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  • 1. DeLuca, S.
    et al.
    Sitara, D.
    Kang, K.
    Marsell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Taguchi, T.
    Erben, R. G.
    Razzaque, M. S.
    Lanske, Beate
    Amelioration of the premature ageing-like features of Fgf-23 knockout mice by genetically restoring the systemic actions of FGF-232008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, no 3, p. 345-355Article in journal (Refereed)
    Abstract [en]

    Genetic ablation of fibroblast growth factor 23 from mice (Fgf-23−/−) results in a short lifespan with numerous abnormal biochemical and morphological features. Such features include kyphosis, hypogonadism and associated infertility, osteopenia, pulmonary emphysema, severe vascular and soft tissue calcifications, and generalized atrophy of various tissues. To determine whether these widespread anomalies in Fgf-23−/− mice can be ameliorated by genetically restoring the systemic actions of FGF-23, we generated Fgf-23−/− mice expressing the human FGF-23 transgene in osteoblasts under the control of the 2.3 kb α1(I) collagen promoter (Fgf-23−/−/hFGF-23-Tg double mutants). This novel mouse model is completely void of all endogenous Fgf-23 activity, but produces human FGF-23 in bone cells that is subsequently released into the circulation. Our results suggest that lack of Fgf-23 activities results in extensive premature ageing-like features and early mortality of Fgf-23−/− mice, while restoring the systemic effects of FGF-23 significantly ameliorates these phenotypes, with the resultant effect being improved growth, restored fertility, and significantly prolonged survival of double mutants. With regard to their serum biochemistry, double mutants reversed the severe hyperphosphataemia, hypercalcaemia, and hypervitaminosis D found in Fgf-23−/− littermates; rather, double mutants show hypophosphataemia and normal serum 1,25-dihydroxyvitamin D3 levels similar to pure FGF-23 Tg mice. These changes were associated with reduced renal expression of NaPi2a and 1α-hydroxylase, compared to Fgf-23−/− mice. FGF-23 acts to prevent widespread abnormal features by acting systemically to regulate phosphate homeostasis and vitamin D metabolism. This novel mouse model provides us with an in vivo tool to study the systemic effects of FGF-23 in regulating mineral ion metabolism and preventing multiple abnormal phenotypes without the interference of native Fgf-23.

  • 2.
    Dieterich, Lothar C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mellberg, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Langenkamp, Elise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Salomäki, Henriikka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Teichert, M.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kraus, T.
    Augustin, H. G.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Molema, G.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 228, no 3, p. 378-390Article in journal (Refereed)
    Abstract [en]

    Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.

  • 3.
    Enarsson, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nyberg, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Natl Vet Inst, Dept Microbiol, Uppsala, Sweden.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden;Uppsala Univ, Uppsala Univ Hosp, Dept Med Sci Canc Pharmacol & Computat Med, Uppsala, Sweden.
    Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 249, no 3, p. 295-307Article in journal (Refereed)
    Abstract [en]

    Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1 beta). IL1 beta induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called 'reactive GICs'. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 4.
    Enqvist, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sletten, Knut
    Biotechnology Centre of Oslo, University of Oslo, Norway.
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fibril protein fragmentation pattern in systemic AL-amyloidosis2009In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 219, no 4, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Immunoglobulin light chain (AL)-amyloidosis was one of the first types of amyloidosis discovered and still little is known about its pathogenic mechanisms. One major obstacle is the very heterogeneous condition; in fact, every patient could be considered to have their own disease since symptoms and outcome vary enormously. The reason for this is not known but intrinsic factors of the immunoglobulin light chain (LC) and the fact that every LC is unique seem to be important. Post-translational modifications such as glycosylation and proteolysis are most certainly involved. By using western blotting, we studied in detail the proteolytic pattern in six patients with AL-amyloidosis of kappa type with the aid of three peptide antisera against two domains in the constant segment and one conserved domain in framework 3 of the variable region. Materials from one to five organs were analysed. The result clearly demonstrates that the fragmentation pattern was similar in amyloid of different organs in one patient but differed greatly between patients. Full-length, N-, and C-terminal fragments were detected with the three antisera. The results strongly support the hypothesis that proteolytic cleavage occurs after fibril formation.

  • 5. Hale, L J
    et al.
    Welsh, G I
    Perks, C M
    Hurcombe, J A
    Moore, S
    Hers, I
    Saleem, M A
    Mathieson, P W
    Murphy, A J
    Jeansson, Marie
    Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital.
    Holly, J M
    Hardouin, S N
    Coward, R J
    Insulin-like growth factor-II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse2013In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 230, no 1, p. 95-106Article in journal (Refereed)
    Abstract [en]

    Podocytes are crucial for preventing the passage of albumin into the urine and, when lost, are associated with the development of albuminuria, renal failure and cardiovascular disease. Podocytes have limited capacity to regenerate, therefore pro-survival mechanisms are critically important. Insulin-like growth factor-II (IGF-II) is a potent survival and growth factor; however, its major function is thought to be in prenatal development, when circulating levels are high. IGF-II has only previously been reported to continue to be expressed in discrete regions of the brain into adulthood in rodents, with systemic levels being undetectable. Using conditionally immortalized human and ex vivo adult mouse cells of the glomerulus, we demonstrated the podocyte to be the major glomerular source and target of IGF-II; it signals to this cell via the IGF-I receptor via the PI3 kinase and MAPK pathways. Functionally, a reduction in IGF signalling causes podocyte cell death in vitro and glomerular disease in vivo in an aged IGF-II transgenic mouse that produces approximately 60% of IGF-II due to a lack of the P2 promoter of this gene. Collectively, this work reveals the fundamental importance of IGF-II in the mature podocyte for glomerular health across mammalian species.

  • 6. Hansson, Sara F.
    et al.
    Korsgren, Stella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enteroviruses and the pathogenesis of type 1 diabetes revisited: cross-reactivity of enterovirus capsid protein (VP1) antibodies with human mitochondrial proteins2013In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 229, no 5, p. 719-728Article in journal (Refereed)
    Abstract [en]

    Current or recent enteroviral infections show an association with type 1 diabetes. However, evidence for this has mainly been generated using a particular mouse monoclonal antibody (clone 5-D8/1) which binds the viral capsid protein VP1. Difficulty in confirming these findings using other independent methods has led to the concern that this might be artefactual. To address this, we examined the potential cross-reactivity of clone 5-D8/1 with normal islet proteins. Western blotting, two-dimensional gel electrophoresis, and mass spectrometry were used to identify human islet proteins bound by the clone 5-D8/1. We found a distinct reactivity with two mitochondrial proteins, creatine kinase B-type and ATP synthase beta subunit. Immunohistochemistry using the clone 5-D8/1 revealed a granular cytoplasmic staining pattern in mitochondria-rich cells, ie hepatocytes, ductal epithelial cells, vascular endothelial cells, skeletal muscle cells, and the neoplastic salivary gland oncocytoma cells, whereas connective tissue and infiltrating immune cells were negative. Staining on islets of Langerhans from subjects with recent-onset type 1 diabetes, but not on isolated human islets infected in vitro with enteroviruses, could be blocked after mixing the clone 5-D8/1 with the mitochondrial proteins. Collectively, our data show that the clone 5-D8/1 detects two human mitochondrial enzymes in addition to enteroviral VP1. The notion that the previously reported VP1 positivity in islets of recent-onset type 1 diabetes patients could reflect cross-reactivity to native islet proteins and not the presence of EV is supported by difficulties in demonstrating EV infection by independent techniques such as PCR or in situ hybridization. These findings call for revisiting the presence of enteroviruses in pancreatic islets of patients with type 1 diabetes.

  • 7.
    Horie, Masafumi
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan;RIKEN, Ctr Life Sci Technol, DGT, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa, Japan.
    Miyashita, Naoya
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Mikami, Yu
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Lab Med Reg Skane, Pathol, Lund, Sweden.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan.
    An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 2, p. 154-165Article in journal (Refereed)
    Abstract [en]

    Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.

  • 8. Iggo, Richard
    et al.
    Rudewicz, Justine
    Monceau, Elodie
    Sevenet, Nicolas
    Bergh, Jonas
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Bonnefoi, Herve
    Validation of a yeast functional assay for p53 mutations using clonal sequencing2013In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 231, no 4, p. 441-448Article in journal (Refereed)
    Abstract [en]

    We have previously tested biopsies from 1469 breast tumours with a p53 functional assay in the context of a prospective clinical trial (EORTC 10994/BIG 1-00). The goal of the trial was to determine whether p53 status could be used to select patients who would benefit from inclusion of taxanes in anthracycline-based chemotherapy. The results of the trial were negative. To test whether this was because the functional assay misclassified the tumours, we have reanalysed two groups of biopsies by Sanger sequencing and Roche 454 next generation sequencing (NGS). Comparison of yeast data with pooled cDNA sequencing data in an initial cohort of 69 biopsies showed that conventional sequencing is insensitive when the mutant p53 content is low. A second cohort of 48 biopsies was used to compare directly the yeast assay with Sanger and NGS technology. The mutant sequence was difficult to detect in sequence chromatograms of pooled cDNA, whereas NGS unequivocally identified mutations in every case classified as mutant by the functional assay. The NGS data showed that small deletions, probably caused by PCR splicing, account for most of the unexplained background in the yeast assay. We conclude that mutation detection techniques that test multiple clones, such as the p53 functional assay and NGS, are more reliable than Sanger sequencing of pooled DNA; that the high p53 mutation rate (44%) seen with the yeast assay in the EORTC 10994/BIG 1-00 trial reflects this high sensitivity; and that NGS with Roche 454 technology could be used to identify the p53 mutations in the remaining tumours previously tested in yeast in the EORTC10994/BIG 1-00 trial. 

  • 9.
    Ihse, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ybo, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Suhr, Ob
    Lindqvist, P
    Backman, C
    Westermark, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, no 2, p. 253-61Article in journal (Refereed)
    Abstract [en]

    Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.

  • 10.
    Kiflemariam, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mignardi, Marco
    Ali, Muhammad Akhtar
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Bergh, Anders
    Nilsson, Mats
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    In situ sequencing identifies TMPRSS2-ERG fusion transcripts, somatic point mutations and gene expression levels in prostate cancers2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 234, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    Translocations contribute to the genesis and progression of epithelial tumours and in particular to prostate cancerdevelopment. To better understand the contribution of fusion transcripts and visualize the clonal composition ofmultifocal tumours, we have developed a technology for multiplexin situdetection and identification of expressedfusion transcripts. When compared to immunohistochemistry,TMPRSS2–ERGfusion-negative and fusion-positiveprostate tumours were correctly classified. The most prevalentTMPRSS2–ERGfusion variants were visualized,identified, and quantitated in human prostate cancer tissues, and the ratio of the variant fusion transcripts couldfor the first time be directly determined byin situsequencing. Further, we demonstrate concurrentin situdetectionof gene expression, point mutations, and gene fusions of the prostate cancer relevant targetsAMACR,AR,TP53,andTMPRSS2–ERG. This unified approach toin situanalyses of somatic mutations can empower studies ofintra-tumoural heterogeneity and future tissue-based diagnostics of mutations and translocations.

  • 11.
    Meulmeester, Erik
    et al.
    Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC, Leiden, The Netherlands.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    The dynamic roles of TGF-beta in cancer2011In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 223, no 2, p. 205-218Article, review/survey (Refereed)
    Abstract [en]

    The transforming growth factor-beta (TGF-beta) signalling pathway plays a critical and dual role in the progression of human cancer. During the early phase of tumour progression, TGF-beta acts as a tumour suppressor, exemplified by deletions or mutations in the core components of the TGF-beta signalling pathway. On the contrary, TGF-beta also promotes processes that support tumour progression such as tumour cell invasion, dissemination, and immune evasion. Consequently, the functional outcome of the TGF-beta response is strongly context-dependent including cell, tissue, and cancer type. In this review, we describe the molecular signalling pathways employed by TGF-beta in cancer and how these, when perturbed, may lead to the development of cancer. Concomitantly with our increased appreciation of the molecular mechanisms that govern TGF-beta signalling, the potential to therapeutically target specific oncogenic sub-arms of the TGF-beta pathway increases. Indeed, clinical trials with systemic TGF-beta signalling inhibitors for treatment of cancer patients have been initiated. However, considering the important role of TGF-beta in cardiovascular and many other tissues, careful screening of patients is warranted to minimize unwanted on-target side effects.

  • 12.
    Mezheyeuski, Artur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bergsland, Christian Holst
    Backman, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Bruun, Jarle
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients.2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 244, no 4, p. 421-431Article in journal (Refereed)
    Abstract [en]

    Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore, we evaluated a fluorescence-based multiplexed immunohistochemical method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small-cell lung cancer (NSCLC). A tissue microarray including 57 NSCLC cases was stained with antibodies against CD8, CD20, CD4, FOXP3, CD45RO, and pan-cytokeratin, and immune cells were quantified in epithelial and stromal compartments. The results were compared with those of conventional IHC, and related to corresponding RNA-sequencing (RNAseq) expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r = 0.52), FOXP3 (r = 0.87), CD4 (r = 0.79), CD20 (r = 0.81) and CD8 (r = 0.90) cells. The correlation with RNAseq data for digital quantification (0.35-0.65) was comparable to or better than that for visual quantification (0.38-0.58). Combination of the signals of the five immune markers enabled further subpopulations of lymphocytes to be identified and localized. The specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8(+) T and cancer cells) or the relationships of lymphocyte subclasses with each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis. In conclusion, the fluorescence multiplexed immunohistochemical method, based on only one tissue section, provided reliable quantification and localization of immune cells in cancer tissue. The application of this technique to clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

  • 13. Mizuuchi, Masahito
    et al.
    Cindrova-Davies, Tereza
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Charnock-Jones, D Stephen
    Burton, Graham J
    Yung, Hong Wa
    Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6β: implications for the pathophysiology of human pregnancy complications2016In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 238, no 4, p. 550-561Article in journal (Refereed)
    Abstract [en]

    Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early-onset pre-eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high-risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early-onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down-regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6α and ATF6β in the syncytiotrophoblast of placentas from PE patients. Transcript analysis showed a decrease of PlGF mRNA, and an increase from genes encoding those UPR transcription factors, in placentas from cases of early-onset PE, but not in the late-onset (>34 weeks) PE, compared to term controls. Further investigations indicated a strong correlation between ATF4 and PlGF mRNA levels only (r = -0.73, p<0.05). These results could be recapitulated in trophoblast-like cells exposed to chemical inducers of ER stress or hypoxia/reoxygenation. The stability of PlGF transcripts was unchanged. The use of small interfering RNA specific for transcription factors in the UPR pathways revealed that ATF4 and ATF6β, but not ATF6α, modulate PlGF transcription. To conclude, ATF4 and ATF6β act synergistically in the negative regulation of PlGF mRNA expression, resulting in reduced PlGF secretion by the trophoblast in response to stress. Therefore, these results further support targeting of placental ER stress as a potential new therapeutic intervention for these pregnancy complications.

  • 14.
    Morin, Eric
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sjöberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tjomsland, Vegard
    University of Oslo, Department of Hepato-pancreato-biliary Surgery, Oslo University Hospital, Institute of Clinical Medicine, Oslo, Norway.
    Testini, Chiara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Franklin, Oskar
    Umeå University, Department of Surgery and Perioperative Sciences, Umeå, Sweden.
    Sund, Malin
    Umeå University, Department of Surgery and Perioperative Sciences, Umeå, Sweden.
    Öhlund, Daniel
    Umeå University, Department of Radiation Sciences, Umeå, Sweden ; Umeå University, Wallenberg Centre for Molecular Medicine, Umeå, Sweden.
    Kiflemariam, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöblom, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Claesson-Welsh, Lena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 3, p. 311-322Article in journal (Refereed)
    Abstract [en]

    Unstable and dysfunctional tumor vasculature promotes cancer progression and spread. Signal transduction by the pro-angiogenic vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) is modulated by VEGFA-dependent complex formation with neuropilin 1 (NRP1). NRP1 expressed on tumor cells can form VEGFR2/NRP1 trans-complexes between tumor cells and endothelial cells which arrests VEGFR2 on the endothelial surface, thus interfering with productive VEGFR2 signaling. In mouse fibrosarcoma, VEGFR2/NRP1 trans-complexes correlated with reduced tumor vessel branching and reduced tumor cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) strongly expressed NRP1 on both tumor cells and endothelial cells, in contrast to other common cancer forms. Using proximity ligation assay, VEGFR2/NRP1 trans-complexes were identified in human PDAC tumor tissue, and its presence was associated with reduced tumor vessel branching, reduced tumor cell proliferation, and improved patient survival after adjusting for other known survival predictors. We conclude that VEGFR2/NRP1 trans-complex formation is an independent predictor of PDAC patient survival. 

  • 15. Möller, E.
    et al.
    Stenman, G.
    Mandahl, N.
    Hamberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Mölne, L.
    van den Oord, J. J.
    Brosjö, O.
    Mertens, F.
    Panagopoulos, I.
    POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 1, p. 78-86Article in journal (Refereed)
    Abstract [en]

    The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and MUM in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.

  • 16.
    Pontén, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jirström, K.
    Uhlen, M.
    The Human Protein Atlas: a tool for pathology2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 216, no 4, p. 387-93Article in journal (Refereed)
    Abstract [en]

    Tissue-based diagnostics and research is incessantly evolving with the development of new molecular tools. It has long been realized that immunohistochemistry can add an important new level of information on top of morphology and that protein expression patterns in a cancer may yield crucial diagnostic and prognostic information. We have generated an immunohistochemistry-based map of protein expression profiles in normal tissues, cancer and cell lines. For each antibody, altogether 708 spots of tissues and cells are analysed and the resulting images and data are presented as freely available in the Human Protein Atlas (www.proteinatlas.org). The new version 4 of the atlas, including more than 5 million images of immunohistochemically stained tissues and cells, is based on 6122 antibodies, representing 5011 human proteins encoded by approximately 25% of the human genome. The gene-centric database includes a putative classification of proteins in various protein classes, both functional classes, such as kinases or transcription factors and project-related classes, such as candidate genes for cancer or cardiovascular diseases. For each of the internally generated antibodies, the exact antigen sequence is presented, together with a visualization of application-specific validation data, including a protein array assay, western blot analysis, immunohistochemistry and, in most cases, immunofluorescent-based confocal microscopy. The updated version also includes new search algorithms to allow complex queries regarding expression profiles, protein classes and chromosome location. Thus, the presented Human Protein Atlas provides a resource for pathology-based biomedical research, including protein science and biomarker discovery.

  • 17. Quirke, Phil
    et al.
    Cuvelier, Claude
    Ensari, Arzu
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Laurberg, Soren
    Ortiz, Hector
    Piard, Francoise
    Punt, Comelis J. A.
    Glenthoj, Anders
    Pennickx, Freddy
    Seymour, Matt
    Valentini, Vincenzo
    Williams, Geraint
    Nagtegaal, Iris D.
    Evidence-based medicine: the time has come to set standards for staging2010In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 221, no 4, p. 357-360Article in journal (Refereed)
    Abstract [en]

    For international communication in cancer, staging systems such as TNM are essential; however, the principles and processes used to decide about changes in every new edition of TNM need to be subject to debate. Changes with major impact for patient treatment are introduced without evidence. We think that TNM should be a continual reactive process, rather than a proactive process. Changes should only occur after extensive discussion within the community, and before the introduction of any changes these should be tested for reproducibility and compared to the currently used gold standard. TNM should not be used to test hypotheses. It should introduce established facts that are beneficial to predicting patient prognosis. TNM should thus be restructured on a basis equivalent to evidence-based guidelines. The strength of the evidence should be explicitly stated and the evidence base given. It is time for the principles of staging to be widely debated and new principles and processes to be introduced to ensure that we are not in the same situation in the future. The disparity between therapeutic decision making and TNM staging is marked and we would appeal for the radical overhaul of TNM staging to make it fit for the twenty-first century. TNM is central to the management of cancer patients and we must protect and enhance its reputation.

  • 18. Ribeiro, Ana Sofia
    et al.
    Sousa, Bárbara
    Carreto, Laura
    Mendes, Nuno
    Nobre, Ana Rita
    Ricardo, Sara
    Albergaria, André
    Cameselle-Teijeiro, Jorge F
    Gerhard, Rene
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Seruca, Raquel
    Santos, Manuel A
    Schmitt, Fernando
    Paredes, Joana
    P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model2013In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 229, no 5, p. 705-718Article in journal (Refereed)
    Abstract [en]

    P-cadherin overexpression is associated with worse breast cancer survival, being a poor prognostic marker as well as a putative therapeutic target for the aggressive triple-negative and basal-like carcinomas (TNBCs). Previously, we have shown that P-cadherin promotes breast cancer invasion of cells where membrane E-cadherin was maintained; however, it suppresses invasion in models without endogenous cadherins, like melanomas. Here, we investigated if P-cadherin expression would interfere with the normal adhesion complex and which were the cellular/molecular consequences, constituting, in this way, a new mechanism by which E-cadherin invasive-suppressor function was disrupted. Using breast TNBC models, we demonstrated, for the first time, that P-cadherin co-localizes with E-cadherin, promoting cell invasion due to the disruption caused in the interaction between E-cadherin and cytoplasmic catenins. P-cadherin also induces cell migration and survival, modifying the expression profile of cells expressing wild-type E-cadherin and contributing to alter their cellular behaviour. Additionally, E- and P-cadherin co-expressing cells significantly enhanced in vivo tumour growth, compared with cells expressing only E- or only P-cadherin. Finally, we still found that co-expression of both molecules was significantly correlated with high-grade breast carcinomas, biologically aggressive, and with poor patient survival, being a strong prognostic factor in this disease. Our results show a role for E- and P-cadherin co-expression in breast cancer progression and highlight the potential benefit of targeting P-cadherin in the aggressive tumours expressing high levels of this protein.

  • 19.
    Schwartz, Friederike H.
    et al.
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany.;Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Cai, Qian
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany..
    Fellmann, Eva
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Hartmann, Sylvia
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany..
    Mäyränpää, Mikko I.
    Univ Helsinki, Dept Pathol, Helsinki, Finland.;Univ Helsinki, Div Pathol, Meilahti Labs Pathol, HUSLAB,Cent Hosp, Helsinki, Finland..
    Karjalainen-Lindsberg, Marja-Liisa
    Univ Helsinki, Dept Pathol, Helsinki, Finland.;Univ Helsinki, Div Pathol, Meilahti Labs Pathol, HUSLAB,Cent Hosp, Helsinki, Finland..
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Scholtysik, René
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany..
    Hansmann, Martin-Leo
    Goethe Univ Frankfurt, Med Sch, Dr Senckenberg Inst Pathol, Frankfurt, Germany.;German Canc Consortium DKTK, Heidelberg, Germany..
    Küppers, Ralf
    Univ Duisburg Essen, Med Sch, Inst Cell Biol Canc Res, Virchowstr 173, D-45122 Essen, Germany.;German Canc Consortium DKTK, Heidelberg, Germany..
    TET2 mutations in B cells of patients affected by angioimmunoblastic T-cell lymphoma2017In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 242, no 2, p. 129-133Article in journal (Refereed)
    Abstract [en]

    Angioimmunoblastic T-cell lymphomas (AITLs) frequently carry mutations in the TET2 and IDH2 genes. TET2 mutations represent early genetic lesions as they had already been detected in haematopoietic precursor cells of AITL patients. We show by analysis of whole-tissue sections and microdissected PD1(+) cells that the frequency of TET2-mutated AITL is presumably even higher than reported (12/13 cases in our collection; 92%). In two-thirds of informative AITLs (6/9), a fraction of B cells was also TET2-mutated. Investigation of four AITLs by TET2 and IGHV gene sequencing of single microdissected B cells showed that between 10% and 60% of polyclonal B cells in AITL lymph nodes harboured the identical TET2 mutations of the respective T-cell lymphoma clone. Thus, TET2-mutated haematopoietic precursor cells in AITL patients not only give rise to the T-cell lymphoma but also generate a large population of mutated mature B cells. Future studies will show whether this is a reason why AITL patients frequently also develop B-cell lymphomas. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 20. Sillars-Hardebol, Anke H.
    et al.
    Carvalho, Beatriz
    Belien, Jeroen A. M.
    de Wit, Meike
    Delis-van Diemen, Pien M.
    Tijssen, Marianne
    van de Wiel, Mark A.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fijneman, Remond J. A.
    Meijer, Gerrit A.
    BCL2L1 has a functional role in colorectal cancer and its protein expression is associated with chromosome 20q gain2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 226, no 3, p. 442-450Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the second leading cause of cancer death in the western world. The majority of CRCs, which develop from adenoma precursor lesions, show gain of chromosome arm 20q, where BCL2L1 is located. BCL2L1 is an important apoptosis regulating gene that codes for both an anti-apoptotic (Bcl-xL) and a pro-apoptotic (Bcl-xS) splice variant. The aim of the present study was to investigate whether BCL2L1 contributes to 20q gain-driven colorectal adenoma-to-carcinoma progression. To this end, the functional role of BCL2L1 in cancer-related processes was investigated, and differences in BCL2L1 DNA, mRNA, and protein levels were compared between colorectal adenomas and CRCs, as well as between tumours with and without 20q gain. Down-modulation of BCL2L1 inhibited cell viability and anchorage-independent growth of CRC cells, while invasion was not affected. BCL2L1 DNA copy number and protein expression were increased in CRCs compared to adenomas (p = 0.00005 and p = 0.03, respectively), while mRNA expression was not. Differences in BCL2L1 protein expression were even more pronounced between tumours with and without 20q gain (p = 0.0001). In conclusion, BCL2L1 is functionally involved in several cancer-related processes and its protein expression is associated with 20q gain. This supports a role for 20q gain-dependent expression of BCL2L1 in colorectal adenoma-to-carcinoma progression. However, the absence of a direct correlation between BCL2L1 mRNA and protein expression implies that BCL2L1 protein expression is regulated at the post-transcriptional level by a distinct factor on the 20q amplicon (eg ZNF217, AURKA or miRNAs). Therefore, even though BCL2L1 affects CRC biology in a 20q gain-dependent manner, it is not likely to be a driver of chromosome 20q gain associated adenoma-to-carcinoma progression.

  • 21.
    Thijssen, Victor L. J. L.
    et al.
    Vrije Univ Amsterdam, Dept Med Oncol, Angiogenesis Lab, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands;Vrije Univ Amsterdam, Dept Radiat Oncol, Med Ctr, Amsterdam, Netherlands.
    Paulis, Yvette W. J.
    Vrije Univ Amsterdam, Dept Med Oncol, Angiogenesis Lab, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands;Maastricht Univ, GROW Sch Oncol & Dev Biol, Div Med Oncol, Med Ctr, Maastricht, Netherlands.
    Nowak-Sliwinska, Patrycja
    Vrije Univ Amsterdam, Dept Med Oncol, Angiogenesis Lab, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands;Univ Geneva, Sch Pharmaceut Sci, Geneva, Switzerland.
    Deumelandt, Katrin L.
    Vrije Univ Amsterdam, Dept Med Oncol, Angiogenesis Lab, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands.
    Hosaka, Kayoko
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Soetekouw, Patricia M. M. B.
    Maastricht Univ, GROW Sch Oncol & Dev Biol, Div Med Oncol, Med Ctr, Maastricht, Netherlands.
    Cimpean, Anca M.
    Victor Babes Univ Med & Pharm, Dept Microscop Morphol, Angiogenesis Res Ctr, Histol, Timisoara, Romania.
    Raica, Marius
    Victor Babes Univ Med & Pharm, Dept Microscop Morphol, Angiogenesis Res Ctr, Histol, Timisoara, Romania.
    Pauwels, Patrick
    Antwerp Univ Hosp, Dept Pathol, Edegem, Belgium.
    van den Oord, Joost J.
    Univ Leuven, Lab Translat Cell & Tissue Res, Leuven, Belgium.
    Tjan-Heijnen, Vivianne C. G.
    Maastricht Univ, GROW Sch Oncol & Dev Biol, Div Med Oncol, Med Ctr, Maastricht, Netherlands.
    Hendrix, Mary J.
    Shepherdstown Univ, Shepherd Univ, Dept Biol, Shepherdstown, WV USA.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Cao, Yihai
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Griffioen, Arjan W.
    Vrije Univ Amsterdam, Dept Med Oncol, Angiogenesis Lab, Med Ctr, De Boelelaan 1118, NL-1081 HV Amsterdam, Netherlands.
    Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth2018In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, no 4, p. 447-458Article in journal (Refereed)
    Abstract [en]

    Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

  • 22.
    Wester, Kenneth
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Andersson, Ann-Catrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ranefall, Petter
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Bengtsson, Evert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Cultured human fibroblasts in agarose gel as a multi-functional control for immunohistochemistry: Standardization Of Ki67 (MIB1) assessment in routinely processed urinary bladder carcinoma tissue2000In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 190, no 4, p. 503-11Article in journal (Refereed)
    Abstract [en]

    Immunohistochemistry (IHC) in clinical practice is hampered by lack of standardization and by subjectivity in interpretation and quantitation. This study aimed to develop a control system for IHC in routinely fixed and histoprocessed tissues. Such a system should be easy to handle in clinical practice and should reflect variations in fixation time, section thickness, section storage conditions, and staining protocols. In addition, in image analysis quantitation of immunostained tissues, when using classifiers computed on IHC-control images, the control system should be very stable. Cultured human fibroblasts were suspended in agarose, transferred into a length of tubing and stored at 4 degrees C. Three pieces of the cellgel control were separately fixed, histoprocessed, and paraffin-embedded as external controls. One piece was prepared together with each of 18 bladder carcinoma biopsies as internal controls. Slides with sections from the biopsy and all types of cellgel controls were stored at different temperatures and then stained using three different IHC protocols. The fibroblasts were homogeneously distributed in the agarose gel. Variation in section thickness did not influence immunostaining as evaluated by the MIB1 labelling index (MIB1 LI). The external controls decreased notably in MIB1 LI with increased fixation time. This was not seen in the 18 internal controls that were each fixed with a fresh biopsy. However, section storage and immunostaining conditions influenced the MIB1 expression equally in all control types and to a similar degree to the biopsies. Furthermore, colour-based image analysis quantitation of MIB1 LI in biopsies proved stable and independent of the control type used to compute the classifier.

  • 23.
    Xie, Yuan
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maturi, Naga P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, E-Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marinescu, Voichita D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tirfing, Malin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jin, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Chen, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Jiang, Yiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of Medical Biochemistry and Biophysics, Division of Molecular Neurobiology, Karolinska Institutet, Stockholm, Sweden.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 2, p. 228-240Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5(high)), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5(high)-ELDA(high) cultures were also significantly more malignant and invasive compared to the LGR5(high)-ELDA(low) cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 24.
    Xochelli, Aliki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Bikos, Vasilis
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.
    Polychronidou, Eleftheria
    CERTH, Informat Technol Inst, Thessaloniki, Greece;Ionian Univ, Dept Informat, Corfu, Greece.
    Galigalidou, Chrysi
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Agathangelidis, Andreas
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy;IRCCS San Raffaele Sci Inst, Dept Onco Hematol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Charlotte, Frederic
    Hop La Pitie Salpetriere, Dept Pathol, Paris, France;Sorbonne Univ, Paris, France.
    Moschonas, Panagiotis
    CERTH, Informat Technol Inst, Thessaloniki, Greece.
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Colombo, Monica
    Osped Policlin SanMartino, Mol Pathol, Genoa, Italy.
    Roumelioti, Maria
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece.
    Sutton, Lesley-Ann
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Groenen, Patricia
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands.
    van den Brand, Michiel
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands.
    Boudjoghra, Myriam
    Sorbonne Univ, Paris, France;Hop La Pitie Salpetriere, Dept Hematol, Paris, France.
    Algara, Patricia
    Hosp Virgen de la Salud, Toledo, Spain.
    Traverse-Glehen, Alexandra
    Univ Lyon 1, Hosp Civils Lyon, Dept Pathol & Hematol, Lyon, France.
    Ferrer, Ana
    Hosp Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain.
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Karypidou, Maria
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.
    Kalpadakis, Christina
    Univ Crete, Dept Haematol, Iraklion, Greece.
    Mollejo, Manuella
    Hosp Virgen de la Salud, Toledo, Spain.
    Pangalis, Gerasimos
    Athens Med Ctr, Dept Haematol, Athens, Greece.
    Vlamos, Panayiotis
    Ionian Univ, Dept Informat, Corfu, Greece.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.
    Gonzalez, David
    Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland.
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Pathol Unit, Milan, Italy.
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Giudicelli, Veronique
    Univ Montpellier, IMGTr, UMR CNRS UM, LIGM,IGH, Montpellier, France.
    Lefranc, Marie-Paule
    Univ Montpellier, IMGTr, UMR CNRS UM, LIGM,IGH, Montpellier, France.
    Espinet, Blanca
    Hosp Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain.
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece.
    Piris, Miguel Angel
    IIS Fdn Jimenez Diaz, Pathol Dept, Madrid, Spain.
    Du, Ming-Qing
    Univ Cambridge, Dept Pathol, Div Cellular & Mol Pathol, Cambridge, England.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece.
    Ferrarini, Manlio
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Tzovaras, Dimitrios
    CERTH, Informat Technol Inst, Thessaloniki, Greece.
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy;IRCCS San Raffaele Sci Inst, Dept Onco Hematol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Davi, Frederic
    Sorbonne Univ, Paris, France;Hop La Pitie Salpetriere, Dept Hematol, Paris, France.
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, no 4, p. 416-421Article in journal (Refereed)
    Abstract [en]

    The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.

  • 25. Yung, Hong Wa
    et al.
    Atkinson, Daniel
    Campion-Smith, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Charnock-Jones, D. Stephen
    Burton, Graham J.
    Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 234, no 2, p. 262-276Article in journal (Refereed)
    Abstract [en]

    Based on gestational age at diagnosis and/or delivery, pre-eclampsia (PE) is commonly divided into early-onset (<34 weeks) and late-onset (>= 34 weeks) forms. Recently, the distinction between 'placental' and 'maternal' causation has been proposed, with 'placental' cases being more frequently associated with early-onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress-signalling pathways, including unfolded protein response (UPR) pathways, MAPK stress pathways, heat-shock proteins and AMPK.. in placentae delivered by caesarean section for clinical indications at different gestational ages. Controls included second-trimester, pre-term and normal-term placentae. BeWo cells were used to investigate how these pathways react to different severities of hypoxia-reoxygenation (H/R) and pro-inflammatory cytokines. Activation of placental UPR and stress-response pathways, including P-IRE1 alpha, ATF6, XBP-1, GRP78 and GRP94, P-p38/p38 and HSP70, was higher in early-onset PE than in both late-onset PE and normotensive controls (NTCs), with a clear inflection around 34 weeks. Placentae from >= 34 weeks PE and NTC were indistinguishable. Levels of UPR signalling were similar between second-trimester and term controls, but were significantly higher in pre-term 'controls' delivered vaginally for chorioamnionitis and other conditions. Severe H/R (1/20% O-2) induced equivalent activation of UPR pathways, including P-eIF2 alpha, ATF6, P-IRE1 alpha, GRP78 and GRP94, in BeWo cells. By contrast, the pro-inflammatory cytokines TNF alpha and IL-1 beta induced only mild activation of P-eIF2 alpha and GRP78. AKT, a central regulator of cell proliferation, was reduced in the <34 weeks PE placentae and severe H/R-treated cells, but not in other conditions. These findings provide the first molecular evidence that placental stress may contribute to the pathophysiology of early-onset pre-eclampsia, whereas that is unlikely to be the case in the late-onset form of the syndrome. (c) 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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