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1.
  • La Fleur, Linnea, et al. (författare)
  • Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer
  • 2018
  • Ingår i: International Journal of Cancer. - : WILEY. - 0020-7136 .- 1097-0215. ; 143:7, s. 1741-1752
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.
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2.
  • Salomonsson, A., et al. (författare)
  • Comprehensive analysis of RNA binding motif protein 3 (RBM3) in non-small cell lung cancer
  • 2020
  • Ingår i: Cancer Medicine. - : Blackwell Publishing Ltd. - 2045-7634 .- 2045-7634. ; 9:15, s. 5609-5619
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims High expression of the RNA-binding motif protein 3 (RBM3) correlates with improved prognosis in several major types of cancer. The aim of the present study was to examine the prognostic value of RBM3 protein and mRNA expression in non-small cell lung cancer (NSCLC).Methods and results Immunohistochemical expression of RBM3 was evaluated in surgically treated NSCLC from two independent patient populations (n = 213 and n = 306). Staining patterns were correlated with clinicopathological parameters, overall survival (OS), and recurrence-free interval (RFI). Cases with high nuclear RBM3 protein expression had a prolonged 5-year OS in both cohorts when analyzing adenocarcinomas separately (P = .02 and P = .01). RBM3 remained an independent prognostic factor for OS in multivariable analysis of cohort I (HR 0.44, 95% CI 0.21-0.90) and for RFI in cohort II (HR 0.38, 95% CI 0.22-0.74). In squamous cell carcinoma, there was instead an insignificant association to poor prognosis. Also, the expression levels of RBM3 mRNA were investigated in 2087 lung adenocarcinomas and 899 squamous cell carcinomas assembled from 13 and 8 public gene expression microarray datasets, respectively. The RBM3 mRNA levels were not clearly associated with patient outcome in either adenocarcinomas or squamous cell carcinomas.Conclusions The results from this study support that high protein expression of RBM3 is linked to improved outcome in lung adenocarcinoma.
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3.
  • Ahlén, Anders, et al. (författare)
  • Toward Wireless Control in Industrial Process Automation : A Case Study at a Paper Mill
  • 2019
  • Ingår i: IEEE Control Systems Magazine. - : Institute of Electrical and Electronics Engineers (IEEE). - 1066-033X. ; 39:5, s. 36-57
  • Tidskriftsartikel (refereegranskat)abstract
    • Wireless sensors and networks are used only occasionally in current control loops in the process industry. With rapid developments in embedded and highperformance computing, wireless communication, and cloud technology, drastic changes in the architecture and operation of industrial automation systems seem more likely than ever. These changes are driven by ever-growing demands on production quality and flexibility. However, as discussed in "Summary," there are several research obstacles to overcome. The radio communication environment in the process industry is often troublesome, as the environment is frequently cluttered with large metal objects, moving machines and vehicles, and processes emitting radio disturbances [1], [2]. The successful deployment of a wireless control system in such an environment requires careful design of communication links and network protocols as well as robust and reconfigurable control algorithms.
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4.
  • Backman, Max, et al. (författare)
  • Infiltration of NK and plasma cells is associated with a distinct immune subset in non-small cell lung cancer
  • 2021
  • Ingår i: Journal of Pathology. - : John Wiley and Sons. - 0022-3417. ; 255:3, s. 243-256
  • Tidskriftsartikel (refereegranskat)abstract
    • Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy.
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5.
  • deBejczy, Andrea, et al. (författare)
  • Varenicline for Treatment of Alcohol Dependence: A Randomized, Placebo-Controlled Trial
  • 2015
  • Ingår i: Alcoholism-Clinical and Experimental Research. - : Wiley-Blackwell. - 0145-6008 .- 1530-0277. ; 39:11, s. 2189-2199
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundAlcohol dependence is a devastating illness affecting a large population, and new pharmacological treatments with good efficacy are greatly needed. One potential candidate is varenicline, a smoking cessation agent with partial agonist action at (42) nicotinic acetylcholine receptors. MethodsA total of 160 subjects, 30 to 70years of age, fulfilling DSM-IV criteria for alcohol dependence without any serious physical or mental disorders, were recruited through advertisement at 3 university clinics in Sweden during March 2009 to January 2011. After a 2-week placebo run-in period, subjects received 2mg varenicline daily (titrated from 0.5mg during first week) or placebo for 12weeks in a double-blind manner. ResultsThe primary outcome was the proportion of heavy drinking days, measured by self-reported alcohol consumption. Primary and secondary outcomes were calculated as a mean over the 10-week steady-state active treatment period. In the primary outcome analysis, no effect of varenicline over placebo was found (p=0.73 for the intention to treat [ITT] and 0.92 for per protocol [PP]). Secondary outcome analysis found a significant reduction of specific alcohol marker phosphatidylethanol (PEth) in the blood in the varenicline group compared to placebo (p=0.02 ITT). Craving (p=0.048 PP) and Alcohol Use Disorders Identification Test (AUDIT) scores (p=0.015 ITT) were also reduced in the active treatment group. PEth more strongly correlated with self-reported alcohol consumption than carbohydrate-deficient ttransferrin and -glutamyl transferase, and correlation coefficients were higher in the varenicline group than in the placebo group for all markers. ConclusionsAlthough the results of the main outcome of this study did not support an effect of varenicline in alcohol-dependent individuals, the secondary analyses of PEth, craving and AUDIT score support an effect of varenicline on alcohol consumption. The disclosure of a treatment effect and the lack of a clear placebo effect when using PEth as outcome variable, together with a nonsymmetric bias associated with self-reported data, strongly argue for using the specific biomarker PEth in studies of treatments of alcohol dependence.
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6.
  • Döse, Magnus, 1970-, et al. (författare)
  • Naturally occurring radioactivity in some Swedish concretes and their constituents - Assessment by using I-index and dose-model
  • 2016
  • Ingår i: Journal of Environmental Radioactivity. - : Elsevier. - 0265-931X .- 1879-1700. ; 155-156, s. 105-111
  • Tidskriftsartikel (refereegranskat)abstract
    • The reference level for effective dose due to gamma radiation from building materials and constructionproducts used for dwellings is set to 1 mSv per year (EC, 1996, 1999), (CE, 2014). Given the specificconditions presented by the EC in report 112 (1999) considering building and construction materials, anI-index of 1 may generate an effective dose of 1 mSv per year. This paper presents a comparison of theactivity concentrations of 40K, 226Ra and 232Th of aggregates and when these aggregates constitute a partof concrete. The activity concentration assessment tool for building and construction materials, the Iindex,introduced by the EC in 1996, is used in the comparison. A comparison of the I-indices values arealso made with a recently presented dose model by Hoffman (2014), where density variations of theconstruction material and thickness of the construction walls within the building are considered. Therewas a ~16e19% lower activity index in concretes than in the corresponding aggregates. The model byHoffman further implies that the differences between the I-indices of aggregates and the concretes' finaleffective doses are even larger. The difference is due, mainly to a dilution effect of the added cement withlow levels of natural radioisotopes, but also to a different and slightly higher subtracted backgroundvalue (terrestrial value) used in the modeled calculation of the revised I-index by Hoffman (2014). Onlyvery minimal contributions to the annual dose could be related to the water and additives used, due tot heir very low content of radionuclides reported.
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7.
  • Edlund, K., et al. (författare)
  • CD99 is a novel prognostic stromal marker in non-small cell lung cancer
  • 2012
  • Ingår i: International Journal of Cancer. - : John Wiley and Sons. - 0020-7136 .- 1097-0215. ; 131:10, s. 2264-2273
  • Tidskriftsartikel (refereegranskat)abstract
    • The complex interaction between cancer cells and the microenvironment plays an essential role in all stages of tumourigenesis. Despite the significance of this interplay, alterations in protein composition underlying tumourstroma interactions are largely unknown. The aim of this study was to identify stromal proteins with clinical relevance in non-small cell lung cancer (NSCLC). A list encompassing 203 stromal candidate genes was compiled based on gene expression array data and available literature. The protein expression of these genes in human NSCLC was screened using the Human Protein Atlas. Twelve proteins were selected that showed a differential stromal staining pattern (BGN, CD99, DCN, EMILIN1, FBN1, PDGFRB, PDLIM5, POSTN, SPARC, TAGLN, TNC and VCAN). The corresponding antibodies were applied on tissue microarrays, including 190 NSCLC samples, and stromal staining was correlated with clinical parameters. Higher stromal expression of CD99 was associated with better prognosis in the univariate (p = 0.037) and multivariate (p = 0.039) analysis. The association was independent from the proportion of tumour stroma, the fraction of inflammatory cells and clinical and pathological parameters like stage, performance status and tumour histology. The prognostic impact of stromal CD99 protein expression was confirmed in an independent cohort of 240 NSCLC patients (p = 0.008). Furthermore, double-staining confocal fluorescence microscopy showed that CD99 was expressed in stromal lymphocytes as well as in cancer-associated fibroblasts. Based on a comprehensive screening strategy the membrane protein CD99 was identified as a novel stromal factor with clinical relevance. The results support the concept that stromal properties have an important impact on tumour progression.
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8.
  • Eltahir, Mohamed, et al. (författare)
  • Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade
  • 2021
  • Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:13
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.
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9.
  • Eriksson, H., et al. (författare)
  • The Proportion Cured of Patients with Resected Stage II-III Cutaneous Melanoma in Sweden
  • 2021
  • Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:10
  • Tidskriftsartikel (refereegranskat)abstract
    • Simple summary Patients diagnosed with stage II-III cutaneous melanoma (CM) are at high risk of recurrences, but the CM-specific survival ranges from approximately 40-70%. Here, the cure proportions and survival among uncured stage II-III CM patients were estimated. The 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018. Proportions cured by surgery are low for sub-groups of stage II-III cutaneous melanoma showing that cure analyses can serve as a complement to established survival analyses. Background: Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II-III cutaneous melanoma (CM) patients. Methods: 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden (n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018. Results: Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77-0.83) stage IIA; 0.62 (95% CI 0.59-0.66) stage IIB; 0.42 (95% CI 0.37-0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68-0.84) stage IIIA; 0.52 (95% CI 0.45-0.59) stage IIIB; 0.35 (95% CI 0.30-0.39) for stage IIIC-D). Conclusions: The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II-III CM, specifically within stages IIB-C CM.
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10.
  • Gunnarsson, Rebeqa, et al. (författare)
  • 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
  • Ingår i: Genes, Chromosomes and Cancer. - : John Wiley and Sons. - 1045-2257 .- 1098-2264. ; 93, s. 0536-0536
  • 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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