Publications by authors named "Anna Karlsson"

225 Publications

Coordinated pyruvate kinase activity is crucial for metabolic adaptation and cell survival during mitochondrial dysfunction.

Hum Mol Genet 2021 Jun 24. Epub 2021 Jun 24.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.

Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok-/-) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok-/- mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.
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http://dx.doi.org/10.1093/hmg/ddab168DOI Listing
June 2021

Pan-cancer application of a lung-adenocarcinoma-derived gene-expression-based prognostic predictor.

Brief Bioinform 2021 May 10. Epub 2021 May 10.

Lund University, Sweden.

Gene-expression profiling can be used to classify human tumors into molecular subtypes or risk groups, representing potential future clinical tools for treatment prediction and prognostication. However, it is less well-known how prognostic gene signatures derived in one malignancy perform in a pan-cancer context. In this study, a gene-rule-based single sample predictor (SSP) called classifier for lung adenocarcinoma molecular subtypes (CLAMS) associated with proliferation was tested in almost 15 000 samples from 32 cancer types to classify samples into better or worse prognosis. Of the 14 malignancies that presented both CLAMS classes in sufficient numbers, survival outcomes were significantly different for breast, brain, kidney and liver cancer. Patients with samples classified as better prognosis by CLAMS were generally of lower tumor grade and disease stage, and had improved prognosis according to other type-specific classifications (e.g. PAM50 for breast cancer). In all, 99.1% of non-lung cancer cases classified as better outcome by CLAMS were comprised within the range of proliferation scores of lung adenocarcinoma cases with a predicted better prognosis by CLAMS. This finding demonstrates the potential of tuning SSPs to identify specific levels of for instance tumor proliferation or other transcriptional programs through predictor training. Together, pan-cancer studies such as this may take us one step closer to understanding how gene-expression-based SSPs act, which gene-expression programs might be important in different malignancies, and how to derive tools useful for prognostication that are efficient across organs.
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http://dx.doi.org/10.1093/bib/bbab154DOI Listing
May 2021

Synthetic computed tomography data allows for accurate absorbed dose calculations in a magnetic resonance imaging only workflow for head and neck radiotherapy.

Phys Imaging Radiat Oncol 2021 Jan 11;17:36-42. Epub 2021 Jan 11.

Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background And Purpose: Few studies on magnetic resonance imaging (MRI) only head and neck radiation treatment planning exist, and none using a generally available software. The aim of this study was to evaluate the accuracy of absorbed dose for head and neck synthetic computed tomography data (sCT) generated by a commercial convolutional neural network-based algorithm.

Materials And Methods: For 44 head and neck cancer patients, sCT were generated and the geometry was validated against computed tomography data (CT). The clinical CT based treatment plan was transferred to the sCT and recalculated without re-optimization, and differences in relative absorbed dose were determined for dose-volume-histogram (DVH) parameters and the 3D volume.

Results: For overall body, the results of the geometric validation were (Mean ± 1sd): Mean error -5 ± 10 HU, mean absolute error 67 ± 14 HU, Dice similarity coefficient 0.98 ± 0.05, and Hausdorff distance difference 4.2 ± 1.7 mm. Water equivalent depth difference for region Th1-C7, mid mandible and mid nose were -0.3 ± 3.4, 1.1 ± 2.0 and 0.7 ± 3.8 mm respectively. The maximum mean deviation in absorbed dose for all DVH parameters was 0.30% (0.12 Gy). The absorbed doses were considered equivalent (p-value < 0.001) and the mean 3D gamma passing rate was 99.4 (range: 95.7-99.9%).

Conclusions: The convolutional neural network-based algorithm generates sCT which allows for accurate absorbed dose calculations for MRI-only head and neck radiation treatment planning. The sCT allows for statistically equivalent absorbed dose calculations compared to CT based radiotherapy.
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http://dx.doi.org/10.1016/j.phro.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058030PMC
January 2021

Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate.

Front Genet 2021 1;12:658446. Epub 2021 Apr 1.

Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.

Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, thiamine diphosphate (ThDP), is a coenzyme of central metabolism, also known to affect transcriptional activity of the master metabolic regulator and genome guardian p53. A direct transcriptional target of p53, p21, regulates cell cycle dynamics and DNA damage response. Our work focuses on dependence of the action of the DNA damaging anticancer drug cisplatin on metabolic regulation through p53/p21 axes and cellular thiamine status in human lung adenocarcinoma cells A549. These cells are used as a model of a hardly curable cancer, known to develop chemoresistance to platinum drugs, such as cisplatin. Compared to wild type (A549), a stable line with a 60% knockdown of p21 (A549) is less sensitive to antiproliferative action of cisplatin. In contrast, in the thiamine-deficient medium, cisplatin impairs the viability of A549 cells more than that of A549 cells. Analysis of the associated metabolic changes in the cells indicates that (i) p21 knockdown restricts the production of 2-oxoglutarate glutamate oxidation, stimulating that within the tricarboxylic acid (TCA) cycle; (ii) cellular cisplatin sensitivity is associated with a 4-fold upregulation of glutamic-oxaloacetic transaminase (GOT2) by cisplatin; (iii) cellular cisplatin resistance is associated with a 2-fold upregulation of p53 by cisplatin. Correlation analysis of the p53 expression and enzymatic activities upon variations in cellular thiamine/ThDP levels indicates that p21 knockdown substitutes positive correlation of the p53 expression with the activity of 2-oxoglutarate dehydrogenase complex (OGDHC) for that with the activity of glutamate dehydrogenase (GDH). The knockdown also changes correlations of the levels of OGDHC, GDH and GOT2 with those of the malate and isocitrate dehydrogenases. Thus, a p53/p21-dependent change in partitioning of the glutamate conversion to 2-oxoglutarate through GOT2 or GDH, linked to NAD(P)-dependent metabolism of 2-oxoglutarate in affiliated pathways, adapts A549 cells to thiamine deficiency or cisplatin treatment. Cellular thiamine deficiency may interfere with antiproliferative action of cisplatin due to their common modulation of the p53/p21-dependent metabolic switch between the glutamate oxidation and transamination.
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http://dx.doi.org/10.3389/fgene.2021.658446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047112PMC
April 2021

Staphylococcus aureus lipoproteins promote abscess formation in mice, shielding bacteria from immune killing.

Commun Biol 2021 03 30;4(1):432. Epub 2021 Mar 30.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Despite being a major bacterial factor in alerting the human immune system, the role of Staphylococcus aureus (S. aureus) lipoproteins (Lpp) in skin infections remains largely unknown. Here, we demonstrated that subcutaneous injection of S. aureus Lpp led to infiltration of neutrophils and monocytes/macrophages and induced skin lesions in mice. Lipid-moiety of S. aureus Lpp and host TLR2 was responsible for such effect. Lpp-deficient S. aureus strains exhibited smaller lesion size and reduced bacterial loads than their parental strains; the altered phenotype in bacterial loads was TLR2-independent. Lpp expression in skin infections contributed to imbalanced local hemostasis toward hypercoagulable state. Depletion of leukocytes or fibrinogen abrogated the effects induced by Lpp in terms of skin lesions and bacterial burden. Our data suggest that S. aureus Lpp induce skin inflammation and promote abscess formation that protects bacteria from innate immune killing. This suggests an intriguing bacterial immune evasion mechanism.
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http://dx.doi.org/10.1038/s42003-021-01947-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010101PMC
March 2021

Detection of Non-Small Lung Cell Carcinoma-Associated Genetic Alterations Using a NanoString Gene Expression Platform Approach.

Methods Mol Biol 2021 ;2279:91-107

Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

In non-small cell lung cancer (NSCLC), mutation detection and fusion gene status are treatment predictive and, hence, key factors in clinical management. Lately, alternate splicing variants of MET have gained focus as NSCLC tumors harboring a MET exon 14 skipping event have proven sensitive toward targeted therapy. Reliable methods for detection of genetic alterations in NSCLC have proven to be of increased importance. This chapter provides with hands-on experience of the NanoString gene expression platform for detection of genetic alterations in NSCLC.
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http://dx.doi.org/10.1007/978-1-0716-1278-1_8DOI Listing
April 2021

Effluent solids recirculation to municipal sludge digesters enhances long-chain fatty acids degradation capacity.

Biotechnol Biofuels 2021 Mar 4;14(1):56. Epub 2021 Mar 4.

Biogas Research Center, Linköping University, 58183, Linköping, Sweden.

Background: Slow degradation kinetics of long-chain fatty acids (LCFA) and their accumulation in anaerobic digesters disrupt methanogenic activity and biogas production at high loads of waste lipids. In this study, we evaluated the effect of effluent solids recirculation on microbial LCFA (oleate) degradation capacity in continuous stirred-tank sludge digesters, with the overall aim of providing operating conditions for efficient co-digestion of waste lipids. Furthermore, the impacts of LCFA feeding frequency and sulfide on process performance and microbial community dynamics were investigated, as parameters that were previously shown to be influential on LCFA conversion to biogas.

Results: Effluent solids recirculation to municipal sludge digesters enabled biogas production of up to 78% of the theoretical potential from 1.0 g oleate l day. In digesters without effluent recirculation, comparable conversion efficiency could only be reached at oleate loading rates up to 0.5 g l day. Pulse feeding of oleate (supplementation of 2.0 g oleate l every second day instead of 1.0 g oleate l every day) did not have a substantial impact on the degree of oleate conversion to biogas in the digesters that operated with effluent recirculation, while it marginally enhanced oleate conversion to biogas in the digesters without effluent recirculation. Next-generation sequencing of 16S rRNA gene amplicons of bacteria and archaea revealed that pulse feeding resulted in prevalence of fatty acid-degrading Smithella when effluent recirculation was applied, whereas Candidatus Cloacimonas prevailed after pulse feeding of oleate in the digesters without effluent recirculation. Combined oleate pulse feeding and elevated sulfide level contributed to increased relative abundance of LCFA-degrading Syntrophomonas and enhanced conversion efficiency of oleate, but only in the digesters without effluent recirculation.

Conclusions: Effluent solids recirculation improves microbial LCFA degradation capacity, providing possibilities for co-digestion of larger amounts of waste lipids with municipal sludge.
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http://dx.doi.org/10.1186/s13068-021-01913-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934545PMC
March 2021

Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Mol Oncol 2020 11 3;14(11):2759-2774. Epub 2020 Sep 3.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49 vs 54.79, P = 1.03 × 10) and included a higher proportion of current smokers than LUAD patients (28.24% vs 34.09%, P = 0.037). cg05293407 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10). We conclude that cg05293407 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607178PMC
November 2020

Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Mol Oncol 2020 11 3;14(11):2759-2774. Epub 2020 Sep 3.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49 vs 54.79, P = 1.03 × 10) and included a higher proportion of current smokers than LUAD patients (28.24% vs 34.09%, P = 0.037). cg05293407 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10). We conclude that cg05293407 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607178PMC
November 2020

Item recognition and lure discrimination in younger and older adults are supported by alpha/beta desynchronization.

Neuropsychologia 2020 11 16;148:107658. Epub 2020 Oct 16.

Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany. Electronic address:

Our episodic memories vary in their specificity, ranging from a mere sense of familiarity to detailed recollection of the initial experience. Recent work suggests that alpha/beta desynchronization promotes information flow through the cortex, tracking the richness in detail of recovered memory representations. At the same time, as we age, memories become less vivid and detailed, which may be reflected in age-related reductions in alpha/beta desynchronization during retrieval. To understand age differences in the specificity of episodic memories, we investigated differences in alpha/beta desynchronization between younger (18-26 years, n = 31) and older (65-76 years, n = 27) adults during item recognition and lure discrimination. Alpha/beta desynchronization increased linearly with the demand for memory specificity, i.e., the requirement to retrieve details for an accurate response, across retrieval situations (correct rejections < item recognition < lure discrimination). Stronger alpha/beta desynchronization was related to memory success, as indicated by reliable activation differences between correct and incorrect memory responses. In line with the assumption of a loss of mnemonic detail in older age, older adults had more difficulties than younger adults to discriminate lures from targets. Importantly, they also showed a reduced modulation of alpha/beta desynchronization across retrieval demands. Together, these results extend previous findings by demonstrating that alpha/beta desynchronization dissociates between item recognition and the retrieval of highly detailed memories as required in lure discrimination, and that age-related impairments in episodic retrieval are accompanied by attenuated modulations in the alpha/beta band. Thus, we provide novel findings suggesting that alpha/beta desynchronization tracks mnemonic specificity and that changes in these oscillatory mechanisms may underlie age-related declines in episodic memory.
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http://dx.doi.org/10.1016/j.neuropsychologia.2020.107658DOI Listing
November 2020

A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis.

Int J Cancer 2021 01 12;148(1):238-251. Epub 2020 Aug 12.

Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.

Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.
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http://dx.doi.org/10.1002/ijc.33242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689824PMC
January 2021

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers.

Nat Commun 2020 07 27;11(1):3747. Epub 2020 Jul 27.

Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-22381, Lund, Sweden.

Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
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http://dx.doi.org/10.1038/s41467-020-17537-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385112PMC
July 2020

Methylation Patterns and Chromatin Accessibility in Neuroendocrine Lung Cancer.

Cancers (Basel) 2020 Jul 22;12(8). Epub 2020 Jul 22.

Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE 22381 Lund, Sweden.

Lung cancer is the worldwide leading cause of death from cancer. Epigenetic modifications such as methylation and changes in chromatin accessibility are major gene regulatory mechanisms involved in tumorigenesis and cellular lineage commitment. We aimed to characterize these processes in the context of neuroendocrine (NE) lung cancer. Illumina 450K DNA methylation data were collected for 1407 lung cancers including 27 NE tumors. NE differentially methylated regions (NE-DMRs) were identified and correlated with gene expression data for 151 lung cancers and 31 human tissue entities from the Genotype-Tissue Expression (GTEx) consortium. Assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) were performed on eight lung cancer cell lines, including three NE cell lines, to identify neuroendocrine specific gene regulatory elements. We identified DMRs with methylation patterns associated with differential gene expression and an NE tumor phenotype. DMR-associated genes could further be split into six functional modules, including one highly specific gene module for NE lung cancer showing high expression in both normal and malignant brain tissue. The regulatory potential of NE-DMRs was further validated in vitro using paired ATAC- and RNA-seq and revealed both proximal and distal regulatory elements of canonical NE-marker genes such as CHGA, NCAM1, INSM1, as well as a number of novel candidate markers of NE lung cancer. Using multilevel genomic analyses of both tumor bulk tissue and lung cancer cell lines, we identified a large catalogue of gene regulatory elements related to the NE phenotype of lung cancer.
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http://dx.doi.org/10.3390/cancers12082003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464146PMC
July 2020

Epigenome-wide gene-age interaction analysis reveals reversed effects of DNA methylation on survival between young and elderly early-stage NSCLC patients.

Aging (Albany NY) 2020 06 8;12(11):10642-10662. Epub 2020 Jun 8.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation-age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354, with effects significantly modified by age ( = 0.989; 95% CI: 0.986-0.994; = 9.18×10-7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard ( = 2.44; 95% CI: 1.26-4.72; = 8.34×10-3; = 0.58; 95% CI: 0.42-0.82; = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354 methylation and elderly age ( = 0.21; 95% CI: 0.11-0.40; = 2.20×10-6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.
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http://dx.doi.org/10.18632/aging.103284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346054PMC
June 2020

Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action.

Int J Mol Sci 2020 May 26;21(11). Epub 2020 May 26.

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.

Genetic up-regulation of mitochondrial 2-oxoglutarate dehydrogenase is known to increase reactive oxygen species, being detrimental for cancer cells. Thiamine diphosphate (ThDP, cocarboxylase) is an essential activator of the enzyme and inhibits p53-DNA binding in cancer cells. We hypothesize that the pleiotropic regulator ThDP may be of importance for anticancer therapies. The hypothesis is tested in the present work on lung adenocarcinoma cells A549 possessing the p53-p21 pathway as fully functional or perturbed by p21 knockdown. Molecular mechanisms of ThDP action on cellular viability and their interplay with the cisplatin and p53-p21 pathways are characterized. Despite the well-known antioxidant properties of thiamine, A549 cells exhibit decreases in their reducing power and glutathione level after incubation with 5 mM ThDP, not observed in non-cancer epithelial cells Vero. Moreover, thiamine deficiency elevates glutathione in A549 cells. Viability of the thiamine deficient A549 cells is increased at a low (0.05 mM) ThDP. However, the increase is attenuated by 5 mM ThDP, p21 knockdown, specific inhibitor of the 2-oxoglutarate dehydrogenase complex (OGDHC), or cisplatin. Cellular levels of the catalytically competent ThDP·OGDHC holoenzyme are dysregulated by p21 knockdown and correlate negatively with the A549 viability. The inverse relationship between cellular glutathione and holo-OGDHC is corroborated by their comparison in the A549 and Vero cells. The similarity, non-additivity, and p21 dependence of the dual actions of ThDP and cisplatin on A549 cells manifest a common OGDHC-mediated mechanism of the viability decrease. High ThDP saturation of OGDHC compromises the redox state of A549 cells under the control of p53-p21 axes.
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http://dx.doi.org/10.3390/ijms21113759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312097PMC
May 2020

Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission.

Alzheimers Res Ther 2020 05 26;12(1):63. Epub 2020 May 26.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.

Background: Alzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration.

Methods: The aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media.

Results: We found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested.

Conclusion: Our results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.
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http://dx.doi.org/10.1186/s13195-020-00635-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251689PMC
May 2020

Ulnar Nerve Entrapment in Diabetes: Patient-reported Outcome after Surgery in National Quality Registries.

Plast Reconstr Surg Glob Open 2020 Apr 24;8(4):e2740. Epub 2020 Apr 24.

Department of Translational Medicine-Hand Surgery, Lund University, Skåne University Hospital, Malmö, Sweden.

Background: Ulnar nerve entrapment at the elbow (UNE) is overrepresented in patients with diabetes, but the outcome of surgery is unknown. We aimed to evaluate patient-reported outcome in patients with and without diabetes, and to assess potential sex differences and compare surgical treatment methods.

Methods: Data on patients operated for UNE (2010-2016, n = 1354) from the Swedish National Registry for Hand Surgery were linked to the Swedish National Diabetes Register. Symptoms were assessed preoperatively (n = 389), and 3 (n = 283), and at 12 months postoperatively (n = 267) by QuickDASH and HQ-8 (specific hand surgery questionnaire-8 questions). Only simple decompressions were included when comparing groups.

Results: Men with diabetes reported higher postoperative QuickDASH scores than men without diabetes. Women scored their disability higher than men on all time-points in QuickDASH, but showed larger improvement between preoperative and 12 months postoperative values. Patients operated with transposition scored 10.8 points higher on QuickDASH than patients who had simple decompression at 12 months (95% confidence interval 1.98-19.6).

Conclusions: Women with diabetes benefit from simple decompression for UNE to the same extent as women without diabetes. Men with diabetes risk not to benefit from simple decompression as much as women do. Ulnar nerve transposition had a higher risk of residual symptoms compared to simple decompression.
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http://dx.doi.org/10.1097/GOX.0000000000002740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209826PMC
April 2020

The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis.

Sci Rep 2020 05 13;10(1):7936. Epub 2020 May 13.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. The clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. Newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis.
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http://dx.doi.org/10.1038/s41598-020-64879-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221087PMC
May 2020

Hydrodynamic modelling of traffic-related microplastics discharged with stormwater into the Göta River in Sweden.

Environ Sci Pollut Res Int 2020 Jul 18;27(19):24218-24230. Epub 2020 Apr 18.

Department of Architecture and Civil Engineering, Chalmers University of Technology, Sven Hultins gata 6, SE-412 96, Gothenburg, Sweden.

Microplastics (MP) are transported from land-based sources from rivers to marine waters. However, there is currently little knowledge about MP fate from land sources to marine waters. Traffic is estimated to be one of the largest sources of MP; hence, stormwater is expected to be an important transportation route of MP to marine waters. The aim of this study was to investigate the effect of the size and density of tyre wear particles in road run-off on their fate in the Göta River in Sweden using hydrodynamic modelling. The model of the stretch of Göta River, Sweden's largest river, passing through Gothenburg (Sweden's second largest city) and out to the sea, was set up using MIKE 3 FM software. Literature data were used to define the MP characteristics: concentrations in stormwater, prevalent particle sizes, density of MP commonly occurring in road run-off and settling velocities. Results show that higher concentrations of MP are found on the south side of the river, compared with the north side, due to higher annual average daily traffic loads along the south side of the river. The mixing processes in the river and the MP concentrations were generally influenced by the vertical water density gradient caused by saline water from the Kattegat strait. While most MP with higher density and larger size settle in the river, smaller MP with density close to 1.0 g/cm do not settle in the river and therefore reach the Kattegat strait and the marine environments. Further research is needed to describe the fate and transport of microplastics in the stormwater system, including treatment facilities, i.e. biofouling, aggregation, degradation and/or further fragmentation and settling.
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http://dx.doi.org/10.1007/s11356-020-08637-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326794PMC
July 2020

Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects.

Chest 2020 08 28;158(2):808-819. Epub 2020 Feb 28.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA; Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions.

Research Question: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis?

Study Design And Methods: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated.

Results: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC, 0.88 [95% CI, 0.83-0.93]; and AUC, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively.

Interpretation: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.
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http://dx.doi.org/10.1016/j.chest.2020.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417380PMC
August 2020

Sulfide level in municipal sludge digesters affects microbial community response to long-chain fatty acid loads.

Biotechnol Biofuels 2019 2;12:259. Epub 2019 Nov 2.

1Department of Thematic Studies-Environmental Change and Biogas Research Center, Linköping University, 581 83 Linköping, Sweden.

Background: Waste lipids are attractive substrates for co-digestion with primary and activated sewage sludge (PASS) to improve biogas production at wastewater treatment plants. However, slow conversion rates of long-chain fatty acids (LCFA), produced during anaerobic digestion (AD), limit the applicability of waste lipids as co-substrates for PASS. Previous observations indicate that the sulfide level in PASS digesters affects the capacity of microbial communities to convert LCFA to biogas. This study assessed the microbial community response to LCFA loads in relation to sulfide level during AD of PASS by investigating process performance and microbial community dynamics upon addition of oleate (C) and stearate (C) to PASS digesters at ambient and elevated sulfide levels.

Results: Conversion of LCFA to biogas was limited (30% of theoretical biogas potential) during continuous co-digestion with PASS, which resulted in further LCFA accumulation. However, the accumulated LCFA were converted to biogas (up to 66% of theoretical biogas potential) during subsequent batch-mode digestion, performed without additional substrate load. Elevated sulfide level stimulated oleate (but not stearate) conversion to acetate, but oleate and sulfide imposed a synergistic limiting effect on acetoclastic methanogenesis and biogas formation. Next-generation sequencing of 16S rRNA gene amplicons of bacteria and archaea showed that differences in sulfide level and LCFA type resulted in microbial community alterations with distinctly different patterns. Taxonomic profiling of the sequencing data revealed that the phylum Cloacimonetes is likely a key group during LCFA degradation in PASS digesters, where different members take part in degradation of saturated and unsaturated LCFA; genus W5 (family Cloacimonadaceae) and family W27 (order Cloacimonadales), respectively. In addition, LCFA-degrading , which is commonly present in lipid-fed digesters, increased in relative abundance after addition of oleate at elevated sulfide level, but not without sulfide or after stearate addition. Stearate conversion to biogas was instead associated with increasing abundance of hydrogen-producing and hydrogenotrophic .

Conclusions: Long-chain fatty acid chain saturation and sulfide level are selective drivers for establishment of LCFA-degrading microbial communities in municipal sludge digesters.
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http://dx.doi.org/10.1186/s13068-019-1598-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825336PMC
November 2019

Contamination of heavy metals and metalloids in biomass and waste fuels: Comparative characterisation and trend estimation.

Sci Total Environ 2020 Jan 8;700:134382. Epub 2019 Oct 8.

Fibre and Polymer Technology, KTH Royal Institute of Technology, SE-100 44 Stockholm, Sweden.

The use of contaminated biomass and waste fuels is essential for waste management, waste to energy (WtE) and mitigating carbon emissions. The contamination of heavy metals and metalloids is specially concerned by environmental regulation and waste to energy processes. In this study, comparative characterisation is performed for three typical contaminated biomass and waste fuels. i.e. recycled woods, combustible municipal solid waste, and industrial and commercial wastes. The contamination characteristics are further analysed using statistical methods (e.g. significance, correlation, profile, and principal component analyses) to identify specific contamination features, relations among the contaminants and potential contamination sources. Contamination trend is estimated based on the continuously monitoring fuel qualities, the driving forces for regulating and reduction of the contaminations, and potential changes in major contamination sources. The comparative characterisation combined with statistical analyses provides a better way to understand the contamination mechanisms. The approach can also relate the fuel contamination with the contamination sources and their changes for trend estimation. Generally, the toxic heavy metals and metalloids are expected to be significantly reduced due to stricter regulations, but there is no general trend for the reduction of other metals and metalloids because of the complicated changes in contamination sources and waste recycling streams in the near future.
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http://dx.doi.org/10.1016/j.scitotenv.2019.134382DOI Listing
January 2020

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma.

Aging (Albany NY) 2019 08 21;11(16):6312-6335. Epub 2019 Aug 21.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups ( = 0.01 and = 2.71×10). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.
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http://dx.doi.org/10.18632/aging.102189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738411PMC
August 2019

Age-related metabolic changes limit efficacy of deoxynucleoside-based therapy in thymidine kinase 2-deficient mice.

EBioMedicine 2019 Aug 24;46:342-355. Epub 2019 Jul 24.

Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Background: Thymidine kinase 2 (TK2) catalyses the phosphorylation of deoxythymidine (dThd) and deoxycytidine (dCtd) within mitochondria. TK2 deficiency leads to mtDNA depletion or accumulation of multiple deletions. In patients, TK2 mutations typically manifest as a rapidly progressive myopathy with infantile onset, leading to respiratory insufficiency and encephalopathy in the most severe clinical presentations. TK2-deficient mice develop the most severe form of the disease and die at average postnatal day 16. dThd+dCtd administration delayed disease progression and expanded lifespan of a knockin murine model of the disease.

Methods: We daily administered TK2 knockout mice (Tk2) from postnatal day 4 with equimolar doses of dThd+dCtd, dTMP+dCMP, dThd alone or dCtd alone. We monitored body weight and survival and studied different variables at 12 or 29 days of age. We determined metabolite levels in plasma and target tissues, mtDNA copy number in tissues, and the expression and activities of enzymes with a relevant role in mitochondrial dNTP anabolism or catabolism.

Findings: dThd+dCtd treatment extended average lifespan of Tk2 mice from 16 to 34 days, attenuated growth retardation, and rescued mtDNA depletion in skeletal muscle and other target tissues of 12-day-old mice, except in brain. However, the treatment was ineffective in 29-day-old mice that still died prematurely. Bioavailability of dThd and dCtd markedly decreased during mouse development. Activity of enzymes catabolizing dThd and dCtd increased with age in small intestine. Conversely, the activity of the anabolic enzymes decreased in target tissues during mouse development. We also found that administration of dThd alone had the same impact on survival to that of dThd+dCtd, whereas dCtd alone had no influence on lifespan.

Interpretation: dThd+dCtd treatment recruits alternative cytosolic salvage pathways for dNTP synthesis, suggesting that this therapy would be of benefit for any Tk2 mutation. dThd accounts for the therapeutic effect of the combined treatment in mice. During the first weeks after birth, mice experience marked tissue-specific metabolic regulations and ontogenetic changes in dNTP metabolism-related enzymes that limit therapeutic efficacy to early developmental stages. FUND: This study was funded by grants from the Spanish Ministry of Industry, Economy and Competitiveness, the Spanish Instituto de Salud Carlos III, the Fundación Inocente, Inocente, AFM Téléthon and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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http://dx.doi.org/10.1016/j.ebiom.2019.07.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711114PMC
August 2019

The YIN and YANG of lipoproteins in developing and preventing infectious arthritis by Staphylococcus aureus.

PLoS Pathog 2019 06 21;15(6):e1007877. Epub 2019 Jun 21.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.
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http://dx.doi.org/10.1371/journal.ppat.1007877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608979PMC
June 2019

Severe mtDNA depletion and dependency on catabolic lipid metabolism in DGUOK knockout mice.

Hum Mol Genet 2019 09;28(17):2874-2884

Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, 141 86 Stockholm, Sweden.

Deoxyguanosine kinase (DGUOK) provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, and its deficiency in humans leads to hepatocerebral mtDNA depletion syndrome or to isolated hepatic disease. There are poor treatment options for DGUOK deficiency and the aim of this study was to generate a model for further studies of the disease that could reveal novel treatment strategies. We report a Dguok-deficient mouse strain that, similar to humans, is most severely affected in the liver. The Dguok complete knockout mice (Dguok-/-) were born normal, but began to lose weight at week 6. A change of fur color from black to blueish grey started at week 16 and was complete at week 20. The movements and behavior were indistinguishable compared to wild-type (wt) mice. A decrease of mtDNA copy number occurred in multiple tissues, with the liver being the most severely affected. The mtDNA-encoded protein cytochrome c oxidase was much lower in Dguok-/- liver tissue than in the wt, whereas the expression of the nuclear-encoded succinate dehydrogenase complex subunit A was unaffected. Histopathology showed severe alterations and immunohistochemistry showed signs of both oxidative stress and regeneration in Dguok-/- liver. The subcutaneous fat layer was undetectable in Dguok-/-, which, in addition to gene expression analysis, indicated an altered lipid metabolism. We conclude that Dguok has a major role for the synthesis of deoxyribonucleotides for mtDNA replication particularly in the liver, similar to the human disorder. Our data also show a catabolic lipid metabolism in liver tissue of Dguok-/-.
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http://dx.doi.org/10.1093/hmg/ddz103DOI Listing
September 2019

Evidence-based nursing-How is it understood by bedside nurses? A phenomenographic study in surgical settings.

J Nurs Manag 2019 Sep 17;27(6):1216-1223. Epub 2019 Jun 17.

Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.

Aim: The aim was to identify and describe nurses' understanding of working with evidence-based nursing (EBN) in clinical practice.

Background: Evidence-based health care is recognized as fundamental to nursing practice, but it is challenging to implement. How nurses understand this part of their work can affect their practice.

Methods: Using a qualitative explorative design with a phenomenographic approach, we interviewed 21 nurses working in Swedish surgical wards.

Results: We identified three understandings of EBN among nurses in surgical care: A. a fragmentary and difficult concept that is not integrated or used in clinical practice; B. an important approach guided by knowledgeable colleagues and students; and C. a process that nurses are responsible for developing and leading.

Conclusion: Nurses' understandings of working with EBN in surgical wards vary widely. Nurse managers have an important task to create a common outlook among nurses about integrating research, patient experience and clinical experience in decision-making.

Implication For Nursing Management: These findings could inspire nurse managers to reflect on how to move nurses towards a more comprehensive understanding of EBN and how to identify nurses who could act as facilitators in quality improvement work.
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http://dx.doi.org/10.1111/jonm.12802DOI Listing
September 2019

Intracellular Neutrophil Oxidants: From Laboratory Curiosity to Clinical Reality.

J Immunol 2019 06;202(11):3127-3134

Department of Oral Microbiology and Immunology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, S-430 05 Gothenburg, Sweden.

The phagocyte NADPH oxidase is responsible for the neutrophil's great capacity to produce reactive oxygen species (ROS). The NADPH oxidase can be assembled in the plasma membrane, as well as in membranes of intracellular vesicles, giving neutrophils the ability to direct ROS production to distinct subcellular sites. Neutrophil ROS contribute to microbial killing, trigger formation of neutrophil extracellular traps and appear to partake in inflammation control. Consequently, function-disrupting mutations in the NADPH oxidase lead to chronic granulomatous disease, characterized by severe infections and inflammatory disorders. Recent experimental data and description of a novel chronic granulomatous disease subtype (p40-deficiency) imply that ROS generated in intracellular compartments are key for NETosis and for controlling inflammatory signaling. We foresee boosted interest in intracellular ROS production. To fully understand where and how such ROS function, however, limitations of assay systems to measure ROS need to be appreciated, and the development of novel techniques/reagents would be highly useful.
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http://dx.doi.org/10.4049/jimmunol.1900235DOI Listing
June 2019

Dietary Polyunsaturated Fatty Acids Promote Neutrophil Accumulation in the Spleen by Altering Chemotaxis and Delaying Cell Death.

Infect Immun 2019 08 23;87(8). Epub 2019 Jul 23.

Department of Physiology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

Neutrophils are the most abundant circulating leukocytes in humans and are essential for the defense against invading pathogens. Like many other cells of an organism, neutrophils can be highly influenced by the diet. We have previously described that mice fed a high-fat diet rich in polyunsaturated fatty acids (HFD-P) present a higher frequency of neutrophils in bone marrow than mice fed a high-fat diet rich in saturated fatty acids (HFD-S). Interestingly, such an increase correlated with improved survival against bacterium-induced sepsis. In this study, we aimed to investigate the effects of dietary polyunsaturated and saturated fatty acids on neutrophil homeostasis. We found that HFD-P specifically induced the accumulation of neutrophils in the marginal pools of the spleen and liver. The accumulation of neutrophils in the spleen was a result of a dual effect of polyunsaturated fatty acids on neutrophil homeostasis. First, polyunsaturated fatty acids enhanced the recruitment of neutrophils from the circulation into the spleen via chemokine secretion. Second, they delayed neutrophil cell death in the spleen. Interestingly, these effects were not observed in mice fed a diet rich in saturated fatty acids, suggesting that the type of fat rather than the amount of fat mediates the alterations in neutrophil homeostasis. In conclusion, our results show that dietary polyunsaturated fatty acids have a strong modulatory effect on neutrophil homeostasis that may have future clinical applications.
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http://dx.doi.org/10.1128/IAI.00270-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652767PMC
August 2019

SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis.

Mol Oncol 2019 05 17;13(5):1235-1248. Epub 2019 Apr 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Smoking cessation prolongs survival and decreases mortality of patients with non-small-cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome-wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two-stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early-stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology-stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rate-q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology-specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510 ) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)  = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 × 10 ]. Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510 . Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 × 10 ) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510 . Moreover, there was an antagonistic interaction between elevated methylation of cg02268510 and smoking cessation (HR  = 2.1835; 95% CI: 1.27-3.74; P = 4.46 × 10 ). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510 . The results have implications for not only smoking cessation after diagnosis, but also possible methylation-specific drug targeting.
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http://dx.doi.org/10.1002/1878-0261.12482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487703PMC
May 2019
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