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  • 1.
    Andersson, Christian
    et al.
    University of Skövde, School of Life Sciences.
    Pesonen, John
    University of Skövde, School of Life Sciences.
    Anhörigas upplevelser av omvårdnaden av närstående i särskilt boende i Västra Götaland år 20102010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Introduction: When a senior person has a large need for special care there is an option to relocate to a nursing home. The seniors every day varies there for it is of outmost importance the nursing care staff can support the senior that he maybe adapt to the new situation. Purpose: The purpose with this study is to enlighten how relatives experience their close ones in special nursing home receive good care treatment. Method: A quality approach with empirical elements is used where relatives experiences of care, being part of and recievment was collected with the help of interviews. Results: Three categories Care, Involvment and Recievment with nine sub categories. An important part in care is to create good contact between relatives and nursing care staff to evolve good ways for communication. It was revealed how important it is as a health care patient to feel they’re being looked upon for who they are and they be part of treatment measures and decisions made by nursing care staff. Discussion: The results can contribute to an increased understanding to how relatives experience care is being conducted in a special accommodation. When relatives are made more involved in care, may lead to a better care for care patient in a nursing home. Conclusion: The results which have been concluded could be used in educational purposes when the care of senior people demands that nursing care staff continuously renews their knowledges. This could be of use for the nurse, the relatives and the seniors living in a nursing home.

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  • 2.
    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 A2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 6, article id e0218258Article in journal (Refereed)
    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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  • 3.
    Chaudhari, Aditi
    et al.
    University of Gothenburg.
    Ejeskär, Katarina
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    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 activity2017In: F1000 Research, E-ISSN 2046-1402, Vol. 6, article id 1600Article in journal (Refereed)
    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.

  • 4.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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 activity2015In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, no 19, p. 3258-3273Article in journal (Refereed)
    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.

  • 5.
    Ejeskär, Katarina
    et al.
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden.
    Vickes, Oscar
    University of Skövde, The Systems Biology Research Centre.
    Kuchipudi, Arunakar
    University of Skövde, The Systems Biology Research Centre.
    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 vivo2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0127497Article in journal (Refereed)
    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.

  • 6.
    Erlingsson, Cecilia
    University of Skövde, School of Health and Education.
    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 credits / 30 HE creditsStudent thesis
    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.

  • 7.
    Gustafson, Deborah R.
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Department of Neurology, State University of New York Downstate Medical Center, New York, USA.
    Adipose Tissue Complexities in Dyslipidemias2019In: Dyslipidemia / [ed] Samy I. McFarlane, London: IntechOpen , 2019, p. 1-22Chapter in book (Refereed)
    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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  • 8.
    Horning, Aaron M.
    et al.
    University of Texas Health Science Center, San Antonio, USA.
    Awe, Julius Adebayo
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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 Recurrence2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1790-1801Article in journal (Refereed)
    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.

  • 9.
    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
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. 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 spectrum2016In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, no 1, p. 1-5, article id 109Article in journal (Refereed)
    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.

  • 10.
    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
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    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 Hypoplasia2019In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 6, p. 1294-1301Article in journal (Refereed)
    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.

  • 11.
    Keane, Simon
    et al.
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Améen, Sophie
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Lindlöf, Angelica
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival2020In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 18, no 1, article id 65Article in journal (Refereed)
    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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  • 12.
    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
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. 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 bodies2018In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, no 6, p. 841-847Article in journal (Refereed)
    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.

  • 13.
    Pfister, Anna
    Sahlgrenska Academy at University of Gothenburg.
    Outcomes of Myosin 1C Gene Expression Depletion on Cancer-related Pathways, in Vitro and in Clinical Samples2016Licentiate thesis, comprehensive summary (Other academic)
    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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  • 14.
    Synnergren, Jane
    et al.
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment.
    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 vivo2020In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 52, no 2, p. 110-120Article in journal (Refereed)
    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.

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