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  • 1.
    Alvarez, Laura
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid—Consejo Superior de Investigaciones Científicas, Madrid, Spain.
    Quintáns, Nieves G.
    Blesa, Alba
    Baquedano, Ignacio
    Mencía, Mario
    Bricio, Carlos
    Berenguer, José
    Hierarchical control of nitrite respiration by transcription factors encoded within mobile gene clusters of Thermus thermophilus2017In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, no 12, article id 361Article in journal (Refereed)
    Abstract [en]

    Denitrification in Thermus thermophilus is encoded by the nitrate respiration conjugative element (NCE) and nitrite and nitric oxide respiration (nic) gene clusters. A tight coordination of each cluster's expression is required to maximize anaerobic growth, and to avoid toxicity by intermediates, especially nitric oxides (NO). Here, we study the control of the nitrite reductases (Nir) and NO reductases (Nor) upon horizontal acquisition of the NCE and nic clusters by a formerly aerobic host. Expression of the nic promoters PnirS, PnirJ, and PnorC, depends on the oxygen sensor DnrS and on the DnrT protein, both NCE-encoded. NsrR, a nic-encoded transcription factor with an iron-sulfur cluster, is also involved in Nir and Nor control. Deletion of nsrR decreased PnorC and PnirJ transcription, and activated PnirS under denitrification conditions, exhibiting a dual regulatory role never described before for members of the NsrR family. On the basis of these results, a regulatory hierarchy is proposed, in which under anoxia, there is a pre-activation of the nic promoters by DnrS and DnrT, and then NsrR leads to Nor induction and Nir repression, likely as a second stage of regulation that would require NO detection, thus avoiding accumulation of toxic levels of NO. The whole system appears to work in remarkable coordination to function only when the relevant nitrogen species are present inside the cell.

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  • 2. Asim, Muhammad Nabeel
    et al.
    Malik, Muhammad Imran
    Zehe, Christoph
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Corporate Research, Sartorius Stedim Data Analytics, Umeå, Sweden.
    Dengel, Andreas
    Ahmed, Sheraz
    MirLocPredictor: A ConvNet-Based Multi-Label MicroRNA Subcellular Localization Predictor by Incorporating k-Mer Positional Information2020In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, no 12, article id 1475Article in journal (Refereed)
    Abstract [en]

    MicroRNAs (miRNA) are small noncoding RNA sequences consisting of about 22 nucleotides that are involved in the regulation of almost 60% of mammalian genes. Presently, there are very limited approaches for the visualization of miRNA locations present inside cells to support the elucidation of pathways and mechanisms behind miRNA function, transport, and biogenesis. MIRLocator, a state-of-the-art tool for the prediction of subcellular localization of miRNAs makes use of a sequence-to-sequence model along with pretrained k-mer embeddings. Existing pretrained k-mer embedding generation methodologies focus on the extraction of semantics of k-mers. However, in RNA sequences, positional information of nucleotides is more important because distinct positions of the four nucleotides define the function of an RNA molecule. Considering the importance of the nucleotide position, we propose a novel approach (kmerPR2vec) which is a fusion of positional information of k-mers with randomly initialized neural k-mer embeddings. In contrast to existing k-mer-based representation, the proposed kmerPR2vec representation is much more rich in terms of semantic information and has more discriminative power. Using novel kmerPR2vec representation, we further present an end-to-end system (MirLocPredictor) which couples the discriminative power of kmerPR2vec with Convolutional Neural Networks (CNNs) for miRNA subcellular location prediction. The effectiveness of the proposed kmerPR2vec approach is evaluated with deep learning-based topologies (i.e., Convolutional Neural Networks (CNN) and Recurrent Neural Network (RNN)) and by using 9 different evaluation measures. Analysis of the results reveals that MirLocPredictor outperform state-of-the-art methods with a significant margin of 18% and 19% in terms of precision and recall.

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  • 3.
    Gnanasundram, Sivakumar Vadivel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bonczek, Ondrej
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno, Czech Republic.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chen, Sa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno, Czech Republic; Inserm UMRS1131, Institut de Genetique Moleculaire, Universite Paris 7, Hopital St Louis, Paris, France; International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland.
    P53 mRNA metabolism links with the DNA damage response2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 9, article id 1446Article, review/survey (Refereed)
    Abstract [en]

    Human cells are subjected to continuous challenges by different genotoxic stress attacks. DNA damage leads to erroneous mutations, which can alter the function of oncogenes or tumor suppressors, resulting in cancer development. To circumvent this, cells activate the DNA damage response (DDR), which mainly involves cell cycle regulation and DNA repair processes. The tumor suppressor p53 plays a pivotal role in the DDR by halting the cell cycle and facilitating the DNA repair processes. Various pathways and factors participating in the detection and repair of DNA have been described, including scores of RNA-binding proteins (RBPs) and RNAs. It has become increasingly clear that p53’s role is multitasking, and p53 mRNA regulation plays a prominent part in the DDR. This review is aimed at covering the p53 RNA metabolism linked to the DDR and highlights the recent findings.

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  • 4.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Lixiao
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Regional Centre for Applied Molecular Oncology (RECAMO), Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institute of Molecular Genetics, University Paris 7, St. Louis Hospital, Paris, France.
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Transfer-RNA-Derived Fragments Are Potential Prognostic Factors in Patients with Squamous Cell Carcinoma of the Head and Neck2020In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, no 11, article id 1344Article in journal (Refereed)
    Abstract [en]

    Transfer-RNA-derived fragments (tRFs) are a class of small non-coding RNAs that are functionally different from their parental transfer RNAs (tRNAs). tRFs can regulate gene expression by several mechanisms, and are involved in a variety of pathological processes. Here, we aimed at understanding the composition and abundance of tRFs in squamous cell carcinoma of the head and neck (SCCHN), and evaluated the potential of tRFs as prognostic markers in this cancer type. We obtained tRF expression data from The Cancer Genome Atlas (TCGA) HNSC cohort (523 patients) using MINTbase v2.0, and correlated to available TCGA clinical data. RNA-binding proteins were predicted according to the calculated Position Weight Matrix (PWM) score from the RNA-Binding Protein DataBase (RBPDB). A total of 10,158 tRFs were retrieved and a high diversity in expression levels was seen. Fifteen tRFs were found to be significantly associated with overall survival (Kaplan-Meier survival analysis, log rank test p-value < 0.01). The top prognostic marker, tRF-20-S998LO9D (p < 0.001), was further measured in tumor and tumor-free samples from 16 patients with squamous cell carcinoma of the oral tongue and 12 healthy controls, and was significantly upregulated in tumor compared to matched tumor-free tongue (p < 0.001). Results suggest that tRFs are useful prognostic markers in SCCHN

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  • 5.
    Gélinas-Marion, Ariane
    et al.
    School of Natural Sciences, University of Tasmania, Sandy Bay, Hobart, Australia.
    Eléouët, Morgane P.
    Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Plas Gogerddan, Aberystwyth, United Kingdom.
    Cook, Sam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vander Schoor, Jacqueline K.
    School of Natural Sciences, University of Tasmania, Sandy Bay, Hobart, Australia.
    Abel, Steven A. G.
    School of Natural Sciences, University of Tasmania, Sandy Bay, Hobart, Australia.
    Nichols, David S.
    Central Science Laboratory, University of Tasmania, Sandy Bay, Hobart, Australia.
    Smith, Jason A.
    School of Natural Sciences, University of Tasmania, Sandy Bay, Hobart, Australia.
    Hofer, Julie M. I.
    Institute of Biological, Environmental and Rural Sciences, Aberystwyth University, Plas Gogerddan, Aberystwyth, United Kingdom.
    Ross, John J.
    School of Natural Sciences, University of Tasmania, Sandy Bay, Hobart, Australia.
    Plant development in the garden pea as revealed by mutations in the Crd/PsYUC1 gene2023In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 14, no 12, article id 2115Article in journal (Refereed)
    Abstract [en]

    In common with other plant species, the garden pea (Pisum sativum) produces the auxin indole-3-acetic acid (IAA) from tryptophan via a single intermediate, indole-3-pyruvic acid (IPyA). IPyA is converted to IAA by PsYUC1, also known as Crispoid (Crd). Here, we extend our understanding of the developmental processes affected by the Crd gene by examining the phenotypic effects of crd gene mutations on leaves, flowers, and roots. We show that in pea, Crd/PsYUC1 is important for the initiation and identity of leaflets and tendrils, stamens, and lateral roots. We also report on aspects of auxin deactivation in pea.

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  • 6.
    Isaksson, Hanna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Integrated Science Lab, Umeå University, Umeå, Sweden.
    Conlin, Peter L.
    Georgia Institute of Technology, School of Biological Sciences, GA, Atlanta, United States.
    Kerr, Ben
    BEACON Center for the Study of Evolution in Action, Department of Biology, University of Washington, WA, Seattle, United States.
    Ratcliff, William C.
    Georgia Institute of Technology, School of Biological Sciences, GA, Atlanta, United States.
    Libby, Eric
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Integrated Science lab, Umeå University, Umeå, Sweden; Santa Fe Institute, NM, Santa Fe, United States.
    The consequences of budding versus binary fission on adaptation and aging in primitive multicellularity2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 5, article id 661Article in journal (Refereed)
    Abstract [en]

    Early multicellular organisms must gain adaptations to outcompete their unicellular ancestors, as well as other multicellular lineages. The tempo and mode of multicellular adaptation is influenced by many factors including the traits of individual cells. We consider how a fundamental aspect of cells, whether they reproduce via binary fission or budding, can affect the rate of adaptation in primitive multicellularity. We use mathematical models to study the spread of beneficial, growth rate mutations in unicellular populations and populations of multicellular filaments reproducing via binary fission or budding. Comparing populations once they reach carrying capacity, we find that the spread of mutations in multicellular budding populations is qualitatively distinct from the other populations and in general slower. Since budding and binary fission distribute age-accumulated damage differently, we consider the effects of cellular senescence. When growth rate decreases with cell age, we find that beneficial mutations can spread significantly faster in a multicellular budding population than its corresponding unicellular population or a population reproducing via binary fission. Our results demonstrate that basic aspects of the cell cycle can give rise to different rates of adaptation in multicellular organisms.

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  • 7.
    Koch, Elise
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Lundquist, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Kauppi, Karolina
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Solna, Sweden.
    Polygenic Risk for Schizophrenia Has Sex-Specific Effects on Brain Activity during Memory Processing in Healthy Individuals2022In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 13, no 3, article id 412Article in journal (Refereed)
    Abstract [en]

    Genetic risk for schizophrenia has a negative impact on memory and other cognitive abilities in unaffected individuals, and it was recently shown that this effect is specific to males. Using functional MRI, we investigated the effect of a polygenic risk score (PRS) for schizophrenia on brain activation during working memory and episodic memory in 351 unaffected participants (167 males and 184 females, 25–95 years), and specifically tested if any effect of PRS on brain activation is sex-specific. Schizophrenia PRS was significantly associated with decreased brain activation in the left dorsolateral prefrontal cortex (DLPFC) during working-memory manipulation and in the bilateral superior parietal lobule (SPL) during episodic-memory encoding and retrieval. A significant interaction effect between sex and PRS was seen in the bilateral SPL during episodic-memory encoding and retrieval, and sex-stratified analyses showed that the effect of PRS on SPL activation was male-specific. These results confirm previous findings of DLPFC inefficiency in schizophrenia, and highlight the SPL as another important genetic intermediate phenotype of the disease. The observed sex differences suggest that the previously shown male-specific effect of schizophrenia PRS on cognition translates into an additional corresponding effect on brain functioning.

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  • 8.
    Mihai, Ionut Sebastian
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Maršalkaite, Gabija
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meta-analysis of gene popularity: Less than half of gene citations stem from gene regulatory networks2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 2, p. 1-13, article id 319Article in journal (Refereed)
    Abstract [en]

    The reasons for selecting a gene for further study might vary from historical momentum to funding availability, thus leading to unequal attention distribution among all genes. However, certain biological features tend to be overlooked in evaluating a gene’s popularity. Here we present a meta-analysis of the reasons why different genes have been studied and to what extent, with a focus on the gene-specific biological features. From unbiased datasets we can define biological properties of genes that reasonably may affect their perceived importance. We make use of both linear and nonlinear computational approaches for estimating gene popularity to then compare their relative importance. We find that roughly 25% of the studies are the result of a historical positive feedback, which we may think of as social reinforcement. Of the remaining features, gene family membership is the most indicative followed by disease relevance and finally regulatory pathway association. Disease relevance has been an important driver until the 1990s, after which the focus shifted to exploring every single gene. We also present a resource that allows one to study the impact of reinforcement, which may guide our research toward genes that have not yet received proportional attention.

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  • 9.
    Osmanovic, Alma
    et al.
    Department of Human Genetics, Hannover Medical School, Hannover, Germany; Department of Neurology, Hannover Medical School, Hannover, Germany; Essen Center for Rare Diseases (EZSE), University Hospital Essen, Essen, Germany.
    Gogol, Isabel
    Department of Human Genetics, Hannover Medical School, Hannover, Germany; Department of Neurology, Hannover Medical School, Hannover, Germany.
    Martens, Helge
    Department of Human Genetics, Hannover Medical School, Hannover, Germany.
    Widjaja, Maylin
    Department of Human Genetics, Hannover Medical School, Hannover, Germany; Department of Neurology, Hannover Medical School, Hannover, Germany.
    Müller, Kathrin
    Department of Neurology, University of Ulm, Ulm, Germany.
    Schreiber-Katz, Olivia
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Feuerhake, Friedrich
    Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
    Langhans, Claus-Dieter
    GCMS Laboratory, Dietmar Hopp Metabolic Center, University Children’s Hospital, Heidelberg, Germany.
    Schmidt, Gunnar
    Department of Human Genetics, Hannover Medical School, Hannover, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Ludolph, Albert C.
    Department of Neurology, University of Ulm, Ulm, Germany.
    Weishaupt, Jochen H.
    Department of Neurology, University of Ulm, Ulm, Germany; Division for Neurodegenerative Diseases, Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
    Brand, Frank
    Department of Human Genetics, Hannover Medical School, Hannover, Germany.
    Petri, Susanne
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Weber, Ruthild G.
    Department of Human Genetics, Hannover Medical School, Hannover, Germany.
    Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients2022In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 13, no 1, article id 84Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.

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  • 10. Shahid, Muhammad
    et al.
    Imran, Qari Muhammad
    Hussain, Adil
    Khan, Murtaza
    Lee, Sang Uk
    Mun, Bong Gyu
    Yun, Byung-Wook
    Comprehensive Analyses of Nitric Oxide-Induced Plant Stem Cell-Related Genes in Arabidopsis thaliana2019In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 10, no 3, article id 190Article in journal (Refereed)
    Abstract [en]

    Plant stem cells are pluripotent cells that have diverse applications in regenerative biology and medicine. However, their roles in plant growth and disease resistance are often overlooked. Using high-throughput RNA-seq data, we identified approximately 20 stem cell-related differentially expressed genes (DEGs) that were responsive to the nitric oxide (NO) donor S-nitrosocysteine (CySNO) after six hours of infiltration. Among these DEGs, the highest number of positive correlations (R ≥ 0.8) was observed for CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) 12. Gene ontology (GO) terms for molecular function showed DEGs associated with signal transduction and receptor activity. A promoter study of these DEGs showed the presence of cis-acting elements that are involved in growth as well as the regulation of abiotic and biotic stress. Phylogenetic analysis of the Arabidopsis stem cell-related genes and their common orthologs in rice, soybean, poplar, and tomato suggested that most soybean stem cell-related genes were grouped with the Arabidopsis CLE type of stem cell genes, while the rice stem cell-related genes were grouped with the Arabidopsis receptor-like proteins. The functional genomic-based characterization of the role of stem cell DEGs showed that under control conditions, the clv1 mutant showed a similar phenotype to that of the wild-type (WT) plants; however, under CySNO-mediated nitrosative stress, clv1 showed increased shoot and root length compared to WT. Furthermore, the inoculation of clv1 with virulent Pst DC3000 showed a resistant phenotype with fewer pathogens growing at early time points. The qRT-PCR validation and correlation with the RNA-seq data showed a Pearson correlation coefficient of >0.8, indicating the significantly high reliability of the RNA-seq analysis.

  • 11.
    Sjögren, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Herantis Pharma Plc, Bertel Jungin Aukio 1, Espoo, Finland.
    Huttunen, Henri J.
    Herantis Pharma Plc, Bertel Jungin Aukio 1, Espoo, Finland.
    Svenningsson, Per
    Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
    Widner, Håkan
    Department of Neurology, Lund University Hospital, Lund, Sweden.
    Genetically targeted clinical trials in parkinson's disease: Learning from the successes made in oncology2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 10, article id 1529Article, review/survey (Refereed)
    Abstract [en]

    Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson's disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.

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  • 12.
    Westin, Ida Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Viberg, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lower fractions of TCF4 transcripts spanning over the CTG18.1 trinucleotide repeat in human corneal endothelium2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 12, article id 2006Article in journal (Refereed)
    Abstract [en]

    Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral disease of the cornea caused by gradual loss of corneal endothelial cells. Late-onset FECD is strongly associated with the CTG18.1 trinucleotide repeat expansion in the Transcription Factor 4 gene (TCF4), which forms RNA nuclear foci in corneal endothelial cells. To date, 46 RefSeq transcripts of TCF4 are annotated by the National Center of Biotechnology information (NCBI), however the effect of the CTG18.1 expansion on expression of alternative TCF4 transcripts is not completely understood. To investigate this, we used droplet digital PCR for quantification of TCF4 transcripts spanning over the CTG18.1 and transcripts with transcription start sites immediately downstream of the CTG18.1. TCF4 expression was analysed in corneal endothelium and in whole blood of FECD patients with and without CTG18.1 expansion, in non-FECD controls without CTG18.1 expansion, and in five additional control tissues. Subtle changes in transcription levels in groups of TCF4 transcripts were detected. In corneal endothelium, we found a lower fraction of transcripts spanning over the CTG18.1 tract compared to all other tissues investigated.

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  • 13. Öfverholm, Anna
    et al.
    Einbeigi, Zakaria
    Wigermo, Antonia
    Umeå University, Faculty of Medicine.
    Holmberg, Erik
    Karsson, Per
    Increased Overall Mortality Even after Risk Reducing Surgery for BRCA-Positive Women in Western Sweden2019In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 10, no 12, article id 1046Article in journal (Refereed)
    Abstract [en]

    Women with BRCA variants have a high lifetime risk of developing breast and ovarian cancer. The aim of this study was to investigate the standard incidence ratios (SIR) for breast and ovarian cancer and standard mortality ratios (SMR) in a population-based cohort of women in Western Sweden, under surveillance and after risk reducing surgery. Women who tested positive for a BRCA variant between 1995–2016 (n = 489) were prospectively registered and followed up for cancer incidence, risk reducing surgery and mortality. The Swedish Cancer Register was used to compare breast and ovarian cancer incidence and mortality with and without risk reducing surgery for women with BRCA variants in comparison to women in the general population. SIR for breast cancer under surveillance until risk-reducing mastectomy (RRM) was 14.0 (95% CI 9.42–20.7) and decreased to 1.93 (95% CI 0.48–7.7) after RRM. The SIR for ovarian cancer was 124.6 (95% CI 59.4–261.3) under surveillance until risk reducing salpingo-oophorectomy (RRSO) and decreased to 13.5 (95% CI 4.34–41.8) after RRSO. The SMR under surveillance before any risk reducing surgery was 5.56 (95% 2.09–14.8) and after both RRM and RRSO 4.32 (95% CI 1.62–11.5). Women with cancer diagnoses from the pathology report after risk reducing surgery were excluded from the analyses. Risk reducing surgery reduced the incidence of breast and ovarian cancer in women with BRCA variants. However, overall mortality was significantly increased in comparison to the women in the general population and remained elevated even after risk reducing surgery. These findings warrant further research regarding additional measures for these women.

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