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Journal of Pathology

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https://www.readbyqxmd.com/read/28497579/modulation-of-basal-cell-fate-during-productive-and-transforming-hpv16-infection-is-mediated-by-progressive-e6-driven-depletion-of-notch
#1
Christian Kranjec, Christina Holleywood, Diane Libert, Heather Griffin, Radma Mahmood, Erin Isaacson, John Doorbar
In stratified epithelia such as the epidermis, homeostasis is maintained by the proliferation of cells in the lower epithelial layers, and the concomitant loss of differentiated cells from the epithelial surface. These differentiating keratinocytes progressively stratify, and form a self-regenerating multi-layered barrier that protects the underlying dermis. In such tissue, the continual loss and replacement of differentiated cells also limits the accumulation of oncogenic mutations within the tissue. Inactivating mutations in key driver genes, such as TP53 and NOTCH1, reduce the proportion of differentiating cells allowing for the long-term persistence of expanding mutant clones in the tissue...
May 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28497484/cd44-variant-isoform-9-emerges-in-response-to-injury-and-contributes-to-the-regeneration-of-the-gastric-epithelium
#2
Nina Bertaux-Skeirik, Mark Wunderlich, Emma Teal, Jayati Chakrabarti, Jacek Biesiada, Maxime Mahe, Nambirajan Sundaram, Joel Gabre, Jennifer Hawkins, Jian Gao, Amy C Engevik, Li Yang, Jiang Wang, James R Goldenring, Joseph E Qualls, Mario Medvedovic, Michael A Helmrath, Tayyab Diwan, James C Mulloy, Yana Zavros
Cluster-of-differentiation gene 44, in particular CD44 variant isoform 9 (CD44v9), emerges during regeneration of the gastric epithelium in response to injury. In particular, CD44v9 is expressed within Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) glands during gastric repair, but the function is unknown. Here we tested the hypothesis that age dependent expression of CD44v9 marks a regenerative cell lineage responsive to infiltrating macrophages during regeneration of the gastric epithelium. Acetic acid injury was induced in CD44-deficient (CD44KO) and C57BL/6 (BL6) mice...
May 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28493484/cytoplasmic-overexpression-of-rna-binding-protein-hur-is-a-marker-of-poor-prognosis-in-meningioma-and-hur-knockdown-decreases-meningioma-cell-growth-and-resistance-to-hypoxia
#3
Guillaume Gauchotte, Sébastien Hergalant, Charlène Vigouroux, Jean-Matthieu Casse, Rémi Houlgatte, Tony Kaoma, Déborah Helle, Lydia Brochin, Fabien Rech, Matthieu Peyre, François Labrousse, Laurent Vallar, Jean-Louis Gueant, Jean-Michel Vignaud, Shyue-Fang Battaglia-Hsu
HuR regulates cytoplasmic mRNA stability and translatability, and the HuR expression level has been shown to correlate with poor disease outcome in several cancer types; however, the prognostic value and potential pro-oncogenic properties of HuR in meningioma remain unclear. Thus, in the present study we analyzed 85 meningioma tissue samples to establish the relationship between HuR expression, tumor-cell proliferation, and/or patient survival. In addition, we examined the anti-proliferative effects of HuR knockdown in two meningioma cell lines (IOMM-Lee and Ben-Men1), and conducted transcriptome-wide analyses (IOMM-Lee cells) to elucidate the molecular consequences of HuR knockdown...
May 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28493366/frequent-idh2-r172-mutations-in-undifferentiated-and-poorly-differentiated-sinonasal-carcinomas
#4
Snjezana Dogan, Deborah J Chute, Bin Xu, Ryan N Ptashkin, Raghu Chandramohan, Jacklyn Casanova-Murphy, Khedoudja Nafa, Justin A Bishop, Simion I Chiosea, Edward B Stelow, Ian Ganly, David G Pfister, Nora Katabi, Ronald A Ghossein, Michael F Berger
Sinonasal undifferentiated carcinoma (SNUC) is a high-grade malignancy with limited treatment options and poor outcome. A morphologic spectrum of 47 sinonasal tumors including 17 (36.2%) SNUCs were analyzed at genomic level. Thirty carcinomas (Cohort 1) were subjected to a hybridization exon-capture next-generation sequencing assay (MSK-IMPACT(TM) ) to interrogate somatic variants in 279 or 410 cancer-related genes. Seventeen sinonasal tumors (Cohort 2) were examined only for presence of IDH1/2 exon 4 mutations by Sanger sequencing...
May 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28466555/hic1-loss-promotes-prostate-cancer-metastasis-by-triggering-epithelial-mesenchymal-transition
#5
Mingang Hao, Yue Li, Jinglong Wang, Jun Qin, Yingying Wang, Yufeng Ding, Min Jiang, Xueqing Sun, Lidong Zu, Kun Chang, Guowen Lin, Jiangyuan Du, Vladimir Korinek, Din-Wei Ye, Jianhua Wang
Metastatic disease is the leading cause of death due to prostate cancer (PCa). Although the HIC1 (hypermethylated in cancer 1) gene has been observed to be epigenetically modified in PCa, its intrinsic role and mechanism in PCa metastasis still remain unsettled. Here we show that hypermethylation of the HIC1 promoter markedly reduces its suppressive function in metastatic PCa tissues compared to primary and adjacent normal prostate tissues, and is associated with poor patient survival. Prostate cancers in cancer-prone mice homozygous for a prostate-targeted Hic1 conditional knockout displayed stronger metastatic behaviour than heterozygous animals, as a result of epithelial-mesenchymal transition (EMT)...
May 3, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28466475/prognostic-role-of-m2-tumour-associated-macrophages-in-lymphoproliferative-disorders
#6
LETTER
Emanuele Cencini, Alberto Fabbri, Monica Bocchia
We read with great interest the recently published paper by De Beule and colleagues showing tumour-associated macrophages (TAMs) influenced survival of multiple myeloma (MM) cells through STAT3 activation.
May 3, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28444909/the-histone-methyltransferase-ezh2-is-a-therapeutic-target-in-small-cell-carcinoma-of-the-ovary-hypercalcemic-type
#7
Yemin Wang, Shary Yuting Chen, Anthony N Karnezis, Shane Colborne, Nancy Dos Santos, Jessica D Lang, William P D Hendricks, Krystal A Orlando, Damian Yap, Friedrich Kommoss, Marcel B Bally, Gregg B Morin, Jeffrey M Trent, Bernard E Weissman, David G Huntsman
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but aggressive and untreatable malignancy affecting young women. We and others recently discovered that SMARCA4, a gene encoding the ATPase of the SWI/SNF chromatin-remodeling complex, is the only gene recurrently mutated in the majority of SCCOHT. The low somatic complexity of SCCOHT genomes and the prominent role of the SWI/SNF chromatin-remodeling complex in transcriptional control of genes suggest that SCCOHT cells may rely on epigenetic rewiring for oncogenic transformation...
April 26, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28444899/tumour-vascular-leakage-defect-due-to-endothelium-targeted-fak-kinase-dead-mutation-is-abrogated-by-fak-y397e-expression
#8
Annika N Alexopoulou, Delphine M Lees, Natalia Bodrug, Tanguy Lechertier, Isabelle Fernandez, Gabriela D'Amico, Matthew Dukinfield, Silvia Batista, Bernardo Tavora, Bryan Serrels, Kairbaan Hodivala-Dilke
Focal adhesion kinase (FAK) inhibitors have been developed as potential anti-cancer agents and are in clinical trials. In vitro activation of FAK kinase domain triggers autophosphorylation of tyrosine 397 (Y397), Src activation and subsequent phosphorylation of other FAK tyrosine residues. However, how FAK-Y397 mutations affect FAK-kinase-dead phenotypes in tumour angiogenesis in vivo is unknown. We developed three Pdgfb-iCre(ert) -driven endothelial-cell (EC)-specific, tamoxifen-inducible homozygous mutant mouse lines: FAK wild-type (WT), FAK kinase-dead (KD), and double mutant (DM); KD with a putatively phosphomimetic Y397E mutation...
April 26, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28418194/accelerated-tumor-metastasis-due-to-ifn%C3%AE-receptor-mediated-dissociation-of-perivascular-cells-from-blood-vessels
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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