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  • 1.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long non-coding RNA and Polycomb: an intricate partnership in cancer biology2018In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 23, p. 2106-2132Article in journal (Refereed)
    Abstract [en]

    High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including X-inactive specific transcript (XIST), antisense non-coding RNA in the INK4 locus (ANRIL), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and HOX transcript antisense RNA (HOTAIR).

  • 2.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Walsh, Martin J.
    The N6-Methyladenosine RNA modification in pluripotency and reprogramming2017In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to manipulate the existing transcriptome, allowing rapid responses to the changing environment further enriching the regulatory capacity of RNA. N-6-Methyladenosine(m(6)A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. M(6)A modification affects a broad spectrum of cellular functions, including maintenance of the pluripotency of embryonic stem cells (ESCs) and the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the most recent findings on m(6)A modification with special focus on the different studies describing how m(6)A is implicated in ESC self-renewal, cell fate specification and iPSC generation.

  • 3. Alberione, Maria Pia
    et al.
    Moeller, Rebecca
    Kirui, Jared
    Ginkel, Corinne
    Doepke, Mandy
    Stroeh, Luisa J.
    Machtens, Jan-Philipp
    Pietschmann, Thomas
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Single-nucleotide variants in human CD81 influence hepatitis C virus infection of hepatoma cells2020In: Medical Microbiology and Immmunology, ISSN 0300-8584, E-ISSN 1432-1831Article in journal (Refereed)
    Abstract [en]

    An estimated number of 71 million people are living with chronic hepatitis C virus (HCV) infection worldwide and 400,000 annual deaths are related to the infection. HCV entry into the hepatocytes is complex and involves several host factors. The tetraspanin human CD81 (hCD81) is one of the four essential entry factors and is composed of one large extracellular loop, one small extracellular loop, four transmembrane domains, one intracellular loop and two intracellular tails. The large extracellular loop interacts with the E2 glycoprotein of HCV. Regions outside the large extracellular loop (backbone) of hCD81 have a critical role in post-binding entry steps and determine susceptibility of hepatocytes to HCV. Here, we investigated the effect of five non-synonymous single-nucleotide variants in the backbone of hCD81 on HCV susceptibility. We generated cell lines that stably express the hCD81 variants and infected the cells using HCV pseudoparticles and cell culture-derived HCV. Our results show that all the tested hCD81 variants support HCV pseudoparticle entry with similar efficiency as wild-type hCD81. In contrast, variants A54V, V211M and M220I are less supportive to cell culture-derived HCV infection. This altered susceptibility is HCV genotype dependent and specifically affected the cell entry step. Our findings identify three hCD81 genetic variants that are impaired in their function as HCV host factors for specific viral genotypes. This study provides additional evidence that genetic host variation contributes to inter-individual differences in HCV infection and outcome.

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  • 4. Aspberg, Johan
    et al.
    Heijl, Anders
    Jóhannesson, Gauti
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Linden, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Andersson-Geimer, Sabina
    Bengtsson, Boel
    Intraocular Pressure Lowering Effect of Latanoprost as First-line Treatment for Glaucoma2018In: Journal of glaucoma, ISSN 1057-0829, E-ISSN 1536-481X, Vol. 27, no 11, p. 976-980Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study was to assess the intraocular pressure (IOP) - reducing effect of latanoprost in treatment-naïve patients with newly detected open-angle glaucoma with no restriction of the level of untreated IOP.

    METHODS: Eighty-six patients (105 eyes) with a diagnosis of open-angle glaucoma received IOP-lowering therapy with latanoprost. The IOP reduction 1 and 3 months after initiation of treatment was recorded.

    RESULTS: Mean untreated IOP for all eyes was 26.2 mm Hg (ranging from 10 to 51 mm Hg). The mean pressure reduction was 7.9 mm Hg (28%), with equivalent average levels at 1 and 3 months. The reduction in IOP ranged from -2.3 to 25.3 mm Hg after 1 month, and from -1.3 to 33.3 mm Hg after 3 months. The pressure-lowering effect was considerably more pronounced in eyes with higher untreated IOP; the reduction increased by 0.55 mm Hg per mm Hg higher untreated IOP. Four eyes, with untreated IOP within statistically normal limits, had no or negative IOP-reduction. A regression model predicted that IOP reduction ended at untreated IOP≤16 mm Hg. Multiple regression analysis showed that an additional IOP-lowering effect of 1.28 mm Hg was achieved in eyes with pseudoexfoliation glaucoma.

    CONCLUSIONS: To the best of our knowledge, this paper is the first to report the IOP-reducing effect of latanoprost treatment at all untreated IOP levels in newly detected glaucoma patients. The effect was proportional to the untreated IOP at all levels above 16 mm Hg and better at higher untreated IOP levels, also in relative terms. Our results further confirm the indication of latanoprost as a first-line therapy for glaucoma.

  • 5.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulating the dynamic interactions between herpes simplex viruses and cell -surface glycosaminoglycans2019In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 48, p. S41-S41Article in journal (Other academic)
    Abstract [en]

    Virus entry is a complex dynamic multistep process requiring a series of fine-tuned events mediating virus diffusion through the glycocalyx, its attachment to the cell membrane and lateral diffusion to the point of entry. A number of enveloped viruses, including herpes simplex viruses (HSV) attach to susceptible host cells via interaction between their glycoproteins and cell-surface glycosaminoglycans (GAGs). In our work, we study the molecular and physical mechanisms modulating HSV binding, diffusion and release from cell-surface glycosaminoglycans. Using single virus tracking in combination with either in vitro minimal models of the cell surface or live cell microscopy, we gain insights into the modulatory function of protein glycosylation (the presence of mucin-like regions on viral glycoproteins) and interrogate the role of GAG sulfation in the process. We show that mucin-like regions found on the glycoproteins of HSV-1 and HSV-2 play an important role in modulating the interaction, an observation further supported by cell experiments. We further show that the diffusion of virions on the surface depends on the type of GAGs and their degree of sulfation. Taken together, our research contributes to a better understanding of the mechanisms underlying the interaction between a virus and the surface of its host. Such insights will without doubt facilitate the design of more efficient antiviral drugs or vaccines.

  • 6. Becker, Nina
    et al.
    Kalpouzos, Grégoria
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Laukka, Erika J.
    Brehmer, Yvonne
    Structure-function associations of successful associative encoding2019In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 201, article id 116020Article in journal (Refereed)
    Abstract [en]

    Functional magnetic resonance imaging (MRI) studies have demonstrated a critical role of hippocampus and inferior frontal gyrus (IFG) in associative memory. Similarly, evidence from structural MRI studies suggests a relationship between gray-matter volume in these regions and associative memory. However, how brain volume and activity relate to each other during associative-memory formation remains unclear. Here, we used joint independent component analysis (jICA) to examine how gray-matter volume and brain activity would be associated during associative encoding, especially in medial-temporal lobe (MTL) and IFG. T1-weighted images were collected from 27 young adults, and functional MRI was employed during intentional encoding of object pairs. A subsequent recognition task tested participants' memory performance. Unimodal analyses using voxel-based morphometry revealed that participants with better associative memory showed larger gray-matter volume in left anterior hippocampus. Results from the jICA revealed one component that comprised a covariance pattern between gray-matter volume in anterior and posterior MTL and encoding-related activity in IFG. Our findings suggest that gray matter within the MTL modulates distally distinct parts of the associative encoding circuit, and extend previous studies that demonstrated MTL-IFG functional connectivity during associative memory tasks.

  • 7.
    Bodén, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Shivappa, Nitin
    Hébert, James R
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0214551Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

    METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

    RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

    CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

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  • 8.
    Boström, Petrus
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kverneng Hultberg, Daniel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Haapamäki, Markku
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Oncological Impact of High Vascular Tie After Surgery for Rectal Cancer: A Nationwide Cohort Study2019In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140Article in journal (Refereed)
    Abstract [en]

    Objective: The purpose of this study was to investigate the impact of tie level on oncological outcomes in rectal cancer surgery.

    Summary background data: Theoretically, a high tie of the inferior mesenteric artery could facilitate removal of apical node metastases and improve tumor staging accuracy. However, no appropriately sized randomized controlled trial exists and results from observational studies are not consistent.

    Methods: All stage I–III rectal cancer patients who underwent abdominal surgery with curative intention in 2007 to 2014 were identified and followed, using the Swedish Colorectal Cancer Registry. Primary outcome was cancer-specific survival, whereas overall and relative survival, locoregional and distant recurrence, and lymph node harvest were secondary outcomes, with high tie as exposure. We used propensity score matching to emulate a randomized controlled trial, and then performed Cox regression analyses to estimate hazard ratios (HRs) with confidence intervals (CIs).

    Results: Some 8287 patients remained for analysis, of which 37% had high tie surgery. After propensity score matching, the 5-year cancer-specific survival rate was overall 86% and we found no association between the level of tie and cancer-specific (HR 0.92, 95% CI 0.79–1.07) or overall (HR 0.98, 95% CI 0.89–1.08) survival, nor to locoregional (HR 0.85, 95% CI 0.59–1.23) or distant (HR 1.01, 95% CI 0.88–1.15) recurrence, nor to relative survival (HR 1.05, 95% CI 0.85–1.28). Stratification and sensitivity analyses were similarly insignificant, after adjustment for confounding. Total lymph node harvest was, however, increased after high tie surgery (P < 0.01), but no differences were seen regarding positive nodes (P = 0.72).

    Conclusion: In this nationwide cohort study, the level of tie did not influence any patient-oriented oncological outcome, neither overall nor in node-positive patients. This would allow the patient's anatomical configuration and the surgeon's preferences to determine the level of tie.

  • 9.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045Article in journal (Refereed)
    Abstract [en]

    Background: Taxane treatment may be a suitable therapeutic option for patients with castration‐resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR‐Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR‐V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored.

    Methods: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3. Two cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole‐genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis.

    Results: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, both showed upregulation of the ATP‐binding cassette sub‐family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR‐antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1‐CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment.

    Conclusions: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR‐V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti‐androgens.

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  • 10. Bruening, Janina
    et al.
    Lasswitz, Lisa
    Banse, Pia
    Kahl, Sina
    Marinach, Carine
    Vondran, Florian W.
    Kaderali, Lars
    Silvie, Olivier
    Pietschmann, Thomas
    Meissner, Felix
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB2018In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, no 7, article id e1007111Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.

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  • 11. Delguste, Martin
    et al.
    Peerboom, Nadia
    Le Brun, Gregoire
    Trybala, Edward
    Olofsson, Sigvard
    Bergström, Tomas
    Alsteens, David
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 3, p. 534-542Article in journal (Refereed)
    Abstract [en]

    Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.

  • 12. Emilsson, Gustav
    et al.
    Röder, Evelyn
    Malekian, Bita
    Xiong, Kunli
    Manzi, John
    Tsai, Feng-Ching
    Cho, Nam-Joon
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Dahlin, Andreas
    Nanoplasmonic Sensor Detects Preferential Binding of IRSp53 to Negative Membrane Curvature2019In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 7, article id 1Article in journal (Refereed)
    Abstract [en]

    Biosensors based on plasmonic nanostructures are widely used in various applications and benefit from numerous operational advantages. One type of application where nanostructured sensors provide unique value in comparison with, for instance, conventional surface plasmon resonance, is investigations of the influence of nanoscale geometry on biomolecular binding events. In this study, we show that plasmonic "nanowells" conformally coated with a continuous lipid bilayer can be used to detect the preferential binding of the insulin receptor tyrosine kinase substrate protein (IRSp53) I-BAR domain to regions of negative surface curvature, i.e., the interior of the nanowells. Two different sensor architectures with and without an additional niobium oxide layer are compared for this purpose. In both cases, curvature preferential binding of IRSp53 (at around 0.025 nm(-1) and higher) can be detected qualitatively. The high refractive index niobium oxide influences the near field distribution and makes the signature for bilayer formation less clear, but the contrast for accumulation at regions of negative curvature is slightly higher. This work shows the first example of analyzing preferential binding of an average-sized and biologically important protein to negative membrane curvature in a label-free manner and in real-time, illustrating a unique application for nanoplasmonic sensors.

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  • 13.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Wanzhong
    Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed)
    Abstract [en]

    The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

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  • 14.
    Garoff, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ahlqvist, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Edin, Linda-Tereza
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Jensen, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Levring Jäghagen, Eva
    Umeå University, Faculty of Medicine, Department of Odontology.
    Petäjäniemi, Fredrik
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Department of Clinical Sciences, Danderyd hospital, Stockholm, Sweden.
    Johansson, Elias
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bilateral vessel-outlining carotid artery calcifications in panoramic radiographs: an independent risk marker for vascular events2019In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 19, no 1, article id 225Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In odontology, panoramic radiographs (PRs) are regularly performed. PRs depict the teeth and jaws as well as carotid artery calcifications (CACs). Patients with CACs on PRs have an increased risk of vascular events compared to healthy controls without CACs, but this association is often caused by more vascular events and risk factors at baseline. However, the risk of vascular events has only been analyzed based on the presence of CACs, and not their shape. Thus, this study determined if the shape of CACs in PRs affects the risk of future vascular events.

    METHODS: The study cohort included 117 consecutive patients with CACs in PRs and 121 age-matched controls without CACs. CAC shape in PRs was dichotomized into bilateral vessel-outlining CACs and other CAC shapes. Participants were followed prospectively for an endpoint of vascular events including myocardial infarction, stroke, and vascular death.

    RESULTS: Patients with bilateral vessel-outlining CACs had more previous vascular events than those with other CAC shapes and the healthy controls (p < 0.001, χ2). The mean follow-up duration was 9.5 years. The endpoint was reached in 83 people. Patients with bilateral vessel-outlining CACs had a higher annual risk of vascular events (7.0%) than those with other CAC shapes (4.4%) and the controls (2.6%) (p < 0.001). In multivariate analysis, bilateral vessel-outlining CACs (hazard ratio: 2.2, 95% confidence interval: 1.1-4.5) were independent risk markers for the endpoint.

    CONCLUSIONS: Findings of bilateral vessel-outlining CACs in PRs are independent risk markers for future vascular events.

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  • 15.
    Gerold, Gisa
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Moeller, Rebecca
    Pietschmann, Thomas
    Hepatitis C Virus Entry: Protein Interactions and Fusion Determinants Governing Productive Hepatocyte Invasion2020In: Cold Spring Harbor Perspectives in Medicine, ISSN 0103-3247, E-ISSN 2157-1422, Vol. 10, no 2, article id a036830Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) entry is among the best-studied uptake processes for human pathogenic viruses. Uptake follows a spatially and temporally tightly controlled program. Numerous host factors including proteins, lipids, and glycans promote productive uptake of HCV particles into human liver cells. The virus initially attaches to surface proteoglycans, lipid receptors such as the scavenger receptor BI (SR-BI), and to the tetraspanin CD81. After lateral translocation of virions to tight junctions, claudin-1 (CLDN1) and occludin (OCLN) are essential for entry. Clathrin-mediated endocytosis engulfs HCV particles, which fuse with endosoma I membranes after pH drop. Uncoating of the viral RNA genome in the cytoplasm completes the entry process. Here we systematically review and classify HCV entry factors by their mechanistic role, relevance, and level of evidence. Finally, we report on more recent knowledge on determinants of membrane fusion and close with an outlook on future implications of HCV entry research.

  • 16.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; .
    A Hierarchical Bayesian Mixture Modeling Approach for Analysis of Resting-State Functional Brain Connectivity: An Alternative to ThresholdingManuscript (preprint) (Other academic)
  • 17.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden..
    Bayesian mixture modeling for longitudinal fMRI connectivity studies with dropoutManuscript (preprint) (Other academic)
  • 18.
    Gu, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Aviv, Richard I.
    Fox, Allan J.
    Johansson, Elias
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Symptomatic carotid near-occlusion causes a high risk of recurrent ipsilateral ischemic stroke2020In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 267, p. 522-530Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the risk of recurrent ipsilateral ischemic stroke in patients with symptomatic near-occlusion with and without full collapse.

    Methods: Included were consecutive patients eligible for revascularization, grouped into symptomatic conventional ≥ 50% carotid stenosis (n = 266), near-occlusion without full collapse (n = 57) and near-occlusion with full collapse (n = 42). The risk of preoperative recurrent ipsilateral ischemic stroke was analyzed, or, for cases not revascularized within 90 days, 90-day risk was analyzed.

    Results: The risk of a preoperative recurrent ipsilateral ischemic stroke or ipsilateral retinal artery occlusion was 15% (95% CI 9–20%) for conventional ≥ 50% stenosis, 22% (95% CI 6–38%) among near-occlusion without full collapse and 30% (95% CI 16–44%) among near-occlusion with full collapse (p = 0.01, log rank test). In multivariate analysis, near-occlusion with full collapse had a higher risk of recurrent ipsilateral ischemic stroke (adjusted HR 2.6, 95% CI 1.3–5.3) and near-occlusion without full collapse tended to have a higher risk (adjusted HR 2.0, 95% CI 0.9–4.5) than conventional ≥ 50% stenosis. Only 24% of near-occlusion with full collapse underwent revascularization, common causes for abstaining were misdiagnosis as occlusion (31%), deemed surgically unfeasible (21%) and low perceived benefit (10%).

    Conclusions: Symptomatic carotid near-occlusion has a high short-term risk of recurrent ipsilateral ischemic stroke, especially near-occlusion with full collapse.

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  • 19.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lång, Kenneth
    Department of Medicine, Piteå Hospital , Piteå , Sweden..
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Westermark, Per
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 6, p. 372-376Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

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  • 20. Herrador, Antonio
    et al.
    Fedeli, Chiara
    Radulovic, Emilia
    Campbell, Kevin P.
    Moreno, Hector
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology. TWINCORE - Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus2019In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, no 2, article id e02869-18Article in journal (Refereed)
    Abstract [en]

    Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG's function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG's function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention.

    Importance: Recognition of cellular receptors allows emerging viruses to break species barriers and is an important determinant for their disease potential. Many virus receptors have complex tissue-specific interactomes, and preexisting protein-protein interactions may influence their function. Combining shotgun proteomics with a biochemical approach, we characterize the molecular composition of the functional receptor complexes used by the highly pathogenic Lassa virus (LASV) to invade susceptible human cells. We show that the specific composition of the receptor complexes affects productive entry of the virus, providing proof-of-concept. In uninfected cells, these functional receptor complexes undergo dynamic turnover involving an endocytic pathway that shares some characteristics with viral entry. However, steady-state receptor uptake and virus endocytosis critically differ in kinetics and underlying signaling, indicating that the pathogen can manipulate the receptor complex according to its needs. Our study highlights a remarkable complexity of LASV-receptor interaction and identifies possible targets for therapeutic antiviral intervention.

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  • 21.
    Holmgren, Klas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Anterior resection for rectal cancer in Sweden: validation of a registry-based method to determine long-term stoma outcome2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 12, p. 1631-1638Article in journal (Refereed)
    Abstract [en]

    Background: A permanent stoma after anterior resection for rectal cancer is common. Nationwide registries provide sufficient power to evaluate factors influencing this phenomenon, but validation is required to ensure the quality of registry-based stoma outcomes.

    Methods: Patients who underwent anterior resection for rectal cancer in the Northern healthcare region of Sweden between 1 January 2007 and 31 December 2013 were reviewed by medical records and followed until 31 December 2014 with regard to stoma outcome. A registry-based method to determine nationwide long-term stoma outcomes, using data from the National Patient Registry and the Swedish Colorectal Cancer Registry, was developed and internally validated using the chart reviewed reference cohort. Accuracy was evaluated with positive and negative predictive values and Kappa values. Following validation, the stoma outcome in all patients treated with an anterior resection for rectal cancer in Sweden during the study period was estimated. Possible regional differences in determined stoma outcomes between the six Swedish healthcare regions were subsequently evaluated with the χ2 test.

    Results: With 312 chart reviewed patients as reference, stoma outcome was accurately predicted through the registry-based method in 299 cases (95.8%), with a positive predictive value of 85.1% (95% CI 75.8%-91.8%), and a negative predictive value of 100.0% (95% CI 98.4%-100.0%), while the Kappa value was 0.89 (95% CI 0.82-0.95). In Sweden, 4768 patients underwent anterior resection during the study period, of which 942 (19.8%) were determined to have a permanent stoma. The stoma rate varied regionally between 17.8-29.2%, to a statistically significant degree (p = .001).

    Conclusion: Using data from two national registries to determine long-term stoma outcome after anterior resection for rectal cancer proved to be reliable in comparison to chart review. Permanent stoma prevalence after such surgery remains at a significant level, while stoma outcomes vary substantially between different healthcare regions in Sweden.

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  • 22.
    Johansson, Elias
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Aviv, Richard I.
    Fox, Allan J.
    Atherosclerotic ICA stenosis coinciding with ICA asymmetry associated with Circle of Willis variations can mimic near-occlusion2020In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 62, p. 101-104Article in journal (Refereed)
    Abstract [en]

    Differentiating carotid near-occlusion (tight atherosclerotic stenosis causing distal artery size reduction) from conventional stenosis is the first step when grading carotid stenoses with NASCET method. The internal carotid artery (ICA) can be asymmetrically associated with Circle of Willis variations. When such ICA asymmetry coincides with stenosis, it may mimic near-occlusion. We studied ICA anatomical variant prevalence in 4042 consecutive CTA exams from all indications, 53 excluded due to carotid occlusion, 814 with any >= 50% steno-occlusive disease intra- or extracranially, 3228 without. Of the 3989 included cases, 568 (14%) had ICA asymmetry, of which 335 (59%) were from associated with Circle of Willis variations. Of 3228 patients without >= 50% stenosis or other steno-occlusive disease intra- and extracranially; 257 (8.0%) demonstrated ICA asymmetry associated with Circle of Willis variations, equally common among sexes and age unrelated and most frequently attributed to an ipsilateral A1 hypoplasia/aplasia, less often attributed to large contralateral posterior communicating artery. As ICA asymmetry associated with Circle of Willis variations are common, caution should be exercised diagnosing near-occlusion on asymmetry alone.

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  • 23.
    Johansson, Elias
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Gu, Thomas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences.
    Aviv, Richard I.
    Fox, Allan J.
    Carotid near-occlusion is often overlooked when CT angiography is assessed in routine practice2020In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084Article in journal (Refereed)
    Abstract [en]

    Objective: Assess the sensitivity and specificity of computed tomography angiography (CTA) for carotid near-occlusion diagnosis interpreted in clinical practice against expert assessment.

    Methods: CTAs were graded by two expert interpreters for near-occlusion. Findings were compared with clinical reports in 383 consecutive cases with symptomatic ≥ 50% carotid stenosis. In addition, 14 selected CTA exams (8 near-occlusions and 6 controls) were analyzed in a national effort by 13 radiologists experienced with carotid CTA.

    Results: In clinical practice, imaging reports were 20% (95% CI 12–28%) sensitive for near-occlusion, ranging 0–58% between different radiologists; specificity was 99%. Among the 13 radiologists reviewing the same 8 near-occlusions, the average sensitivity was 8%, ranging 0–75%; specificity was 100%.

    Conclusions: Carotid near-occlusion is systematically under-reported in clinical routine practice, caused by limited application of grading criteria when assessing CTA.

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  • 24.
    Johansson, Jarkko
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet & Stockholm University, Gavlegatan € 16, S11330, Stockholm, Sweden .
    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.
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    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 Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Longitudinal evidence that reduced hemispheric encoding/retrieval asymmetry predicts episodic-memory impairment in aging2020In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 137, article id 107329Article in journal (Refereed)
    Abstract [en]

    The HERA (Hemispheric Encoding/Retrieval Asymmetry) model captures hemispheric lateralization of prefrontal cortex (PFC) brain activity during memory encoding and retrieval. Reduced HERA has been observed in cross-sectional aging studies, but there is no longitudinal evidence, to our knowledge, on age-related changes in HERA and whether maintained or reduced HERA relates to well-preserved memory functioning. In the present study we set out to explore HERA in a longitudinal neuroimaging sample from the Betula study [3 Waves over 10 years; Wave-1: n = 363, W2: n = 227, W3: n = 101]. We used fMRI data from a face-name paired-associates task to derive a HERA index. In support of the HERA model, the mean HERA index was positive across the three imaging waves. The longitudinal age-HERA relationship was highly significant (p < 10(-11)), with a HERA decline occurring after age 60. The age-related HERA decline was associated with episodic memory decline (p < 0.05). Taken together, the findings provide large-scale support for the HERA model, and suggest that reduced HERA in the PFC reflects pathological memory aging possibly related to impaired ability to bias mnemonic processing according to the appropriate encoding or retrieval state.

  • 25.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Damber, Jan-Erik
    Welén, Karin
    AR-V7 expression in circulating tumor cells as a potential prognostic marker in metastatic hormone-sensitive prostate cancer2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 11, p. 1660-1664Article in journal (Refereed)
    Abstract [en]

    Treatment of patients with metastatic hormone-sensitive (mHSPC) depends on androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling. Although the majority of patients respond well to ADT, castration-resistant prostate cancer (CRPC) inevitably develops. Addition of docetaxel, abiraterone acetate, or enzalutamide, to ADT significantly increases cancer-specific survival (CSS) [1–3]. The drawback is that not all patients respond to the therapies equally well and biomarkers to enable personalized treatment are urgently needed. Prostate-specific antigen (PSA) is a powerful biomarker for diagnosis of PC, but there are no validated biomarkers to prognosticate prognosis, let alone prediction of therapy response, of metastatic disease prior to ADT. Mechanisms important for resistance to ADT and development of CRPC include increased AR levels, constitutively active AR variants such as AR-V7, and intratumoral steroid production to sustain AR signaling despite castrate levels of steroids [4–7]. Although these changes mainly have been reported in CRPC, inherent expression could indicate predisposition for CRPC and poor response to ADT and other therapies targeting AR signaling.

    To identify patients with optimal therapeutic benefit from drugs with conceptually different targets, their metastatic disease needs to be characterized. Given the difficulty to access metastatic tissue for analysis, circulating tumor cells (CTCs) have a potential to provide phenotypic information of the tumor, in addition to the prognostic value associated with their abundance [8]. We have demonstrated that gene expression in circulating tumor cells (CTCs) reflects the phenotype of prostate cancer metastases [9]. It has also been suggested that detection of AR-V7 mRNA and AR-V7 localization to the nucleus in CTCs predict poor response to drugs targeting the androgen signaling axis, such as abiraterone acetate and enzalutamide, in patients with CRPC [10,11]. Although the biomarker potential of CTCs mostly has been evaluated in CRPC [10,12,13], two studies have described the presence of CTCs as a prognostic marker for overall survival, progression-free survival (PFS), and time to CRPC also in mHSPC [14,15]. In addition, we previously showed that detection of EGFR mRNA in CTCs is a negative prognostic biomarker for CSS in mHSPC [16].

    The present study investigates expression of genes associated with development of CRPC [17] for their prognostic value in mHSPC response to ADT. We showed that mRNA for the steroidogenic enzymes AKR1C3 and CYP17A1 can be detected in CTCs in high volume mHSPC, and that the detection of mRNA for AR-V7 in CTCs before ADT has prognostic value.

  • 26.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Larsson, Karin
    Freyhult, Eva
    Damber, Jan-Erik
    Welén, Karin
    Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells2020In: Cancers, ISSN 2072-6694, Vol. 12, no 1, article id 39Article in journal (Refereed)
    Abstract [en]

    Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

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  • 27.
    Jóhannesson, Gauti
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Linden, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Intracranial and Intraocular Pressure at the Lamina Cribrosa: Gradient Effects2018In: Current Neurology and Neuroscience Reports, ISSN 1528-4042, E-ISSN 1534-6293, Vol. 18, no 5, article id 25Article, review/survey (Refereed)
    Abstract [en]

    Purpose of Review: A pressure difference between the intraocular and intracranial compartments at the site of the lamina cribrosa has been hypothesized to have a pathophysiological role in several optic nerve head diseases. This paper reviews the current literature on the translamina cribrosa pressure difference (TLCPD), the associated pressure gradient, and its potential pathophysiological role, as well as the methodology to assess TLCPD.

    Recent Findings: For normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory.

    Summary: Data from studies on the elevated TLCPD as a pathophysiological factor of NTG are equivocal. From the identification of potential postural effects on the cerebrospinal fluid (CSF) communication between the intracranial and retrolaminar space, we hypothesize that the missing link could be a dysfunction of an occlusion mechanism of the optic nerve sheath around the optic nerve. In upright posture, this could cause an elevated TLCPD even with normal ICP and we suggest that this should be investigated as a pathophysiological component in NTG patients.

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  • 28.
    Jóhannesson, Gauti
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Ophthalmology, Faculty of Medicine, National University Hospital, University of Iceland, Reykjavik, Iceland.
    Gottfredsdottir, Maria Soffia
    Asgrimsdottir, Gudrun Marta
    Loftsson, Thorsteinn
    Stefansson, Einar
    Can postoperative dexamethasone nanoparticle eye drops replace mitomycin C in trabeculectomy?2020In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768Article in journal (Refereed)
    Abstract [en]

    Purpose: Compare (a) nonmitomycin C (MMC) trabeculectomy and 1.5% dexamethasone nanoparticle (DexNP) eye drops postoperatively with (b) trabeculectomy with MMC and Maxidex® eye drops postoperatively.

    Methods: Randomized prospective single masked clinical trial with 20 patients with primary open‐angle glaucoma undergoing primary trabeculectomy. The study group consisted of 10 patients without MMC intraoperatively and postoperative DexNP eye drops, and the control group consisted of 10 patients treated with MMC intraoperatively and postoperative Maxidex®. The drops were tapered out over 8 weeks. The main outcome measures were as follows: rates of complete success, that is intraocular pressure (IOP) within target pressures at different time‐points without IOP‐lowering medication, or reoperation. Secondary outcome measures included the following: relative success rate (with IOP‐lowering medications), number of glaucoma medications and reoperations. Patients were followed for 36 months.

    Results: Both groups showed similar postoperative course and IOP reduction. Intraocular pressures (IOPs) in the DexNP group and in the control group were 25.6 and 24.4 mmHg, respectively, at baseline. Intraocular pressures (IOPs) were reduced to 13.2 and 14.5 mmHg at 12 months, 11.7 and 12.6 mmHg at 24 months and 11.7 and 12.1 mmHg at 36 months, respectively. There were no statistically significant differences between the groups in absolute (p = 0.36) or relative (p = 1.0) success rates, number of medications (p = 0.71) or reoperations (p = 1.0) between the groups at any time‐point.

    Conclusions: DexNP eye drops are effective postoperative treatment following trabeculectomy. The potent anti‐inflammatory and antifibrotic effect of DexNP may offer an alternative to mitomycin C in glaucoma surgery.

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  • 29.
    Karalija, Nina
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Jonasson, Lars S.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Papenberg, Goran
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Karolinska Institutet; Stockholm University.
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Boraxbekk, Carl-Johan
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Copenhagen University Hospital, Hvidovre, Denmark.
    High long-term test-retest reliability for extrastriatal 11C-raclopride binding in healthy older adults2019In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016Article in journal (Refereed)
    Abstract [en]

    In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal 11C-raclopride binding potential (BPND) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64-78 years). Mean 11C-raclopride BPND values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND values (rho = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: rho = 0.92; p < 0.001; excluding striatum: rho = 0.75; p = 0.067). These observations suggest that extrastriatal 11C-raclopride measurements represent a true D2 signal.

  • 30.
    Karalija, Nina
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Ek, Jesper
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Papenberg, Goran
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet & Stockholm University, Tomtebodavägen 18A,S-17165, Stockholm, Sweden.
    Brandmaier, Andreas M.
    Köhncke, Ylva
    Johansson, Jarkko
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lövdén, Martin
    Lindenberger, Ulman
    Bäckman, Lars
    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.
    Cardiovascular factors are related to dopamine integrity and cognition in aging2019In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 6, no 11, p. 2291-2303Article in journal (Refereed)
    Abstract [en]

    Objective: The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age‐related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.

    Methods: The present work used magnetic resonance imaging and positron emission tomography with 11C‐raclopride to jointly examine vascular parameters (white‐matter lesions and perfusion), DA D2‐receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64–68 years) from the Cognition, Brain, and Aging (COBRA) study.

    Results: Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White‐matter lesion burden was negatively correlated with caudate DA D2‐receptor availability and white‐matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2‐receptor availability, white‐matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey‐matter volumes, a larger number of white‐matter lesions, and lower episodic memory performance.

    Interpretation: Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age‐sensitive cognitive functions, with emphasis on DA integrity.

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  • 31. Kohestani, Kimia
    et al.
    Wallström, Jonas
    Dehlfors, Niclas
    Sponga, Ole Martin
    Månsson, Marianne
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Urology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlsson, Sigrid
    Hellstrom, Mikael
    Hugosson, Jonas
    Performance and inter-observer variability of prostate MRI (PI-RADS version 2) outside high-volume centres2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, no 5, p. 304-311Article in journal (Refereed)
    Abstract [en]

    Objective: Despite the growing trend to embrace pre-biopsy MRI in the diagnostic pathway for prostate cancer (PC), its performance and inter-observer variability outside high-volume centres remains unknown. This study aims to evaluate sensitivity of and variability between readers of prostate MRI outside specialized units with radical prostatectomy (RP) specimen as the reference standard.

    Materials and methods: Retrospective study comprising a consecutive cohort of all 97 men who underwent MRI and subsequent RP between January 2012 and December 2014 at a private hospital in Sweden. Three readers, blinded to clinical data, reviewed all images (including 11 extra prostate MRI to reduce bias). A tumour was considered detected if the overall PI-RADS v2 score was 3-5 and there was an approximate match (same or neighbouring sector) of tumour sector according to a 24 sector system used for both MRI and whole mount sections.

    Results: Detection rate for the index tumour ranged from 67 to 76%, if PI-RADS 3-5 lesions were considered positive and 54-66% if only PI-RADS score 4-5 tumours were included. Detection rate for aggressive tumours (GS >= 4 + 3) was higher; 83.1% for PI-RADS 3-5 and 79.2% for PI-RADS 4-5. The agreement between readers showed average values of 0.41 for PI-RADS score 3-5 and 0.51 for PI-RADS score 4-5.

    Conclusions: Prostate MRI evidenced a moderate detection rate for clinically significant PC with a rather large variability between readers. Clinics outside specialized units must have knowledge of their performance of prostate MRI before considering omitting biopsies in men with negative MRI.

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  • 32.
    Kverneng Hultberg, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Svensson, Johan
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Jutesten, Henrik
    Department of Surgery, Skåne University Hospital, Malmö, Lund University, Lund, Sweden.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lydrup, Marie-Louise
    Department of Surgery, Skåne University Hospital, Malmö, Lund University, Lund, Sweden.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    The Impact of Anastomotic Leakage on Long-Term Function after Anterior Resection for Rectal Cancer2020In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 63, no 5, p. 619-628Article in journal (Refereed)
    Abstract [en]

    Background: It is still not clear whether anastomotic leakage after anterior resection for rectal cancer affects long-term functional outcome.

    Objective: To evaluate how anastomotic leakage following anterior resection for rectal cancer influences defecatory, urinary and sexual function.

    Design: In this retrospective population-based cohort study, patients were identified through the Swedish Colorectal Cancer Registry, which was also used for information on the exposure variable anastomotic leakage, and covariates.

    Settings: A nationwide register was used for including patients.

    Patients: All patients undergoing anterior resection for rectal cancer in Sweden from April 2011– June 2013 were included.

    Main Outcome Measures: Outcome was any defecatory, sexual or urinary dysfunction, assessed two years after surgery by a postal questionnaire. The association between anastomotic leakage and function was assessed in multivariable logistic and linear regression models, with adjustment for confounding.

    Results: Response rate was 82%, resulting in 1180 included patients. Anastomotic leakage occurred in 7.5%. A permanent stoma was more common among leak patients (44% vs. 9%; p<0.001). Leakage patients had an increased risk of aid use for fecal incontinence (OR 2.27; 95% CI 1.20-4.30) and reduced sexual activity (90% vs. 82%; p=0.003), while the risk of urinary incontinence was decreased (OR 0.53; 95% CI 0.31-0.90). A sensitivity analysis assuming that a permanent stoma was created due to anorectal dysfunction strengthened the negative impact of leakage on defecatory dysfunction.

    Limitations: Limitations include the used questionnaire not having been previously validated, underreporting of anastomotic leakage in the register, and small patient numbers in the analysis of sexual symptoms.

    Conclusions:a Anastomotic leakage was found to statistically significantly increase the risk of aid use due to fecal incontinence and reduced sexual activity, though the impact on defecatory dysfunction might be underestimated, as permanent stomas are sometimes fashioned due to anorectal dysfunction. Further research is warranted, especially regarding urogenital function.

  • 33. Lasswitz, Lisa
    et al.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Glycomics and Proteomics Approaches to Investigate Early Adenovirus-Host Cell Interactions2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1863-1882Article in journal (Refereed)
    Abstract [en]

    Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.

  • 34.
    Linden, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Heijl, Anders
    Jóhannesson, Gauti
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Aspberg, Johan
    Andersson Geimer, Sabina
    Bengtsson, Boel
    Initial intraocular pressure reduction by mono‐ versus multi‐therapy in patients with open‐angle glaucoma: results from the Glaucoma Intensive Treatment Study2018In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 6, p. 567-572Article in journal (Refereed)
    Abstract [en]

    Purpose: To study newly diagnosed glaucoma patients given mono‐ or multi‐therapy regarding differences in initial intraocular pressure (IOP) reduction, target IOP levels reached and influence of untreated baseline IOP on IOP reduction.

    Methods: Patients newly diagnosed with manifest primary open‐angle glaucoma and included in the Glaucoma Intensive Treatment Study (GITS) were randomized to immediate intensive treatment with any of three different IOP‐lowering substances supplied in two bottles plus 360° laser trabeculoplasty or to conventional stepwise treatment starting with a single‐drug. Intraocular pressure reduction was analysed 1 month after initiation of treatment.

    Results: One hundred eighteen patients (143 eyes) received mono‐therapy and 122 patients (152 eyes) multi‐therapy. Median baseline IOP was 24.0 (min: 9.7, max: 56.0) mmHg in mono‐therapy eyes and 24.0 (min: 12.3, max: 48.5) mmHg in multi‐therapy eyes (p = 0.56). After 1 month in the two groups, respectively, values for median IOP reduction were 6.3 (range: −5.3–31.0) and 11.0 (range: 0.7–34.5) mmHg, and for mean relative decline 26.8 (range: −32.0–55.4) and 46.0 (range: 4.6–81.6) % (p = 0.000). A larger proportion of the multi‐therapy patients reached each target IOP level (p = 0.000). The higher the baseline IOP, the larger the observed pressure reduction, considering both absolute and relative figures. The effect was more pronounced in eyes with multi‐therapy than in those with mono‐therapy (p = 0.000). For every mmHg higher IOP at baseline, the IOP was reduced by an additional 0.56 (mono‐therapy) or 0.84 (multi‐therapy) mmHg.

    Conclusion: Intensive treatment led to considerably greater IOP reduction than mono‐therapy. Among patients with IOP ≥30 mmHg at diagnosis an IOP of <16 was reached in 2/3 of those with multi‐therapy but in none with mono‐therapy. The IOP reduction was highly dependent on the untreated IOP level.

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  • 35.
    Lopatko Lindman, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Weidung, Bodil
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Department of Public Health and Caring Sciences, Geriatric Medicine, Uppsala University, Uppsala, Sweden.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Josefsson, Maria
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Kok, Eloise
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Lövheim, Hugo
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease2019In: Alzheimer's & dementia, ISSN 1552-5279, Vol. 5, p. 697-704Article in journal (Refereed)
    Abstract [en]

    Introduction: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis.

    Methods: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). APOE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland.

    Results: The interaction between APOEε4 heterozygosity (APOEε24 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01).

    Discussion: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

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  • 36.
    Malla, Sandhya
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Melguizo-Sanchis, Dario
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Steering pluripotency and differentiation with N6-methyladenosine RNA modification2019In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, no 3, p. 394-402Article in journal (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to modulate the existing transcriptome, allowing the cells to adapt rapidly to the changing environment. Among these modifications, N6-methyladenosine (m6A) has recently emerged as a widely prevalent mark of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. m6A modification modulates a broad spectrum of biochemical processes, including mRNA decay, translation and splicing. Both m6A modification and the enzymes that control m6A metabolism are essential for normal development. In this review, we summarized the most recent findings on the role of m6A modification in maintenance of the pluripotency of embryonic stem cells (ESCs), cell fate specification, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), and differentiation of stem and progenitor cells.

  • 37. Martínez-Carranza, Markel
    et al.
    Blasco, Pilar
    Gustafsson, Robert
    Dong, Min
    Berntsson, Ronnie Per-Arne
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Widmalm, Göran
    Stenmark, Pål
    Synaptotagmin Binding to Botulinum Neurotoxins2020In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 59, no 4, p. 491-498Article in journal (Refereed)
    Abstract [en]

    Botulinum neurotoxins (BoNTs) are exceptionally toxic proteins that cause paralysis but are also extensively used as treatment for various medical conditions. Most BoNTs bind two receptors on neuronal cells, namely, a ganglioside and a protein receptor. Differences in the sequence between the protein receptors from different species can impact the binding affinity and toxicity of the BoNTs. Here we have investigated how BoNT/B, /DC, and /G, all three toxins that utilize synaptotagmin I and II (Syt-I and Syt- II, respectively) as their protein receptors, bind to Syt-I and -II of mouse/rat, bovine, and human origin by isothermal titration calorimetry analysis. BoNT/G had the highest affinity for human Syt-I, and BoNT/DC had the highest affinity for bovine Syt-II. As expected, BoNT/B, /DC, and /G showed very low levels of binding to human Syt-II. Furthermore, we carried out saturation transfer difference (STD) and STD-TOCSY NMR experiments that revealed the region of the Syt peptide in direct contact with BoNT/G, which demonstrate that BoNT/G recognizes the Syt peptide in a model similar to that in the established BoNT/B-Syt-II complex. Our analyses also revealed that regions outside the Syt peptide's toxin-binding region are important for the helicity of the peptide and, therefore, the binding affinity.

  • 38. Meershoek, A. J. A.
    et al.
    de Vries, E.E.
    Veen, D.
    den Ruijter, H.M
    Meta-analysis of the outcomes of treatment of internal carotid arterynear occlusion2019In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 106, no 6, p. 665-671Article in journal (Refereed)
    Abstract [en]

    Background: Guidelines recommend treating patients with an internal carotid artery near occlusion (ICANO) with best medical therapy (BMT) based on weak evidence. Consequently, patients with ICANO were excluded from randomized trials. The aim of this individual‐patient data (IPD) meta‐analysis was to determine the optimal treatment approach.

    Methods: A systematic search was performed in MEDLINE, EMBASE and the Cochrane Library databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analysed by multivariable mixed‐effect logistic regression. The secondary outcome was the occurrence of any stroke or death beyond 30 days up to 1 year after treatment, evaluated by Kaplan–Meier survival analysis.

    Results: The search yielded 1526 articles, of which 61 were retrieved for full‐text review. Some 32 studies met the inclusion criteria and pooled IPD were available from 11 studies, including some 703 patients with ICANO. Within 30 days, any stroke or death was reported in six patients (1·8 per cent) in the carotid endarterectomy (CEA) group, five (2·2 per cent) in the carotid artery stenting (CAS) group and seven (4·9 per cent) in the BMT group. This resulted in a higher 30‐day stroke or death rate after BMT than after CEA (odds ratio 5·63, 95 per cent c.i. 1·30 to 24·45; P = 0·021). No differences were found between CEA and CAS. The 1‐year any stroke‐ or death‐free survival rate was 96·1 per cent for CEA, 94·4 per cent for CAS and 81·2 per cent for BMT.

    Conclusion: These data suggest that BMT alone is not superior to CEA or CAS with respect to 30‐day or 1‐year stroke or death prevention in patients with ICANO. These patients do not appear to constitute a high‐risk group for surgery, and consideration should made to including them in future RCTs of internal carotid artery interventions.

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  • 39. Moreno, Hector
    et al.
    Moeller, Rebecca
    Fedeli, Chiara
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. TWINCORE–Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Comparison of the Innate Immune Responses to Pathogenic and Nonpathogenic Clade B New World Arenaviruses2019In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 93, no 19, article id e00148-19Article in journal (Refereed)
    Abstract [en]

    The New World (NW) arenaviruses are a diverse group of zoonotic viruses, including several causative agents of severe hemorrhagic fevers in humans. All known human-pathogenic NW arenaviruses belong to Glade B, where they group into sublineages with phylogenetically closely related nonpathogenic viruses, e.g., the highly pathogenic Junin (JUNV) and Machupo viruses with the nonpathogenic Tacaribe virus (TCRV). Considering the close genetic relationship of nonpathogenic and pathogenic NW arenaviruses, the identification of molecular determinants of virulence is of great importance. The host cell's innate antiviral defense represents a major barrier for zoonotic infection. Here, we performed a side-by-side comparison of the innate immune responses against JUNV and TCRV in human cells. Despite similar levels of viral replication, infection with TCRV consistently induced a stronger type I interferon (IFN-I) response than JUNV infection did. Transcriptome profiling revealed upregulation of a largely overlapping set of interferon-stimulated genes in cells infected with TCRV and JUNV. Both viruses were relatively insensitive to IFN-I treatment of human cells and induced similar levels of apoptosis in the presence or absence of an IFN-I response. However, in comparison to JUNV, TCRV induced stronger activation of the innate sensor double-strand RNA-dependent protein kinase R (PKR), resulting in phosphorylation of eukaryotic translation initiation factor eIF2 alpha. Confocal microscopy studies revealed similar subcellular colocalizations of the JUNV and TCRV viral replication-transcription complexes with PKR. However, deletion of PKR by CRISPR/Cas9 hardly affected JUNV but promoted TCRV multiplication, providing the first evidence for differential innate recognition and control of pathogenic and nonpathogenic NW arenaviruses by PKR.

    IMPORTANCE New World (NW) arenaviruses are a diverse family of emerging zoonotic viruses that merit significant attention as important public health problems. The close genetic relationship of nonpathogenic NW arenaviruses with their highly pathogenic cousins suggests that few mutations may be sufficient to enhance virulence. The identification of molecular determinants of virulence of NW arenaviruses is therefore of great importance. Here we undertook a side-by-side comparison of the innate immune responses against the highly pathogenic Junin virus (JUNV) and the related nonpathogenic Tacaribe virus (TCRV) in human cells. We consistently found that TCRV induces a stronger type I interferon (IFN-I) response than JUNV. Transcriptome profiling revealed an overlapping pattern of IFN-induced gene expression and similar low sensitivities to IFN-I treatment. However, the double-stranded RNA (dsRNA)-dependent protein kinase R (PKR) contributed to the control of TCRV, but not JUNV, providing the first evidence for differential innate recognition and control of JUNV and TCRV.

  • 40.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed)
    Abstract [en]

    Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

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  • 41.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

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  • 42. Neesse, Albrecht
    et al.
    Bauer, Christian Alexander
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lauth, Matthias
    Buchholz, Malte
    Michl, Patrick
    Tuveson, David A.
    Gress, Thomas M.
    Stromal biology and therapy in pancreatic cancer: ready for clinical translation?2019In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 1, p. 159-171Article in journal (Refereed)
    Abstract [en]

    Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

  • 43.
    Nilsson, Lena Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Winkvist, Anna
    Esberg, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dairy Products and Cancer Risk in a Northern Sweden Population2019In: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914Article in journal (Refereed)
    Abstract [en]

    The role of dairy products in cancer is unclear. We assessed consumption of fermented milk, non-fermented milk, cheese, and butter, estimated from semi-quantitative food frequency questionnaires, in relation to prospective risk of breast, prostate, colorectal, smoking-, and obesity-related cancers in 101,235 subjects, including 12,552 cancer cases, in the population-based Northern Sweden Health and Disease Study. Most analyses (n = 20) rendered null results. In men, we observed an increased prostate cancer risk among high-consumers of cheese (hazard ratio (HR) for highest vs. lowest quintile (Q5-Q1), 1.11; 95% CI, 0.97-1.27; Ptrend = 0.013). In women, high-consumers of cheese had a decreased risk of overall cancer (HR Q5-Q1, 0.95; 95% CI, 0.88-1.04; Ptrend = 0.039), smoking-related (HR Q5-Q1, 0.84; 95% CI, 0.72-0.97; Ptrend ≤ 0.001), and colorectal cancers (HR Q5-Q1, 0.82; 95% CI, 0.63-1.07; Ptrend = 0.048). Butter yielded a weak decreased obesity-related cancer risk in women (HR Q5-Q1, 0.91; 95% CI, 0.81-1.02; Ptrend = 0.049). Fermented milk yielded HRs below zero in women, but with no clear linear associations. In conclusion, this study does not support any major adverse or beneficial effects of fermented milk, non-fermented milk, cheese, and butter in the diet from a cancer risk perspective.

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  • 44. Norling, Karin
    et al.
    Bernasconi, Valentina
    Hernandez, Victor Agmo
    Parveen, Na Ma
    Edwards, Katarina
    Lycke, Nils Y.
    Hook, Fredrik
    Bally, Marta
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Gel Phase 1,2-Distearoyl-sn-glycero-3-phosphocholine-Based Liposomes Are Superior to Fluid Phase Liposomes at Augmenting Both Antigen Presentation on Major Histocompatibility Complex Class II and Costimulatory Molecule Display by Dendritic Cells in Vitro2019In: ACS Infectious Diseases, ISSN 2373-8227, Vol. 5, no 11, p. 1867-1878Article in journal (Refereed)
    Abstract [en]

    Lipid-based nanoparticles have in recent years attracted increasing attention as pharmaceutical carriers. In particular, reports of them having inherent adjuvant properties combined with their ability to protect antigen from degradation make them suitable as vaccine vectors. However, the physicochemical profile of an ideal nanoparticle for vaccine delivery is still poorly defined. Here, we used an in vitro dendritic cell assay to assess the immunogenicity of a variety of liposome formulations as vaccine carriers and adjuvants. Using flow cytometry, we investigated liposome-assisted antigen presentation as well as the expression of relevant costimulatory molecules on the cell surface. Cytokine secretion was further evaluated with an enzyme-linked immunosorbent assay (ELISA). We show that liposomes can successfully enhance antigen presentation and maturation of dendritic cells, as compared to vaccine fusion protein (CTA1-3E alpha-DD) administered alone. In particular, the lipid phase state of the membrane was found to greatly influence the vaccine antigen processing by dendritic cells. As compared to their fluid phase counterparts, gel phase liposomes were more efficient at improving antigen presentation. They were also superior at upregulating the costimulatory molecules CD80 and CD86 as well as increasing the release of the cytokines IL-6 and IL-1 beta. Taken together, we demonstrate that gel phase liposomes, while nonimmunogenic on their own, significantly enhance the antigen-presenting ability of dendritic cells and appear to be a promising way forward to improve vaccine immunogenicity.

  • 45.
    Nyberg, Lars
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    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.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Aging Research Center, Karolinska Institutet and Stockholm University, Solna, Sweden.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Frontal Contribution to Hippocampal Hyperactivity During Memory Encoding in Aging2019In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 12, article id 229Article in journal (Refereed)
    Abstract [en]

    Hippocampal hypo- as well as hyper-activation have been reported during memory encoding in older individuals. Prefrontal cortex (PFC) provides top-down state signals to the hippocampus that bias its computation during memory encoding and retrieval, and disturbed top-down signals could contribute to hippocampal hyper-activation. Here, we used >500 cross-sectional and longitudinal observations from a face-name encoding-retrieval fMRI task to examine hippocampal hypo-and hyper-activation in aging. Age-related anterior hippocampal hypo-activation was observed during memory encoding. Next, older individuals who longitudinally dropped-out were compared with those who remained in the study. Older dropouts had lower memory performance and higher dementia risk, and hyper-activated right anterior and posterior hippocampus during memory encoding. During encoding, the dropouts also activated right prefrontal regions that instead were active during retrieval in younger and older remainers. Moreover, the dropouts showed altered frontal-hippocampal functional connectivity, notably elevated right PFC to anterior hippocampus (aHC) connectivity during encoding. In the context of a general pattern of age-related anterior hippocampal hypo-activation during encoding, these findings support a top-down contribution to paradoxically high anterior hippocampal activity in older dropouts who were at elevated risk of pathology.

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  • 46.
    Nyrén, Rakel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Makoveichuk, Elena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Kersten, Sander
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet2019In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 3, p. F558-F571Article in journal (Refereed)
    Abstract [en]

    Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL, colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin, indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4-/- mice. In Angptl4-/- mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confirm that LPL appears to have a minor role for lipid uptake in this organ.

  • 47. Papenberg, Goran
    et al.
    Jonasson, Lars S.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Karalija, Nina
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Koehncke, Ylva
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Tomtebodavägen 18A, 171 65 Solna, Sweden.
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Lindenberger, Ulman
    Lovden, Martin
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Backman, Lars
    Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride2019In: Brain Structure and Function, ISSN 1863-2653, E-ISSN 1863-2661, Vol. 224, no 8, p. 2871-2882Article in journal (Refereed)
    Abstract [en]

    The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [C-11]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [C-11]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [C-11]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.

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  • 48. Papenberg, Goran
    et al.
    Karalija, Nina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lindenberger, Ulman
    Lövdén, Martin
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bäckman, Lars
    Balance between Transmitter Availability and Dopamine D2 Receptors in Prefrontal Cortex Influences Memory Functioning2019In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, article id bhz142Article in journal (Refereed)
    Abstract [en]

    Insufficient or excessive dopaminergic tone impairs cognitive performance. We examine whether the balance between transmitter availability and dopamine (DA) D2 receptors (D2DRs) is important for successful memory performance in a large sample of adults (n = 175, 64-68 years). The Catechol-O-Methyltransferase polymorphism served as genetic proxy for endogenous prefrontal DA availability, and D2DRs in dorsolateral prefrontal cortex (dlPFC) were measured with [11C]raclopride-PET. Individuals for whom D2DR status matched DA availability showed higher levels of episodic and working-memory performance than individuals with insufficient or excessive DA availability relative to the number of receptors. A similar pattern restricted to episodic memory was observed for D2DRs in caudate. Functional magnetic resonance imaging data acquired during working-memory performance confirmed the importance of a balanced DA system for load-dependent brain activity in dlPFC. Our data suggest that the inverted-U-shaped function relating DA signaling to cognition is modulated by a dynamic association between DA availability and receptor status.

  • 49. Peerboom, Nadia
    et al.
    Schmidt, Eneas
    Trybala, Edward
    Block, Stephan
    Bergström, Tomas
    Pace, Hudson P.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cell Membrane Derived Platform To Study Virus Binding Kinetics and Diffusion with Single Particle Sensitivity2018In: Acs Infectious Diseases, ISSN 2373-8227, Vol. 4, no 6, p. 944-953Article in journal (Refereed)
    Abstract [en]

    Discovery and development of new antiviral therapies essentially rely on two key factors: an in-depth understanding of the mechanisms involved in viral infection and the development of fast and versatile drug screening platforms. To meet those demands, we present a biosensing platform to probe virus-cell membrane interactions on a single particle level. Our method is based on the formation of supported lipid bilayers from cell membrane material. Using total internal reflection fluorescence microscopy, we report the contribution of viral and cellular components to the interaction kinetics of herpes simplex virus type 1 with the cell membrane. Deletion of glycoprotein C (gC), the main viral attachment glycoprotein, or deletion of heparan sulfate, an attachment factor on the cell membrane, leads to an overall decrease in association of virions to the membrane and faster dissociation from the membrane. In addition to this, we perform binding inhibition studies using the antiviral compound heparin to estimate its IC50 value. Finally, single particle tracking is used to characterize the diffusive behavior of the virus particles on the supported lipid bilayers. Altogether, our results promote this platform as a complement to existing bioanalytical assays, being at the interface between simplified artificial membrane models and live cell experiments.

  • 50.
    Rasmuson, Erika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Lindén, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Lundberg, Björn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Jóhannesson, Gauti
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Efficacy and safety of transscleral cyclophotocoagulation in Swedish glaucoma patients2019In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 97, no 8, p. 764-770Article in journal (Refereed)
    Abstract [en]

    Purpose: To retrospectively evaluate the efficacy and safety of all transscleral cyclophotocoagulation (TCP) treatments performed during a 5-year period.

    Methods: Medical records of all patients, who had undergone TCP treatment between 2010 and 2014 at Umea University Hospital, Sweden, were evaluated. Clinical data including intraocular pressure (IOP), visual acuity (VA), number of topical glaucoma medications, use of oral acetazolamide, retreatments and complications during a 2-year follow-up were registered. Global success was defined as IOP 6-18 mmHg with or without glaucoma medication. 

    Results: Three hundred patients underwent TCP during the time period. Mean IOP at baseline was 29.3 11.0 (mean +/- standard deviation) mmHg (n = 297) with a mean reduction of 11.5 (+/- 12.0) mmHg at 1 year (n = 258; p < 0.001) and 12.6 (<plus/minus>12.0) mmHg at 2-year follow-up (n = 245; p < 0.001). Global success at 2 years was 64%, achieved by a mean of 1.2 treatments (n = 257). The number of topical glaucoma medications at baseline was 3.1 (<plus/minus>1.0; n = 296) and was reduced by 0.9 (+/- 1.0) medications at 2 years (n = 244; p < 0.001). Use of oral acetazolamide decreased from 30% (n = 90) at baseline to 5.3% (n = 13) at 2 years. In eyes with Snellen VA <greater than or equal to> 0.1, the mean VA at baseline was 0.55 (+/- 0.3) logarithm of the minimum angle of resolution (logMAR; n = 132) and 1.1 (+/- 0.9) logMAR (n = 76) at 2 years (p < 0.001). No cases of phthisis bulbi were found.

    Conclusion: This study displays a substantial and long-term reduction of IOP following TCP with a decrease in topical and oral glaucoma medications. The treatment appears to be safe but the decrease in VA during follow-up is a concern that needs further evaluation.

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