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  • The T‐box transcription factor brachyury behaves as a tumor suppressor in gliomas
    J. Pathol. (IF 5.942) Pub Date : 2020-04-04
    Filipe Pinto; Ângela M Costa; Gisele C Santos; Marcus M Matsushita; Sandra Costa; Viviane AO Silva; Vera Miranda‐Gonçalves; Celeste M Lopes; Carlos A Clara; Aline P Becker; Luciano Neder; Glaucia NM Hajj; Isabela W da Cunha; Chris Jones; Raquel P Andrade; Rui M Reis

    The oncogene brachyury (TBXT) is a T‐box transcription factor that is overexpressed in multiple solid tumors and is associated with tumor aggressiveness and poor patient prognosis. Gliomas comprise the most common and aggressive group of brain tumors, and at the present time the functional and clinical impact of brachyury expression has not been investigated previously in these neoplasms. Brachyury

  • Ocular cytomegalovirus latency exacerbates the development of choroidal neovascularization
    J. Pathol. (IF 5.942) Pub Date : 2020-04-03
    Jinxian Xu; Xinglou Liu; Xinyang Zhang; Brendan Marshall; Zheng Dong; Yutao Liu; Diego G. Espinosa‐Heidmann; Ming Zhang

    Age‐related macular degeneration (AMD) is a complex, multifactorial, progressive disease, which represents a leading cause of irreversible visual impairment and blindness in older individuals. Human cytomegalovirus (HCMV), which infects 50 to 80% of humans, is usually acquired during early life and persists in a latent state for the life of the individual. In view of its previously described pro‐angiogenic

  • Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development
    J. Pathol. (IF 5.942) Pub Date : 2020-04-01
    Anthony W‐H Chan; Yi Pan; Joanna H‐M Tong; Raymond W‐M Lung; Johnny S‐H Kwan; Chit Chow; Edith K‐Y Tin; Lau‐Ying Chung; Hui Li; Shela S‐Y Wong; Shuk‐Ling Chau; Yuk Yu Chan; Tony W‐C Mak; Simon Siu‐Man Ng; Ka‐Fai To

    Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15

  • FHITlow/pHER2high signature in non‐small cell lung cancer is predictive of anti‐HER2 molecule efficacy
    J. Pathol. (IF 5.942) Pub Date : 2020-04-01
    Jordan Da Silva; Amina Jouida; Julien Ancel; Véronique Dalstein; Julie Routhier; Gonzague Delepine; Jérôme Cutrona; Antoine Jonquet; Maxime Dewolf; Philippe Birembaut; Gaëtan Deslée; Myriam Polette; Béatrice Nawrocki‐Raby

    Despite its efficacy in solid tumours, in particular HER2+ breast cancer, HER2‐targeted therapy has given rise to disappointing results in non‐small cell lung cancer (NSCLC).

  • Applying single-cell technologies to clinical pathology: progress in nephropathology.
    J. Pathol. (IF 5.942) Pub Date : 2020-03-31
    Benjamin J Stewart,Menna R Clatworthy

    Cells represent the basic building blocks of living organisms. Accurate characterisation of cellular phenotype, intercellular signalling networks, and the spatial organisation of cells within organs is crucial to deliver a better understanding of the processes underpinning physiology, and the perturbations that lead to disease. Single-cell methodologies have rapidly increased in scale and scope in

  • Control of neutrophil influx during peritonitis by transcriptional cross‐regulation of chemokine CXCL1 by IL‐17 and IFN‐γ
    J. Pathol. (IF 5.942) Pub Date : 2020-03-31
    Rusan A. Catar; Lei Chen; Simone M. Cuff; Ann Kift‐Morgan; Matthias Eberl; Ralph Kettritz; Julian Kamhieh‐Milz; Guido Moll; Qing Li; Hongfan Zhao; Edyta Kawka; Daniel Zickler; Gita Parekh; Paul Davis; Donald J. Fraser; Duska Dragun; Kai‐Uwe Eckardt; Achim Jörres; Janusz Witowski

    Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)‐related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal

  • Critical role for iron accumulation in the pathogenesis of fibrotic lung disease.
    J. Pathol. (IF 5.942) Pub Date : 2020-03-30
    Md Khadem Ali,Richard Y Kim,Alexandra C Brown,Chantal Donovan,Kanth S Vanka,Jemma R Mayall,Gang Liu,Amber L Pillar,Bernadette Jones-Freeman,Dikaia Xenaki,Theo Borghuis,Rafia Karim,James W Pinkerton,Ritambhara Aryal,Moones Heidari,Kristy L Martin,Janette K Burgess,Brian G Oliver,Debbie Trinder,Daniel M Johnstone,Elizabeth A Milward,Philip M Hansbro,Jay C Horvat

    Increased iron levels and/or dysregulated iron homeostasis occurs in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron and histological samples from

  • Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut
    J. Pathol. (IF 5.942) Pub Date : 2020-03-28
    Nadine Mikuda; Ruth Schmidt‐Ullrich; Eva Kärgel; Laura Golusda; Jana Wolf; Uta E. Höpken; Claus Scheidereit; Anja A. Kühl; Marina Kolesnichenko

    The IκB‐Kinase (IKK)‐NF‐κB signalling pathway plays a multifaceted role in inflammatory bowel disease (IBD): on the one hand, it protects from apoptosis; on the other, it activates transcription of numerous inflammatory cytokines and chemokines. Although several murine models of IBD rely on disruption of IKK‐NF‐κB signalling, these involve either knockouts of a single family‐member of NF‐κB, or of

  • T cell exhaustion interrelates with immune cytolytic activity to shape inflamed tumor microenvironment
    J. Pathol. (IF 5.942) Pub Date : 2020-03-28
    Mei‐Chun Cai; Xiaojing Zhao; Min Cao; Pengfei Ma; Minjiang Chen; Jie Wu; Chenqiang Jia; Chunming He; Yujie Fu; Li Tan; Xinying Xue; Zhuang Yu; Guanglei Zhuang

    Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint‐based treatment remains poorly investigated. We sought to systematically characterize the pan‐cancer landscape and molecular hallmarks of T cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T cell exhaustion through analyzing differential

  • Characteristics, dynamic changes, and prognostic significance of TCR repertoire profiling in renal cell carcinoma patients.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-19
    Liping Guo,Xingang Bi,Yajian Li,Li Wen,Wen Zhang,Weixing Jiang,JianHui Ma,Lin Feng,Kaitai Zhang,Jianzhong Shou

    The co-evolving tumour cells and the systemic immune environment are mutually dysregulated. Tumours affect the immune response in a complex manner. For example, while lymphocytes are mobilized in response to tumours, their function is impaired by tumour progression. This study aimed to explore how the baseline and dynamic renal cell carcinoma (RCC) tumour burdens affect the T cell repertoire, and whether

  • Effects of host-directed therapies on the pathology of tuberculosis.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-28
    Liana Tsenova,Amit Singhal

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has co-evolved with the human immune system and utilizes multiple strategies to persist within infected cells, to hijack several immune mechanisms and to cause severe pathology and tissue damage in the host. This delays the efficacy of current antibiotic therapy and contributes to the evolution of multi-drug resistant strains. These

  • The CD151-midkine pathway regulates the immune microenvironment in inflammatory breast cancer.
    J. Pathol. (IF 5.942) Pub Date : 2020-03-04
    Steven Hayward,Mariam Gachehiladze,Nahla Badr,Regina Andrijes,Guerman Molostvov,Liliia Paniushkina,Barbora Sopikova,Zuzana Slobodová,Giorgi Mgebrishvili,Nisha Sharma,Yoshiya Horimoto,Dominic Burg,Graham Robertson,Andrew Hanby,Fiona Hoar,Daniel Rea,Bedrich L Eckhardt,Naoto T Ueno,Irina Nazarenko,Heather M Long,Steven van Laere,Abeer M Shaaban,Fedor Berditchevski

    The immune microenvironment in inflammatory breast cancer (IBC) is poorly characterised, and molecular and cellular pathways that control accumulation of various immune cells in IBC tissues remain largely unknown. Here, we discovered a novel pathway linking the expression of the tetraspanin protein CD151 in tumour cells with increased accumulation of macrophages in cancerous tissues. Importantly, elevated

  • Cisd2: A promising new target in Alzheimer's disease
    J. Pathol. (IF 5.942) Pub Date : 2020-03-24
    Nobili Annalisa; Paraskevi Krashia; Marcello D'Amelio

    The CISD2 gene encodes the CDGSH iron–sulfur domain‐containing protein 2. Cisd2 is involved in mammalian life‐span control, the unfolded protein response, Ca2+ buffering and autophagy regulation. It has been demonstrated previously that Cisd2 deficiency causes an accelerated ageing phenotype characterised by the accumulation of damaged mitochondria, while Cisd2 overexpression leads to mitochondrial

  • Dissecting expression profiles of gastric precancerous lesions and early gastric cancer to explore crucial molecules in intestinal‐type gastric cancer tumorigenesis
    J. Pathol. (IF 5.942) Pub Date : 2020-03-24
    Yajing Zhang; Xi Wu; Chengli Zhang; Jiaqi Wang; Guijun Fei; Xuebing Di; Xinghua Lu; Lin Feng; Shujun Cheng; Aiming Yang

    Intestinal‐type gastric cancer (IGC) has a clear and multistep histological evolution. No studies have comprehensively explored gastric tumorigenesis from inflammation through low‐grade intraepithelial neoplasia (LGIN) and high‐grade intraepithelial neoplasia (HGIN) to early gastric cancer (EGC). We sought to investigate the characteristics participating in IGC tumorigenesis and identify related prognostic

  • A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-19
    Chisato Nakada,Naoki Hijiya,Yoshiyuki Tsukamoto,Shinji Yano,Tomoki Kai,Tomohisa Uchida,Mami Kimoto,Mika Takahashi,Tsutomu Daa,Keiko Matsuura,Toshitaka Shin,Hiromitsu Mimata,Masatsugu Moriyama

    Previously we reported that the microRNA miR-210 is aberrantly upregulated in clear cell renal cell carcinoma (ccRCC) via deregulation of the VHL-HIF pathway. In the present study, to investigate the biological impact of miR-210 in ccRCC tumorigenesis, we developed a transgenic mouse line expressing miR-210 in proximal tubule cells under control of the mouse SGLT2/Slc5a2 promoter. Light microscopy

  • Recent advances in the biology of tumour hypoxia with relevance to diagnostic practice and tissue-based research.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-21
    Philip S Macklin,Atsushi Yamamoto,Lisa Browning,Monika Hofer,Julie Adam,Christopher W Pugh

    In this review article, we examine the importance of low levels of oxygen (hypoxia) in cancer biology. We provide a brief description of how mammalian cells sense oxygen. The hypoxia-inducible factor (HIF) pathway is currently the best characterised oxygen sensing system, but recent work has revealed that mammals also use an oxygen-sensing system found in plants to regulate the abundance of some proteins

  • Long non-coding RNAs in development and disease: conservation to mechanisms.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-26
    Ioannis Tsagakis,Katerina Douka,Isabel Birds,Julie L Aspden

    Our genomes contain the blueprint of what makes us human and many indications as to why we develop disease. Until the last ten years, most studies had focussed on protein-coding genes, more specifically DNA sequences coding for proteins. However, this represents less than 5% of our genomes. The other 95% is referred to as the 'dark matter' of our genomes, our understanding of which is extremely limited

  • Plasma Membrane Receptors of Tissue Macrophages: Functions and Role in Pathology.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-22
    Siamon Gordon,Annette Plüddemann,Subhankar Mukhopadhyay

    The cells of the Mononuclear Phagocyte System constitute a dispersed organ, which is distributed throughout the body. Macrophages in different tissues display distinctive mosaic phenotypes as resident and recruited cells of embryonic and bone marrow origin, respectively. They help to maintain homeostasis during development and throughout adult life, yet contribute to the pathogenesis of many disease

  • The stressful tumour environment drives plasticity of cell migration programmes, contributing to metastasis.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-14
    Savvas Nikolaou,Laura M Machesky

    Tumours evolve to cope with environmental stresses or challenges such as nutrient starvation, depletion of survival factors and unbalanced mechanical forces. The uncontrolled growth and aberrant deregulation of core cell homeostatic pathways induced by genetic mutations creates an environment of stress. Here, we explore how the adaptations of tumours to the changing environment can drive changes in

  • Biology and therapeutic targeting of tumour-associated macrophages.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-21
    Tim Beltraminelli,Michele De Palma

    Macrophages sustain tumour progression by facilitating angiogenesis, promoting immunosuppression, and enhancing cancer cell invasion and metastasis. They also modulate tumour response to anti-cancer therapy in pre-clinical models. This knowledge has motivated the development of agents that target tumour-associated macrophages (TAMs), some of which have been investigated in early clinical trials. Here

  • Function and mutual interaction of BiP‐, PERK‐ and IRE1α –dependent signalling pathways in vascular tumours
    J. Pathol. (IF 5.942) Pub Date : 2020-03-13
    Laura Anspach; Roman Tsaryk; Larissa Seidmann; Ronald E. Unger; Caren Jayasinghe; Nektaria Simiantonaki; C. James Kirkpatrick; Felicitas Pröls

    Spontaneously regressing infantile haemangiomas and aggressive angiosarcomas are vascular tumours with excessive angiogenesis. When analysing haemangiomas and angiosarcomas immunohistochemically with respect to their chaperone profiles we found that angiosarcomas have significantly elevated protein levels of BiP and PERK with concomitant attenuated IRE1α levels while haemangioma tissue exhibits the

  • Macrophage subsets in atherosclerosis as defined by single-cell technologies.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-31
    Lisa Willemsen,Menno P J de Winther

    Macrophages play a major role in the pathogenesis of atherosclerosis. Many studies have shone light on the different phenotypes and functions that macrophages can acquire upon exposure to local cues. The microenvironment of the atherosclerotic plaque contains a plethora of macrophage controlling factors, such as cytokines, oxidized low-density lipoproteins, and cell debris. Previous research has determined

  • HPV16 is sufficient to induce squamous cell carcinoma specifically in the tongue base in transgenic mice.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-28
    Verónica F Mestre,Beatriz Medeiros-Fonseca,Diogo Estêvão,Fátima Casaca,Sandra Silva,Ana Félix,Fernanda Silva,Bruno Colaço,Fernanda Seixas,Margarida M S M Bastos,Carlos Lopes,Rui Medeiros,Paula A Oliveira,Rui M Gil da Costa

    Head and neck squamous cell carcinomas (HNSCC) associated with human papillomavirus (HPV) occur specifically in the tonsils and the tongue base, but the reasons for this specificity remain unknown. We studied the distribution of oral and pharyngeal lesions in HPV16-transgenic mice where the expression of all the HPV16 early genes is targeted to keratinizing squamous epithelia by the cytokeratin 14

  • Methylation-based algorithms for diagnosis: experience from neuro-oncology.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-14
    Jessica C Pickles,Thomas J Stone,Thomas S Jacques

    Brain tumours are the commonest tumour-related cause of death in young people. Survivors are at risk of significant disability, at least in part related to the effects of treatment. Therefore, there is a need for precise diagnosis that stratifies patients for the most suitable treatment, matched to the underlying biology of their tumour. While traditional histopathology has been accurate in predicting

  • Intraductal papillary neoplasms of the bile duct are consisted of two distinct types specifically associated with clinicopathological features and molecular phenotypes.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-26
    Yasutaka Aoki,Masamichi Mizuma,Tatsuo Hata,Takeshi Aoki,Yuko Omori,Yusuke Ono,Yusuke Mizukami,Michiaki Unno,Toru Furukawa

    Intraductal papillary neoplasm of the bile duct (IPNB) is a grossly visible papillary biliary neoplasm with morphological variations and occasional invasion. Recently, a new classification of IPNB into type 1 and type 2 was proposed in which the type 1 IPNBs consist of fine papillary neoplastic glands whereas the type 2 IPNBs consist of complex branching glands seldom with foci of solid-tubular components

  • A streamlined mass spectrometry‐based proteomics workflow for large scale FFPE tissue analysis
    J. Pathol. (IF 5.942) Pub Date : 2020-03-10
    Fabian Coscia; Sophia Doll; Jacob Mathias Bech; Lisa Schweizer; Andreas Mund; Ernst Lengyel; Jan Lindebjerg; Gunvor Iben Madsen; José M. A. Moreira; Matthias Mann

    Formalin fixation and paraffin‐embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)‐based proteomics has so far proven challenging. Here, we describe an MS‐based

  • The use of Mendelian randomisation to identify causal cancer risk factors: promise and limitations
    J. Pathol. (IF 5.942) Pub Date : 2020-03-10
    Harvinder Gala; Ian Tomlinson

    The use of observational analyses, such as classical epidemiological studies or randomised controlled trials (RCTs), to infer causality in cancer may be problematic due to both ethical reasons and technical issues, such as confounding variables and reverse causation. Mendelian randomisation (MR) is an epidemiological technique that uses genetic variants as proxies for exposures in an attempt to determine

  • Purpuric drug eruptions induced by EGFR tyrosine kinase inhibitors are associated with IQGAP1-mediated increase in vascular permeability.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-07
    Yi-Shuan Sheen,Ming-Hsien Lin,Wen-Chia Tzeng,Chia-Yu Chu

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used as a treatment for non-small cell lung cancer. There have been some reports of EGFR-TKIs being associated with vascular adverse events. We found that EGFR-TKIs decreased the proliferation of HMEC-1 (immortalized human dermal microvascular endothelial cells) and HMVEC (human dermal microvascular endothelial cells), and

  • Molecular Pathology of Lynch Syndrome
    J. Pathol. (IF 5.942) Pub Date : 2020-03-06
    G Cerretelli; A Ager; MJ Arends; IM Frayling

    Lynch syndrome (LS) is characterised by predisposition to colorectal, endometrial and other cancers and is caused by inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. It is probably the most common predisposition to cancer, having an estimated prevalence of between 1/100 and 1/180. Resources such as the International Society for Gastrointestinal

  • MicroRNAs in grey and white matter Multiple Sclerosis lesions: Impact on pathophysiology.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-19
    Sarah Teuber-Hanselmann,Edgar Meinl,Andreas Junker

    Multiple sclerosis (MS) is a chronic disease of the central nervous system, hallmarked by inflammation and demyelination. Early stages of the disease frequently show active lesions containing numerous foamy macrophages and inflammatory cells. Disease progression is highlighted by increasing numbers of mixed active/inactive or inactive lesions showing sparse inflammation and pronounced astrogliosis

  • Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor.
    J. Pathol. (IF 5.942) Pub Date : 2020-02-19
    Derek Wong,Stephen Yip

    Capicua, encoded by the gene CIC, is an evolutionarily conserved high-mobility group-box transcription factor downstream of the receptor tyrosine kinase and mitogen-activated protein kinase pathways. It was initially discovered and studied in Drosophila. Recurrent mutations in CIC were first identified in oligodendroglioma, a subtype of low-grade glioma. Subsequent studies have identified CIC aberrations

  • The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers into breast cancer clinical trials and daily practice.
    J. Pathol. (IF 5.942) Pub Date : 2020-03-04
    Paula I Gonzalez-Ericsson,Elisabeth S Stovgaard,Luz F Sua,Emily Reisenbichler,Zuzana Kos,Jodi M Carter,Stefan Michiels,John Le Quesne,Torsten O Nielsen,Anne-Vibeke Laenkholm,Stephen B Fox,Julien Adam,John Ms Bartlett,David L Rimm,Cecily Quinn,Dieter Peeters,Maria V Dieci,Anne Vincent-Salomon,Ian Cree,Akira I Hida,Justin M Balko,Harry R Haynes,Isabel Frahm,Gabriela Acosta-Haab,Marcelo Balancin,Enrique

    Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However

  • A critical role for Akt1 signaling in acute pancreatitis progression†
    J. Pathol. (IF 5.942) Pub Date : 2020-02-25
    Rim SJ Sarker; Katja Steiger

    Acute pancreatitis (AP) is an inflammatory disease of the pancreas that causes significant morbidity and mortality worldwide. Unfortunately, there is no specific treatment available to date. Several studies have previously shown that inhibitors of the PI3K/Akt axis downregulate the degree of inflammation in animal models of AP. However, studies on in vivo side‐effects of such inhibitors are still lacking

  • LIGHT/TNFSF14 regulates estrogen deficiency‐induced bone loss
    J. Pathol. (IF 5.942) Pub Date : 2020-02-25
    Giacomina Brunetti; Giuseppina Storlino; Angela Oranger; Graziana Colaianni; Maria F Faienza; Giuseppe Ingravallo; Mariasevera Di Comite; Janne E Reseland; Monica Celi; Umberto Tarantino; Giovanni Passeri; Carl F Ware; Maria Grano; Silvia Colucci

    Bone loss induced by ovariectomy is due to the direct activity on bone cells and mesenchymal cells and to the dysregulated activity of bone marrow cells, including immune cells and stromal cells, but the underlying mechanisms are not completely known. Here, we demonstrate that ovariectomy induces the T‐cell co‐stimulatory cytokine LIGHT, which stimulates both osteoblastogenesis and osteoclastogenesis

  • Software‐assisted decision support in digital histopathology
    J. Pathol. (IF 5.942) Pub Date : 2020-02-25
    Ralf Huss; Sarah E Coupland

    Tissue diagnostics is the world of pathologists, and it is increasingly becoming digitalised to leverage the enormous potential of personalised medicine and of stratifying patients, enabling the administration of modern therapies. Therefore, the daily task for pathologists is changing drastically and will become increasingly demanding in order to take advantage of the development of modern computer

  • Negative regulation of dendritic cell activation in psoriasis mediated via CD100-plexin-B2.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-14
    Chunying Xiao,Yang Luo,Chen Zhang,Zhenlai Zhu,Luting Yang,Hongjiang Qiao,Meng Fu,Gang Wang,Xu Yao,Wei Li

    Psoriasis is a chronic inflammatory skin disease in which dendritic cells (DCs) play a pivotal role by inducing Th1/Th17 immune responses; however, the regulation of DC activation in psoriasis remains largely unknown. Previously we found that the level of soluble CD100 was increased in sera of psoriasis patients, and CD100 promoted the activation of inflammasome in keratinocytes. In the present study

  • Radiation-induced tissue damage and response.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-28
    William H McBride,Dörthe Schaue

    Normal tissue responses to ionizing radiation have been a major subject for study since the discovery of X-rays at the end of the 19th century. Shortly thereafter, time-dose relationships were established for some normal tissue endpoints that led to investigations into how the size of dose per fraction and the quality of radiation affected outcome. The assessment of the radiosensitivity of bone marrow

  • Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Pablo Rodríguez-Núñez,Laura Romero-Pérez,Ana T Amaral,Pilar Puerto-Camacho,Carmen Jordán,David Marcilla,Thomas Gp Grünewald,Javier Alonso,Enrique de Alava,Juan Díaz-Martín

    YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized

  • Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Koichiro Haruki,Keisuke Kosumi,Tsuyoshi Hamada,Tyler S Twombly,Juha P Väyrynen,Sun A Kim,Yohei Masugi,Zhi Rong Qian,Kosuke Mima,Yoshifumi Baba,Annacarolina da Silva,Jennifer Borowsky,Kota Arima,Kenji Fujiyoshi,Mai Chan Lau,Peilong Li,Chunguang Guo,Yang Chen,Mingyang Song,Jonathan A Nowak,Reiko Nishihara,Katsuhiko Yanaga,Xuehong Zhang,Kana Wu,Susan Bullman,Wendy S Garrett,Curtis Huttenhower,Jeffrey

    Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti-tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal

  • Interpretation of somatic POLE mutations in endometrial carcinoma.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-12
    Alicia León-Castillo,Heidi Britton,Melissa K McConechy,Jessica N McAlpine,Remi Nout,Stefan Kommoss,Sara Y Brucker,Joseph W Carlson,Elisabeth Epstein,Tilman T Rau,Tjalling Bosse,David N Church,C Blake Gilks

    Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours ('POLE-ultramutated') within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base

  • p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-12
    Naveena Singh,Anna M Piskorz,Tjalling Bosse,Mercedes Jimenez-Linan,Brian Rous,James D Brenton,C Blake Gilks,Martin Köbel

    TP53 mutations are considered a surrogate biomarker of the serous-like 'copy number high' molecular subtype of endometrial carcinoma (EC). In ovarian carcinoma, p53 immunohistochemistry (IHC) accurately reflects mutational status with almost 100% specificity but its performance in EC has not been established. This study tested whether p53 IHC reliably predicts TP53 mutations identified by next-generation

  • Inverted urothelial papilloma and urothelial carcinoma with inverted growth are histologically and molecularly distinct entities.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-31
    Nima Almassi,Eugene J Pietzak,Judy Sarungbam,Satish K Tickoo,Victor E Reuter,David B Solit,Hikmat A Al-Ahmadie

    A commentary on our manuscript ‘Genomic landscape of inverted urothelial papilloma and urothelial papilloma of the bladder’ was recently published in the Journal of Pathology. In their manuscript, the authors highlighted the major findings of our study including the distinct genetic profiles of inverted urothelial papilloma and urothelial papilloma compared to urothelial carcinoma. They also pointed

  • Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Eric Morin,Cecilia Lindskog,Martin Johansson,Lars Egevad,Per Sandström,Ulrika Harmenberg,Lena Claesson-Welsh,Elin Sjöberg

    Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10-15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in

  • Prekallikrein - an emerging therapeutic target for Klebsiella pneumoniae infection?†.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-13
    Zena Lam,Alison M Condliffe

    Klebsiella pneumoniae is a Gram-negative bacterium that is increasingly difficult to treat due to the emergence of multidrug resistant strains. In a recent article, Ding et al demonstrate that prekallikrein depletion in mice followed by intranasal instillation of K. pneumoniae leads to a reduced bacterial burden and prolonged host survival, together with evidence of reduced distant organ damage. These

  • Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-20
    Carlos R Figueiredo,Helen Kalirai,Joseph J Sacco,Ricardo A Azevedo,Andrew Duckworth,Joseph R Slupsky,Judy M Coulson,Sarah E Coupland

    Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour infiltrating lymphocytes

  • Loss of GATA4 causes ectopic pancreas in the stomach.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-25
    Elisa Rodríguez-Seguel,Laura Villamayor,Noelia Arroyo,Mónica P De Andrés,Francisco X Real,Franz Martín,David A Cano,Anabel Rojas

    Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox ; Pdx1-Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation

  • Angioimmunoblastic T-cell lymphoma contains multiple clonal T-cell populations derived from a common TET2 mutant progenitor cell.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-20
    Wen-Qing Yao,Fangtian Wu,Wenyan Zhang,Shih-Sung Chuang,Joe S Thompson,Zi Chen,Shao-Wei Zhang,Alexandra Clipson,Ming Wang,Hongxiang Liu,Hani Bibawi,Yuanxue Huang,Luis Campos,John W Grant,Penny Wright,Hesham Ei-Daly,Lívia Rásó-Barnett,Lorant Farkas,George A Follows,Zifen Gao,Ayoma D Attygalle,Margaret Ashton-Key,Weiping Liu,Ming-Qing Du

    Angioimmunoblastic T-cell lymphoma (AITL) is a neoplastic proliferation of T follicular helper cells with clinical and histological presentations suggesting a role of antigenic drive in its development. Genetically, it is characterized by a stepwise acquisition of somatic mutations, with early mutations involving epigenetic regulators (TET2, DNMT3A) and occurring in haematopoietic stem cells, with

  • Immunoproteasome subunit β5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice.
    J. Pathol. (IF 5.942) Pub Date : 2019-11-22
    Jiawei Liao,Yunpeng Xie,Qiuyue Lin,Xiaolei Yang,Xiangbo An,Yunlong Xia,Jie Du,Feng Wang,Hui-Hua Li

    The immunoproteasome contains three catalytic subunits (β1i, β2i and β5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between β5i and human atherosclerotic plaque instability; however, the causative role of β5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice

  • Proteins in stool as biomarkers for non-invasive detection of colorectal adenomas with high risk of progression.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-13
    Malgorzata A Komor,Linda Jw Bosch,Veerle Mh Coupé,Christian Rausch,Thang V Pham,Sander R Piersma,Sandra Mongera,Chris Jj Mulder,Evelien Dekker,Ernst J Kuipers,Mark A van de Wiel,Beatriz Carvalho,Remond Ja Fijneman,Connie R Jimenez,Gerrit A Meijer,Meike de Wit

    Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool-based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker

  • Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-14
    Yi-Fan Chen,Tzu-Yu Chou,I-Hsuan Lin,Chung-Guang Chen,Cheng-Heng Kao,Guo-Jen Huang,Liang-Kung Chen,Pei-Ning Wang,Ching-Po Lin,Ting-Fen Tsai

    CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated

  • Inhibition of tissue non-specific alkaline phosphatase; a novel therapy against arterial media calcification?
    J. Pathol. (IF 5.942) Pub Date : 2019-12-20
    Britt Opdebeeck,Patrick C D'Haese,Anja Verhulst

    Arterial media calcification refers to ectopic mineralization in the arterial wall and favors arterial stiffness and cardiovascular events. Patients with chronic kidney disease (CKD), diabetes, or osteoporosis are highly vulnerable to the development of arterial media calcifications. Tissue non-specific alkaline phosphatase (TNAP) is upregulated in calcified arteries and plays a key role in the degradation

  • Diabetic pre-programming of myelopoiesis impairs tissue repair.
    J. Pathol. (IF 5.942) Pub Date : 2020-01-12
    Yagna Pr Jarajapu

    Bone marrow-derived monocyte-macrophages promote healing of injured tissue cooperatively with vasculogenic hematopoietic stem/progenitor cells. However, diabetes dysregulates hematopoiesis and attenuates bone marrow-derived tissue-reparative responses. In a recent issue of The Journal of Pathology, Barman et al extensively characterized myelopoietic responses in bone marrow following skin wounding

  • Clinicopathological and molecular characterisation of 'multiple-classifier' endometrial carcinomas.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-12
    Alicia León-Castillo,Ester Gilvazquez,Remi Nout,Vincent Thbm Smit,Jessica N McAlpine,Melissa McConechy,Stefan Kommoss,Sara Y Brucker,Joseph W Carlson,Elisabeth Epstein,Tilman T Rau,Robert A Soslow,Raji Ganesan,Xavier Matias-Guiu,Esther Oliva,Beth T Harrison,David N Church,C Blake Gilks,Tjalling Bosse

    Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal

  • Real-time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study.
    J. Pathol. (IF 5.942) Pub Date : 2019-11-22
    Rachel Barrow-McGee,Julia Procter,Julie Owen,Natalie Woodman,Cristina Lombardelli,Ashutosh Kothari,Tibor Kovacs,Michael Douek,Simi George,Peter A Barry,Kelvin Ramsey,Amy Gibson,Richard Buus,Erle Holgersen,Rachael Natrajan,Syed Haider,Michael J Shattock,Cheryl Gillett,Andrew Nj Tutt,Sarah E Pinder,Kalnisha Naidoo

    Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain

  • Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression.
    J. Pathol. (IF 5.942) Pub Date : 2019-10-14
    Sabine Galland,Ivan Stamenkovic

    Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose - based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack

  • Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next-generation sequencing.
    J. Pathol. (IF 5.942) Pub Date : 2019-11-09
    Carolina C Gomes,Marina G Diniz,Victor C Bastos,Vanessa F Bernardes,Ricardo S Gomez

    Next-generation sequencing has revealed mutations in several bone-related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional

  • Proteome analysis of formalin-fixed paraffin-embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas.
    J. Pathol. (IF 5.942) Pub Date : 2019-11-14
    Pierre Sohier,Romain Sanson,Marjorie Leduc,Anne Audebourg,Cédric Broussard,Virginie Salnot,Pierre-Alexandre Just,Eric Pasmant,Patrick Mayeux,François Guillonneau,Béatrice Romagnolo,Christine Perret,Benoît Terris

    Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of

  • Clarin-1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-04
    Lei Xu,Susan N Bolch,Clayton P Santiago,Frank M Dyka,Omar Akil,Ekaterina S Lobanova,Yuchen Wang,Kirill A Martemyanov,William W Hauswirth,W Clay Smith,James T Handa,Seth Blackshaw,John D Ash,Astra Dinculescu

    Usher syndrome type 3 (USH3) is an autosomal recessively inherited disorder caused by mutations in the gene clarin-1 (CLRN1), leading to combined progressive hearing loss and retinal degeneration. The cellular distribution of CLRN1 in the retina remains uncertain, either because its expression levels are low or because its epitopes are masked. Indeed, in the adult mouse retina, Clrn1 mRNA is developmentally

  • Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine.
    J. Pathol. (IF 5.942) Pub Date : 2019-11-05
    Corry-Anke Brandsma,Maarten Van den Berge,Tillie-Louise Hackett,Guy Brusselle,Wim Timens

    Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback

  • The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma.
    J. Pathol. (IF 5.942) Pub Date : 2019-12-03
    Vincent Roh,Agnès Hiou-Feige,Vinko Misetic,Jean-Paul Rivals,Jana Sponarova,Muy-Teck Teh,Silvia Ferreira Lopes,Zinnia Truan,Maxime Mermod,Yan Monnier,Jochen Hess,Genrich V Tolstonog,Christian Simon

    Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor-supporting pathways. Using shRNA-mediated knockdown, we demonstrate a minimal

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