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Journal of Pathology

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https://www.readbyqxmd.com/read/28418194/accelerated-tumor-metastasis-due-to-ifn%C3%AE-receptor-mediated-dissociation-of-perivascular-cells-from-blood-vessels
#1
Chen Ni, Pan Ma, Liwei Qu, Fan Wu, Junfeng Hao, Ruirui Wang, Yu Lu, Wei Yang, Ulrike Erben, Zhihai Qin
Angiostasis mediated by IFNγ is a key mechanism of anti-tumor immunity; however, the effect of IFNγ on host VEGFA-expressing cells during tumor progression is still elusive. Here, we developed transgenic mice with IFNγ receptor (IFNγR) expression under control of the Vegfa promoter (V-γR). In these mice, the IFNγ responsiveness of VEGFA -expressing cells led to a dramatic growth suppression of transplanted lung carcinoma cells. Surprisingly, increased mortality and tumor metastasis were observed in the tumor-bearing V-γR mice, in comparison to the control wild type and IFNγR-deficient mice...
April 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28418093/hypoxia-inducible-factor-1-alpha-does-not-regulate-osteoclastogenesis-but-enhances-bone-resorption-activity-via-prolyl-4-hydroxylase-2
#2
Philippa A Hulley, Tammie Bishop, Aude Vernet, Jurgen E Schneider, James R Edwards, Nick A Athanasou, Helen J Knowles
Osteogenic-angiogenic coupling is promoted by the Hypoxia-Inducible Factor 1-alpha (HIF-1α) transcription factor, provoking interest in HIF activation as a therapeutic strategy to improve osteoblast mineralisation and treat pathological osteolysis. However, HIF also enhances the bone resorbing activity of mature osteoclasts. It is therefore essential to determine the full effect(s) of HIF on both the formation and bone-resorbing function of osteoclasts in order to understand how they might respond to such a strategy...
April 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28418084/epstein-barr-virus-infection-induces-genome-wide-de-novo-dna-methylation-in-non-neoplastic-gastric-epithelial-cells
#3
Keisuke Matsusaka, Sayaka Funata, Masaki Fukuyo, Yasuyuki Seto, Hiroyuki Aburatani, Masashi Fukayama, Atsushi Kaneda
Epstein-Barr virus (EBV)-positive gastric cancer (GC) shows a higher DNA methylation epigenotype. EBV infection can causally induce genome-wide aberrant DNA methylation, as previously demonstrated by in vitro infection experiments in the low-methylation GC cell line MKN7. However, whether EBV exerts DNA methylation remodelling properties in non-neoplastic epithelial cells remains unclear. We here performed post-infection time-series DNA methylation analyses using the immortalised normal gastric epithelial cell line, GES1...
April 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28418072/myb-gata1-fusion-promotes-basophilic-leukaemia-involvement-of-il33-and-nerve-growth-factor-receptors
#4
Stéphane Ducassou, Valérie Prouzet-Mauléon, Marie-Céline Deau, Philippe Brunet de la Grange, Bruno Cardinaud, Hayssam Soueidan, Cathy Quelen, Pierre Brousset, Jean-Max Pasquet, François Moreau-Gaudry, Michel Arock, François-Xavier Mahon, Eric Lippert
Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. We previously described a recurrent t(X;6)(p11;q23) translocation generating a MYB-GATA1 fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive hematopoietic progenitors which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity (CD34), of granulocytic lineage (CD33, CD117) and of basophilic differentiation (CD203c, FcƐRI)...
April 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28393364/sirt1-and-ampk-pathways-are-essential-for-the-proliferation-and-survival-of-primary-effusion-lymphoma-cells
#5
Meilan He, Brandon Tan, Karthik Vasan, Hongfeng Yuan, Fan Cheng, Suzane Ramos da Silva, Chun Lu, Shou-Jiang Gao
Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma with a dismal prognosis caused by infection of Kaposi's sarcoma-associated herpesvirus. Despite the findings that numerous viral genes and cellular pathways are essential for the proliferation and survival of PEL cells, there is currently no effective therapeutic treatment for PEL. Here, we report that the metabolic sensor SIRT1 is functionally required for sustaining the proliferation and survival of PEL cells. Knockdown of SIRT1 with specific shRNAs or inhibition of SIRT1 with an inhibitor (Tenovin-6) induced cell cycle arrest and apoptosis in PEL cells...
April 9, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28390068/hostile-takeover-how-tumors-hijack-pre-existing-vascular-environments-to-thrive
#6
Frank Winkler
An increasing body of evidence suggests that solid tumors do not require the generation of new blood vessels, angiogenesis, to successfully grow, and to colonize normal tissue. Many tumor cells rather make best use of what they find: pre-existing blood vessels of the host. In these cases, the host vasculature is incorporated by the growing tumor, resulting in a new organ consisting of malignant and nonmalignant cell types. In consequence, pre-existing vessels are exploited by the tumor for optimal access to oxygen and nutrients...
April 8, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28378416/tubulin-%C3%AE-iii-modulates-seizure-activity-in-epilepsy
#7
Xin Xu, Yafei Shangguan, Shanshan Lu, Wei Wang, Chao Du, Fei Xiao, Yida Hu, Jing Luo, Liang Wang, Changlong He, Yong Yang, Yanke Zhang, Xi Lu, QinYang, Xuefeng Wang
Beta-III tubulin (TUBB3) is the most dynamic β-tubulin isoform expressed in neurons, and is highly expressed in the central nervous system. However, the relationship between TUBB3 and epileptic seizures has not been thoroughly investigated. This study aimed to investigate the expression of TUBB3 in patients with temporal lobe epilepsy and two different rat models of chronic epilepsy and to determine the specific roles of TUBB3 in epilepsy. TUBB3 expression was upregulated in human and rat epileptic tissue...
April 5, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28378394/fusion-gene-addiction-can-tumours-be-forced-to-give-up-the-habit
#8
Joanna L Selfe, Janet Shipley
Fusion of genes in tumours can have oncogenic roles in reprogramming cells through overexpression of oncogenes or the production of novel fusion proteins. A fundamental question in cancer biology is what genetic events are critical for initiation and whether these are also required for cancer progression. In recent work published in The Journal of Pathology, dependency on a fusion protein was addressed using a model of alveolar rhabdomyosarcomas - a sarcoma subtype with frequent fusion of PAX3 and FOXO1 genes that is associated with poor outcome...
April 5, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28378341/nlrp3-inflammasome-induced-liver-graft-injury-through-activation-of-telomere-independent-rap1-kc-axis
#9
Hui Liu, Oscar Wai Ho Yeung, Chang Xian Li, Xiao Bing Liu, Xiang Qi, Kevin Tak Pan Ng, Jiang Liu, Yuen Yuen Ma, Yin Fan Lam, Qizhou Lian, See Ching Chan, Chung Mau Lo, Kwan Man
Acute phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes was significantly up-regulated post-transplantation...
April 5, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28369925/cousins-not-twins-intra-and-inter-tumoral-heterogeneity-in-syndromic-neuroendocrine-tumours
#10
Aidan Flynn, Trisha Dwight, Diana Benn, Siddhartha Deb, Andrew J Colebatch, Stephen Fox, Jessica Harris, Emma L Duncan, Bruce Robinson, Annette Hogg, Jason Ellul, Henry To, Cuong Duong, Julie A Miller, Christopher Yates, Paul James, Alison Trainer, Anthony J Gill, Roderick Clifton-Bligh, Rodney J Hicks, Richard W Tothill
Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common co-operative changes required for tumorigenesis, while controlling for the genetic background of the individual...
March 31, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28369983/microinsertions-in-prkaca-cause-activation-of-the-protein-kinase-a-pathway-in-cardiac-myxoma
#11
I-Ching Tseng, Wei-Ju Huang, Yu-Ling Jhuang, Ya-Yun Chang, Hung-Pin Hsu, Yung-Ming Jeng
Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterised by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutation in PRKACA, the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases...
March 28, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28349562/palbociclib-has-anti-tumor-effects-on-pten-deficient-endometrial-neoplasias
#12
Maria Alba Dosil, Cristina Mirantes, Núria Eritja, Isidre Felip, Raúl Navaridas, Sònia Gatius, Maria Santacana, Eva Colàs, Cristian Moiola, Joan Antoni Schoenenberger, Mario Encinas, Eloi Garí, Xavier Matias-Guiu, Xavier Dolcet
PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to a dysregulation of cell division and promotes the accumulation of cell cycle complexes such as Cyclin D1-CDK4/6, which is an important feature of the tumor phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs...
March 27, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28337768/tet2-mutations-in-b-cells-of-patients-affected-by-angioimmunoblastic-t-cell-lymphoma
#13
Friederike H Schwartz, Qian Cai, Eva Fellmann, Sylvia Hartmann, Mikko I Mäyränpää, Marja-Liisa Karjalainen-Lindsberg, Christer Sundström, René Scholtysik, Martin-Leo Hansmann, Ralf Küppers
Angioimmunoblastic T cell lymphomas (AITL) frequently carry mutations in the TET2 and IDH2 genes. TET2 mutations represent early genetic lesions as they were already detected in hematopoietic 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 AITL (6/9) also a fraction of B cells was TET2-mutated. Investigation of four AITL by TET2 and IGHV gene sequencing of single microdissected B cells showed that between 10-60% of polyclonal B cells in AITL lymph nodes harboured the identical TET2 mutations of the respective T cell lymphoma clone...
March 24, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28337746/thymidylate-synthase-is-functionally-associated-with-zeb1-and-contributes-to-the-epithelial-to-mesenchymal-transition-of-cancer-cells
#14
Aarif Siddiqui, Maria Eleni Vazakidou, Annemarie Schwab, Francesca Napoli, Cristina Fernandez-Molina, Ida Rapa, Marc P Stemmler, Marco Volante, Thomas Brabletz, Paolo Ceppi
Thymidylate synthase (TS) is a fundamental enzyme of nucleotide metabolism and one of the oldest anti-cancer targets. Beginning from the analysis of gene array data from the NCI-60 panel of cancer cell lines, we identified a significant correlation at both gene and protein level between TS and the markers of epithelial-to-mesenchymal transition (EMT), a developmental process that allows cancer cells to acquire features of aggressiveness, like motility and chemoresistance. TS levels were found to be significantly augmented in mesenchymal-like compared to epithelial-like cancer cells, to be regulated by EMT induction, and to negatively correlate with micro-RNAs (miRNAs) usually expressed in epithelial-like cells and known to actively suppress EMT...
March 24, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28299802/bmp-and-notch-interaction-in-crc-subtypes
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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), and is often accompanied by the accumulation of ascitic fluid. The peritoneal cavity is lined by mesothelial cells (MCs), which can be converted 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 transforming growth factor (TGF)-β signalling - are differentially regulated, and a gene signature was verified in peritoneal implants from OvCa patients...
March 1, 2017: Journal of Pathology
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