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  • 1.
    Andersson, Christian
    et al.
    Högskolan i Skövde, Institutionen för vård och natur.
    Pesonen, John
    Högskolan i Skövde, Institutionen för vård och natur.
    Anhörigas upplevelser av omvårdnaden av närstående i särskilt boende i Västra Götaland år 20102010Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Inledning: När en äldre människa har ett stort omvårdnadsbehov finns möjligheten att flytta till ett särskilt boende. Då äldres vardag ser olika ut är det av yttersta vikt att omvårdnadspersonalen kan ge stöd och hjälp så att den äldre skall kunna anpassa sig till den nya situationen. Syfte: Syftet med denna studie är att belysa hur anhöriga upplever att deras närstående i särskilt boende får en god omvårdnad. Metod: En kvalitativ ansats med empiriskt inslag användes där anhörigas upplevelser av omvårdnad, delaktighet och bemötande insamlades med hjälp av intervjuer. Resultat: Tre olika kategorier Omvårdnad, Delaktighet och Bemötande med nio underkategorier. En betydelsefull del i omvårdnaden är att det skapas en god kontakt mellan anhöriga och omvårdnadspersonalen för att finna ett bra sätt att kommunicera på. Det framkom hur viktigt det är att som vårdtagare känna att de blir sedda för den de är och att de får vara delaktiga i de omvårdnadsåtgärder som beslutas av omvårdnadspersonalen. Diskussion: Resultatet kan bidra till en ökad förståelse för anhörigas upplevelser av hur omvårdnaden bedrivs i särskilt boende. När anhöriga göras mer delaktiga i omvårdnaden, kan det leda till en bättre omvårdnad för vårdtagaren i särskilt boende. Slutsats: Resultatet som författarna kom fram till skulle kunna användas i utbildningssyfte då omsorgen av äldre människor kräver att omvårdnadspersonalen ständigt förnyar sina kunskaper. Detta kan vara till gagn för sjuksköterskan, de anhöriga och de äldre som bor i särskilt boende.

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  • 2.
    Asp, Julia
    et al.
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för vård och natur. Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Jonsson, Marianne
    Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, the Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Goran
    Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Comparison of human cardiac gene expression profiles in paired samples of right atrium and left ventricle collected in vivo2012Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, nr 1, s. 89-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studies of expressed genes in human heart provide insight into both physiological and pathophysiological mechanisms. This is of importance for extended understanding of cardiac function as well as development of new therapeutic drugs. Heart tissue for gene expression studies is generally hard to obtain, particularly from the ventricles. Since different parts of the heart have different functions, expression profiles should likely differ between these parts. The aim of the study was therefore to compare the global gene expression in cardiac tissue from the more accessible auricula of the right atrium to expression in tissue from the left ventricle. Tissue samples were collected from five men undergoing aortic valve replacement or coronary artery bypass grafting. Global gene expression analysis identified 542 genes as differentially expressed between the samples extracted from these two locations, corresponding to similar to 2% of the genes covered by the microarray; 416 genes were identified as abundantly expressed in right atrium, and 126 genes were abundantly expressed in left ventricle. Further analysis of the differentially expressed genes according to available annotations, information from curated pathways and known protein interactions, showed that genes with higher expression in the ventricle were mainly associated with contractile work of the heart. Transcription in biopsies from the auricula of the right atrium on the other hand indicated a wider area of functions, including immunity and defense. In conclusion, our results suggest that biopsies from the auricula of the right atrium may be suitable for various genetic studies, but not studies directly related to muscle work.

  • 3.
    Bachelet, Delphine
    et al.
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
    Albert, Thilo
    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Germany.
    Mbogning, Cyprien
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
    Hässler, Signe
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
    Zhang, Yuan
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.
    Schultze-Strasser, Stephan
    University Hospital Frankfurt, Goethe University, Department of Pediatrics, Molecular Haemostasis and Immunodeficiency, Frankfurt am Main, Germany.
    Repessé, Yohann
    CHU Caen, Hématologie Biologique, Caen, Caen, France.
    Rayes, Julie
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
    Pavlova, Anna
    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
    Pezeshkpoor, Behnaz
    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
    Liphardt, Kerstin
    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
    Davidson, Julie E.
    GlaxoSmithKline, Uxbridge, Middlesex, United Kingdom.
    Hincelin-Méry, Agnès
    Sanofi, Chilly-Mazarin, France.
    Dönnes, Pierre
    SciCross AB, Skövde, Sweden.
    Lacroix-Desmazes, Sébastien
    Sorbonne Universités, UPMC Univ Paris 06, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
    Königs, Christoph
    University Hospital Frankfurt, Goethe University, Department of Pediatrics, Molecular Haemostasis and Immunodeficiency, Frankfurt am Main, Germany.
    Oldenburg, Johannes
    Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.
    Broët, Philippe
    CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France / AP-HP, Paris-Sud University Hospitals, Villejuif, France.
    Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A2019Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 14, nr 6, artikkel-id e0218258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

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  • 4.
    Badam, Tejaswi V. S.
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    de Weerd, Hendrik A.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    Martínez-Enguita, David
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    Olsson, Tomas
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Alfredsson, Lars
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden ; Institute of Environmental Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Kockum, Ingrid
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Jagodic, Maja
    Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
    Lubovac-Pilav, Zelmina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Gustafsson, Mika
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping university, Sweden.
    A validated generally applicable approach using the systematic assessment of disease modules by GWAS reveals a multi-omic module strongly associated with risk factors in multiple sclerosis2021Inngår i: BMC Genomics, E-ISSN 1471-2164, Vol. 22, nr 1, artikkel-id 631Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There exist few, if any, practical guidelines for predictive and falsifiable multi-omic data integration that systematically integrate existing knowledge. Disease modules are popular concepts for interpreting genome-wide studies in medicine but have so far not been systematically evaluated and may lead to corroborating multi-omic modules. Result: We assessed eight module identification methods in 57 previously published expression and methylation studies of 19 diseases using GWAS enrichment analysis. Next, we applied the same strategy for multi-omic integration of 20 datasets of multiple sclerosis (MS), and further validated the resulting module using both GWAS and risk-factor-associated genes from several independent cohorts. Our benchmark of modules showed that in immune-associated diseases modules inferred from clique-based methods were the most enriched for GWAS genes. The multi-omic case study using MS data revealed the robust identification of a module of 220 genes. Strikingly, most genes of the module were differentially methylated upon the action of one or several environmental risk factors in MS (n = 217, P = 10− 47) and were also independently validated for association with five different risk factors of MS, which further stressed the high genetic and epigenetic relevance of the module for MS. Conclusions: We believe our analysis provides a workflow for selecting modules and our benchmark study may help further improvement of disease module methods. Moreover, we also stress that our methodology is generally applicable for combining and assessing the performance of multi-omic approaches for complex diseases. 

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  • 5.
    Behboudi, Afrouz
    Department of Cell and Molecular Biology - Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Cytogenetic and Molecular Changes Involving Rat Chromosome 10 in Experimental Endometrial Adenocarcinoma2002Doktoravhandling, med artikler (Annet vitenskapelig)
  • 6.
    Behboudi, Afrouz
    et al.
    Department of Clinical Genetics, Institute of Biomedicine, Göteborg University, Sweden.
    Stenman, Göran
    Department of Clinical Genetics, Institute of Biomedicine, Göteborg University, Sweden.
    Skin: Clear cell hidradenoma of the skin (CCH)2006Inngår i: Atlas of Genetics and Cytogenetics in Oncology and Haematology, E-ISSN 1768-3262, Vol. 10, nr 4, s. 285-287Artikkel, forskningsoversikt (Fagfellevurdert)
    Fulltekst (pdf)
    fulltext
  • 7.
    Behboudi, Afrouz
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Thelander, Tilia
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Yazici, Duygu
    Koc University Research Center for Translational Medicine (KUTTAM), Koc University Hospital, Istanbul, Turkey.
    Celik, Yeliz
    Koc University Research Center for Translational Medicine (KUTTAM), Koc University Hospital, Istanbul, Turkey.
    Yucel-Lindberg, Tülay
    Department of Dental Medicine, Karolinska Institute, Stockholm, Sweden.
    Thunström, Erik
    Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Peker, Yüksel
    Koc University Research Center for Translational Medicine (KUTTAM), Koc University Hospital, Istanbul, Turkey ; Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Sciences, Respiratory Medicine and Allergology, Faculty of Medicine, Lund University, Lund, Sweden ; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, PA, USA.
    Association of TNF-alpha (-308G/A) Gene Polymorphism with Circulating TNF-alpha Levels and Excessive Daytime Sleepiness in Adults with Coronary Artery Disease and Concomitant Obstructive Sleep Apnea2021Inngår i: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 10, nr 15, artikkel-id 3413Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), in which inflammatory activity has a crucial role. The manifestation of OSA varies significantly between individuals in clinical cohorts; not all adults with OSA demonstrate the same set of symptoms; i.e., excessive daytime sleepiness (EDS) and/or increased levels of inflammatory biomarkers. The further exploration of the molecular basis of these differences is therefore essential for a better understanding of the OSA phenotypes in cardiac patients. In this current secondary analysis of the Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA (RICCADSA) trial (Trial Registry: ClinicalTrials.gov; No: NCT 00519597), we aimed to address the association of tumor necrosis factor alpha (TNF-α)-308G/A gene polymorphism with circulating TNF-α levels and EDS among 326 participants. CAD patients with OSA (apnea–hypopnea-index (AHI) ≥ 15 events/h; n = 256) were categorized as having EDS (n = 100) or no-EDS (n = 156) based on the Epworth Sleepiness Scale score with a cut-off of 10. CAD patients with no-OSA (AHI < 5 events/h; n = 70) were included as a control group. The results demonstrated no significant differences regarding the distribution of the TNF-α alleles and genotypes between CAD patients with vs. without OSA. In a multivariate analysis, the oxygen desaturation index and TNF-α genotypes from GG to GA and GA to AA as well as the TNF-α-308A allele carriage were significantly associated with the circulating TNF-α levels. Moreover, the TNF-α-308A allele was associated with a decreased risk for EDS (odds ratio 0.64, 95% confidence interval 0.41–0.99; p = 0.043) independent of age, sex, obesity, OSA severity and the circulating TNF-α levels. We conclude that the TNF-α-308A allele appears to modulate circulatory TNF-α levels and mitigate EDS in adults with CAD and concomitant OSA.

    Fulltekst (pdf)
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  • 8.
    Benrick, Anna
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Pillon, Nicolas J.
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Nilsson, Emma
    Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.
    Lindgren, Eva
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Krook, Anna
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Ling, Charlotte
    Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden.
    Stener-Victorin, Elisabet
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
    Electroacupuncture mimics exercise-induced changes in skeletal muscle gene expression in women with polycystic ovary syndrome2020Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 105, nr 6, s. 2027-2041Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context

    Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown.

    Objective

    To identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS).

    Design/Participants

    In a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays.

    Results

    A single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q < 0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q < 0.20), and these changes correlated with altered expression of 101 genes (P < 0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these 2 genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis.

    Conclusion

    Our findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.

    Fulltekst (pdf)
    fulltext
  • 9.
    Bergman, Annika
    et al.
    Department of Medical and Clinical genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    Abel, Frida
    Department of Medical and Clinical genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    Behboudi, Afrouz
    Department of Medical and Clinical genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    Yhr, Maria
    Department of Medical and Clinical genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    Mattsson, Jan
    Department of Surgery, Sahlgrenska University hospital, Gothenburg, Sweden.
    Svensson, Jan H.
    Department of Surgery, Skaraborg hospital, Skövde, Sweden.
    Karlsson, Per
    Department of Oncology, Sahlgrenska University hospital, Gothenburg, Sweden.
    Nordling, Margareta
    Department of Medical and Clinical genetics, Sahlgrenska Academy, Gothenburg, Sweden.
    No germline mutations in supposed tumour suppressor genes SAFB1 and SAFB2 in familial breast cancer with linkage to 19p2008Inngår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 9, nr 1, artikkel-id 108Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    The scaffold attachment factor B1 and B2 genes, SAFB1/SAFB2 (both located on chromosome 19p13.3) have recently been suggested as tumour suppressor genes involved in breast cancer development. The assumption was based on functional properties of the two genes and loss of heterozygosity of intragenic markers in breast tumours further strengthened the postulated hypothesis. In addition, linkage studies in Swedish breast cancer families also indicate the presence of a susceptibility gene for breast cancer at the 19p locus. Somatic mutations in SAFB1/SAFB2 have been detected in breast tumours, but to our knowledge no studies on germline mutations have been reported. In this study we investigated the possible involvement of SAFB1/SAFB2 on familiar breast cancer by inherited mutations in either of the two genes.

    Results

    Mutation analysis in families showing linkage to the SAFB1/2 locus was performed by DNA sequencing. The complete coding sequence of the two genes SAFB1 and SAFB2 was analyzed in germline DNA from 31 affected women. No missense or frameshift mutations were detected. One polymorphism was found in SAFB1 and eight polymorphisms were detected in SAFB2. MLPA-anlysis showed that both alleles of the two genes were preserved which excludes gene inactivation by large deletions.

    Conclusion

    SAFB1 and SAFB2 are not likely to be causative of the hereditary breast cancer syndrome in west Swedish breast cancer families.

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  • 10.
    Björn, Niclas
    et al.
    Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Sweden.
    Badam, Tejaswi
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Spalinskas, Rapolas
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle Hospital, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle Hospital, Sweden / Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Lewensohn, Rolf
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    De Petris, Luigi
    Thoracic Oncology Unit, Tema Cancer, Karolinska University Hospital, and Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Lubovac-Pilav, Zelmina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sahlén, Pelin
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Lundeberg,, Joakim
    Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
    Gustafsson, Mika
    Bioinformatics, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Gréen, Henrik
    Clinical Pharmacology, Division of Drug Research, Department of Biomedical and Clinical Sciences, Linköping University, Sweden / Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden / Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Whole-genome sequencing and gene network modules predict gemcitabine/carboplatin-induced myelosuppression in non-small cell lung cancer patients2020Inngår i: NPJ Systems Biology and Applications, E-ISSN 2056-7189, Vol. 6, nr 1, artikkel-id 25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gemcitabine/carboplatin chemotherapy commonly induces myelosuppression, including neutropenia, leukopenia, and thrombocytopenia. Predicting patients at risk of these adverse drug reactions (ADRs) and adjusting treatments accordingly is a long-term goal of personalized medicine. This study used whole-genome sequencing (WGS) of blood samples from 96 gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients and gene network modules for predicting myelosuppression. Association of genetic variants in PLINK found 4594, 5019, and 5066 autosomal SNVs/INDELs with p ≤ 1 × 10−3 for neutropenia, leukopenia, and thrombocytopenia, respectively. Based on the SNVs/INDELs we identified the toxicity module, consisting of 215 unique overlapping genes inferred from MCODE-generated gene network modules of 350, 345, and 313 genes, respectively. These module genes showed enrichment for differentially expressed genes in rat bone marrow, human bone marrow, and human cell lines exposed to carboplatin and gemcitabine (p < 0.05). Then using 80% of the patients as training data, random LASSO reduced the number of SNVs/INDELs in the toxicity module into a feasible prediction model consisting of 62 SNVs/INDELs that accurately predict both the training and the test (remaining 20%) data with high (CTCAE 3–4) and low (CTCAE 0–1) maximal myelosuppressive toxicity completely, with the receiver-operating characteristic (ROC) area under the curve (AUC) of 100%. The present study shows how WGS, gene network modules, and random LASSO can be used to develop a feasible and tested model for predicting myelosuppressive toxicity. Although the proposed model predicts myelosuppression in this study, further evaluation in other studies is required to determine its reproducibility, usability, and clinical effect.

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  • 11.
    Chatron, Nicolas
    et al.
    Genetics Department, Lyon University Hospital, France / Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    Becker, Felicitas
    Department of Neurology, University of Ulm, Germany / University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Germany.
    Morsy, Heba
    Human Genetics Department, Medical Research Institute, Alexandria University, Egypt.
    Schmidts, Miriam
    Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen, The Netherlands / Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands / Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Germany.
    Hardies, Katia
    Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Belgium.
    Tuysuz, Beyhan
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Roselli, Sandra
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Najafi, Maryam
    Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen, The Netherlands / Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
    Alkaya, Dilek Uludag
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Ashrafzadeh, Farah
    Department of Paediatric Neurology, Ghaem Medical Centre, School of Medicine, Mashhad University of Medical Sciences, Iran.
    Nabil, Amira
    Human Genetics Department, Medical Research Institute, Alexandria University, Egypt.
    Omar, Tarek
    Pediatrics Department, Faculty of Medicine, Alexandria University, Egypt.
    Maroofian, Reza
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London, UK.
    Karimiani, Ehsan Ghayoor
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London, UK / Innovative medical research center, Mashhad branch, Islamic Azad University, Mashhad, Iran.
    Hussien, Haytham
    Pediatrics Department, Faculty of Medicine, Alexandria University, Egypt.
    Kok, Fernando
    Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, SP, Brazil.
    Ramos, Luiza
    Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, SP, Brazil.
    Gunes, Nilay
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Bilguvar, Kaya
    Department of Genetics, Yale Center for Genome Analysis (YCGA), Yale University, School of Medicine, New Haven, Connecticut.
    Labalme, Audrey
    Genetics Department, Lyon University Hospital, France.
    Alix, Eudeline
    Genetics Department, Lyon University Hospital, France.
    Sanlaville, Damien
    Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    de Bellescize, Julitta
    Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, ERN EpiCARE, University Hospitals of Lyon, France.
    Poulat, Anne-Lise
    Department of Pediatric Neurology, Lyon University Hospital, Lyon, France.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Lerche, Holger
    University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Germany.
    May, Patrick
    Luxemburg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
    Lesca, Gaetan
    Genetics Department, Lyon University Hospital, France / Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    Weckhuysen, Sarah
    Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Belgium / Department of Neurology, University Hospital Antwerp, Belgium.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy2020Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 143, nr 5, s. 1447-1461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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  • 12.
    Chaudhari, Aditi
    et al.
    University of Gothenburg.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande.
    Wettergren, Yvonne
    University of Gothenburg, Sahlgrenska University Hospital/Östra.
    Kahn, Ronald
    Joslin Diabetes Center and Harvard Medical School, United States.
    Rotter Sopasakis, Victoria
    University of Gothenburg / Joslin Diabetes Center and Harvard Medical School, United states.
    Hepatic deletion of p110α and p85α results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity2017Inngår i: F1000 Research, E-ISSN 2046-1402, Vol. 6, artikkel-id 1600Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110α results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85α results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110α and p85α (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis.Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks.Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K.Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110α/p85α by signaling through other nodes than Akt/Protein Kinase B.

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  • 13.
    Chaudhari, Aditi
    et al.
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Krumlinde, Daniel
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Lundqvist, Annika
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Akyürek, Levent M.
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Bandaru, Sashidhar
    Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
    Skålén, Kristina
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Ståhlman, Marcus
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Borén, Jan
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
    Wettergren, Yvonne
    Department of Surgery, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Medical and Clinical Genetics, University of Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity2015Inngår i: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, nr 19, s. 3258-3273Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

  • 14.
    Deland, Lily
    et al.
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Keane, Simon
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Bontell, Thomas O.
    Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden ; Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Fagman, Henrik
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sjögren, Helene
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lind, Anders E.
    Clinical Genomics Gothenburg, SciLife Labs, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Carén, Helena
    Sahlgrenska Center for Cancer Research, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Tisell, Magnus
    Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Nilsson, Jonas A.
    Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Sabel, Magnus
    Childhood Cancer Centre, Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden ; Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Abel, Frida
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden ; Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Novel TPR::ROS1 Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma2022Inngår i: Cancer Genomics & Proteomics, ISSN 1109-6535, E-ISSN 1790-6245, Vol. 19, nr 6, s. 711-726Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND/AIM: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusion-positive solid tumors. PATIENT AND METHODS: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. RESULTS: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K- and JAK/STAT- pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. CONCLUSION: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse. 

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  • 15.
    Ejeskär, Katarina
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Vickes, Oscar
    Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Kuchipudi, Arunakar
    Högskolan i Skövde, Forskningscentrum för Systembiologi.
    Wettergren, Yvonne
    Department of General Surgery, Gothenburg University, Gothenburg, Sweden.
    Uv, Anne
    Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Rotter Sopasakis, Victoria
    Department of Molecular and Clinical Medicine, Institute of Medicine, Wallenberg Laboratory, Gothenburg University, Gothenburg, Sweden.
    The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo2015Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 5, artikkel-id e0127497Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37δ, an alternatively spliced product of human PI3K p110δ, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37δ in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C-terminal region of human p37δ further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37δ both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37δ prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over-expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase-independent function of the PI3K catalytic subunit.

  • 16.
    Erlingsson, Cecilia
    Högskolan i Skövde, Institutionen för hälsa och lärande.
    Polymorphism in IL-6 promoter region and obstructive sleep apnea: A gene association study from the Swedish RICCADSA  trial2019Independent thesis Basic level (degree of Bachelor), 20 poäng / 30 hpOppgave
    Abstract [en]

    Obstructive sleep apnea (OSA) affects up to 15% of the population with a prevalence higher in men than in women and increases with age, with obesity as the most recognised risk factor. OSA manifests as disrupted breathing during sleep, causing a general decrease in life quality of patients, including daytime sleepiness and reduced cognitive function. OSA has been shown to be influenced by both environmental and genetic factors, where the later has resulted in several studies focusing on possible associations between different genetic variations and prevalence of the disorder. Some studies have found association with a single nucleotide polymorphism at the promoter region of IL-6  (IL-6 -174G/C), which has been suggested to alter expression of the inflammatory cytokine interleukin-6. In this study 261 Swedish OSA and 70 non-OSA patients, all having coronary artery disease (CAD), were genotyped at IL-6 -174G/C by polymerase chain reaction - restriction fragment polymorphism, and statistical analyses were conducted to assess suggested potential association between the disorder and allele frequency at this position. Earlier reports regarding this has shown conflicting results and we found no significant association between IL-6 -174G/C and prevalence of OSA, nor with selected clinical parameters. However, a significant association was found between the IL-6 -174C allele and occurrence of daytime sleepiness in abdominally obese Swedish OSA patients with CAD. Our results confirm and extends some earlier findings indicating an intricate relationship between multiple clinical, genetic and environmental factors and the complexity of OSA, pointing to the need of further studies.

  • 17.
    Gustafson, Deborah R.
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande. Department of Neurology, State University of New York Downstate Medical Center, New York, USA.
    Adipose Tissue Complexities in Dyslipidemias2019Inngår i: Dyslipidemia / [ed] Samy I. McFarlane, London: IntechOpen , 2019, s. 1-22Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Adipose tissue is the largest organ in the human body and, in excess, contributes to dyslipidemias and the dysregulation of other vascular and metabolic processes. Adipose tissue is heterogeneous, comprised of several cell types based on morphology, cellular age, and endocrine and paracrine function. Adipose tissue depots are also regional, primarily due to sex differences and genetic variation. Adipose tissue is also characterized as subcutaneous vs. visceral. In addition, fatty deposits exist outside of adipose tissue, such as those surrounding the heart, or as infiltration of skeletal muscle. This review focuses on adipose tissue and its contribution to dyslipidemias. Dyslipidemias are defined as circulating blood lipid levels that are too high or altered. Lipids include both traditional and nontraditional species. Leaving aside traditional definitions, adipose tissue contributes to dyslipidemias in a myriad of ways. To address a small portion of this topic, we reviewed (a) adipose tissue location and cell types, (b) body composition, (c) endocrine adipose, (d) the fat-brain axis, and (e) genetic susceptibility. The influence of these complex aspects of adipose tissue on dyslipidemias and human health, illustrating that, once again, that adipose tissue is a quintessential, multifunctional tissue of the human body, will be summarized.

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  • 18.
    Hamta, A.
    et al.
    CMB-Genetics, Göteborg University, Sweden.
    Adamovic, T.
    CMB-Genetics, Göteborg University, Sweden.
    Samuelson, Emma
    CMB-Genetics, Göteborg University, Sweden.
    Helou, K.
    Department of Oncology, Göteborg University, Sweden.
    Behboudi, Afrouz
    CMB-Genetics, Göteborg University, Sweden.
    Levan, Göran
    CMB-Genetics, Göteborg University, Sweden ; CMB-Genetics, Göteborg, Sweden.
    Chromosome ideograms of the laboratory rat (Rattus norvegicus) based on high-resolution banding, and anchoring of the cytogenetic map to the DNA sequence by FISH in sample chromosomes2006Inngår i: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 115, nr 2, s. 158-168Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A detailed banded ideogram representation of the rat chromosomes was constructed based on actual G-banded prometaphase chromosomes. The approach yielded 535 individual bands, a significant increase compared to previously presented ideograms. The new ideogram was adapted to the existing band nomenclature. The gene locus positions in the rat draft DNA sequence were compared to the chromosomal positions as determined by dual-color FISH, using rat (RNO) chromosomes 6 and 15 and a segment of RNO4 as sample regions. It was found that there was generally an excellent correlation in the chromosome regions tested between the relative gene position in the DNA molecules and the sub-chromosomal localization by FISH and subsequent information transfer on ideograms from measurements of chromosomal images. However, in the metacentric chromosome (RNO15), the correlation was much better in the short arm than in the long arm, suggesting that the centromeric region may distort the linear relationship between the chromosomal image and the corresponding DNA molecule.

  • 19.
    Horning, Aaron M.
    et al.
    University of Texas Health Science Center, San Antonio, USA.
    Awe, Julius Adebayo
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada / Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wang, Chiou-Miin
    University of Texas Health Science Center, San Antonio, USA.
    Liu, Joseph
    University of Texas Health Science Center, San Antonio, USA.
    Lai, Zhao
    University of Texas Health Science Center, San Antonio, USA.
    Wang, Vickie Yao
    University of Texas Health Science Center, San Antonio, USA.
    Jadhav, Rohit R.
    University of Texas Health Science Center, San Antonio, USA.
    Louie, Anna D.
    University of Texas Health Science Center, San Antonio, USA.
    Lin, Chun-Lin
    University of Texas Health Science Center, San Antonio, USA.
    Kroczak, Tad
    University of Manitoba, Winnipeg, Manitoba, Canada.
    Chen, Yidong
    University of Texas Health Science Center, San Antonio, USA.
    Jin, Victor X.
    University of Texas Health Science Center, San Antonio, USA.
    Abboud-Werner, Sherry L.
    University of Texas Health Science Center, San Antonio, USA.
    Leach, Robin J.
    University of Texas Health Science Center, San Antonio, USA.
    Hernandez, Javior
    University of Texas Health Science Center, San Antonio, USA.
    Thompson, Ian M.
    University of Texas Health Science Center, San Antonio, USA.
    Saranchuk, Jeff
    University of Manitoba, Winnipeg, Canada.
    Drachenberg, Darrel
    University of Manitoba, Winnipeg, Canada.
    Chen, Chun-Liang
    University of Texas Health Science Center, San Antonio, USA.
    Mai, Sabine
    University of Manitoba, Winnipeg, Canada.
    Huang, Tim Hui-Ming
    University of Texas Health Science Center, San Antonio, USA.
    DNA Methylation Screening of Primary Prostate Tumors Identifies SRD5A2 and CYP11A1 as Candidate Markers for Assessing Risk of Biochemical Recurrence2015Inngår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, nr 15, s. 1790-1801Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND. Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)-related genes in patients' plasma cell-free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR). METHODS. Methyl-binding domain capture sequencing (MBDCap-seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post-radical prostatectomy (RP) using univariate and multivariate prediction analyses. RESULTS. Putative DMRs in 13 of 30 ABP-related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci-SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post-RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy. CONCLUSIONS. Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post-RP further suggests their utility as predictive markers for PCa recurrence. (C) 2015 Wiley Periodicals, Inc.

  • 20.
    Jurcevic, Sanja
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Keane, Simon
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Borgmästars, Emmy
    Department of Surgical and Perioperative Sciences/Surgery, Umeå University, Sweden.
    Lubovac-Pilav, Zelmina
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Högskolan i Skövde, Institutionen för biovetenskap.
    Bioinformatics analysis of miRNAs in the neuroblastoma 11q-deleted region reveals a role of miR-548l in both 11q-deleted and MYCN amplified tumour cells2022Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikkel-id 19729Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neuroblastoma is a childhood tumour that is responsible for approximately 15% of all childhood cancer deaths. Neuroblastoma tumours with amplification of the oncogene MYCN are aggressive, however, another aggressive subgroup without MYCN amplification also exists; rather, they have a deleted region at chromosome arm 11q. Twenty-six miRNAs are located within the breakpoint region of chromosome 11q and have been checked for a possible involvement in development of neuroblastoma due to the genomic alteration. Target genes of these miRNAs are involved in pathways associated with cancer, including proliferation, apoptosis and DNA repair. We could show that miR-548l found within the 11q region is downregulated in neuroblastoma cell lines with 11q deletion or MYCN amplification. In addition, we showed that the restoration of miR-548l level in a neuroblastoma cell line led to a decreased proliferation of these cells as well as a decrease in the percentage of cells in the S phase. We also found that miR-548l overexpression suppressed cell viability and promoted apoptosis, while miR-548l knockdown promoted cell viability and inhibited apoptosis in neuroblastoma cells. Our results indicate that 11q-deleted neuroblastoma and MYCN amplified neuroblastoma coalesce by downregulating miR-548l.

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  • 21.
    Kariminejad, Ariana
    et al.
    Najmabadi Pathology & Genetics Center, Tehran, Iran.
    Ghaderi-Sohi, Siavash
    Najmabadi Pathology & Genetics Center, Tehran, Iran.
    Hossein-Nejad Nedai, Hamid
    Department of Pathology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Varasteh, Vahid
    Division of Thoracic Surgery, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningscentrum för Systembiologi. Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum2016Inngår i: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 17, nr 1, s. 1-5, artikkel-id 109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses.

    METHODS AND RESULTS: Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis.

    CONCLUSIONS: RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling.

  • 22.
    Kariminejad, Ariana
    et al.
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Szenker-Ravi, Emmanuelle
    Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore.
    Lekszas, Caroline
    Institute of Human Genetics, Julius-Maximilians-Universität, Würzburg, Germany.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande.
    Moslemi, Ali-Reza
    Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Sweden.
    Naert, Thomas
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Tran, Hong Thi
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Ahangari, Fatemeh
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehra, Iran.
    Rajaei, Minoo
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Nasseri, Mojila
    Pardis Clinical and Genetics Laboratory, Mashhad, Iran.
    Haaf, Thomas
    Institute of Human Genetics, Julius-Maximilians-Universität, Würzburg, Germany.
    Azad, Afrooz
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Superti-Furga, Andrea
    Division of Genetic Medicine, Lausanne University Hospital (CHUV), University of Lausanne, Switzerland.
    Maroofian, Reza
    Molecular and Clinical Sciences Institute, St. George’s University of London, UK.
    Ghaderi-Sohi, Siavash
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran.
    Najmabadi, Hossein
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran / Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
    Abbaszadegan, Mohammad Reza
    Pardis Clinical and Genetics Laboratory, Mashhad, Iran / Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
    Vleminckx, Kris
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Nikuei, Pooneh
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Reversade, Bruno
    Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore / Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore / Department of Medical Genetics, Koç University, School of Medicine, Topkapı, Istanbul, Turkey.
    Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia2019Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, nr 6, s. 1294-1301Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113 and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113 stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

  • 23.
    Karlsson, Ida K.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Gerontology and Aging Research Network – Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Sweden.
    Ericsson, Malin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wang, Yunzhang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Jylhävä, Juulia
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Hägg, Sara
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Dahl Aslan, Anna K.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Gerontology and Aging Research Network – Jönköping (ARN-J), School of Health and Welfare, Jönköping University, Sweden.
    Reynolds, Chandra A.
    Department of Psychology, University of California, Riverside, United States.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles, United States.
    Epigenome-wide association study of level and change in cognitive abilities from midlife through late life2021Inngår i: Clinical Epigenetics, ISSN 1868-7075, Vol. 13, nr 1, artikkel-id 85Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Epigenetic mechanisms are important in aging and may be involved in late-life changes in cognitive abilities. We conducted an epigenome-wide association study of leukocyte DNA methylation in relation to level and change in cognitive abilities, from midlife through late life in 535 Swedish twins. Results: Methylation levels were measured with the Infinium Human Methylation 450 K or Infinium MethylationEPIC array, and all sites passing quality control on both arrays were selected for analysis (n = 250,816). Empirical Bayes estimates of individual intercept (age 65), linear, and quadratic change were obtained from latent growth curve models of cognitive traits and used as outcomes in linear regression models. Significant sites (p &lt; 2.4 × 10–7) were followed up in between-within twin pair models adjusting for familial confounding and full-growth modeling. We identified six significant associations between DNA methylation and level of cognitive abilities at age 65: cg18064256 (PPP1R13L) with processing speed and spatial ability; cg04549090 (NRXN3) with spatial ability; cg09988380 (POGZ), cg25651129 (-), and cg08011941 (ENTPD8) with working memory. The genes are involved in neuroinflammation, neuropsychiatric disorders, and ATP metabolism. Within-pair associations were approximately half that of between-pair associations across all sites. In full-growth curve models, associations between DNA methylation and cognitive level at age 65 were of small effect sizes, and associations between DNA methylation and longitudinal change in cognitive abilities of very small effect sizes. Conclusions: Leukocyte DNA methylation was associated with level, but not change in cognitive abilities. The associations were substantially attenuated in within-pair analyses, indicating they are influenced in part by genetic factors. 

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  • 24.
    Keane, Simon
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Améen, Sophie
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Lindlöf, Angelica
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival2020Inngår i: Cell Communication and Signaling, E-ISSN 1478-811X, Vol. 18, nr 1, artikkel-id 65Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Neuroblastoma (NB) is a childhood neural crest tumor. There are two groups of aggressive NBs, one with MYCN amplification, and another with 11q chromosomal deletion; these chromosomal aberrations are generally mutually exclusive. The DLG2 gene resides in the 11q-deleted region, thus makes it an interesting NB candidate tumor suppressor gene. METHODS: We evaluated the association of DLG2 gene expression in NB with patient outcomes, stage and MYCN status, using online microarray data combining independent NB patient data sets. Functional studies were also conducted using NB cell models and the fruit fly. RESULTS: Using the array data we concluded that higher DLG2 expression was positively correlated to patient survival. We could also see that expression of DLG2 was inversely correlated with MYCN status and tumor stage. Cell proliferation was lowered in both 11q-normal and 11q-deleted NB cells after DLG2 over expression, and increased in 11q-normal NB cells after DLG2 silencing. Higher level of DLG2 increased the percentage of cells in the G2/M phase and decreased the percentage of cells in the G1 phase. We detected increased protein levels of Cyclin A and Cyclin B in fruit fly models either over expressing dMyc or with RNAi-silenced dmDLG, indicating that both events resulted in enhanced cell cycling. Induced MYCN expression in NB cells lowered DLG2 gene expression, which was confirmed in the fly; when dMyc was over expressed, the dmDLG protein level was lowered, indicating a link between Myc over expression and low dmDLG level. CONCLUSION: We conclude that low DLG2 expression level forces cell cycle progression, and that it predicts poor NB patient survival. The low DLG2 expression level could be caused by either MYCN-amplification or 11q-deletion. Video Abstract.

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  • 25.
    Lindholm, Heléne
    et al.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Morrison, India
    Center for Social and Affective Neuroscience, Linköping University, Sweden.
    Krettek, Alexandra
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Sweden ; Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
    Malm, Dan
    Department of Nursing Sciences, School of Health and Welfare, Jönköping University, Sweden.
    Novembre, Giovanni
    Center for Social and Affective Neuroscience, Linköping University, Sweden.
    Handlin, Linda
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Genetic risk-factors for anxiety in healthy individuals: polymorphisms in gene simportant for the HPA axis2020Inngår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 21, artikkel-id 184Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals.

    Methods

    DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire.

    Results

    Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01).

    Conclusion

    This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.

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  • 26.
    Maroofian, Reza
    et al.
    Department of Neuromuscular Diseases, University College London, Institute of Neurology, United Kingdom.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Severino, Mariasavina
    Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
    Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders2023Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, nr 12, s. 5031-5043Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. 

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  • 27.
    Nilipour, Yalda
    et al.
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Nafissi, Shahriar
    Tehran University of Medical Sciences, Iran.
    Tjust, Anton E.
    Umeå University, Sweden.
    Ravenscroft, Gianina
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Hossein-Nejad Nedai, Hamid
    Shahid Beheshti University of Medical Sciences, Iran.
    Taylor, Rhonda L.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Varasteh, Vahid
    Shahid Beheshti University of Medical Sciences, Iran.
    Pedrosa Domellöf, Fatima
    Umeå University, Sweden.
    Zangi, Mahdi
    National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Iran.
    Tonekaboni, Seyed Hassan
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Olivé, M.
    IDIBELL-Hospital de Bellvitge, Barcelona, Spain.
    Kiiski, Kirsi
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Sagath, L.
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Davis, Mark R.
    Pathwest, QEII Medical Centre, Nedlands, Western Australia.
    Laing, Nigel G.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsa och lärande. Högskolan i Skövde, Forskningsspecialiseringen Hälsa och Lärande. The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies2018Inngår i: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, nr 6, s. 841-847Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Nemaline myopathy has been associated with mutations in twelve genes to date. However, for some patients diagnosed with nemaline myopathy, definitive mutations are not identified in the known genes, suggesting there are other genes involved. This study describes compound heterozygosity for rare variants in RYR3 in one such patient.

    Results: Clinical examination of the patient at 22 years of age revealed a long-narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear areas, subsarcolemmal and within the cytoplasm. No likely pathogenic mutations in known nemaline myopathy genes were identified. Copy number variation in known nemaline myopathy genes was excluded by nemaline myopathy targeted array-CGH. Next generation sequencing revealed compound heterozygous missense variants in the ryanodine receptor type 3 gene (RYR3).  RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain or cauda equina samples. Immunofluorescence of human skeletal muscle revealed a "single-row" appearance of RYR3, interspaced between the "double-rows" of RYR1 at each A-I junction.

    Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

  • 28.
    Ollila, Hanna M.
    et al.
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland ; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States ; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States ; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
    Sinnott-Armstrong, Nasa
    Department of Genetics, School of Medicine, Stanford University, CA, United States.
    Kantojärvi, Katri
    Population Health, Finnish Institute for Health and Welfare, Helsinki, Finland ; Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Finland.
    Broberg, Martin
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Palviainen, Teemu
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Jones, Samuel
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Ripatti, Vili
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Pandit, Anita
    Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
    Rong, Robin
    Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States.
    Kristiansson, Kati
    Population Health, Finnish Institute for Health and Welfare, Helsinki, Finland.
    Sandman, Nils
    Department of Psychology and Speech-Language Pathology, and Turku Brain and Mind Center, University of Turku, Finland.
    Valli, Katja
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Department of Psychology and Speech-Language Pathology, and Turku Brain and Mind Center, University of Turku, Finland.
    Hublin, Christer
    Finnish Institute of Occupational Health, Helsinki, Finland.
    Ripatti, Samuli
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland ; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States ; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States.
    Widen, Elisabeth
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Kaprio, Jaakko
    Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
    Saxena, Richa
    Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States ; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United States ; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States ; Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States.
    Paunio, Tiina
    Population Health, Finnish Institute for Health and Welfare, Helsinki, Finland ; Department of Psychiatry and SleepWell Research Program, Faculty of Medicine, University of Helsinki and Helsinki University Central Hospital, Finland.
    Nightmares share genetic risk factors with sleep and psychiatric traits2024Inngår i: Translational Psychiatry, E-ISSN 2158-3188, Vol. 14, nr 1, artikkel-id 123Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nightmares are vivid, extended, and emotionally negative or negative dreams that awaken the dreamer. While sporadic nightmares and bad dreams are common and generally harmless, frequent nightmares often reflect underlying pathologies of emotional regulation. Indeed, insomnia, depression, anxiety, or alcohol use have been associated with nightmares in epidemiological and clinical studies. However, the connection between nightmares and their comorbidities are poorly understood. Our goal was to examine the genetic risk factors for nightmares and estimate correlation or causality between nightmares and comorbidities. We performed a genome-wide association study (GWAS) in 45,255 individuals using a questionnaire-based assessment on the frequency of nightmares during the past month and genome-wide genotyping data. While the GWAS did not reveal individual risk variants, heritability was estimated at 5%. In addition, the genetic correlation analysis showed a robust correlation (rg > 0.4) of nightmares with anxiety (rg = 0.671, p = 7.507e−06), depressive (rg = 0.562, p = 1.282e−07) and posttraumatic stress disorders (rg = 0.4083, p = 0.0152), and personality trait neuroticism (rg = 0.667, p = 4.516e−07). Furthermore, Mendelian randomization suggested causality from insomnia to nightmares (beta = 0.027, p = 0.0002). Our findings suggest that nightmares share genetic background with psychiatric traits and that insomnia may increase an individual’s liability to experience frequent nightmares. Given the significant correlations with psychiatric and psychological traits, it is essential to grow awareness of how nightmares affect health and disease and systematically collect information about nightmares, especially from clinical samples and larger cohorts. 

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  • 29.
    Osborn, Daniel Peter Sayer
    et al.
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Emrahi, Leila
    Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University Tehran, Iran.
    Clayton, Joshua
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Tabrizi, Mehrnoush Toufan
    Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
    Wan, Alex Yui Bong
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Maroofian, Reza
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Yazdchi, Mohammad
    Centre for Neuroscience Research center, Tabriz University of medical science, Tabriz, Iran.
    Garcia, Michael Leon Enrique
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Galehdari, Hamid
    Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Iran.
    Hesse, Camila
    Institute of Biomedicine, Sahlgrenska academy, University of Gothenburg, Sweden.
    Shariati, Gholamreza
    Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
    Mazaheri, Neda
    Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Iran.
    Sedaghat, Alireza
    Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of medical Sciences, Ahvaz, Iran.
    Goullée, Hayley
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Laing, Nigel
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Jamshidi, Yalda
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL32021Inngår i: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 23, nr 4, s. 787-792Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. Methods: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. Results: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood–onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C&gt;A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G&gt;T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G&gt;A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G&gt;T or the missense c.170C&gt;A variants. Minigene assay of the c.482-1G&gt;A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. Conclusions: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function. 

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  • 30.
    Pagnamenta, Alistair T.
    et al.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Diaz-Gonzalez, Francisca
    NGEMM, IdiPAZ and Skeletal Dysplasia Multidisciplinary Unit (UMDE, ERN-BOND), Hospital Universitario La Paz, Madrid, Spain.
    Banos-Pinero, Benito
    Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Ferla, Matteo P.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Toosi, Mehran B.
    Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Iran.
    Calder, Alistair D.
    Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
    Karimiani, Ehsan G.
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George’s, University of London, UK ; Next Generation Genetic Polyclinic, Razavi International Hospital, Mashhad, Iran.
    Doosti, Mohammad
    Next Generation Genetic Polyclinic, Razavi International Hospital, Mashhad, Iran.
    Wainwright, Andrew
    Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Wordsworth, Paul
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK ; Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Bailey, Kathryn
    Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Lester, Tracy
    Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Maroofian, Reza
    Department of Neuromuscular Disorders, Queen Square Institute of Neurology, UCL, London, UK.
    Heath, Karen E.
    INGEMM, IdiPAZ and Skeletal Dysplasia Multidisciplinary Unit (UMDE, ERN-BOND), Hospital Universitario La Paz, Madrid, Spain ; CIBERER, ISCIII, Madrid, Spain .
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Shears, Deborah
    Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Taylor, Jenny C.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Variable skeletal phenotypes associated with biallelic variants in PRKG22022Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 59, nr 10, s. 947-950Artikkel i tidsskrift (Fagfellevurdert)
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  • 31.
    Pedersen, Nancy L.
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Gatz, Margaret
    Center for Economic and Social Research, University of Southern California, Los Angeles, CA, United States.
    Finch, Brian K.
    Center for Economic and Social Research, University of Southern California, Los Angeles, CA, United States.
    Finkel, Deborah
    Department of Psychology, Indiana University Southeast, New Albany, IN, United States.
    Butler, David A.
    Office of Military and Veterans Health, Health and Medicine Division, National Academies of Sciences, Engineering, and Medicine, Washington, DC, United States.
    Dahl Aslan, Anna
    Institute of Gerontology and Aging Research Network – Jönköping (ARN-J) ; School of Health and Welfare, Jönköping University, Sweden.
    Franz, Carol E.
    Department of Psychiatry, University of California San Diego, San diego, CA, United States.
    Kaprio, Jaakko
    Department of Public Health,Faculty of Medicine, Institute for Molecular Medicine FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
    Lapham, Susan
    Research and Evaluation, American Institutes for Research, Washington, DC, United States.
    McGue, Matt
    Department of Psychology, University of Minnesota, Minneapolis, MN, USA ; Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark.
    Mosing, Miriam A.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Neiderhiser, Jenae
    Department of Psychology, Penn State University, University Park, PA, United States.
    Nygaard, Marianne
    Danish Twin Registry, University of Southern Denmark, Odense C, Denmark.
    Panizzon, Matthew
    Department of Psychiatry, University of California San Diego, San diego, CA, United States.
    Prescott, Carol A.
    Department of Psychology, University of Southern California, Los Angeles, CA, United States.
    Reynolds, Chandra A.
    Department of Psychology, University of California-Riverside, Riverside, CA, United States.
    Sachdev, Perminder
    Centre for Healthy Brain Ageing (CHeBA), University of New South Wales, Sydney, NSW, Australia.
    Whitfield, Keith E.
    Department of Psychology, Wayne State University, Detroit, MI, United States.
    IGEMS: The Consortium on Interplay of Genes and Environment Across Multiple Studies - An Update2019Inngår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 22, nr 6, s. 809-816Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Interplay of Genes and Environment across Multiple Studies (IGEMS) is a consortium of 18 twin studies from 5 different countries (Sweden, Denmark, Finland, United States, and Australia) established to explore the nature of gene-environment (GE) interplay in functioning across the adult lifespan. Fifteen of the studies are longitudinal, with follow-up as long as 59 years after baseline. The combined data from over 76,000 participants aged 14-103 at intake (including over 10,000 monozygotic and over 17,000 dizygotic twin pairs) support two primary research emphases: (1) investigation of models of GE interplay of early life adversity, and social factors at micro and macro environmental levels and with diverse outcomes, including mortality, physical functioning and psychological functioning; and (2) improved understanding of risk and protective factors for dementia by incorporating unmeasured and measured genetic factors with a wide range of exposures measured in young adulthood, midlife and later life.

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  • 32.
    Pfister, Anna
    Sahlgrenska Academy at University of Gothenburg.
    Outcomes of Myosin 1C Gene Expression Depletion on Cancer-related Pathways, in Vitro and in Clinical Samples2016Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The unconventional myosin IC has previously been suggested to be a haploinsufficient tumour suppressor. The mechanism for this action has hitherto been unknown, however, and hence we decided to attempt to elucidate the genes involved. The first study involved knock-down of MYO1C using siRNA technology followed by whole transcriptiome microarray analysis performed on samples taken at different time points post transfection. This revealed a cornucopia of differential expressions compared to the negative control, among them we found an early up-regulation of the PI3K/AKT pathway and the pathway for prostate cancer. Among the down regulated pathways we found endometrial-, colorectal cancer and small cell lung cancer as well as the cell cycle pathway which was a little counter intuitive to the hypothesis that MYO1C suppresses cancer. For the next study six different genes (CCND1, CCND2, CDKN2B, CDKN2C, MYC, RBL1) important for the transitions into S-phase of the cell cycle were therefore chosen for validation using qPCR. These six genes and MYO1C were analysed on both the original time series and a new biological replicate as well as a well stratified set of endometrial carcinoma samples. We were able to verify the significant down-regulation of CCND2 in both time series indicating that this is caused by the depletion of MYO1C. In the tumour samples we saw a negative correlation between the expression of MYO1C and FIGO grade corroborating results previously found by our group when looking at protein expression.

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  • 33.
    Potter, Ryan
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Sahlgrenska Academy, Gothenburg University, Sweden.
    Ayala, Marcelo
    Skaraborgs Sjukhus, Skövde, Sweden ; Karolinska Institutet: Stockholm, Sweden ; Sahlgrenska Academy, Gothenburg University, Sweden.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Identification of biomarker candidates for exfoliative glaucoma from autoimmunity profiling2024Inngår i: BMC Ophthalmology, E-ISSN 1471-2415, Vol. 24, nr 1, artikkel-id 44Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Exfoliative glaucoma (XFG) is a subtype of open-angle glaucoma characterized by distinctive extracellular fibrils and a yet unknown pathogenesis potentially involving immune-related factors. The aim of this exploratory study was to identify biomarkers for XFG using data from autoimmunity profiling performed on blood samples from a Scandinavian cohort of patients. Methods: Autoantibody screening was analyzed against 258 different protein fragments in blood samples taken from 30 patients diagnosed with XFG and 30 healthy donors. The 258 protein fragments were selected based on a preliminary study performed on 3072 randomly selected antigens and antigens associated with the eye. The “limma” package was used to perform moderated t-tests on the proteomic data to identify differentially expressed reactivity between the groups. Results: Multiple associated genes were highlighted as possible biomarker candidates including FUT2, CDH5, and the LOX family genes. Using seven variables, our binary logistic regression model was able to classify the cases from the controls with an AUC of 0.85, and our reduced model using only one variable corresponding to the FUT2 gene provided an AUC of 0.75, based on LOOCV. Furthermore, over-representation gene analysis was performed to identify pathways that were associated with antigens differentially bound to self-antibodies. This highlighted the enrichment of pathways related to collagen fibril formation and the regulatory molecules mir-3176 and mir-876-5p. Conclusions: This study suggests several potential biomarkers that may be useful in developing further models of the pathology of XFG. In particular, CDH5, FUT2, and the LOX family seem to have a relationship which merits additional exploration. 

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  • 34.
    Reynolds, Chandra A.
    et al.
    Department of Psychology, University of California Riverside, CA, USA.
    Gatz, Margaret
    Department of Psychology, University of Southern California, Los Angeles, CA, USA ; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Christensen, Kaare
    Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, Odense C, Denmark ; Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
    Christiansen, Lene
    Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, Odense C, Denmark.
    Dahl Aslan, Anna K.
    Institute of Gerontology, School of Health and Welfare, Jönköping University, Sweden ; Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Kaprio, Jaakko
    Department of Public Health & Institute for Molecular Medicine FIMM, University of Helsinki, Finland.
    Korhonen, Tellervo
    Department of Public Health, University of Helsinki, Finland ; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
    Kremen, William S.
    Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
    Krueger, Robert
    Department of Psychology, University of Minnesota, Minneapolis, MN, USA .
    McGue, Matt
    Department of Psychology, University of Minnesota, Minneapolis, MN, USA ; Epidemiology, Biostatistics and Bio-demography, Institute of Public Health, University of Southern Denmark, Odense C, Denmark.
    Neiderhiser, Jenae M.
    Department of Psychology, The Pennsylvania State University, University Park, PA, USA.
    Pedersen, Nancy L.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden ; Department of Psychology, University of Southern California, Los Angeles, CA, USA.
    Gene-Environment Interplay in Physical, Psychological, and Cognitive Domains in Mid to Late Adulthood: Is APOE a Variability Gene?2016Inngår i: Behavior Genetics, ISSN 0001-8244, E-ISSN 1573-3297, Vol. 46, nr 1, s. 4-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite emerging interest in gene-environment interaction (GxE) effects, there is a dearth of studies evaluating its potential relevance apart from specific hypothesized environments and biometrical variance trends. Using a monozygotic within-pair approach, we evaluated evidence of G×E for body mass index (BMI), depressive symptoms, and cognition (verbal, spatial, attention, working memory, perceptual speed) in twin studies from four countries. We also evaluated whether APOE is a 'variability gene' across these measures and whether it partly represents the 'G' in G×E effects. In all three domains, G×E effects were pervasive across country and gender, with small-to-moderate effects. Age-cohort trends were generally stable for BMI and depressive symptoms; however, they were variable-with both increasing and decreasing age-cohort trends-for different cognitive measures. Results also suggested that APOE may represent a 'variability gene' for depressive symptoms and spatial reasoning, but not for BMI or other cognitive measures. Hence, additional genes are salient beyond APOE.

  • 35.
    Rosenhahn, Erik
    et al.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    O'Brien, Thomas J.
    MRC London Institute of Medical Sciences, United Kingdom.
    Zaki, Maha S.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Sorge, Ina
    Department of Pediatric Radiology, University Hospital Leipzig, Germany.
    Wieczorek, Dagmar
    Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
    Rostasy, Kevin
    Department of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany.
    Vitobello, Antonio
    UF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France.
    Nambot, Sophie
    Centre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France.
    Alkuraya, Fowsan S.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
    Hashem, Mais O.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
    Alhashem, Amal
    Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia ; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Tabarki, Brahim
    Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Alamri, Abdullah S.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Al Safar, Ayat H.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Bubshait, Dalal K.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Alahmady, Nada F.
    Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Gleeson, Joseph G.
    Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA.
    Abdel-Hamid, Mohamed S.
    Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Lesko, Nicole
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Ygberg, Sofia
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Correia, Sandrina P.
    Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wredenberg, Anna
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Alavi, Shahryar
    Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran.
    Seyedhassani, Seyed M.
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Ebrahimi Nasab, Mahya
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Hussien, Haytham
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Omar, Tarek E. I.
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Harzallah, Ines
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Touraine, Renaud
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Morsy, Heba
    UCL Queen Square Institute of Neurology, University College London, UK.
    Houlden, Henry
    UCL Queen Square Institute of Neurology, University College London, UK.
    Shahrooei, Mohammad
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium.
    Ghavideldarestani, Maryam
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
    Abdel-Salam, Ghada M. H.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Torella, Annalaura
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy.
    Zanobio, Mariateresa
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
    Terrone, Gaetano
    Child Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
    Brunetti-Pierri, Nicola
    Telethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy.
    Omrani, Abdolmajid
    Division of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran.
    Hentschel, Julia
    Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
    Lemke, Johannes R.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany.
    Sticht, Heinrich
    Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Abou Jamra, Rami
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Brown, Andre E. X.
    MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ; .
    Maroofian, Reza
    UCL Queen Square Institute of Neurology, University College London, UK.
    Platzer, Konrad
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications2022Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, nr 8, s. 1421-1435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. 

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  • 36.
    Saffari, Afshin
    et al.
    Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA ; Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital, Germany.
    Tajsharghi, Homa
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Maroofian, Reza
    Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, UK.
    The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders2023Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, nr 8, s. 3273-3288, artikkel-id awad039Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

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  • 37.
    Samuelson, Emma
    et al.
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden ; Department of Cell and Molecular Biology, Genetics, Lundberg Laboratory, University of Gothenburg, Sweden.
    Hedberg, Carola
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden ; Department of Cell and Molecular Biology, Genetics, Lundberg Laboratory, University of Gothenburg, Sweden.
    Nilsson, Staffan
    Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Behboudi, Afrouz
    Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Academy, Sweden.
    Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats2009Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 16, nr 1, s. 99-111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (β-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.

  • 38.
    Samuelson, Emma
    et al.
    University of Gothenburg, Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Karlsson, Sandra
    University of Gothenburg, Clinical Genetics SU/Sahlgrenska Hospital, Göteborg, Sweden.
    Behboudi, Afrouz
    University of Gothenburg, Clinical Genetics SU/Sahlgrenska Hospital, Göteborg, Sweden.
    Positional cloning of t(3;6) in rat endometrial cancer2008Inngår i: European Journal of Cancer Supplements, ISSN 1359-6349, E-ISSN 1878-1217, Vol. 6, nr 9, s. 72-72Artikkel i tidsskrift (Fagfellevurdert)
  • 39.
    Samuelson, Emma
    et al.
    Cell and Molecular Biology-Genetics, Göteborg University, Sweden.
    Levan, Karin
    Department of Oncology, Göteborg University, Sweden.
    Horvath, G.
    Department of Oncology, Göteborg University, Sweden.
    Levan, Göran
    Department of Clinical Genetics, Göteborg University, Sweden.
    Behboudi, Afrouz
    Department of Clinical Genetics, Göteborg University, Sweden.
    321 POSTER FISH analysis revealed amplifications of genes in both BDII rat model for endometrial adenocarcinomas and human type I endometrial tumors2007Inngår i: European Journal of Cancer Supplements, ISSN 1359-6349, E-ISSN 1878-1217, Vol. 5, nr 4, s. 63-63Artikkel i tidsskrift (Fagfellevurdert)
  • 40.
    Samuelson, Emma
    et al.
    Genetics, Cell and Molecular Biology, University of Gothenburg, Sweden ; Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Nilsson, Johanna
    Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Walentinsson, Anna
    Genetics, Cell and Molecular Biology, University of Gothenburg, Sweden.
    Szpirer, Claude
    IBMM, Université Libre de Bruxelles, Gosselies, Belgium.
    Behboudi, Afrouz
    Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Absence of Ras mutations in rat DMBA-induced mammary tumors2009Inngår i: Molecular Carcinogenesis, ISSN 0899-1987, E-ISSN 1098-2744, Vol. 48, nr 2, s. 150-155Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Animal cancer models reduce genetic background heterogeneity and thus, may facilitate identification and analysis of specific genetic aberrations in tumor cells. Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness. Thus, spontaneous and carcinogen (e.g., NMU and DMBA)-induced rat mammary models are valuable tools for genetic studies of breast cancer. In NMU-induced rat mammary tumors, activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process. Involvement of Ras mutations in DMBA-induced tumors is less clear. In the present study we investigated the mutation status of the three Ras genes, Hras, Kras, and Nras, in DMBA-induced rat mammary tumors. We examined codons 12, 13, and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample. No activating Ras gene mutation was found. Thus, in contrast to NMU-induced rat mammary tumor, tumorigenesis in DMBA-induced rat mammary tumors seems to be independent on activating mutations in the Ras genes. Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent, again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells. © 2008 Wiley-Liss, Inc.

  • 41.
    Sandstedt, Mikael
    et al.
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Johansson, Markus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Magnusson, Rasmus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Hultén, Lillemor Mattsson
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Göran
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Molecular and Clinical Medicine, Cardiothoracic Surgery, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lindahl, Anders
    Sahlgrenska University Hospital, Göteborg, University of Gothenburg, Sweden.
    Synnergren, Jane
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Sandstedt, Joakim
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Regional transcriptomic profiling reveals immune system enrichment in nonfailing atria as well as all chambers of the failing human heart2023Inngår i: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 325, nr 6, s. H1430-H1445Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The different chambers of the human heart demonstrate regional physiological traits and may be differentially affected during pathologic remodeling, resulting in heart failure. Few previous studies have, however, characterized the different chambers at a transcriptomic level. We therefore conducted whole-tissue RNA sequencing and gene set enrichment analysis of biopsies collected from the four chambers of adult failing (n = 8) and nonfailing (n = 11) human hearts. Atria and ventricles demonstrated distinct transcriptional patterns. Compared to nonfailing ventricles, the transcriptional pattern of nonfailing atria was enriched for a large number of gene sets associated with cardiogenesis, the immune system and bone morphogenetic protein (BMP), transforming growth factor beta (TGF beta), MAPK/JNK and Wnt signaling. Differences between failing and nonfailing hearts were also determined. The transcriptional pattern of failing atria was distinct compared to that of nonfailing atria and enriched for gene sets associated with the innate and adaptive immune system, TGF beta/SMAD signaling, and changes in endothelial, smooth muscle cell and cardiomyocyte physiology. Failing ventricles were also enriched for gene sets associated with the immune system. Based on the transcriptomic patterns, upstream regulators associated with heart failure were identified. These included many immune response factors predicted to be similarly activated for all chambers of failing hearts. In summary, the heart chambers demonstrate distinct transcriptional patterns that differ between failing and nonfailing hearts. Immune system signaling may be a hallmark of all four heart chambers in failing hearts, and could constitute a novel therapeutic target.

  • 42.
    Shamozada, Rahimakhanim
    Högskolan i Skövde, Institutionen för hälsovetenskaper.
    Discovery of disease-causing genes for rare genetic condition2024Independent thesis Basic level (degree of Bachelor), 15 poäng / 22,5 hpOppgave
    Abstract [en]

    Rare genetic diseases pose significant challenges in diagnosis and treatment due to their complexity and rarity. Next-generation sequencing (NGS) is a revolutionary genomic technology that enables rapid and cost-effective analysis of DNA or RNA sequences on a large scale, allowing for simultaneous sequencing of millions of DNA fragments in parallel. This study presents a comprehensive approach to identifying disease-causing genes and pathways associated with a rare genetic condition in a patient from consanguineous parents. Through clinical evaluation, whole exome sequencing (WES), and advanced bioinformatics analysis, female patient exhibiting mental disability, psychomotor retardation, depressive mood, and seizures since childhood was investigated. WES, followed by variant annotation using QIAGEN Clinical Insight (QCI) software, facilitated the identification of potentially pathogenic variants. Variant prioritization was based on allele frequency, conservation, pathogenicity prediction, and literature review. This integrative approach revealed candidate variants associated with potential disease-causing genes and pathways, providing insights into the molecular mechanisms underlying the rare genetic disorder. Further research is warranted to validate these findings and elucidate the pathophysiology for improved diagnosis and personalized treatment strategies.

  • 43.
    Silventoinen, K.
    et al.
    Department of Social Research, Department University of Helsinki, Finland ; Center for Twin Research, Osaka University Graduate School of Medicine, Japan.
    Dahl Aslan, Anna K.
    Kaprio, J.
    Department of Public Health, University of Helsinki, Finland ; Institute for Molecular Medicine Finland FIMM, Helsinki, Finland.
    The CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins2019Inngår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 22, s. 800-808Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

  • 44.
    Silventoinen, Karri
    et al.
    Department of Social Research, University of Helsinki, Finland ; Osaka University Graduate School of Medicine, Osaka University, Japan.
    Dahl Aslan, Anna K.
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Institute of Gerontology and Aging Research Network–Jönköping (ARN-J), School of Health and Welfare Jönköping University, Sweden.
    Kaprio, Jaakko
    Department of Public Health, University of Helsinki, Finland ; Institute for Molecular Medicine FIMM, Helsinki, Finland.
    Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts2021Inngår i: Hormones and Behavior, ISSN 0018-506X, E-ISSN 1095-6867, Vol. 136, artikkel-id 105054Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = −0.05 educational years, 95% CI −0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers. 

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  • 45.
    Sjöling, Åsa
    et al.
    Department of Cell and Molecular Biology-Genetics, Göteborg University, Sweden.
    Lindholm, Heléne
    Högskolan i Skövde, Institutionen för naturvetenskap.
    Samuelson, E.
    Department of Cell and Molecular Biology-Genetics, Göteborg University, Sweden.
    Yamasaki, Y.
    Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
    Watanabe, T. K.
    Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
    Tanigami, A.
    Otsuka GEN Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
    Levan, G.
    Department of Cell and Molecular Biology-Genetics, Göteborg University, Sweden.
    Analysis of chromosomal aberrations involving chromosome 1q31-->q53 in a DMBA-induced rat fibrosarcoma cell line: amplification and overexpression of Jak22001Inngår i: Cytogenetics and Cell Genetics, ISSN 0301-0171, E-ISSN 1421-9816, Vol. 95, nr 3-4, s. 202-209Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In a study of DMBA-induced rat fibrosarcomas we repeatedly found deletions and/or amplifications in the long arm of rat chromosome 1 (RNO1). Comparative genome hybridization showed that there was amplification involving RNO1q31-->q53 in one of the DMBA-induced rat fibrosarcoma tumors (LB31) and a cell culture derived from it. To identify the amplified genes we physically mapped rat genes implicated in cancer and analyzed them for signs of amplification. The genes were selected based on their locations in comparative maps between rat and man. The rat proto-oncogenes Ccnd1, Fgf4, and Fgf3 (HSA11q13.3), were mapped to RNO1q43 by fluorescence in situ hybridization (FISH). The Ems1 gene was mapped by radiation hybrid (RH) mapping to the same rat chromosome region and shown to be situated centromeric to Ccnd1 and Fgf4. In addition, the proto-oncogenes Hras (HSA11p15.5) and Igf1r (HSA15q25-->q26) were mapped to RNO1q43 and RNO1q32 by FISH and Omp (HSA11q13.5) was assigned to RNO1q34. PCR probes for the above genes together with PCR probes for the previously mapped rat genes Bax (RNO1q31) and Jak2 (RNO1q51-->q53) were analyzed for signs of amplification by Southern blot hybridization. Low copy number increases of the Omp and Jak2 genes were detected in the LB31 cell culture. Dual color FISH analysis of tumor cells confirmed that chromosome regions containing Omp and Jak2 were amplified and were situated in long marker chromosomes showing an aberrant banding pattern. The configuration of the signals in the marker chromosomes suggested that they had arisen by a break-fusion-bridge (BFB) mechanism.

  • 46.
    Sjöling, Åsa
    et al.
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Samuelson, Emma
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Adamovic, Tatjana
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Behboudi, Afrouz
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Röhme, Dan
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Levan, Göran
    Department of Cell and Molecular Biology–Genetics, Lundberg Laboratory, Göteborg University, Gothenburg, Sweden.
    Recurrent allelic imbalance at the rat Pten locus in DMBA-induced fibrosarcomas2002Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 36, nr 1, s. 70-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tumor-suppressor gene PTEN (phosphatase and tensin homolog) is frequently inactivated in different types of human tumors. Less is known about the involvement of the homologous gene Pten in animal model systems of cancer. By sequencing one of the introns of rat Pten, we found an informative intragenic PCR marker suitable for genetic studies. Through use of this marker, the position of Pten in the genetic linkage map was localized to the distal part of rat chromosome 1 (RNO1) by analysis of F2 progeny from an intercross between inbred strains BN and LE. Subsequently, 22 markers from this region (including the intragenic Pten marker) were used to study the occurrence of allelic imbalance in distal RNO1 in fibrosarcomas that had been induced by DMBA in F1(BN×LE) rats. The analysis revealed that allelic imbalance was common in the vicinity of Pten, and there was loss or reduction of one of the Pten alleles in more than 60% of the fibrosarcomas. DNA sequencing was preformed to investigate whether the Pten allele remaining in the tumors was inactivated by mutation. However, no mutations were detected in the genomic sequence of Pten exons 5 to 9 in any of the fibrosarcomas, and normal mRNA transcripts were expressed in all tumors. Thus, based on the targeted selection for loss of Pten observed in some of these tumors and the absence of inactivation of the remaining allele, we suggest that haploinsufficiency of Pten may be an important factor in rat DMBA-induced fibrosarcomas. © 2002 Wiley-Liss, Inc.

  • 47.
    Sjöling, Åsa
    et al.
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden ; Department of Medical Microbiology and Immunology, Göteborg, Sweden.
    Walentinsson, Anna
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Nordlander, Carola
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Karlsson, Åsa
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Behboudi, Afrouz
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Samuelson, Emma
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Levan, Göran
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Röhme, Dan
    Department of Cell and Molecular Biology-Genetics, Göteborg, Sweden.
    Assessment of allele dosage at polymorphic microsatellite loci displaying allelic imbalance in tumors by means of quantitative competitive-polymerase chain reaction2005Inngår i: Cancer Genetics and Cytogenetics, ISSN 0165-4608, E-ISSN 1873-4456, Vol. 157, nr 2, s. 97-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Analysis of allelic imbalance at polymorphic marker loci is usually employed to identify chromosomal regions affected by recurrent aberrations in tumor genomes. Such regions are likely to harbor genes involved in the onset and/or progression of cancer. Although often used to identify regions of loss of heterozygosity caused by deletions/rearrangements near tumor suppressor gene loci, allelic imbalance can also reflect regional amplification, indicating the presence of oncogenes. It is difficult to tell these two situations apart after ordinary polymerase chain reaction (PCR), but here we describe a method that distinguishes allelic loss from allelic gain. The level of allelic imbalance was determined by quantitative PCR (QPCR) in the presence of an internal control DNA that displayed a third allele at the locus studied. To validate the efficiency of allele quantitation, we analyzed an amplified region in a set of rat fibrosarcomas. In four tumor samples with amplification of the Met oncogene, we could show with QPCR that there was amplification of one of the alleles at a microsatellite marker located close to Met. QPCR may be useful for cancer studies because experiments may be predesigned for using either suitable microsatellite markers or the abundant and polymorphic poly-A tails of rodent identifier sequences.

  • 48.
    Synnergren, Jane
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Vukusic, Kristina
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dönnes, Pierre
    SciCross AB, Sweden.
    Jonsson, Marianne
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Lindahl, Anders
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Dellgren, Göran
    Department of Cardiothoracic Surgery, Sahlgrenska University Hospital Gothenburg, Sweden and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Jeppsson, Anders
    Department of Cardiothoracic Surgery, Sahlgrenska University Hospital Gothenburg, Sweden and Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Asp, Julia
    Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden / Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Transcriptional sex and regional differences in paired human atrial and ventricular cardiac biopsies collected in vivo2020Inngår i: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 52, nr 2, s. 110-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transcriptional studies of the human heart provide insight into physiological and pathophysiological mechanisms, essential for understanding the fundamental mechanisms of normal cardiac function and how they are altered by disease. To improve the understanding of why men and women may respond differently to the same therapeutic treatment it is crucial to learn more about sex-specific transcriptional differences. In this study the transcriptome of right atrium and left ventricle was compared across sex and regional location. Paired biopsies from five male and five female patients undergoing aortic valve replacement or coronary artery bypass grafting were included. Gene expression analysis identified 620 differentially expressed transcripts in atrial and ventricular tissue in men and 471 differentially expressed transcripts in women. In total 339 of these transcripts overlapped across sex but notably, 281 were unique in the male tissue and 162 in the female tissue, displaying marked sex differences in the transcriptional machinery. The transcriptional activity was significantly higher in atrias than in ventricles as 70% of the differentially expressed genes were upregulated in the atrial tissue. Furthermore, pathway- and functional annotation analyses performed on the differentially expressed genes showed enrichment for a more heterogeneous composition of biological processes in atrial compared with the ventricular tissue, and a dominance of differentially expressed genes associated with infection disease was observed. The results reported here provide increased insights about transcriptional differences between the cardiac atrium and ventricle but also reveal transcriptional differences in the human heart that can be attributed to sex.

  • 49.
    Tilevik, Diana
    et al.
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Pernestig, Anna-Karin
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Fagerlind, Magnus
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Tilevik, Andreas
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi.
    Ljungström, Lars
    Department of Infectious Diseases, Skaraborg Hospital, Skövde, Sweden.
    Johansson, Markus
    1928 Diagnostics, Arvid Hedvalls backe, Gothenburg, Sweden.
    Enroth, Helena
    Högskolan i Skövde, Institutionen för biovetenskap. Högskolan i Skövde, Forskningsmiljön Systembiologi. Molecular Microbiology, Laboratory Medicine, Unilabs AB, Skaraborg Hospital, Skövde.
    Sequence-based genotyping of extra-intestinal pathogenic Escherichia coli isolates from patients with suspected community-onset sepsis, Sweden2022Inngår i: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 173, nr Part A, artikkel-id 105836Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extra-intestinal pathogenic Escherichia coli (ExPEC) strains are responsible for a large number of human infections globally. The management of infections caused by ExPEC has been complicated by the emergence of antimicrobial resistance, most importantly the increasing recognition of isolates producing extended-spectrum β-lactamases (ESBL). Herein, we used whole-genome sequencing (WGS) on ExPEC isolates for a comprehensive genotypic characterization. Twenty-one ExPEC isolates, nine with and 12 without ESBL-production, from 16 patients with suspected sepsis were sequenced on an Illumina MiSeq platform. Analysis of WGS data was performed with widely used bioinformatics software and tools for genotypic characterization of the isolates. A higher number of plasmids, virulence and resistance genes were observed in the ESBL-producing isolates than the non-ESBL-producing, although not statistically significant due to the low sample size. All nine ESBL-producing ExPEC isolates presented with at least one bla gene, as did three of the 12 without ESBL-production. Multi-locus sequence typing analysis revealed a diversity of sequence types whereas phylogroup A prevailed among isolates both with and without ESBL-production. In conclusion, this limited study shows that analysis of WGS data can be used for genotypic characterization of ExPEC isolates to obtain in-depth information of clinical relevance.

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  • 50.
    Tomić, Tajana Tešan
    et al.
    Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden.
    Olausson, Josefin
    Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden.
    Rehammar, Anna
    Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Deland, Lily
    Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden.
    Muth, Andreas
    Department of Surgery, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden / Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Section of endocrine and sarcoma surgery, Gothenburg, Sweden.
    Ejeskär, Katarina
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering.
    Nilsson, Staffan
    Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden / Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Kristiansson, Erik
    Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Wassén, Ola Nilsson
    Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Abel, Frida
    Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Sweden.
    MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression2020Inngår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 16, nr 6, artikkel-id e1008803Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.

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