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Journal of Pathology

Daniel Nava Rodrigues, Gunther Boysen, Semini Sumanasuriya, George Seed, Angelo M De Marzo, Johann de Bono
Prostate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognized as biomarkers of resistance to AR-targeted therapy such as abiraterone or enzalutamide...
October 18, 2016: Journal of Pathology
Hilaire C Lam, Julie S Nijmeh, Elizabeth P Henske
In just the past five years, dramatic changes have occurred in the clinical management of Tuberous Sclerosis Complex (TSC). Detailed knowledge about the role of the TSC proteins in regulating the activity of the mammalian Target of Rapamycin Complex 1 (mTORC1) underlies this paradigm-shifting progress. Advances continue to be made in understanding the genetic pathogenesis of the different tumours that occur in TSC, including pivotal discoveries using next-generation sequencing (NGS). For example, the pathogenesis of angiofibromas is now known to involve UV-induced mutations, and the pathogenesis of multifocal renal cell carcinoma (RCC) in TSC is now known to result from distinct second-hit mutations...
October 18, 2016: Journal of Pathology
Yoshihiro Komohara, Motohiro Takeya
Many non-tumour host cells such as inflammatory cells, fibroblasts and endothelial cells are present in the tumour microenvironment and affect the malignant potential and chemo-resistance of the tumour cells. Macrophages and fibroblasts are the main components of infiltrating stromal cells and are referred to as tumour-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), respectively. TAMs and CAFs are reported to be involved in tumour progression, although their functions change to those of an anti-tumour phenotype under specific conditions...
October 18, 2016: Journal of Pathology
Martina Gatzka
Tumor necrosis factor alpha (TNF-α) and Interleukin 17 (IL-17) are key cytokines driving psoriasis and other inflammatory autoimmune diseases and thus represent effective targets for anti-psoriatic therapy. In a recent issue of The Journal of Pathology, Leite Dantas et al. explore a mouse model of TNF-mediated psoriasiform dermatitis and arthritis with Doxycyclin-inducible general over-expression of human TNF (ihTNFtg mice) for the contributions of macrophages and T cells in skin inflammation - with some unexpected and interesting findings...
October 17, 2016: Journal of Pathology
Youn Jin Choi, Je-Keun Rhee, Soo Young Hur, Min Sung Kim, Sung Hak Lee, Yeun-Jun Chung, Tae-Min Kim, Sug Hyung Lee
Intra-individual tumoural heterogeneity (ITH) is a hallmark of solid tumours and impedes accurate genomic diagnosis and selection of proper therapy. The purpose of this study was to identify ITH of ovarian high-grade serous carcinomas (OSCs) and to determine the utility of ascitic cancer cells as a resource for mutation profiling in spite of ITH. We performed whole-exome sequencing, copy number profiling, and DNA methylation profiling of four OSC genomes using multiregional biopsy from 13 intra-ovarian lesions, 12 extra-ovarian tumour lesions (omentum/peritoneum), and ascitic cells...
October 14, 2016: Journal of Pathology
Yan Sun, Ping Ji, Tao Chen, Xinhui Zhou, Da Yang, Yuhong Guo, Yuexin Liu, Limei Hu, Dianren Xia, Yanxue Liu, Asha S Multani, Ilya Shmulevich, Raju Kucherlapati, Scott Kopetz, Anil K Sood, Stanley R Hamilton, Baocun Sun, Wei Zhang
The gene encoding Migration and Invasion Inhibitory Protein (MIIP), located on 1p36.22, is a potential tumour suppressor gene in glioma. In this study, we aimed to explore the role and mechanism of action of MIIP in colorectal cancer (CRC). MIIP protein expression gradually decreased along the colorectal adenoma-carcinoma sequence and was negatively correlated with lymph node and distant metastasis in 526 colorectal tissue samples (P<0.05 for all). Analysis of The Cancer Genome Atlas (TCGA) data showed that decreased MIIP expression was significantly associated with MIIP hemizygous deletion (P=0...
October 14, 2016: Journal of Pathology
Trevor A Graham, Andrea Sottoriva
The temporal dynamics of cancer evolution remain elusive because it is impractical to longitudinally observe cancers unperturbed by treatment. Consequently, our knowledge of how cancers grow largely derives from inferences made from a single point in time - the end point in the cancer's evolution when it is removed from the body and studied in the lab. Fortuitously however, the cancer genome, by virtue of on-going mutations that uniquely mark clonal lineages within the tumour, provides a rich yet surreptitious record of cancer development...
October 14, 2016: Journal of Pathology
Mariia Lunova, Peggy Schwarz, Renwar Nuraldeen, Kateryna Levada, Deniz Kuscuoglu, Michael Stützle, Maja Vujic, Johannes Haybaeck, Piotr Ruchala, Milan Jirsa, Jean-Christophe Deschemin, Sophie Vaulont, Christian Trautwein, Pavel Strnad
Iron is both an essential and a potentially toxic element and its systemic homeostasis is controlled by the iron-hormone hepcidin. Hepcidin binds to the cellular iron exporter ferroportin, causes its degradation and thereby diminishes iron uptake from the intestine and the release of iron from macrophages. Given that hepcidin-resistant ferroportin mutant mice display exocrine pancreas dysfunction, we analysed pancreata of aging hepcidin knockout mice (KOs). Hepcidin and Hfe KOs were compared to wild type animals (WTs) kept on standard or iron-rich diets...
October 14, 2016: Journal of Pathology
Lin Xiao, Andrew C Dudley
In the heart and other organs, endothelial-mesenchymal transition (EndMT) has emerged as an important developmental process that involves coordinated migration, differentiation, and proliferation of the endothelium. In multiple disease states including cancer angiogenesis and cardiovascular disease, the processes that regulate EndMT are recapitulated, albeit in an uncoordinated and dysregulated manner. Members of the transforming growth factor beta (TGFβ) super-family are well known to impart cellular plasticity during EndMT by the timely activation (or repression) of transcription factors and miRNAs in addition to epigenetic regulation of gene expression...
October 4, 2016: Journal of Pathology
Jason C H Chiang, David W Ellison
Advances in our understanding of the biology of paediatric central nervous system (CNS) tumours have encouraged pathologists to use molecular markers alongside histopathological analysis for disease classification or prognostication and treatment stratification. In this article, we review molecular genetic alterations in paediatric CNS tumours, including those in low-grade and high-grade gliomas, ependymomas, and embryonal tumours. Some of these molecular changes with clinicopathological utility have been used for the first time in the most recent edition of the World Health Organization (WHO) classification of CNS tumours to define entities like ependymoma, RELA fusion-positive or diffuse midline glioma, H3 K27M-mutant...
October 4, 2016: Journal of Pathology
Giuseppe Arena, Enza Maria Valente
The gene PINK1 [phosphatase and tensin homolog (PTEN)-induced putative kinase 1] encodes a serine/threonine kinase which was initially linked to the pathogenesis of a familial form of Parkinson's disease. Research on PINK1 has recently unravelled that its multiple functions extend well beyond neuroprotection, implicating this eclectic protein in a growing number of human pathologies, including cancer, diabetes, cardiopulmonary dysfunctions and inflammation. Extensive studies have identified PINK1 as a crucial player in the mitochondrial quality control pathway, required to label damaged mitochondria and promote their elimination through an autophagic process (mitophagy)...
October 4, 2016: Journal of Pathology
Sofia Theodoropoulou, David A Copland, Jian Liu, Jiahui Wu, Peter J Gardner, Ema Ozaki, Sarah L Doyle, Matthew Campbell, Andrew D Dick
Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. Loss of retinal pigment epithelium (RPE) is a major pathological hallmark in AMD with or without pathological neovascularization. Although activation of the immune system is implicated in disease progression, pathological pathways remain diverse and unclear. Here, we report an unexpected protective role of a pro-inflammatory cytokine, interleukin-33 (IL-33) in ocular angiogenesis. IL-33 and its receptor (ST2) are expressed constitutively in human and murine retina and choroid...
October 4, 2016: Journal of Pathology
Daniel Peckham, Thomas Scambler, Sinisa Savic, Michael F McDermott
Immune-mediated autoinflammatory diseases are occupying an increasingly prominent position among the pantheon of debilitating conditions that afflict mankind. This review focuses on some of the key developments which have occurred since the original description of autoinflammatory disease in 1999, and focuses on underlying mechanisms that trigger autoinflammation. The monogenic autoinflammatory disease range has expanded considerably during that time, and now includes a broad spectrum of disorders, including relatively common conditions such as cystic fibrosis and subsets of systemic lupus erythematosus...
September 29, 2016: Journal of Pathology
Lei Wang, Marisol Cano, Sayantan Datta, Hong Wei, Katayoon B Ebrahimi, Yara Gorashi, Cecilia Garlanda, James T Handa
The discovery that genetic abnormalities in complement factor H (FH) are associated with increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of innate immunity that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components...
September 23, 2016: Journal of Pathology
Sara J Brown
Atopic eczema (synonymous with atopic dermatitis and eczema) is a common heterogeneous phenotype with a wide spectrum of severity from mild transient disease to a severe chronic disorder with atopic and non-atopic co-morbidities. Eczema is a complex trait, resulting from the interaction of multiple genetic and environmental factors. The skin, as an organ that can be biopsied easily, provides opportunities for detailed molecular genetic analysis. Strategies applied to the investigation of atopic eczema include candidate gene and genome-wide studies, extreme phenotypes and comparative analysis of inflammatory skin diseases...
September 23, 2016: Journal of Pathology
Charlotte L Alston, Mariana C Rocha, Nichola Z Lax, Doug M Turnbull, Robert W Taylor
Mitochondria are double membrane-bound organelles that are present in all nucleated eukaryotic cells and responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control - the 16.6 kb mitochondrial genome encoding just 37 genes with the remaining ~1300 proteins of the mitoproteome encoded by nuclear genes. Mitochondrial dysfunction can arise due to defects in either mtDNA or nuclear mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity with symptoms affecting a single organ or tissue, or multisystem involvement...
September 23, 2016: Journal of Pathology
Hsuan-Shun Huang, Che-Fang Hsu, Sung-Chao Chu, Pao-Chu Chen, Dah-Ching Ding, Meng-Ya Chang, Tang-Yuan Chu
Fallopian tube fimbrial epithelium is considered the major origin of ovarian high-grade serous carcinoma, with p53 loss being the earliest and universal change. We previously reported that reactive oxygen species (ROS) in the ovulatory follicular fluids (FFs) are mutagenic and cytotoxic to fimbrial epithelial cells that bathe in the peritoneal fluid mixed with FFs. Here, we observed that ferryl haemoglobin (Hb), which was abundantly present in ovulatory FFs and pelvic peritoneal fluids, could rescue p53-deficient immortalized fimbrial epithelial (FE25) cells and oviduct epithelial cells from Trp53-null mice from lethal ovulatory ROS stress...
September 14, 2016: Journal of Pathology
Janette K Burgess, Thais Mauad, Gavin Tjin, Jenny C Karlsson, Gunilla Westergren-Thorsson
The lung is built of airways and lung parenchyma and the extracellular matrix (ECM) contains the main building blocks of both components. The ECM provides physical support and stability to the lung, and as such it has in the past been regarded as an inert structure. More recent research has provided novel insights revealing that ECM is also a bioactive environment that orchestrates the cellular responses in its environs. Changes in the ECM in the airway or parenchymal tissues are now recognised in the pathological profile of many respiratory diseases, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF)...
September 14, 2016: Journal of Pathology
Rowan S Hardy, Craig L Doig, Zahrah Hussain, Mary O'Leary, Stuart A Morgan, Mark J Pearson, Amy Naylor, Simon W Jones, Andrew Filer, Paul M Stewart, Christopher D Buckley, Gareth G Lavery, Mark S Cooper, Karim Raza
Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC-activating enzyme that is potently upregulated by inflammation within mesenchymal-derived tissues. We assessed the regulation of this enzyme with inflammation in muscle, and examined its functional impact on muscle. The expression of 11β-HSD1 in response to proinflammatory stimuli was determined in a transgenic murine model of chronic inflammation (TNF-Tg) driven by overexpression of tumour necrosis factor (TNF)-α within tissues, including muscle...
August 31, 2016: Journal of Pathology
Elisa Gomez Perdiguero, Athanasia Liabotis-Fontugne, Mélanie Durand, Clément Faye, Sylvie Ricard-Blum, Manuel Simonutti, Sébastien Augustin, Bryan M Robb, Michel Paques, David M Valenzuela, Andrew J Murphy, George D Yancopoulos, Gavin Thurston, Ariane Galaup, Catherine Monnot, Stéphane Germain
Dynamic control of endothelial cell junctions is essential for vascular homeostasis and angiogenesis. We recently provided genetic evidence that ANGPTL4 is a key regulator of vascular integrity both during developmental and hypoxia-induced pathological conditions. The purpose of the present study is to decipher the molecular mechanisms through which ANGPTL4 regulates vascular integrity. Using surface plasmon resonance and proximity ligation assays, we show that ANGPTL4 binds αvβ3 integrin. In vitro and in vivo functional assays using Angptl4-deficient mice demonstrate that ANGPTL4/αvβ3 interaction is necessary to mediate ANGPTL4-vasoprotective effects...
August 31, 2016: Journal of Pathology
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