et al. (författare)
  • Transcriptome-wide association study reveals candidate causal genes for lung cancer
  • 2020
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136. ; 146:7, s. 1862-1878
  • Tidskriftsartikel (refereegranskat)abstract
    • We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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3.
  • Brunnstrom, Hans, et al. (författare)
  • PD-L1 immunohistochemistry in clinical diagnostics of lung cancer : inter-pathologist variability is higher than assay variability
  • 2017
  • Ingår i: Modern Pathology. - NATURE PUBLISHING GROUP. - 0893-3952 .- 1530-0285. ; 30:10, s. 1411-1421
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Assessment of programmed cell death ligand 1 (PD-L1) immunohistochemical staining is used for decision on treatment with programmed cell death 1 and PD-L1 checkpoint inhibitors in lung adenocarcinomas and squamous cell carcinomas. This study aimed to compare the staining properties of tumor cells between the antibody clones 28-8, 22C3, SP142, and SP263 and investigate interrater variation between pathologists to see if these stainings can be safely evaluated in the clinical setting. Using consecutive sections from a tissue microarray with tumor tissue from 55 resected lung cancer cases, staining with five PD-L1 assays (28-8 from two different vendors, 22C3, SP142, and SP263) was performed. Seven pathologists individually evaluated the percentage of positive tumor cells, scoring each sample applying cutoff levels used in clinical studies: &lt; 1% positive tumor cells (score 0), 1-4% (score 1), 5-9% (score 2), 10-24% (score 3), 25-49% (score 4), and &gt; 50% positive tumor cells (score 5). Pairwise analysis of antibody clones showed weighted kappa values in the range of 0.45-0.91 with the highest values for comparisons with 22C3 and 28-8 and the lowest involving SP142. Excluding SP142 resulted in kappa 0.75-0.91. Weighted kappa for interobserver variation between pathologists was 0.71-0.96. Up to 20% of the cases were differently classified as positive or negative by any pathologist compared with consensus score using &gt;= 1% positive tumor cells as cutoff. A significantly better agreement between pathologists was seen using &gt;= 50% as cutoff (0-5% of cases). In conclusion, the concordance between the PD-L1 antibodies 22C3, 28-8 and SP263 is relatively good when evaluating lung cancers and suggests that any one of these assays may be sufficient as basis for decision on treatment with nivolumab, pembrolizumab, and durvalumab. The scoring of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.</p>
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4.
  • Dai, Juncheng, et al. (författare)
  • Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk
  • 2020
  • Ingår i: International Journal of Cancer. - John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:10, s. 2855-2864
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung ncer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant netic polymorphisms in the human genome. INDELs are highly associated with multiple human seases, including lung cancer. However, limited studies with large-scale samples have been available to stematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta- alysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional notations were performed to further explore the potential function of lung cancer risk INDELs. nditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci re identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 x 10(- ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 x 10(-7); 12p13.31: rs71450133, Deletion, OR = 09, p = 8.83 x 10(-7); and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 x 10(-8)). The eQTL alysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by gulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, e INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be tentially functional genetic variants for lung cancer risk. Further functional experiments are needed to tter understand INDEL mechanisms in carcinogenesis.</p>
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5.
  • Dai, Juncheng, et al. (författare)
  • Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk
  • ????
  • Ingår i: International Journal of Cancer. - John Wiley and Sons Inc.. - 0020-7136.
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10−8; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10−7; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10−7; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10−8). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.
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6.
  • Djureinovic, Dijana, et al. (författare)
  • Profiling cancer testis antigens in non-small-cell lung cancer
  • 2016
  • Ingår i: JCI Insight. - The American Society for Clinical Investigation. - 2379-3708. ; 1:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.
7.
  • Djureinovic, Dijana, et al. (författare)
  • Profiling cancer testis antigens in non-small-cell lung cancer
  • 2016
  • Ingår i: JCI INSIGHT. - American Society for Clinical Investigation. - 2379-3708. ; 1:10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.</p>
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8.
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9.
  • Grinberg, Marianna, et al. (författare)
  • Reaching the limits of prognostication in non-small cell lung cancer : an optimized biomarker panel fails to outperform clinical parameters
  • 2017
  • Ingår i: Modern Pathology. - Nature Publishing Group. - 1530-0285. ; 30:7, s. 964-977
  • Tidskriftsartikel (refereegranskat)abstract
    • Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.
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10.
  • Han, Hongya, et al. (författare)
  • Human 15-lipoxygenase-1 is a regulator of dendritic-cell spreading and podosome formation
  • 2017
  • Ingår i: The FASEB Journal. - FEDERATION AMER SOC EXP BIOL. - 0892-6638 .- 1530-6860. ; 31:2, s. 491-504
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Dendritic cells (DCs) involved in proinflammatory immune responses derive mainly from peripheral monocytes, and the cells subsequently mature and migrate into the inflammatory micromilieu. Here we report that suppressing of 15-lipoxygenase-1 led to a substantial reduction in DC spreading and podosome formation in vitro. The surface expression of CD83 was significantly lower in both sh-15-lipoxygenase-1 (15-LOX-1)-transduced cells and DCs cultivated in the presence of a novel specific 15-LOX-1 inhibitor. The T-cell response against tetanus-pulsed DCs was only affected to a minor extent on inhibition of 15-LOX-1. In contrast, endocytosis and migration ability of DCs were significantly suppressed on 15-LOX-1 inhibition. The expression of 15-LOX-1 in DCs was also demonstrated in affected human skin in atopic and contact dermatitis, showing that the enzyme is indeed expressed in inflammatory diseases in vivo. This study demonstrated that inhibiting 15-LOX-1 led to an impaired podosome formation in DCs, and consequently suppressed antigen uptake and migration capacity. These results indicated that 15-LOX-1 is a potential target for inhibiting the trafficking of DCs to lymphoid organs and inflamed tissues and decreasing the inflammatory response attenuating symptoms of certain immunologic and inflammatory disorders such as dermatitis.-Han, H., Liang, X., Ekberg, M., Kritikou, J. S., Brunnstro " m, angstrom., Pelcman, B., Matl, M., Miao, X., Andersson, M., Yuan, X., Schain, F., Parvin, S., Melin, E., Sjoberg, J., Xu, D., Westerberg, L. S., Bjorkholm, M., Claesson, H.- E. Human 15-lipoxygenase- 1 is a regulator of dendritic-cell spreading and podosome formation.</p>
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