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Journal of Pathology

Luting Yang, Shaolong Zhang, Gang Wang
Keratin 17 (K17) is a type I intermediate filament mainly expressed in the basal cells of epithelia. As a multifaceted cytoskeletal protein, K17 regulates a myriad of biological processes, including cell proliferation and growth, skin inflammation and hair follicle cycling. Aberrant overexpression of K17 is found in various diseases ranging from psoriasis to malignancies such as breast, cervical, oral squamous and gastric carcinomas. Moreover, genetic mutation in KRT17 is related to tissue-specific diseases, represented by steatocystoma multiplex and pachyonychia congenita...
October 10, 2018: Journal of Pathology
Neil Ashley, Djamila Ouaret, Walter F Bodmer
Colonic epithelial cells are highly polarised with a lumen-facing apical membrane, termed the brush border, and a basal membrane in contact with the underlying extracellular matrix (ECM). This polarity is often maintained in cancer tissue in the form of neoplastic glands and has prognostic value. We compared the cellular polarity of several ex vivo spheroid colonic cancer cultures with their parental tumours and found that those grown as non-attached colonies exhibited apical brush border proteins on their outer cellular membranes...
October 10, 2018: Journal of Pathology
Eliana Amato, Andrea Mafficini, Kenichi Hirabayashi, Rita T Lawlor, Matteo Fassan, Caterina Vicentini, Stefano Barbi, Pietro Delfino, Katarzyna Sikora, Borislav Rusev, Michele Simbolo, Irene Esposito, Davide Antonello, Antonio Pea, Elisabetta Sereni, Maria Ballotta, Laura Maggino, Giovanni Marchegiani, Nobuyuki Ohike, Laura D Wood, Roberto Salvia, Günter Klöppel, Giuseppe Zamboni, Aldo Scarpa, Vincenzo Corbo
Solid pseudopapillary neoplasms (SPN) of the pancreas are rare, low-grade malignant neoplasms that metastasise to the liver or peritoneum in 10-15% of cases. They almost invariably present somatic activating mutations of CTNNB1. No comprehensive molecular characterization of metastatic disease has been conducted to date. We performed whole-exome sequencing and copy-number variation (CNV) analysis of 10 primary SPN and comparative sequencing of 5 matched primary/metastatic tumour specimens by high-coverage targeted sequencing of 409 genes...
October 10, 2018: Journal of Pathology
Naser M Ali, Stefania Niada, Anna T Brini, Mark R Morris, Sathishkumar Kurusamy, Abdullah Alholle, David Huen, Cristina R Antonescu, Franck Tirode, Vaiyapuri Sumathi, Farida Latif
Undifferentiated pleomorphic sarcoma of bone (UPSb), is a rare primary bone sarcoma that lacks a specific line of differentiation. There is very little information about the genetic alterations leading to tumourigenesis or malignant transformation. Distinguishing between UPSb and other malignant bone sarcomas, including dedifferentiated chondrosarcoma and osteosarcoma, can be challenging due to overlapping features. To explore the genomic and transcriptomic landscape of UPSb tumours, whole-exome sequencing (WES) and RNA Sequencing (RNA-Seq) were performed on UPSb tumours...
October 3, 2018: Journal of Pathology
Anna Martner, Ebru Aydin, Kristoffer Hellstrand
The myeloid cell NADPH oxidase NOX2 generates reactive oxygen species (ROS) that participate in defense against microbial pathogens. Humans with compromised NOX2-mediated ROS formation develop chronic granulomatous disease characterized by recurrent bacterial and fungal infections. Additionally, impaired NOX2 function entails hyperactive lymphocytes and autoimmunity in humans and in murine models. The impact of NOX2 and ROS on cancer development is only partly explored. Recent research published in the Journal of Pathology showed that genetic depletion of any of the NOX2 subunits Cyba, Cybb, Ncf1, Ncf2 and Ncf4 reduced the formation of lung metastases following intravenous injection of murine tumor cells...
October 1, 2018: Journal of Pathology
Miguel Eugenio Zoubek, Marius Maximilian Woitok, Svenja Sydor, Leonard J Nelson, Lars P Bechmann, Maria Isabel Lucena, Raul J Andrade, Aalt Bast, Ger H Koek, Christian Trautwein, Francisco Javier Cubero
Ibuprofen is a worldwide used non-steroidal anti-inflammatory drug (NSAID) which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen-induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen-induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c-Jun N-terminal kinase 1 (Jnk1-/- ) or Jnk2 (Jnk2-/- ) expression and included investigations using animals with hepatocyte-specific Jnk deletion either genetically (Jnk1Δhepa ) or by siRNA (siJnk2Δhepa )...
September 27, 2018: Journal of Pathology
Darryl Shibata
A recent article published in this journal illuminates a rare example of somatic evolution where cells improve rather than deteriorate with age. In mitotic intestinal crypts, stem cells with higher levels of a deleterious heteroplasmic germline mitochondrial mutation are purged through time, leading to crypts without the mutation. Similar somatic mitochondrial mutations are not purged from crypts, indicating that special conditions are needed to improve with age. This article is protected by copyright. All rights reserved...
September 23, 2018: Journal of Pathology
Changhu Lee, Min Kim, Jun Ho Lee, Jiyoung Oh, Hyun-Hee Shin, Sang Min Lee, Philipp E Scherer, Hyug Moo Kwon, Jang Hyun Choi, Jiyoung Park
Extracellular matrix dysregulation is associated with chronic liver disease. CollagenVI-alpha3 chain (COL6A3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. High levels of COL6A3 and its cleaved product, endotrophin (ETP) in tumor-neighboring regions are strongly associated with poor prognosis in HCC patients. Here, we report that the high levels of ETP in injured hepatocytes induce JNK-dependent hepatocyte apoptosis and activate non-parenchymal cells to lead further activation of hepatic inflammation, fibrosis, and apoptosis...
September 23, 2018: Journal of Pathology
Linda Holmquist Mengelbier, Simon Lindell-Munther, Hiroaki Yasui, Caroline Jansson, Javanshir Esfandyari, Jenny Karlsson, Kimberly Lau, Chi-Chung Hui, Daniel Bexell, Sevan Hopyan, David Gisselsson
Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3- /Irx5- mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was activated already in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3-/- cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling...
September 23, 2018: Journal of Pathology
Julian Musa, Jing Li, Thomas G P Grünewald
Chronic hepatitis B virus (HBV) infection is a main risk factor for development of liver cirrhosis and hepatocellular carcinoma (HCC). Although HBV vaccination and antiviral therapy lead to substantial risk reduction for HCC development, it is evident that both can reduce, but not completely eliminate the risk. High serum levels of HBV surface antigen (HBsAg) were shown to predict disease progression of chronic HBV infection in patients harboring low viral load, and in line with this, HBV surface proteins were shown to exert oncogenic functions...
September 23, 2018: Journal of Pathology
Maria Catalina Gomez-Puerto, Prasanna Vasudevan Iyengar, Amaya García de Vinuesa, Peter Ten Dijke, Gonzalo Sanchez-Duffhues
Bone morphogenetic proteins (BMPs) are secreted cytokines that were initially discovered on the basis of their ability to induce bone. Several decades of research have now established that these proteins function in a large variety of physio-pathological processes. There are about 15 BMP family members, which signal via three transmembrane type II receptors and four transmembrane type I receptors. Mechanistically, BMP binding leads to phosphorylation of the type I receptor by the type II receptor. This activated heteromeric complex triggers intracellular signaling that is initiated by phosphorylation of receptor-regulated SMAD1, 5 and 8 (also termed R-SMADs)...
September 23, 2018: Journal of Pathology
Kevin M Elias, Petros Tsantoulis, Jean-Christophe Tille, Allison Vitonis, Leona A Doyle, Jason L Hornick, Gurkan Kaya, Laurent Barnes, Daniel W Cramer, Giacomo Puppa, Sarah Stuckelberger, Jagmohan Hooda, Pierre-Yves Dietrich, Michael Goggins, Candace L Kerr, Michael Birrer, Michelle S Hirsch, Ronny Drapkin, S Intidhar Labidi-Galy
Mucinous ovarian tumors (MOT) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCN) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOT and MCN share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOT and MCN. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors...
September 19, 2018: Journal of Pathology
Salvador Pérez, Sergio Rius-Pérez, Isabela Finamor, Pablo Martí-Andrés, Ignacio Prieto, Raquel García, María Monsalve, Juan Sastre
Obesity is associated with local and systemic complications in acute pancreatitis. PPARγ co-activator 1α (PGC-1α) is a transcriptional co-activator and master regulator of mitochondrial biogenesis that exhibits dysregulation in obese subjects. Our aims were 1) to study PGC-1α levels in pancreas from lean or obese rats and mice with acute pancreatitis; and 2) to determine the role of PGC-1α in the inflammatory response during acute pancreatitis elucidating the signaling pathways regulated by PGC-1α. Lean and obese Zucker rats and lean and obese C57BL6 mice were used first, and subsequently wild-type and PGC-1α knock-out (KO) mice with cerulein-induced pancreatitis were used to assess the inflammatory response and expression of target genes...
September 17, 2018: Journal of Pathology
Maria Alba Dosil, Raúl Navaridas, Cristina Mirantes, Jordi Tarragona, Núria Eritja, Isidre Felip, Izaskun Urdanibia, Cristina Megino, Mónica Domingo, Maria Santacana, Sònia Gatius, Carme Piñol, Carla Barceló, Oscar Maiques, Anna Macià, Ana Velasco, Marta Vaquero, Xavier Matias-Guiu, Xavier Dolcet
Many human cancers present PTEN deficiency and between 20-30% of colorectal tumors show PTEN loss. The transcription factor E2F-1 exhibits tumor promoter or suppressive functions depending on cellular type and tissue context however its role in the progression and development of colorectal carcinogenesis was largely unknown. Here, using a tamoxifen-inducible PTEN knock-out mouse model, we have demonstrated that loss of PTEN leads to the development of colorectal tumorigenesis through the serrated pathway. Next, we studied PTEN-loss driven colorectal lesions in the context of E2F-1 deficiency in vivo...
September 11, 2018: Journal of Pathology
Olivier Calvayrac, Ada Nowosad, Stéphanie Cabantous, Lin-Po Lin, Sarah Figarol, Pauline Jeannot, Murielle Serres, Caroline Callot, Renaud T Perchey, Justine Creff, Estelle Taranchon-Clermont, Isabelle Rouquette, Gilles Favre, Anne Pradines, Stephane Manenti, Julien Mazieres, Huei Lee, Arnaud Besson
The cell cycle inhibitor p27Kip1 is a tumor suppressor via the inhibition of CDK complexes in the nucleus. However, p27 also plays other functions in the cell and may acquire oncogenic roles when located in the cytoplasm. Activation of oncogenic pathways such as Ras or PI3K/AKT causes the relocalization of p27 in the cytoplasm where it can promote tumorigenesis by unclear mechanisms. Here, we investigated how cytoplasmic p27 participates in the development of non-small cell lung carcinomas. We provide molecular and genetic evidence that the oncogenic role of p27 is mediated at least in part by binding to and inhibiting the GTPase RhoB, which normally acts as a tumor suppressor in the lung...
September 11, 2018: Journal of Pathology
Yuhong Wang, Lin Hu, Jian Wang, Xiangwei Li, Sana Sahengbieke, Jingjing Wu, Maode Lai
High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by MDM2 (Murine Double Minute 2) in a proteasome-dependent manner. Here, we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in colorectal cancer (CRC) cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 knock-in promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo...
September 3, 2018: Journal of Pathology
Hiroto Kinoshita, Yoku Hayakawa, Mitsuru Konishi, Masahiro Hata, Mayo Tsuboi, Yuki Hayata, Yohko Hikiba, Sozaburo Ihara, Hayato Nakagawa, Tsuneo Ikenoue, Tetsuo Ushiku, Masashi Fukayama, Yoshihiro Hirata, Kazuhiko Koike
Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal-type gastric cancer, and Cdh1 mutation is associated with diffuse-type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage...
August 31, 2018: Journal of Pathology
Michele Cummings, Karen A Massey, Georgia Mappa, Nafisa Wilkinson, Richard Hutson, Sarika Munot, Sam Saidi, David Nugent, Timothy Broadhead, Alexander I Wright, Stuart Barber, Anna Nicolaou, Nicolas M Orsi
Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis, to integrate these with eicosanoid profiles in matched clinical specimens and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes...
August 31, 2018: Journal of Pathology
Peter W Johnson
Professor Eric Walker (Frederick) was well known to members of the Pathological Society of Great Britain and Ireland. Eric was born in Castle Douglas in Dumfriesshire on 21st December, 1934. He attended Kirkcudbright Academy. He graduated MBChB from Glasgow University in 1959 and, after house jobs, started a career in Pathology in Professor Symington's Department at Glasgow Royal Infirmary.
August 30, 2018: Journal of Pathology
Tianhong Su, John P Grady, Sorena Afshar, Stuart Ac McDonald, Robert W Taylor, Doug M Turnbull, Laura C Greaves
Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a stem cell taking over the niche and producing progenies...
August 26, 2018: Journal of Pathology
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