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  • 1. Abdulla, Maysaa
    et al.
    Hollander, Peter
    Pandzic, Tatjana
    Mansouri, Larry
    Ednersson, Susanne Bram
    Andersson, Per-Ola
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fors, Maja
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Petersen, Helga Munch
    Asmar, Fazila
    Gronbaek, Kirsten
    Enblad, Gunilla
    Cavelier, Lucia
    Rosenquist, Richard
    Amini, Rose-Marie
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2020In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, no 1, p. 57-67Article in journal (Refereed)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

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  • 2.
    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).

  • 3.
    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 Noncoding RNAs as Players in Breast Tumorigenesis2020In: The chemical biology of long noncoding RNAs / [ed] Stefan Jurga, Jan Barciszewski, Springer, 2020, , p. 19p. 385-403Chapter in book (Refereed)
    Abstract [en]

    Comprehensive analysis of the mammalian genome uncovered the discovery of pervasive transcription of large RNA transcripts that do not code for proteins, namely, long noncoding RNAs (lncRNAs). LncRNAs play important roles in the regulation of gene expression from integration of chromatin remodeling complexes to transcriptional and posttranscriptional regulation of protein-coding genes. Application of next-generation sequencing technologies to cancer transcriptomes has revealed that aberrant expression of lncRNAs is associated with tumor progression and metastasis. Although thousands of lncRNAs have been shown to be dysregulated in different cancer types, just few of them have been fully characterized. In this book chapter, we aim to highlight recent findings of the mechanistic function of lncRNAs in breast cancer and summarize key examples of lncRNAs that are misregulated during breast tumorigenesis. We have categorized breast cancer–associated lncRNA according to their contribution to tumor suppression or tumor progression based on recent studies. Because some of them are expressed in a specific molecular breast cancer subtype, we have outlined lncRNAs that can potentially serve as diagnostic and prognostic markers, in which expression is linked to chemotherapy resistance. Finally, we have discussed current limitations and perspectives on potential lncRNA targets for use in therapies against breast cancer.

  • 4.
    Adamo, Hanibal
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahl Scherdin, Tove
    Egevad, Lars
    Granfors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcomeManuscript (preprint) (Other academic)
    Abstract [en]

    Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of a tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein-β (C/EBPβ). To explore this further, we examined C/EBPβ expression by quantitative RT-PCR, immunohistochemistry, and western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors―and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    In rats, C/EBPβ mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBPβ was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBPβ expression in the tumor-bearing prostates was associated with tumor size, with distance to the tumor, and with tumor cell metastatic capacity.

    In prostate cancer patients, high expression of C/EBPβ in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and a favorable outcome. High expression of C/EBPβ in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, the presence of metastases at diagnosis, and poor outcome. 

  • 5.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergström, Sofia Halin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 6, article id e0130076Article in journal (Refereed)
    Abstract [en]

    Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT)) with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, >= 2-fold change) in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could hypothetically serve as novel diagnostic and prognostic markers of prostate cancer.

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  • 6.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Scherdin, Tove Dahl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Stattin, Pär
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5, p. 435-445Article in journal (Refereed)
    Abstract [en]

    Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

    Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

    Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

    Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

  • 7.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Strömvall, Kerstin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0141601Article in journal (Refereed)
    Abstract [en]

    In order to grow, tumors need to induce supportive alterations in the tumor-bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues.

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  • 8.
    Adhikari, Deepak
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Flohr, Gilian
    Hogeschool Leiden, Zernikedreef 11,2333 CK Leiden, The Netherlands.
    Gorre, Nagaraju
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shen, Yan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lan, Zijian
    University of Louisville Health Sciences Center, Louisville, Kentucky, USA.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles2009In: Molecular human reproduction, ISSN 1360-9947, E-ISSN 1460-2407, Vol. 15, no 12, p. 765-770Article in journal (Refereed)
    Abstract [en]

    To maintain the length of reproductive life in a woman, it is essential that most of her ovarian primordial follicles are maintained in a quiescent state to provide a continuous supply of oocytes. However, our understanding of the molecular mechanisms that control the quiescence and activation of primordial follicles is still in its infancy. In this study, we provide some genetic evidence to show that the tumor suppressor tuberous sclerosis complex 2 (Tsc2), which negatively regulates mammalian target of rapamycin complex 1 (mTORC1), functions in oocytes to maintain the dormancy of primordial follicles. In mutant mice lacking the Tsc2 gene in oocytes, the pool of primordial follicles is activated prematurely due to elevated mTORC1 activity in oocytes. This results in depletion of follicles in early adulthood, causing premature ovarian failure (POF). Our results suggest that the Tsc1-Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation. Our results also indicate that deregulation of Tsc/mTOR signaling in oocytes may cause pathological conditions of the ovary such as infertility and POF.

  • 9. Adolf, Katja
    et al.
    Wagner, Ludwig
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Ottosen, Peter
    Borre, Michael
    Birkenkamp-Demtröder, Karin
    Orntoft, Torben Falck
    Tørring, Niels
    Secretagogin is a new neuroendocrine marker in the human prostate.2007In: Prostate, ISSN 0270-4137, Vol. 67, no 5, p. 472-84Article in journal (Refereed)
  • 10.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Clinical studies and chemical pathology in normal aging and dementia of Alzheimer type1980Doctoral thesis, comprehensive summary (Other academic)
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    Clinical studies and chemical pathology in normal aging and dementia of alzheimer type
  • 11. Agudo, Antonio
    et al.
    Sala, Naría
    Pera, Guillem
    Capella, Gabriel
    Berenguer, Antonio
    García, Nadia
    Palli, Domenico
    Boeing, Heiner
    Del Giudice, Giuseppe
    Saieva, Calogero
    Carneiro, Fatima
    Berrino, Franco
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Siman, Henrik
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Bilbao, Roberto
    Barricarte, Aurelio
    Navarro, Carmen
    Quiros, José
    Allen, Naomi
    Key, Tim
    Bingham, Sheila
    Khaw, Kay-Tee
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Peeters, Petra H
    Numans, Mattijs E
    Clavel-Chapelon, Francoíse
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lund, Eiliv
    Offerhaus, Johan
    Jenab, Mazda
    Ferrari, Pietro
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition.2006In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 15, no 12, p. 2427-34Article in journal (Refereed)
  • 12. Agudo, Antonio
    et al.
    Sala, Nária
    Pera, Guillem
    Capella, Gabriel
    Berenguer, Antonio
    García, Nadia
    Palli, Domenico
    Boeing, Heiner
    Del Giudice, Giuseppe
    Saieva, Calogero
    Carneiro, Fatima
    Berrino, Franco
    Sacerdote, Carlotta
    Tumino, Rosario
    Panico, Salvatore
    Berglund, Göran
    Siman, Henrik
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Martínez, Carmen
    Amiano, Pilar
    Barricarte, Aurelio
    Navarro, Carmen
    Qui, Jose R
    Allen, Naomi
    Key, Tim
    Bingham, Sheila
    Khaw, Kay-Tee
    Linseisen, Jakob
    Nagel, Gabriele
    Overvad, Kim
    Tjonneland, Anne
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Peeters, Petra H
    Numans, Mattijs E
    Clavel-Chapelon, Francoíse
    Boutron-Ruault, Marie-Christine
    Trichopoulou, Antonia
    Lund, Eiliv
    Báker, Hendrik
    Jenab, Mazda
    Ferrari, Pietro
    Norat, Teresa
    Riboli, Elio
    González, Carlos A
    No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition.2006In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 15, no 5, p. 1043-5Article in journal (Refereed)
  • 13.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Departments of Structural and Chemical Biology, Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Di Cecilia, Serena
    Walsh, Martin J
    Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease2016In: Long non-coding RNAs in human disease, Springer, 2016, Vol. 394, p. 29-39Chapter in book (Refereed)
    Abstract [en]

    The long non-coding RNA CDKN2B-AS1, commonly referred to as the Antisense Non-coding RNA in the INK4 Locus (ANRIL), is a 3.8-kb-long RNA transcribed from the short arm of human chromosome 9 on p21.3 that overlaps a critical region encompassing three major tumor suppressor loci juxtaposed to the INK4b-ARF-INK4a gene cluster and the methyl-thioadenosine phosphorylase (MTAP) gene. Genome-wide association studies have identified this region with a remarkable and growing number of disease-associated DNA alterations and single nucleotide polymorphisms, which corresponds to increased susceptibility to human disease. Recent attention has been devoted on whether these alterations in the ANRIL sequence affect its expression levels and/or its splicing transcript variation, and in consequence, global cellular homeostasis. Moreover, recent evidence postulates that ANRIL not only can regulate their immediate genomic neighbors in cis, but also has the capacity to regulate additional loci in trans. This action would further increase the complexity for mechanisms imposed through ANRIL and furthering the scope of this lncRNA in disease pathogenesis. In this chapter, we summarize the most recent findings on the investigation of ANRIL and provide a perspective on the biological and clinical significance of ANRIL as a putative biomarker, specifically, its potential role in directing cellular fates leading to cancer and cardiovascular disease.

  • 14.
    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.

  • 15. Ahlin, Cecilia
    et al.
    Fernö, Mårten
    Amini, Rose-Marie
    Tolockiene, Egle
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Blomqvist, Carl
    Bergh, Jonas
    Fjällskog, Marie-Louise
    [Ki-67 and cyclin A: prognostic factors in breast cancer. Time to introduce proliferation markers in clinical routine].2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 10, p. 672-675Article in journal (Refereed)
  • 16.
    Ahmadi, Mahboobah
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Human extraocular muscles in ALS2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 7, p. 3494-3501Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.

  • 17.
    Aili, Margareta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Isaksson, Elin L
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hallberg, Bengt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wolf-Watz, Hans
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rosqvist, Roland
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Functional analysis of the YopE GTPase-activating protein (GAP) activity of Yersinia pseudotuberculosis2006In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 8, no 6, p. 1020-1033Article in journal (Refereed)
    Abstract [en]

    YopE of Yersinia pseudotuberculosis inactivates three members of the small RhoGTPase family (RhoA, Rac1 and Cdc42) in vitro and mutation of a critical arginine abolishes both in vitro GTPase-activating protein (GAP) activity and cytotoxicity towards HeLa cells, and renders the pathogen avirulent in a mouse model. To understand the functional role of YopE, in vivo studies of the GAP activity in infected eukaryotic cells were conducted. Wild-type YopE inactivated Rac1 as early as 5 min after infection whereas RhoA was down regulated about 30 min after infection. No effect of YopE was found on the activation state of Cdc42 in Yersinia-infected cells. Single-amino-acid substitution mutants of YopE revealed two different phenotypes: (i) mutants with significantly lowered in vivo GAP activity towards RhoA and Rac1 displaying full virulence in mice, and (ii) avirulent mutants with wild-type in vivo GAP activity towards RhoA and Rac1. Our results show that Cdc42 is not an in vivo target for YopE and that YopE interacts preferentially with Rac1, and to a lesser extent with RhoA, during in vivo conditions. Surprisingly, we present results suggesting that these interactions are not a prerequisite to establish infection in mice. Finally, we show that avirulent yopE mutants translocate YopE in about sixfold higher amount compared with wild type. This raises the question whether YopE's primary function is to sense the level of translocation rather than being directly involved in downregulation of the host defence.

  • 18.
    Alafuzoff, Irina
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Histopathological and immunocytochemical studies in age-associated dementias: the importance of rigorous histopathological criteria for classification of progressive dementia disorders1985Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dementia is an age-associated organic brain disorder, recogniz­able by the essential features of psychological or behavioral abnormality associated with permanent dysfunction of the brain interfering with social and occupational functioning.

    There are two clinical and three histopathological forms of dementia 1) primary degenerative dementia, (PDD), or Alzhei­mer's dementia/Senile dementia of Alzheimers type (AD/SDAT) which is associated with clinical features of uniform progres­sion and insidious onset of symptoms and histopathologically i- dentified by the occurrence of neurofibrillary tangles (NFT) and senile/neuritic plaques (SP/NP) in various cortical and subcor- tical regions; 2) vascular dementia, or multi-infarct dementia (MID), which is associated with clinical features of stepwise progress and patchy distribution of deficits, and histopatholo­gically identified by the occurrence of multiple large and/or small haemorrhagic and/or ischaemic infarcts in various cortical and subcortical regions and 3) intermediate form of dementia or "mixed” ("combined") dementia (AD-MID), which is histopatho- logically associated with the coexistance of symptoms and le­sions observed in AD/SDAT and MID, and clinically referred to the MID group. The DSM-III criteria separate the demented into two groups, AD/SDAT and MID, while there are no unique clinical criteria for the AD-MID patients. The clinical diagnosis of dementia according to the DSM-III criteria was shown to be in­sufficient . Histopathological diagnostic criteria were postu­lated by us for 1) pathological changes developing in mentallyunimpaired ageing, 2) AD/ SPAT, 3) MID and 4) AD-MID.

    These histopathological classes could be separated, by means of multivariate data analysis. The pathology in AD-MID was shown not to be merely a linear combination of the AD/SDATand MID pathology.

    Intrathecal synthesis of Ig, oligoclonal bands or other abnormal proteins in the CSF could not be demonstrated in aged non-demen- ted and demented patients.

    The blood-cerebrospinal barrier (B-CSF-B) or blood-brain barrier (BBB) function alters with age and this alteration was shown to be more pronounced in MID and AD-MID patients. In MID and AD-MID patients the BBB alteration involves primarily the grey matter while in AD/SDAT patients the alteration would appear to involve only the white matter. The BBB dysfunction and a possible complement activation, either through antibody-anti- gen activation or other complement activators, was visualized in MID and AD-MID patients as perivascular serum protein depo­sits in the grey matter, always with a capillary in the center. The occurrence of some serum proteins in plaques, and the previously descibed localization of plaques in close relation­ship to the capillaries, suggest that altered BBB function and serum factors may be involved in the etiology and maturation of plaques while the etiology and maturation of tangles may not be directly dependent on these factors, as they were never labelled with any of the antisera studied.

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  • 19.
    Albertsson, Jakob
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Effekt av förbehandling vid detektion av muterat superoxiddismutas-1 protein: Immunohistokemisk detektion av SOD1 aggregat hos G93A transgena möss2016Independent thesis Basic level (professional degree), 180 HE creditsStudent thesis
  • 20.
    Albertsson, Jakob
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Effekt av förbehandling vid detektion av muterat superoxiddismutas-1 protein: Immunohistokemisk detektion av SOD1 aggregat hos G93A transgena möss2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
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  • 21. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bas Bueno-de-Mesquita, H
    Jansen, Eugene
    van Duijnhoven, Fränzel J B
    Fedirko, Veronika
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Romaguera, Dora
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Masala, Giovanna
    Agnoli, Claudia
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Naska, Androniki
    Bamia, Christina
    Peeters, Petra H
    Rodríguez, Laudina
    Buckland, Genevieve
    Sánchez, María-José
    Dorronsoro, Miren
    Huerta, Jose-María
    Barricarte, Aurelio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E
    Tsilidis, Konstantinos K
    Pischon, Tobias
    Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study.2011In: Cancer prevention research (Philadelphia, Pa.), ISSN 1940-6215, Vol. 4, no 11, p. 1873-83Article in journal (Refereed)
    Abstract [en]

    Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case-control study that included 1,093 incident cases matched (1:1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16-1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57-2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45-2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e.g., RR = 1.91; 95% CI: 1.47-2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02-2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions. Cancer Prev Res; 4(11); 1873-83. ©2011 AACR.

  • 22. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Jansen, Eugene
    van Duijnhoven, Franzel J. B.
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Riboli, Elio
    Gunter, Marc J.
    Westphal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Buckland, Genevieve
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Menendez, Virginia
    Peeters, Petra H.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Allen, Naomi E.
    Crowe, Francesca L.
    Khaw, Kay-Tee
    Wareham, Nickolas
    Pischon, Tobias
    Leptin and soluble leptin receptor in risk of colorectal cancer in the European prospective investigation into Cancer and nutrition cohort2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 20, p. 5328-5337Article in journal (Refereed)
    Abstract [en]

    Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P-trend = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P-trend = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P-trend = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P-trend = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. Cancer Res; 72(20); 5328-37. (C) 2012 AACR.

  • 23. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H Bas
    Jansen, Eugene
    van Duijnhoven, Fränzel JB
    Fedirko, Veronika
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Romaguera, Dora
    Westphal, Sabine
    Overvad, Kim
    Tjønneland, Anne
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Agnoli, Claudia
    Mattiello, Amalia
    Saieva, Calogero
    Vineis, Paolo
    Tumino, Rosario
    Peeters, Petra H
    Argüelles, Marcial
    Bonet, Catalina
    Sánchez, María-José
    Dorronsoro, Miren
    Huerta, Jose-María
    Barricarte, Aurelio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Crowe, Francesca L
    Pischon, Tobias
    Total and high-molecular-weight adiponectin and risk of colorectal cancer: the European prospective investigation into cancer and nutrition study2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 6, p. 1211-1218Article in journal (Refereed)
    Abstract [en]

    Adiponectin - an adipose-tissue-derived protein may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high-molecular-weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite they were hypothesised to have differential biological activities, i.e. regulating insulin sensitivity (HMW-adiponectin) versus inflammatory response (non-HMW-adiponectin). In a prospective nested case-control study we investigated whether pre-diagnostic serum concentrations of total, HMW and non-HMW-adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon, 451 rectal) were matched to 1206 controls using incidence density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW-adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53-0.95, P (trend)=0.03 for total adiponectin and 0.45, 95%CI=0.34-0.61, P (trend)<0.0001 for non-HMW-adiponectin]. HMW-adiponectin concentrations were not associated with CRC risk (RR=0.91, 95%CI=0.68-1.22, P (trend)=0.55). Non-HMW-adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR=0.39, 95%CI=0.26-0.60, P (trend)<0.0001); whereas the association with total adiponectin was no longer significant (RR=0.81, 95%CI=0.60-1.09, P (trend)=0.23). When stratified by cancer site, non-HMW-adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW-adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms.

  • 24. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Nöthlings, Ute
    Jenab, Mazda
    Fedirko, Veronika
    Kaaks, Rudolf
    Lukanova-McGregor, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Boffetta, Paolo
    Trepo, Elisabeth
    Westhpal, Sabine
    Duarte-Salles, Talita
    Stepien, Magdalena
    Overvad, Kim
    Tjønneland, Anne
    Halkjær, Jytte
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Lagiou, Pagona
    Bamia, Christina
    Benetou, Vassiliki
    Agnoli, Claudia
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, Bas
    Peeters, Petra H
    Gram, Inger Torhild
    Lund, Eiliv
    Weiderpass, Elisabete
    Quirós, J Ramón
    Agudo, Antonio
    Sánchez, María-José
    Gavrila, Diana
    Barricarte, Aurelio
    Dorronsoro, Miren
    Ohlsson, Bodil
    Lindkvist, Björn
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C
    Riboli, Elio
    Pischon, Tobias
    Inflammatory and metabolic biomarkers and risk of liver and bilary tract cancer2014In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 60, no 3, p. 858-871Article in journal (Refereed)
    Abstract [en]

    Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however there is little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intra-hepatic bile duct (IBD) and gallbladder and bilary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Over an average of 7.7 years, 296 participants developed HCC (n=125), GBTC (n=137) or IBD (n=34). Using risk set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total, high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured and incidence rate ratios (IRRs) and 95% confidence intervals (CI-s) estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection and adiposity measures, higher concentrations of CRP, IL-6, C-peptide and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95%CI = 1.02-1.46, P=0.03; 1.90; 95%CI = 1.30-2.77, P=0.001; 2.25; 95%CI = 1.43-3.54, P=0.0005 and 2.09; 95%CI = 1.19-3.67, P=0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95%CI = 1.05-1.42, P=0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95%CI = 1.25-2.11, P=0.0003) and IBD (IRR = 10.5; 95%CI = 2.20-50.90, P=0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide and non-HMW adiponectin, and 0.46 for GLDH indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors.

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  • 25. Aleksandrova, Krasimira
    et al.
    Chuang, Shu-Chun
    Boeing, Heiner
    Zuo, Hui
    Tell, Grethe S
    Pischon, Tobias
    Jenab, Mazda
    Bueno-de-Mesquita, Bas
    Vollset, Stein Emil
    Midttun, Øivind
    Ueland, Per Magne
    Fedirko, Veronika
    Johansson, Mattias
    Weiderpass, Elisabete
    Severi, Gianluca
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Kühn, Tilman
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    Jakszyn, Paula
    Sánchez, María-José
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Travis, Ruth C
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Panico, Salvatore
    May, Anne M
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kong, So Yeon J
    Freisling, Heinz
    Gunter, Marc J
    Lu, Yunxia
    Cross, Amanda J
    Riboli, Elio
    Vineis, Paolo
    A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 4, article id djv010Article in journal (Refereed)
    Abstract [en]

    Background: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. Results: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P-difference = .87) and after excluding case patients diagnosed within the first four follow-up years. Conclusions: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

  • 26. Aleksandrova, Krasimira
    et al.
    Drogan, Dagmar
    Boeing, Heiner
    Jenab, Mazda
    Bas Bueno-de-Mesquita, H
    Jansen, Eugene
    van Duijnhoven, Fränzel J B
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Kaaks, Rudolf
    Riboli, Elio
    Gunter, Marc J
    Romaguera, Dora
    Westhpal, Sabine
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Vidalis, Pavlos
    Panico, Salvatore
    Agnoli, Claudia
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Buckland, Genevieve
    Sánchez-Cruz, José-Juan
    Dorronsoro, Miren
    Díaz, María José Tormo
    Barricarte, Aurelio
    Ramon Quiros, J
    Peeters, Petra H
    May, Anne M
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crowe, Francesca L
    Khaw, Kay-Tee
    Wareham, Nickolas
    Pischon, Tobias
    Adiposity, mediating biomarkers and risk of colon cancer in the European prospective investigation into cancer and nutrition study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 3, p. 612-621Article in journal (Refereed)
    Abstract [en]

    Adiposity is a risk factor for colon cancer, but underlying mechanisms are not well understood. We evaluated the extent to which 11 biomarkers with inflammatory and metabolic actions mediate the association of adiposity measures, waist circumference (WC) and body mass index (BMI), with colon cancer in men and women. We analyzed data from a prospective nested case-control study among 662 incident colon cancer cases matched within risk sets to 662 controls. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. The percent effect change and corresponding CIs were estimated after adjusting for biomarkers shown to be associated with colon cancer risk. After multivariable adjustment, WC was associated with colon cancer risk in men (top vs. bottom tertile RR 1.68, 95% CI 1.06-2.65; ptrend  = 0.02) and in women (RR 1.67, 95% CI 1.09-2.56; ptrend  = 0.03). BMI was associated with risk only in men. The association of WC with colon cancer was accounted mostly for by three biomarkers, high-density lipoprotein cholesterol, non-high-molecular-weight adiponectin and soluble leptin receptor, which in combination explained 46% (95% CI 37-57%) of the association in men and 50% (95% CI 40-65%) of the association in women. Similar results were observed for the associations with BMI in men. These data suggest that alterations in levels of these metabolic biomarkers may represent a primary mechanism of action in the relation of adiposity with colon cancer. Further studies are warranted to determine whether altering their concentrations may reduce colon cancer risk.

  • 27. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Boeing, Heiner
    Jansen, Eugene
    Bueno-de-Mesquita, H Bas
    Rinaldi, Sabina
    Riboli, Elio
    Overvad, Kim
    Dahm, Christina C
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Kaaks, Rudolf
    Rohrmann, Sabine
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    van Duijnhoven, Fränzel JB
    Leufkens, Anke M
    Peeters, Petra H
    Rodríguez, Laudina
    Bonet, Catalina
    Sánchez, María-José
    Dorronsoro, Miren
    Navarro, Carmen
    Barricarte, Aurelio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E
    Spencer, Elizabeth
    Romaguera, Dora
    Norat, Teresa
    Pischon, Tobias
    Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition2010In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 172, no 4, p. 407-418Article in journal (Refereed)
    Abstract [en]

    The authors investigated associations between serum C-reactive protein (CRP) concentrations and colon and rectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (1992-2003) among 1,096 incident cases and 1,096 controls selected using risk-set sampling and matched on study center, age, sex, time of blood collection, fasting status, menopausal status, menstrual cycle phase, and hormone replacement therapy. In conditional logistic regression with adjustment for education, smoking, nutritional factors, body mass index, and waist circumference, CRP showed a significant nonlinear association with colon cancer risk but not rectal cancer risk. Multivariable-adjusted relative risks for CRP concentrations of > or = 3.0 mg/L versus <1.0 mg/L were 1.36 (95% confidence interval (CI): 1.00, 1.85; P-trend = 0.01) for colon cancer and 1.02 (95% CI: 0.67, 1.57; P-trend = 0.65) for rectal cancer. Colon cancer risk was significantly increased in men (relative risk = 1.74, 95% CI: 1.11, 2.73; P-trend = 0.01) but not in women (relative risk = 1.06, 95% CI: 0.67, 1.68; P-trend = 0.13). Additional adjustment for C-peptide, glycated hemoglobin, and high density lipoprotein cholesterol did not attenuate these results. These data provide evidence that elevated CRP concentrations are related to a higher risk of colon cancer but not rectal cancer, predominantly among men and independently of obesity, insulin resistance, and dyslipidemia.

  • 28. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Fedirko, Veronika
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Duijnhoven, Franzel J. B.
    Jansen, Eugene
    Rinaldi, Sabina
    Romieu, Isabelle
    Ferrari, Pietro
    Murphy, Neil
    Gunter, Marc J.
    Riboli, Elio
    Westhpal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Trichopoulou, Antonia
    Bamia, Christina
    Orfanos, Philippos
    Agnoli, Claudia
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra H.
    Duell, Eric J.
    Molina-Montes, Esther
    Ramon Quiros, J.
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Pischon, Tobias
    Boeing, Heiner
    Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)2014In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 29, no 4, p. 261-275Article in journal (Refereed)
    Abstract [en]

    A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development.

  • 29.
    Alenius, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    MicroRNAs in plasma as biomarkers for aggressive prostate cancer2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 30. Aleskog, Anna
    et al.
    Tobin, Gerard
    Laurell, Anna
    Thunberg, Ulf
    Lindhagen, Elin
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Nilsson, Kenneth
    Nygren, Peter
    Sundström, Christer
    Hägglund, Martin
    Larsson, Rolf
    Rosenquist, Richard
    VH gene mutation status and cellular drug resistance in chronic lymphocytic leukaemia.2004In: Eur J Haematol, ISSN 0902-4441, Vol. 73, no 6, p. 407-11Article in journal (Refereed)
  • 31.
    Alexeyev, O. A.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jahns, A. C.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sampling and detection of skin Propionibacterium acnes: Current status2012In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 5, p. 479-483Article, review/survey (Refereed)
    Abstract [en]

    A connection between acne vulgaris and Propionibacterium acnes has long been suggested. Over the years, several human skin microbiota sampling methods have been evolved and applied, e.g. swab, scrape, extraction techniques including cyanoacrylate gel sampling as well as punch biopsy. Collected samples have been processed following various methodologies ranging from culture studies to probe labelling and molecular analysis. Direct visualization techniques have recently shown the existence of anatomically distinct skin P acnes populations: epidermal and follicular. P. acnes biofilms appear to be a common phenomenon. Current sampling approaches target different skin populations of P. acnes and the presence of microbial biofilms can influence the retrieval of P. acnes. The anatomical considerations must be taken into account while interpreting microbiological data. (C) 2012 Elsevier Ltd. All rights reserved.

  • 32.
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bacterial landscape of human skin: seeing the forest for the trees2013In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 22, no 7, p. 443-446Article in journal (Refereed)
    Abstract [en]

    Skin harbours large communities of colonizing bacteria. The same bacterial species can exist in different physiological states: viable, dormant, non-viable. Each physiological state can have a different impact on skin health and disease. Various analytical methodologies target different physiological states of bacteria, and this must be borne in mind while interpreting microbiological tests and drawing conclusions about possible cause-effect relationships.

  • 33.
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Is it time to switch on or off the green light for ultraviolet-induced red fluorescence as a surrogate marker for Propionibacterium acnes in vivo?2017In: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 26, no 1, p. 26-27Article in journal (Refereed)
  • 34.
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Psoriasis, gut and microbiome2019In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 181, no 6, p. 1126-1126Article in journal (Other academic)
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  • 35.
    Alexeyev, Oleg A.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dekio, I.
    Layton, A. M.
    Li, H.
    Hughes, H.
    Morris, T.
    Zouboulis, C. C.
    Patrick, S.
    Why we continue to use the name Propionibacterium acnes2018In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 179, no 5, p. 1227-1227Article in journal (Other academic)
  • 36.
    Alexeyev, Oleg A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundskog, Bertil
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ganceviciene, Ruta
    Palmer, Ruth H
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    McDowell, Andrew
    Patrick, Sheila
    Zouboulis, Christos
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Pattern of tissue invasion by Propionibacterium acnes in acne vulgaris2012In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 67, no 1, p. 63-66Article in journal (Refereed)
  • 37.
    Alexeyev, Oleg A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Shannon, Beverley
    Golovleva, Irina
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Charlotte
    Eriksson, Irene
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Cohen, Ronald
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Direct visualization of Propionibacterium acnes in prostate tissue by multicolor fluorescent in situ hybridization assay.2007In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 11, p. 3721-8Article in journal (Refereed)
    Abstract [en]

    Prostate tissues from patients with prostate cancer and benign prostatic hyperplasia (BPH) frequently contain histological inflammation, and a proportion of these patients show evidence of Propionibacterium acnes infection in the prostate gland. We developed a multicolor fluorescent in situ hybridization (FISH) assay targeting P. acnes 23S rRNA along with a 14-kb region of the P. acnes genome. This assay was used to analyze prostate tissues from patients with prostate cancer and BPH. P. acnes infection of the prostate gland was demonstrated in prostatic tissue in 5 of 10 randomly selected prostate cancer patients. FISH analysis and confocal laser microscopy imaging revealed intracellular localization and stromal biofilm-like aggregates as common forms of P. acnes infection in prostate tissues from both prostate cancer and BPH patients. A sequential analysis of prostate tissue from individual patients suggested that P. acnes can persist for up to 6 years in the prostate gland. These results indicate that P. acnes can establish a persistent infection in the prostate gland. Further study is needed to clarify the link between this bacterium and prostatic inflammation which may contribute to the development of BPH and prostate cancer.

  • 38.
    Alexeyev, Oleg A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zouboulis, Christos C
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Shooting at skin propionibacterium acnes: to be or not to be on target2013In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, no 9, p. 2292-2294Article in journal (Refereed)
  • 39.
    Alexeyev, Oleg
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Bergh, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wiklund, Fredrik
    Grönberg, Henrik
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Association between the presence of bacterial 16S RNA in prostate specimens taken during transurethral resection of prostate and subsequent risk of prostate cancer (Sweden)2006In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 17, no 9, p. 1127-1133Article in journal (Refereed)
    Abstract [en]

    Objective: To study bacterial 16S RNA in archival prostate samples from 352 patients with benign prostate hyperplasia (BPH) and evaluate whether the presence of bacterial DNA was different in those who later developed prostate cancer (n = 171) and in the matched controls that did not progress to cancer (n = 181).

    Methods: 16S DNA PCR followed by cloning and sequencing the positive samples.

    Results: In 96/352 (27%) of the prostate tissue specimens 16S RNA were detected. Sequence analysis revealed Propionibacterium acnes as the predominant microorganism (23% of 16S RNA positive patients). The second most frequent isolate—Escherichia coli was found in 12 (12%) patients. The other isolates included Pseudomonas sp. (3 patients), Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P. acnes positive samples 62% exhibited severe histological inflammation versus 50% in the bacteria-negative group (p = 0.602). The presence of P. acnes in the prostate was associated with prostate cancer development (OR 2.17, 95% CI 0.77–6.95).

    Conclusions: This study has revealed P. acnes as the most common bacteria in the prostate in BPH. Further studies are needed to clarify its role in contributing to the development of prostatic inflammation and prostate cancer.

  • 40.
    Alexeyev, Oleg
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olsson, Jan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Is there evidence for a role of Propionibacterium acnes in prostatic disease?2009In: Urology, ISSN 1527-9995, Vol. 73, no 2, p. 220-224Article in journal (Refereed)
  • 41.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Universite catholique de Louvain, Bruxelles, Belgium.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Altered mRNA Expression of Genes Involved in Endocannabinoid Signalling in Squamous Cell Carcinoma of the Oral Tongue2019In: Cancer Investigation, ISSN 0735-7907, E-ISSN 1532-4192, Vol. 37, no 8, p. 327-338Article in journal (Refereed)
    Abstract [en]

    Little is known about the endocannabinoid (eCB) system in squamous cell carcinoma of the oral tongue (SCCOT). Here we have investigated, at the mRNA level, expression of genes coding for the components of the eCB system in tumour and non-malignant samples from SCCOT patients. Expression of NAPEPLD and PLA2G4E, coding for eCB anabolic enzymes, was higher in the tumour tissue than in non-malignant tissue. Among genes coding for eCB catabolic enzymes, expression of MGLL was lower in tumour tissue while PTGS2 was increased. It is concluded that the eCB system may be dysfunctional in SCCOT.

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  • 42.
    Alhouayek, Mireille
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Stafberg, Linda
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Karlsson, Jessica
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Effects of orthotopic implantation of rat prostate tumour cells upon components of the N-acylethanolamine and monoacylglycerol signalling systems: an mRNA study2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6314Article in journal (Refereed)
    Abstract [en]

    There is good evidence that the N-acylethanolamine (NAE)/monoacylglycerol (MAG) signalling systems are involved in the pathogenesis of cancer. However, it is not known how prostate tumours affect these systems in the surrounding non-malignant tissue and vice versa. In the present study we have investigated at the mRNA level 11 components of these systems (three coding for anabolic enzymes, two for NAE/MAG targets and six coding for catabolic enzymes) in rat prostate tissue following orthotopic injection of low metastatic AT1 cells and high metastatic MLL cells. The MLL tumours expressed higher levels of Napepld, coding for a key enzyme in NAE synthesis, and lower levels of Naaa, coding for the NAE hydrolytic enzyme N-acylethanolamine acid amide hydrolase than the AT1 tumours. mRNA levels of the components of the NAE/MAG signalling systems studied in the tissue surrounding the tumours were not overtly affected by the tumours. AT1 cells in culture expressed Faah, coding for the NAE hydrolytic enzyme fatty acid amide hydrolase, at much lower levels than Naaa. However, the ability of the intact cells to hydrolyse the NAE arachidonoylethanolamide (anandamide) was inhibited by an inhibitor of FAAH, but not of NAAA. Treatment of the AT1 cells with interleukin-6, a cytokine known to be involved in the pathogenesis of prostate cancer, did not affect the expression of the components of the NAE/MAG system studied. It is thus concluded that in the model system studied, the tumours show different expressions of mRNA coding for key the components of the NAE/MAG system compared to the host tissue, but that these changes are not accompanied by alterations in the non-malignant tissue.

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  • 43. Allen, Naomi E
    et al.
    Key, Timothy J
    Dossus, Laure
    Rinaldi, Sabina
    Cust, Anne
    Lukanova, Annekatrin
    Peeters, Petra H
    Onland-Moret, N Charlotte
    Lahmann, Petra H
    Berrino, Franco
    Panico, Salvatore
    Larrañaga, Nerea
    Pera, Guillem
    Tormo, Maria-José
    Sánchez, Maria-José
    Ramón Quirós, J
    Ardanaz, Eva
    Tjønneland, Anne
    Olsen, Anja
    Chang-Claude, Jenny
    Linseisen, Jakob
    Schulz, Mandy
    Boeing, Heiner
    Lundin, Eva
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Palli, Domenico
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Bingham, Sheila
    Khaw, Kay-Tee
    Bas Bueno-de-Mesquita, H
    Trichopoulou, Antonia
    Trichopoulos, Dimitiros
    Naska, Androniki
    Tumino, Rosario
    Riboli, Elio
    Kaaks, Rudolf
    Endogenous sex hormones and endometrial cancer risk in women in the European Prospective Investigation into Cancer and Nutrition (EPIC).2008In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 15, no 2, p. 485-497Article in journal (Refereed)
    Abstract [en]

    Epidemiological data show that reproductive and hormonal factors are involved in the etiology of endometrial cancer, but there is little data on the association with endogenous sex hormone levels. We analyzed the association between prediagnostic serum concentrations of sex steroids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition using a nested case-control design of 247 incident endometrial cancer cases and 481 controls, matched on center, menopausal status, age, variables relating to blood collection, and, for premenopausal women, phase of menstrual cycle. Using conditional regression analysis, endometrial cancer risk among postmenopausal women was positively associated with increasing levels of total testosterone, free testosterone, estrone, total estradiol, and free estradiol. The odds ratios (ORs) for the highest versus lowest tertile were 2.66 (95% confidence interval (CI) 1.50-4.72; P=0.002 for a continuous linear trend) for estrone, 2.07 (95% CI 1.20-3.60; P=0.001) for estradiol, and 1.66 (95% CI 0.98-2.82; P=0.001) for free estradiol. For total and free testosterone, ORs for the highest versus lowest tertile were 1.44 (95% CI 0.88-2.36; P=0.05) and 2.05 (95% CI 1.23-3.42; P=0.005) respectively. Androstenedione and dehydroepiandrosterone sulfate were not associated with risk. Sex hormone-binding globulin was significantly inversely associated with risk (OR for the highest versus lowest tertile was 0.57, 95% CI 0.34-0.95; P=0.004). In premenopausal women, serum sex hormone concentrations were not clearly associated with endometrial cancer risk, but numbers were too small to draw firm conclusions. In conclusion, relatively high blood concentrations of estrogens and free testosterone are associated with an increased endometrial cancer risk in postmenopausal women.

  • 44.
    Almanza-Aguilera, Enrique
    et al.
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Guiñón-Fort, Daniel
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Perez-Cornago, Aurora
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Martínez-Huélamo, Miriam
    Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
    Andrés-Lacueva, Cristina
    Biomarkers and Nutrimetabolomics Laboratory, Department of Nutrition, Food Sciences and Gastronomy, Nutrition and Food Safety Research Institute (INSA), Food Innovation Network (XIA), Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark; Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
    Eriksen, Anne Kirstine
    Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
    Katzke, Verena
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Bajracharya, Rashmita
    Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Masala, Giovanna
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network—ISPRO, Florence, Italy.
    Oliverio, Andreina
    Hyblean Association for Epidemiological Research (AIRE-ONLUS), Ragusa, Italy.
    Tumino, Rosario
    Hyblean Association for Epidemiological Research (AIRE-ONLUS), Ragusa, Italy.
    Manfredi, Luca
    Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
    Lasheras, Cristina
    Functional Biology Department, University of Oviedo, Oviedo, Spain.
    Crous-Bou, Marta
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Sánchez, Maria-José
    Granada Cancer Registry, Andalusian School of Public Health (EASP), Instituto de Investigación Biosanitaria Ibs. GRANADA, University of Granada, Granada, Spain; Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
    Amiano, Pilar
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Epidemiology of Chronic and Communicable Diseases Group, BioGipuzkoa Health Research Institute, San Sebastian, Spain.
    Colorado-Yohar, Sandra M.
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
    Guevara, Marcela
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
    Sonestedt, Emily
    Nutritional Epidemiology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Bjartell, Anders
    Department of Urology, Skåne University Hospital, Malmö, Sweden.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Weiderpass, Elisabete
    International Agency for Research on Cancer (IARC/WHO), Lyon, France.
    Aune, Dagfinn
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Nutrition, Oslo New University College, Oslo, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
    Aglago, Elom K.
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Travis, Ruth C.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Zamora-Ros, Raul
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
    Intake of the total, classes, and subclasses of (poly)phenols and risk of prostate cancer: a prospective analysis of the EPIC study2023In: Cancers, ISSN 2072-6694, Vol. 15, no 16, article id 4067Article in journal (Refereed)
    Abstract [en]

    Existing epidemiological evidence regarding the potential role of (poly)phenol intake in prostate cancer (PCa) risk is scarce and, in the case of flavonoids, it has been suggested that their intake may increase PCa risk. We investigated the associations between the intake of the total and individual classes and subclasses of (poly)phenols and the risk of PCa, including clinically relevant subtypes. The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort included 131,425 adult men from seven European countries. (Poly)phenol intake at baseline was assessed by combining validated center/country-specific dietary questionnaires and the Phenol-Explorer database. Multivariable-adjusted Cox proportional hazards models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). In total, 6939 incident PCa cases (including 3501 low-grade and 710 high-grade, 2446 localized and 1268 advanced, and 914 fatal Pca cases) were identified during a mean follow-up of 14 years. No associations were observed between the total intake of (poly)phenols and the risk of PCa, either overall (HRlog2 = 0.99, 95% CI 0.94–1.04) or according to PCa subtype. Null associations were also found between all classes (phenolic acids, flavonoids, lignans, and stilbenes) and subclasses of (poly)phenol intake and the risk of PCa, overall and according to PCa subtype. The results of the current large prospective cohort study do not support any association between (poly)phenol intake and PCa incidence.

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  • 45. Alvarez, S.
    et al.
    Calin, A.
    Sixtensdotter Graffmo, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Moldovan, M.
    Krarup, C.
    PERIPHERAL MOTOR AXONS OF SOD1(G127X) MUTANT MICE ARE SUSCEPTIBLE TO ACTIVITY-DEPENDENT DEGENERATION2013In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 241, p. 239-249Article in journal (Refereed)
    Abstract [en]

    Motor neuron disorders may be associated with mitochondrial dysfunction, and repetitive electrical impulse conduction during energy restriction has been found to cause neuronal degeneration. The aim of this study was to investigate the vulnerability of motor axons of a presymptomatic late-onset, fast-progression SOD1(G127x) mouse model of amyotrophic lateral sclerosis to long-lasting, high-frequency repetitive activity. Tibial nerves were stimulated at ankle in 7 to 8-month-old SOD1(G127X) mice when they were clinically indistinguishable from wild-type (WT) mice. The evoked compound muscle action potentials and ascending compound nerve action potentials were recorded from plantar muscles and from the sciatic nerve, respectively. Repetitive stimulation (RS) was carried out in interrupted trains of 200-Hz for 3 h. During the stimulation-sequence there was progressive conduction failure in WT and, to a lesser extent, in the SOD1(G127x). By contrast, 3 days after RS the electrophysiological responses remained reduced in the SOD1(G127x) but recovered completely in WT. Additionally, morphological studies showed Wallerian degeneration in the disease model. Nerve excitability testing by "threshold-tracking" showed that axons recovering from RS had changes in excitability suggestive of membrane hyperpolarization, which was smaller in the SOD1(G127x) than in WT. Our data provide proof-of-principle that SOD1(G127x) axons are less resistant to activity-induced changes in ion-concentrations. It is possible that in SOD1(G127x) there is inadequate energy-dependent Na+/K+ pumping, which may lead to a lethal Na+ overload. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 46. Al-Zoughool, Mustafa
    et al.
    Dossus, Laure
    Kaaks, Rudolf
    Clavel-Chapelon, Françoise
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Gauthier, Estelle
    Linseisen, Jakob
    Chang-Claude, Jenny
    Boeing, Heiner
    Schulz, Mandy
    Trichopoulou, Antonia
    Chryssa, Travezea
    Trichopoulos, Dimitrios
    Berrino, Franco
    Palli, Domenico
    Mattiello, Amalia
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Peeters, Petra H M
    Gram, Inger T
    Braaten, Tonje
    Lund, Eiliv
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Agudo, Antonio
    Larrañaga, Nerea
    Quirós, Jose Ramon
    Berglund, Göran
    Manjer, Jonas
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Bingham, Sheila
    Allen, Naomi
    Key, Tim
    Jenab, Mazda
    Cust, Anne E
    Rinaldi, Sabina
    Riboli, Elio
    Risk of endometrial cancer in relationship to cigarette smoking: Results from the EPIC study.2007In: International Journal of Cancer, ISSN 1097-0215, Vol. 121, no 12, p. 2741-7Article in journal (Refereed)
  • 47.
    Andersson, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oji, Yusuke
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sugiyama, Haruo
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Prognostic significance of specific anti-WT1 IgG antibody level in plasma in patients with ovarian carcinoma2014In: Cancer Medicine, E-ISSN 2045-7634, Vol. 3, no 4, p. 909-918Article in journal (Refereed)
    Abstract [en]

    Ovarian carcinoma (OC) has a poor prognosis and lack early effective screening markers. Wilm's tumor gene 1 (WT1) is overexpressed in OCs. Therefore, it is of great interest to investigate whether WT1-specific antibody (Ab) measurements in plasma can serve as a biomarker of anti-OC response, and is of importance in relation to patient prognosis. Peripheral blood samples were obtained from a total of 103 women with ovarian tumors with median being 1 day (range 0-48 days) before operation. WT1 IgG Ab levels were evaluated using enzyme-linked immunosorbent assay (ELISA). Immunohistochemical analysis of WT1 protein expression was performed on OC tissue samples. We found that low-WT1 Ab level in plasma was related to improved survival in patients diagnosed at stages III-IV and grade 3 carcinomas. Positive WT1 protein staining on OC tissue samples had a negative impact on survival in the entire cohort, both overall survival (OS) (P = 0.046) and progression-free survival (PFS) (P = 0.006), but not in the serous OC subtype. Combining WT1 IgG Ab levels and WT1 staining, patients with high-WT1 IgG Ab levels in plasma and positive WT1 protein staining in cancer tissues had shorter survival, with a significant association in PFS (P = 0.016). These results indicated that WT1 Ab measurements in plasma and WT1 staining in tissue specimens could be useful as biomarkers for patient outcome in the high-risk subtypes of OCs for postoperative individualized therapy.

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  • 48.
    Andersson Evelönn, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10219-10228Article in journal (Refereed)
    Abstract [en]

    Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

  • 49.
    Andersson Evelönn, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.