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Journal of Pathology

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https://www.readbyqxmd.com/read/28299802/bmp-and-notch-interaction-in-crc-subtypes
#1
Shazia Irshad, Mukesh Bansal, Paolo Guarnieri, Hayley Davis, Ayman Al Haj Zen, Brygida Baran, Claudia Maria Assunta Pinna, Haseeb Rahman, Sujata Biswas, Chiara Bardella, Rosemary Jeffery, Lai Mun Wang, James Edward East, Annabelle Lewis, Ian Tomlinson, Simon John Leedham
The functional role of Bone Morphogenetic Protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes...
March 15, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28299801/bi-allelic-alterations-in-dna-repair-genes-underpin-homologous-recombination-dna-repair-defects-in-breast-cancer
#2
Robert W Mutter, Nadeem Riaz, Charlotte K Y Ng, Rob Delsite, Salvatore Piscuoglio, Marcia Edelweiss, Luciano G Martelotto, Rita A Sakr, Tari A King, Dilip D Giri, Maria Drobnjak, Edi Brogi, Ranjit Bindra, Giana Bernheim, Raymond S Lim, Pedro Blecua, Alexis Desrichard, Dan Higginson, Russell Towers, Ruomu Jiang, William Lee, Britta Weigelt, Jorge S Reis-Filho, Simon N Powell
Homologous recombination (HR) DNA repair deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression and whole-exome sequencing was employed to ascertain the etiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures...
March 15, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28295365/comparative-transcriptome-analysis-of-isogenic-cell-line-models-and-primary-cancers-links-cic-loss-to-activation-of-the-mapk-signalling-cascade
#3
Veronique G LeBlanc, Marlo Firme, Jungeun Song, Susanna Y Chan, Min Hye Lee, Stephen Yip, Suganthi Chittaranjan, Marco A Marra
CIC encodes a transcriptional repressor whose disrupted activity appears to be involved in several cancer types, including Type I low-grade gliomas (LGGs) and stomach adenocarcinomas (STADs). To explore human CIC's transcriptional network in an isogenic background, we developed novel isogenic CIC knockout cell lines as model systems and used these in transcriptome analyses to study the consequences of CIC loss. We also compared our results to analyses of transcriptome data from TCGA for Type I LGGs and STADs...
March 15, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28295343/epithelial-membrane-protein-2-emp2-deficiency-alters-placental-angiogenesis-mimicking-features-of-human-placental-insufficiency
#4
Carmen J Williams, Alison Chu, Wendy N Jefferson, David Casero, Deepthi Sudhakar, Nevil Khurana, Claire P Hogue, Chinmayi Aryasomayajula, Priya Patel, Peggy Sullivan, Elizabeth Padilla-Banks, Shabnam Mohandessi, Carla Janzen, Madhuri Wadehra
Epithelial membrane protein-2 (EMP2) is a tetraspan protein predicted to regulate placental development. Highly expressed in secretory endometrium and trophectoderm cells, previous studies suggest that it may regulate implantation by orchestrating the surface expression of integrins and other membrane proteins. In order to test the role of EMP2 in pregnancy, mice lacking EMP2 (Emp2(-/-) ) were generated. Emp2(-/-) females are fertile but have reduced litter sizes when carrying Emp2(-/-) but not Emp2(+/-) fetuses...
March 14, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28295307/high-expression-of-insulin-receptor-on-tumor-associated-blood-vessels-in-invasive-bladder-cancer-predicts-poor-overall-and-progression-free-survival
#5
Filip Roudnicky, Lothar C Dieterich, Cedric Poyet, Lorenz Buser, Peter Wild, Dave Tang, Peter Camenzind, Chien Hsien Ho, Vivianne I Otto, Michael Detmar
Bladder cancer is a frequently recurring disease with a very poor prognosis when progressed to invasive stages, and tumor-associated blood vessels play a crucial role in this process. In order to identify novel biomarkers associated with progression, we isolated blood vascular endothelial cells (BECs) from human invasive bladder cancers and matched normal bladder tissue, and found that tumor-associated BECs greatly upregulated the expression of insulin receptor (INSR). High expression of INSR on BECs of invasive bladder cancers was significantly associated with shorter progression-free and overall survival...
March 14, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28247413/mesothelial-to-mesenchymal-transition-as-a-possible-therapeutic-target-in-peritoneal-metastasis-of-ovarian-cancer
#6
Angela Rynne-Vidal, Chi Lam Au-Yeung, José A Jiménez-Heffernan, María Luisa Pérez-Lozano, Lucía Cremades-Jimeno, Carmen Bárcena, Ignacio Cristóbal-García, Concepción Fernández-Chacón, Tsz Lun Yeung, Samuel C Mok, Pilar Sandoval, Manuel López-Cabrera
Peritoneal dissemination is the primary metastatic route of ovarian cancer (OvCa), often accompanied by accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can convert into carcinoma-associated fibroblasts (CAFs) through mesothelial-to-mesenchymal transition (MMT). Here, we demonstrate that MCs isolated from ascitic fluid (AFMCs) of OvCa patients with peritoneal implants also undergo MMT and promote subcutaneous tumour growth in mice. RNA sequencing of AFMCs revealed that MMT-related pathways-including TGF-β signalling-are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients...
March 1, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28240350/oncogenic-s1p-signalling-in-ebv-associated-nasopharyngeal-carcinoma-activates-akt-and-promotes-cell-migration-through-s1p-receptor-3
#7
Hui Min Lee, Kwok-Wai Lo, Wenbin Wei, Sai Wah Tsao, Grace Tin Yun Chung, Maha Hafez Ibrahim, Christopher W Dawson, Paul G Murray, Ian C Paterson, Lee Fah Yap
Undifferentiated nasopharyngeal carcinoma (NPC) is a cancer with high metastatic potential that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the functional contribution of sphingosine-1-phosphate (S1P) signalling to the pathogenesis of NPC. We show that EBV infection or ectopic expression of the EBV-encoded latent genes (EBNA1, LMP1 and LMP2A) can up-regulate sphingosine kinase 1 (SPHK1), the key enzyme that produces S1P, in NPC cell lines. Exogenous addition of S1P promotes the migration of NPC cells through the activation of AKT; shRNA knockdown of SPHK1 resulted in a reduction in the levels of activated AKT and inhibition of cell migration...
February 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28207159/the-critical-role-of-the-znf217-oncogene-in-promoting-breast-cancer-metastasis-to-the-bone
#8
Aurélie Bellanger, Caterina F Donini, Julie A Vendrell, Jonathan Lavaud, Irma Machuca-Gayet, Maëva Ruel, Julien Vollaire, Evelyne Grisard, Balázs Győrffy, Ivan Bièche, Olivier Peyruchaud, Jean-Luc Coll, Isabelle Treilleux, Véronique Maguer-Satta, Véronique Josserand, Pascale A Cohen
Bone metastasis affects more than 70% of patients with advanced breast cancer. However, the molecular mechanisms underlying this process remain unclear. Based on the analysis of clinical datasets, and in vitro and in vivo experiments, we report that the ZNF217 oncogene is a crucial mediator and indicator of bone metastasis. Patients with high ZNF217 mRNA expression levels in primary breast tumours had a higher risk of developing bone metastases. MDA-MB-231 breast cancer cells stably transfected with ZNF217 (MDA-MB-231-ZNF217) displayed the dysregulated expression of a set of genes with bone homing and metastasis characteristics, which overlapped with two previously described "osteolytic bone metastasis" gene signatures, while also highlighting the bone morphogenetic protein (BMP) pathway...
February 16, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28195647/molecular-classification-of-urothelial-carcinoma-global-mrna-classification-versus-tumour-cell-phenotype-classification
#9
Gottfrid Sjödahl, Pontus Eriksson, Fredrik Liedberg, Mattias Höglund
Global mRNA expression analysis is efficient for phenotypic profiling of tumours and has been used to define molecular subtypes for almost every major tumour type. A key limitation is that most tumours are communities of both tumour and non-tumour cells. This problem is particularly pertinent when analysing advanced invasive tumours, known to induce major changes and responses in both the tumour and the surrounding tissue. To identify bladder cancer tumour-cell phenotypes and compare classification by tumour-cell phenotype with classification by global gene expression analysis, we analysed 307 advanced bladder cancers (cystectomised) both by genome gene expression analysis and by immunohistochemistry using antibodies for 28 proteins...
February 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28191908/il-1beta-induces-thymic-stromal-lymphopoietin-and-an-atopic-dermatitis-like-phenotype-in-reconstructed-healthy-human-epidermis
#10
Marine Bernard, Cédric Carrasco, Léo Laoubi, Béatrice Guiraud, Aurore Rozières, Catherine Goujon, Hélène Duplan, Sandrine Bessou-Touya, Jean-François Nicolas, Marc Vocanson, Marie-Florence Galliano
Atopic dermatitis (AD) is a common skin inflammatory disease characterized by the production of thymic stromal lymphopoietin (TSLP) and a marked TH 2 polarization. Recent studies suggest that IL-1β contributes to the development of AD skin inflammation. Here, we have investigated the impact of IL-1β signalling on the epidermal homeostasis of both healthy subjects and AD patient [with functional filaggrin (FLG) alleles] with particular attention to TSLP production and keratinocyte differentiation. In healthy reconstructed human epidermis (RHE), IL-1β promoted: (i) a robust secretion of TSLP in an NFkB-dependant manner and (ii) a significant decrease in the expression of filaggrin and other proteins of the epidermal differentiation complex...
February 13, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28188630/genetic-analyses-of-isolated-high-grade-pancreatic-intraepithelial-neoplasia-hg-panin-reveal-paucity-of-alterations-in-tp53-and-smad4
#11
Waki Hosoda, Peter Chianchiano, James F Griffin, Meredith E Pittman, Lodewijk A A Brosens, Michaël Noë, Jun Yu, Koji Shindo, Masaya Suenaga, Neda Rezaee, Raluca Yonescu, Yi Ning, Jorge Albores-Saavedra, Naohiko Yoshizawa, Kenichi Harada, Akihiko Yoshizawa, Keiji Hanada, Shuji Yonehara, Michio Shimizu, Takeshi Uehara, Jaswinder S Samra, Anthony J Gill, Christopher L Wolfgang, Michael G Goggins, Ralph H Hruban, Laura D Wood
High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions...
February 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28188619/generation-of-conditional-oncogenic-chromosomal-translocations-using-crispr-cas9-genomic-editing-and-homology-directed-repair
#12
Lee Spraggon, Luciano G Martelotto, Julija Hmeljak, Tyler D Hitchman, Jiang Wang, Lu Wang, Emily K Slotkin, Pang-Dian Fan, Jorge S Reis-Filho, Marc Ladanyi
Chromosomal rearrangements encoding oncogenic fusion proteins are found in a wide variety of malignancies. The use of programmable nucleases to generate specific double-strand breaks in endogenous loci, followed by non-homologous end joining DNA repair, has allowed several of these translocations to be generated as constitutively expressed fusion genes within a cell population. Here, we describe a novel approach that combines CRISPR-Cas9 technology with homology-directed repair to engineer, capture and modulate the expression of chromosomal translocation products in a human cell line...
February 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28188614/foxa2-a-novel-protein-partner-of-tumour-suppressor-menin-is-deregulated-in-mouse-and-human-men1-glucagonomas
#13
Rémy Bonnavion, Romain Teinturier, Samuele Gherardi, Emmanuelle Leteurtre, Run Yu, Martine Cordier-Bussat, Rui Du, François Pattou, Marie-Christine Vantyghem, Philippe Bertolino, Jieli Lu, Chang Xian Zhang
Foxa2, known as one of the pioneer factors, plays a crucial role in islet development and endocrine functions. Its expression and biological functions are regulated by various factors, including in particular insulin and glucagon. However, its expression and biological role in the adult pancreatic α-cells remain elusive. In the current study, we showed that Foxa2 was overexpressed in islets from α-cell-specific Men1 mutant mice, both at the transcriptional and protein levels. More importantly, immunostaining analyses detected its prominent nuclear accumulation, specifically in α-cells, at a very early stage after Men1-disruption...
February 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28139834/frequent-low-level-mutations-of-protein-kinase-d2-in-angiolipoma
#14
Jakob Hofvander, Elsa Arbajian, Karin G Stenkula, Karin Lindkvist-Petersson, Malin Larsson, Jenny Nilsson, Linda Magnusson, Fredrik Vult von Steyern, Pehr Rissler, Jason L Hornick, Fredrik Mertens
Tumours displaying differentiation towards normal fat constitute the most common subgroup of soft tissue neoplasms. A series of such tumours was investigated by whole-exome sequencing followed by targeted ultra-deep sequencing. Eighty per cent of angiolipomas, but not any other tumour type, displayed mutations in the protein kinase D2 (PRKD2) gene, typically in the part encoding the catalytic domain. The absence of other aberrations at the chromosome or RNA level suggests that PRKD2 mutations are critical for angiolipoma development...
January 31, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28127763/mutational-signature-analysis-identifies-mutyh-deficiency-in-colorectal-cancers-and-adrenocortical-carcinomas
#15
Camilla Pilati, Jayendra Shinde, Ludmil B Alexandrov, Guillaume Assié, Thierry André, Zofia Hélias-Rodzewicz, Romain Doucoudray, Delphine Le Corre, Jessica Zucman-Rossi, Jean-François Emile, Jérôme Bertherat, Eric Letouzé, Pierre Laurent-Puig
Germline alterations in DNA repair genes are implicated in cancer predisposition and can result in characteristic mutational signatures. However, specific mutational signatures associated with base excision repair (BER) defects remain to be characterized. Here, by analysing a series of colorectal cancers (CRC) using exome sequencing, we identified a particular spectrum of somatic mutations characterized by an enrichment of C > A transversions in NpCpA or NpCpT contexts, in three tumours from a MUTYH-associated polyposis (MAP) patient and in two cases harbouring pathogenic germline MUTYH mutations...
January 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28097660/in-brief-myeloid-derived-suppressor-cells-in-cancer
#16
S Solito, L Pinton, S Mandruzzato
The role of myeloid-derived suppressor cells (MDSCs) in cancer development has become clear over recent years and MDSC targeting is an emerging opportunity for enhancing the effectiveness of current anti-cancer therapies. Since MDSCs are not only able to limit anti-tumour T cell responses, but also promote tumour angiogenesis and invasion, their monitoring has prognostic and predictive value. Herein we review the key features of MDSCs in cancer promotion.
January 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28097652/mdm4-is-a-rational-target-for-treating-breast-cancers-with-mutant-p53
#17
Panimaya Jeffreena Miranda, Daniel Buckley, Dinesh Raghu, Jia-Min B Pang, Elena A Takano, Reshma Vijayakumaran, Amina Fas Teunisse, Atara Posner, Tahlia Procter, Marco J Herold, Cristina Gamell, Jean-Christophe Marine, Stephen B Fox, Aart Jochemsen, Sue Haupt, Ygal Haupt
Mutation of the key tumour suppressor p53 defines a transition in the progression towards aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, the p53 mutation frequency exceeds 50% in triple-negative BC. Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells...
January 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28097645/bacterial-subversion-of-camp-signalling-inhibits-cathelicidin-expression-which-is-required-for-innate-resistance-to-mycobacterium-tuberculosis
#18
Shashank Gupta, Kathryn Winglee, Richard Gallo, William R Bishai
Antimicrobial peptides such as cathelicidins are an important component of innate immune defence against inhaled microorganisms and have demonstrated antimicrobial activity against Mycobacterium tuberculosis with in vitro models. Despite this, little is known about the regulation and expression of cathelicidin during tuberculosis in vivo. We sought to determine whether the cathelicidin-related antimicrobial peptide (Cramp) gene, the murine functional homologue of the human cathelicidin gene (CAMP or LL-37), is required for regulating protective immunity during M...
January 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28054715/tubal-origin-of-ovarian-cancer-the-double-edged-sword-of-haemoglobin
#19
Shiou-Fu Lin, Emily Gerry, Ie-Ming Shih
Ovarian high-grade serous carcinoma (HGSC) is the most malignant neoplasm of the gynaecologic tract. While the origins of many human malignant neoplasms are clear, the origin of HGSC remains poorly understood. This lack of knowledge limits our understanding of its pathogenesis and compromises efforts devoted to develop better early detection tools and effective preventative intervention. The tubal origin of HGSC has been put forward since the initial report of dysplastic lesions (now known as serous tubal intraepithelial carcinomas, or STICs) that morphologically resemble HGSC in the fallopian tube...
January 5, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28054337/combined-mirna-profiling-and-proteomics-demonstrates-that-different-mirnas-target-a-common-set-of-proteins-to-promote-colorectal-cancer-metastasis
#20
Sofía Torres, Irene Garcia-Palmero, Rubén A Bartolomé, María Jesús Fernandez-Aceñero, Elena Molina, Eva Calviño, Miguel F Segura, J Ignacio Casal
The process of liver colonisation in colorectal cancer remains poorly characterised. Here, we addressed the role of microRNA (miRNA) dysregulation in metastasis. We first compared miRNA expression profiles between colorectal cancer cell lines with different metastatic properties and then identified target proteins of the dysregulated miRNAs to establish their functions and prognostic value. We found that 38 miRNAs were differentially expressed between highly metastatic (KM12SM/SW620) and poorly metastatic (KM12C/SW480) cancer cell lines...
January 5, 2017: Journal of Pathology
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