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Journal of Pathology

Bin Ren
FoxO1 has emerged as an important regulator of angiogenesis. Recent work published in this Journal shows that FoxO1 regulates VEGF expression in keratinocytes and is required for angiogenesis in wound healing. Since FoxO1 also regulates CD36 transcription, and endothelial cell differentiation and vascular maturation, this transcription factor may be essential for the formation of functional vascular networks via coupling the regulation of CD36 in vascular endothelial cells under physiological and pathological conditions...
April 24, 2018: Journal of Pathology
Laurie K Svoboda, Selina Shiqing K Teh, Sudha Sud, Samuel Kerk, Aaron Zebolsky, Sydney Treichel, Dafydd Thomas, Christopher J Halbrook, Ho-Joon Lee, Daniel Kremer, Li Zhang, Szymon Klossowski, Armand R Bankhead, Brian Magnuson, Mats Ljungman, Tomasz Cierpicki, Jolanta Grembecka, Costas A Lyssiotis, Elizabeth R Lawlor
Developmental transcription programs are epigenetically regulated by multi-protein complexes, including the menin- and MLL-containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin-MLL interaction leads to loss of menin and MLL1 protein expression and to inhibition of growth and tumorigenicity...
April 19, 2018: Journal of Pathology
Hayley T Morris, Loic Fort, Heather J Spence, Rachana Patel, David F Vincent, James H Park, Scott B Snapper, Francis A Carey, Owen J Sansom, Laura M Machesky
N-WASP (WASL) is a widely expressed cytoskeletal signalling and scaffold protein also implicated in regulation of Wnt signalling and homeostatic maintenance of skin epithelial architecture. N-WASP mediates invasion of cancer cells in vitro and its depletion reduces invasion and metastatic dissemination of breast cancer. Given this role in cancer invasion and universal expression in the gastrointestinal tract, we explored a role for N-WASP in the initiation and progression of colorectal cancer. While deletion of N-wasp is not detectably harmful in the murine intestinal tract, numbers of Paneth cells increased, indicating potential changes in the stem cell niche and migration up the crypt-villus axis was enhanced...
April 19, 2018: Journal of Pathology
Marie-Lune Simard, Arnaud Mourier, Laura C Greaves, Robert W Taylor, James B Stewart
Defects in the respiratory chain, interfering with energy production in the cell, are major underlying causes of mitochondrial diseases. In spite of this, the surprising variety of clinical symptoms, disparity between ages of onset as well as the involvement of mitochondrial impairment in ageing and age-related diseases, continues to challenge our understanding of the pathogenic processes. This complexity can be in part attributed to the unique metabolic needs of organs or of various cell types. In this view, it remains essential to investigate mitochondrial dysfunction at the cellular level...
April 16, 2018: Journal of Pathology
Daniel Temko, Inge C Van Gool, Emily Rayner, Mark Glaire, Seiko Makino, Matthew Brown, Laura Chegwidden, Claire Palles, Jeroen Depreeuw, Andrew Beggs, Chaido Stathopoulou, John Mason, Ann-Marie Baker, Marc Williams, Vincenzo Cerundolo, Margarida Rei, Jenny C Taylor, Anna Schuh, Ahmed Ahmed, Frédéric Amant, Diether Lambrechts, Vincent Thbm Smit, Tjalling Bosse, Trevor A Graham, David N Church, Ian Tomlinson
Genomic instability, a hallmark of cancer, is generally thought to occur in the mid to late stages of tumorigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown...
March 31, 2018: Journal of Pathology
Michaël Noë, Ayse Ayhan, Tian-Li Wang, Ie-Ming Shih
The pathogenesis of endometriosis, a common benign but debilitating disease in women, remains elusive. The currently held stem cell theory posits that circulating progenitor/stem cells are deposited outside the uterus where they differentiate into endometrial stroma and glandular tissue to establish endometriosis. Fundamental to testing this hypothesis is to elucidate the evolution of both tissue types. Here, we applied droplet digital PCR to analyze synonymous and missense somatic passenger mutations, which are neutral with respect to clonal selection, among six non-superficial endometriotic lesions...
March 31, 2018: Journal of Pathology
Sofia Karkampouna, Danny van der Helm, Peter C Gray, Lanpeng Chen, Irena Klima, Jöel Grosjean, Mark C Burgmans, Arantza Farina-Sarasqueta, Ewa B Snaar-Jagalska, Deborah M Stroka, Luigi Terracciano, Bart van Hoek, Alexander F Schaapherder, Susan Osanto, George N Thalmann, Hein W Verspaget, Minneke J Coenraad, Marianna Kruithof-de Julio
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens...
March 31, 2018: Journal of Pathology
Stephanie May, Heather Owen, Toby J Phesse, Kirsty R Greenow, Gareth-Rhys Jones, Adam Blackwood, Peter C Cook, Christopher Towers, Awen M Gallimore, Geraint T Williams, Michael Stürzl, Nathalie Britzen-Laurent, Owen J Sansom, Andrew S MacDonald, Adrian P Bird, Alan R Clarke, Lee Parry
Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2-/- mouse has been shown to be (1) resistant to intestinal tumourigenesis and (2) have an enhanced inflammatory/immune response; observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non-epithelial roles in the intestine...
March 30, 2018: Journal of Pathology
Bo He, Arnaud Jabouille, Veronica Steri, Anna Johansson-Percival, Iacovos P Michael, Venkata Ramana Kotamraju, Reimar Junckerstorff, Anna K Nowak, Juliana Hamzah, Gabriel Lee, Gabriele Bergers, Ruth Ganss
High grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK or NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the TNF superfamily member LIGHT (also known as tumor necrosis factor superfamily member 14; TNFSF14) to angiogenic tumour vessels we have generated a reagent which normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity...
March 30, 2018: Journal of Pathology
Hyeran Helen Jeon, Quan Yu, Yongjian Lu, Evelyn Spencer, Chanyi Lu, Tatyana Milovanova, Yang Yang, Chenying Zhang, Olga Stepanchenko, Rameen P Vafa, Paulo G Coelho, Dana T Graves
Angiogenesis is a critical aspect of wound healing. We investigated the role of keratinocytes in promoting angiogenesis in mice with lineage specific deletion of the transcription factor FOXO1. The results indicate that keratinocyte-specific deletion of Foxo1 reduces VEGFA expression in mucosal and skin wounds and leads to the reduced endothelial cell proliferation, reduced angiogenesis and impaired re-epithelialization and granulation tissue formation. In vitro FOXO1 was needed for VEGFA transcription and expression...
March 25, 2018: Journal of Pathology
Tatiana V Kalymbetova, Balachandar Selvakumar, José Alberto Rodríguez-Castillo, Miša Gunjak, Christina Malainou, Miriam Ruth Heindl, Alena Moiseenko, Cho-Ming Chao, István Vadász, Konstantin Mayer, Jürgen Lohmeyer, Saverio Bellusci, Eva Böttcher-Friebertshäuser, Werner Seeger, Susanne Herold, Rory E Morty
Trophic functions for macrophages are emerging as key mediators of developmental processes; including bone, vessel, and mammary gland development. Yolk sac-derived macrophages mature in the distal lung shortly after birth. Myeloid-lineage macrophages are recruited to the lung and are activated under pathological conditions. These pathological conditions include bronchopulmonary dysplasia (BPD), a common complication of preterm birth characterized by stunted lung development, where formation of alveoli is blocked...
March 25, 2018: Journal of Pathology
Gerwin Heller, Corinna Altenberger, Irene Steiner, Thais Topakian, Barbara Ziegler, Erwin Tomasich, György Lang, Adelheid End-Pfützenreuter, Sonja Zehetmayer, Balazs Döme, Britt-Madeleine Arns, Walter Klepetko, Christoph C Zielinski, Sabine Zöchbauer-Müller
De-regulated DNA methylation leading to transcriptional inactivation of certain genes occurs frequently in non-small cell lung cancers (NSCLC). Besides protein-encoding genes also microRNA (miRNA)-encoding genes may be targets for methylation in NSCLCs, however, the number of known methylated miRNA genes is still small. Thus, we investigated methylation of miRNA genes in primary tumours (TU) and corresponding non-malignant lung tissue samples (NL) of 50 NSCLC patients using methylated DNA immunoprecipitation followed by custom designed tiling microarray analyses (MeDIP-chip) and 252 differentially methylated probes between TU and NL samples were identified...
March 23, 2018: Journal of Pathology
Hélène Fe Gleitz, Rafael Kramann, Rebekka K Schneider
Bone marrow fibrosis is the continuous replacement of blood-forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis-driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1+ and leptin receptor+ mesenchymal stromal cells are progenitors of fibrosis-causing myofibroblasts in the bone marrow...
March 23, 2018: Journal of Pathology
Xingchen Zhao, Yuanhan Chen, Xiaofan Tan, Li Zhang, Hong Zhang, Zhilian Li, Shuangxin Liu, Ruizhao Li, Ting Lin, Ruyi Liao, Qianmei Zhang, Wei Dong, Wei Shi, Xinling Liang
Insufficient autophagy in podocytes is related to podocyte injury in diabetic nephropathy (DN). Advanced glycation end-products (AGEs) are major factors of podocyte injury in DN. However, the role and mechanism of AGEs on autophagic dysfunction remains unknown. We investigated autophagic flux in AGEs-stimulated cultured podocytes using multiple assays: western blotting, reverse transcription quantitative PCR, immunofluorescence staining and electron microscopy. We also utilized chloroquine and a fluorescent probe to monitor the formation and turnover of autophagosomes...
March 23, 2018: Journal of Pathology
Wen Ye, Shaoping Ling, Ran-Yi Liu, Zhi-Zhong Pan, Gaoyuan Wang, Shijuan Gao, Jiangxue Wu, Lihua Cao, Lili Dong, Yingchang Li, Yi Zhou, Wuying Du, Xiangqi Meng, Jinna Chen, Xinyuan Guan, Yulong He, Changchuan Pan, X F Steven Zheng, Xuemei Lu, Shuai Chen, Wenlin Huang
Colorectal cancer (CRC) is the third most common cancer worldwide, with more than 1.3 million new cases and 690,000 deaths each year. In China, the incidence of CRC has increased dramatically due to dietary and lifestyle changes, to become the fifth leading cause of cancer-related death. Here, we performed whole-exome sequencing in 50rectal cancer cases among the Chinese population as part of the International Cancer Genome Consortium research project. Frequently-mutated genes and enriched pathways were identified...
March 14, 2018: Journal of Pathology
Erika Gucciardo, Sirpa Loukovaara, Ani Korhonen, Pauliina Repo, Beatriz Martins, Helena Vihinen, Eija Jokitalo, Kaisa Lehti
Proliferative diabetic retinopathy (PDR) is a major diabetic microvascular complication characterized by pathological angiogenesis. Several retinopathy animal models have been developed to study the disease mechanisms and putative targets. However, knowledge on the human proliferative disease remains incomplete, relying on steady-state results from thin histological neovascular tissue sections and vitreous samples. New translational models are thus required to comprehensively understand the disease pathophysiology and develop improved therapeutic interventions...
March 13, 2018: Journal of Pathology
Stefano Menini, Carla Iacobini, Luisa de Latouliere, Isabella Manni, Vittoria Ionta, Claudia Blasetti Fantauzzi, Carlo Pesce, Paola Cappello, Francesco Novelli, Giulia Piaggio, Giuseppe Pugliese
Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, Western diet and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation endproducts (AGEs), which characterizes all the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumor-promoting role of RAGE, the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation...
March 13, 2018: Journal of Pathology
Abdullah Alholle, Marie Karanian, Anna T Brini, Mark R Morris, Vinodh Kannappan, Stefania Niada, Angela Niblett, Dominique Ranchère-Vince, Daniel Pissaloux, Christophe Delfour, Aurelie Maran Gonzalez, Cristina R Antonescu, Vaiyapuri Sumathi, Franck Tirode, Farida Latif
In recent years, undifferentiated small round cell sarcoma (USRCS) have been divided into a variety of new, rare, sarcoma subtypes including the group of Ewing-like sarcoma that has the morphological appearance of Ewing sarcoma but carries CIC-DUX4, BCOR-CCNB3 and other gene fusions different from the classical EWSR1-ETS. Using high-throughput RNA-seq analyses we identified a novel recurrent gene fusion, CRTC1-SS18, in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by RT-PCR, long-range PCR and FISH...
March 13, 2018: Journal of Pathology
Jieun Son, Yuri Park, Sang-Hyuk Chung
Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa). Estradiol (E2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin 14 (K14) promoter. E2 mainly works through estrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa...
March 13, 2018: Journal of Pathology
Ravi Kiran Deevi, Arman Javadi, Jane McClements, Jekaterina Vohhodina, Kienan Savage, Maurice Bernard Loughrey, Emma Evergren, Frederick Charles Campbell
Histological grading provides prognostic stratification of colorectal cancer (CRC) by scoring heterogeneous phenotypes. Features of aggressiveness include aberrant mitotic spindle configurations, chromosomal breakage, and bizarre multicellular morphology, but pathobiology is poorly understood. Protein kinase C zeta (PKCz) controls mitotic spindle dynamics, chromosome segregation, and multicellular patterns, but its role in CRC phenotype evolution remains unclear. Here, we show that PKCz couples genome segregation to multicellular morphology through control of interphase centrosome anchoring...
March 9, 2018: Journal of Pathology
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