MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'The Journal of Pathology' source. Thu, 09 Feb 2012 00:42:21 +0100 http://www.medworm.com/index.php?rid=5651040&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3964 AbstractAppreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface‐anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the trans... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5651040 Fri, 03 Feb 2012 05:33:05 +0100 5651040 http://www.medworm.com/index.php?rid=5651038&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3998 AbstractAbout 40% of osteosarcoma patients die of metastases. Novel strategies to improve treatment of metastatic patients require a better understanding of the processes involved, like angiogenesis, migration and the immune response. However the rarity of osteosarcoma and its heterogeneity make this neoplasm difficult to study. Recently we reported malignant transformation of mouse mesenchymal stem cells (MSCs) which formed osteosarcoma upon transplantation into mice. Here we studied these cells in zebrafish embryos and found that transformed MSCs induced angiogenesis and migrated through the bodies of the embryos, but this was never observed with non‐transformed normal MSCs (progenitors of the transformed MSCs). Whole genomic expression analysis of both the cells and the host showed th... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5651038 Fri, 03 Feb 2012 05:32:13 +0100 5651038 http://www.medworm.com/index.php?rid=5639887&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3997 AbstractGlucocorticoids are stress‐responsive neuroendocrine mediators and play an important role in malignant progression, especially in solid tumors. We demonstrate a novel mechanism by which glucocorticoids modulate p53‐dependent miR‐145 expression in HPV positive cervical cancer cells through induction of E6 proteins. We found that expression of miR‐145 was reduced in cervical cancer tissues. Cortisol induced HPV E6 expression and suppressed p53 and miR‐145 in cervical cancer cells. MiR‐145 expression in cervical cancer cells was wild‐type p53‐dependent, and cortisol‐induced downregulation of miR‐145 expression prevented chemotherapy‐induced apoptosis whereas overexpression of miR‐145 enhanced sensitivity to mitomycin and reversed the chemoresistance induced by ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5639887 Mon, 30 Jan 2012 06:38:06 +0100 5639887 http://www.medworm.com/index.php?rid=5621577&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3996 AbstractWe have investigated the expression and role of galectin‐1 and other galectins in psoriasis and in the Th1/Th17 effector and dendritic cell responses associated with this chronic inflammatory skin condition. To determine differences between psoriasis patients and healthy donors, expression of galectins was analyzed by RT‐PCR in skin samples and on epidermal and peripheral blood dendritic cells by immunofluorescence and flow cytometry. In skin of healthy donors, galectins 1, 3 and 9 were expressed in a high proportion of Langerhans cells. Also, galectins were differentially expressed in peripheral blood dendritic cell subsets; galectin‐1 and galectin‐9 were highly expressed in peripheral myeloid dendritic cells compared with plasmacytoid dendritic cells. We found that non‐... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5621577 Tue, 24 Jan 2012 05:23:43 +0100 5621577 http://www.medworm.com/index.php?rid=5611951&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3995 In conclusion, we assess the oncogenic role of miR‐519d in HCC by characterizing its biological functions including the modulation of response to anticancer treatments and by identifying CDKN1A/p21, PTEN, AKT3 and TIMP2 among its targets. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611951 Sat, 21 Jan 2012 05:02:18 +0100 5611951 http://www.medworm.com/index.php?rid=5611956&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3989 AbstractInflammation contributes to tumor growth, invasion, and angiogenesis. We investigated the contribution of macrophages and their polarization to tumor progression in a model of VEGF‐A‐induced skin carcinogenesis. Transfection of the human non‐tumorigenic keratinocyte cell line HaCaT with murine VEGF‐A leads to malignant tumor growth in vivo. The resulting tumors are characterized by extensive vascularization, invasive growth, and high numbers of M2 polarized macrophages that crucially contribute to the establishment of the malignant phenotype. Accordingly, macrophage depletion from tumor‐bearing animals resulted in reduced tumor growth, inhibition of invasion, decreased proliferation and reduced angiogenesis. In vitro, VEGF‐A exerted a chemo‐attracting effect on macrop... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611956 Thu, 19 Jan 2012 05:00:00 +0100 5611956 http://www.medworm.com/index.php?rid=5611955&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3991 AbstractHER2 signalling by heterodimerization with EGFR and HER3 in breast cancer is associated with worst outcome of the afflicted patients, which is not only attributed to the aggressiveness of such tumours, but also to therapy resistance. In the present study we thus investigated the role of EGFR, HER2, and HER3 lateral signalling in cell migration by applying the MDA‐MB‐468‐HER2 (MDA‐HER2) breast cancer cell line representing a valid model system. Knockdown of HER3 expression by siRNA resulted in decreased pAKT levels, abrogated EGF‐mediated PLC‐?1 activation, and a diminished EGF‐induced migratory activity depicting the interplay of EGFR/HER2/PLC‐?1 and HER2/HER3/PI3K signalling in mediating the migration of EGFR/HER2/HER3 expressing breast cancer cells. Since therapy ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611955 Thu, 19 Jan 2012 05:00:00 +0100 5611955 http://www.medworm.com/index.php?rid=5611954&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3992 AbstractFibrotic disorders of the lung are associated with perturbations in the plasminogen activation system. Specifically, plasminogen activator inhibitor‐1 (PAI‐1) expression is increased relative to the plasminogen activators. A direct role for this imbalance in modulating the severity of lung scarring following injury has been substantiated in the bleomycin model of pulmonary fibrosis. However, it remains unclear whether derangements in the plasminogen activation system contribute more generally to the pathogenesis of lung fibrosis beyond bleomycin injury. To answer this question, we employed an alternative model of lung scarring in which type II alveolar epithelial cells (AEC) are specifically injured by administering diphtheria toxin (DT) to mice genetically engineered to expres... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611954 Thu, 19 Jan 2012 05:00:00 +0100 5611954 http://www.medworm.com/index.php?rid=5611953&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3993 AbstractA loss of balance between cell membrane‐associated proteases and their inhibitors may underlie cancer invasion and metastasis. We analyzed the roles of a membrane‐ associated serine protease inhibitor, HAI‐1, in oral squamous cell carcinoma (OSCC). While membranous HAI‐1 was widely observed in cancer cells of human OSCC tissues, this was significantly reduced at the infiltrative invasion front. In vitro, HAI‐1 was detected in all eight OSCC cell lines examined, in which its cognate membrane protease, matriptase was also expressed. HAI‐1 expression knock down (KD) in OSCC lines, SAS and HSC‐3, reduced growth of both lines in vitro, but significantly enhanced SAS tumorigenicity in vivo, which was accompanied by histological changes suggestive of the epithelial to mesenc... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611953 Thu, 19 Jan 2012 05:00:00 +0100 5611953 http://www.medworm.com/index.php?rid=5611952&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3994 We examined whether autophagy might be involved in survival of CSC despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSC and autophagy are co‐expressed in patient‐derived tissue of PDA. Hypoxia‐starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem‐like properties (CSChigh), while pancreatic tumour cells with less stem cell markers (CSClow) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSChigh cells, which exhibited higher expression of autophagy‐related genes under normoxic conditions and relative to CSClow cells as found by RT‐PCR and Western blot analysis. LC3 was alr... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5611952 Thu, 19 Jan 2012 05:00:00 +0100 5611952 http://www.medworm.com/index.php?rid=5599901&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3973 (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599901 Wed, 18 Jan 2012 06:02:29 +0100 5599901 http://www.medworm.com/index.php?rid=5599892&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3990 AbstractThe mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, the acquisition of new genetic aberrations or non‐genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCIS and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDCs were retrieved from 13 patients and subjected to microarray‐based comparative genomic hybridisation (aCGH), and... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599892 Wed, 18 Jan 2012 06:01:20 +0100 5599892 http://www.medworm.com/index.php?rid=5562674&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3981 AbstractFibrosis of the liver and its end‐stage, cirrhosis, represent major health problems worldwide. In these fibrotic conditions activated fibroblasts and hepatic stellate cells display a net deposition of collagen. This collagen deposition is a major factor leading to liver dysfunction, thus making it crucially important to understand both the collagen synthesis and turnover mechanisms in this condition. Here we show that the endocytic collagen receptor, uPARAP/Endo180, is a major determinant in governing the balance between collagen deposition and degradation. Cirrhotic human livers displayed a marked upregulation of uPARAP/Endo180 in activated fibroblasts and hepatic stellate cells located close to the collagen deposits. In a hepatic stellate cell line, uPARAP/Endo180 was shown to ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562674 Wed, 04 Jan 2012 05:00:00 +0100 5562674 http://www.medworm.com/index.php?rid=5562673&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3982 In this report, we provide direct evidence that it is the detergent soluble, non‐desmosomal Dsg3 that regulates the activity of Src and its association with E‐cadherin in adherens junction formation. Modulation of Dsg3 levels, either by Dsg3 silencing or overexpression, alters Src activity and its association with E‐cadherin. Dsg3 silencing caused retardation of calcium‐induced E‐cadherin junction assembly and a reduction of desmosomal protein expression. Furthermore, we provide evidence that this signalling pathway is involved, at least in part, in the pathophysiology of pemphigus. Along with the reduced expression of Dsg3, loss and disruption of E‐cadherin and a concomitant decreased pSrc signalling was identified in the basal keratinocytes surrounding the blisters in PV. The... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562673 Wed, 04 Jan 2012 05:00:00 +0100 5562673 http://www.medworm.com/index.php?rid=5562672&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3983 AbstractMicro‐RNAs (miRNAs) are frequently dysregulated in a range of human malignancies, many have been shown to act either as tumour supressors or oncogenes, and several have been implicated in breast cancer. However, breast cancer is a diverse disease, and little is known about the relationships between miRNA expression, clinical outcome, and tumour subtype. We used locked nucleic acid probe in situ hybridisation (LNA‐ISH) to visualise, in tissue micro‐arrays (TMAs) of 2919 formalin‐fixed paraffin‐embedded (FFPE) archival breast tumours, the expression of two key miRNAs which are frequently lost in a range of solid malignancies, let‐7b and miR‐205. These miRNAs were also quantified by quantitative reverse transcription PCR in cores of FFPE tissue from 40 of these cases, de... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562672 Wed, 04 Jan 2012 05:00:00 +0100 5562672 http://www.medworm.com/index.php?rid=5562671&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3984 AbstractHyperthyroidism is characterised by rats increased energy expenditure and marked hyperphagia. The alterations of thermogenesis linked to hyperthyroidism are associated to dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism‐induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti‐related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR colocalizes with thyroid hormone receptor alpha (TR I). Central administration of t... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562671 Wed, 04 Jan 2012 05:00:00 +0100 5562671 http://www.medworm.com/index.php?rid=5562670&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3985 AbstractClear cell sarcoma of kidney (CCSK) is classified as a tumour of unfavourable histology by the National Wilms' Tumor Study Group. It has worse clinical outcomes than Wilms' tumour. Virtually nothing is known about CCSK biology, as there have been very few genetic aberrations identified to act as pointers in this cancer. Three cases of CCSK bearing a chromosomal translocation, t(10;17)(q22;p13), have been individually reported, but not further investigated to‐date. The aim of this research was to characterise t(10;17)(q22;p13) in CCSK to identify the genes involved in the translocation breakpoints. Using fluorescently labelled Bacterial Artificial Chromosomes [BACs] and a chromosome‐walking strategy on an index case of CCSK with t(10;17)(q22;p13) by karyotype, we identified the ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562670 Wed, 04 Jan 2012 05:00:00 +0100 5562670 http://www.medworm.com/index.php?rid=5562669&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3986 AbstractSoft‐tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers, and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST), and desmoid‐type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here, we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show t... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562669 Wed, 04 Jan 2012 05:00:00 +0100 5562669 http://www.medworm.com/index.php?rid=5585683&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3988 AbstractHepatoma‐derived growth factor (HDGF) participates in tumorigenesis but its role in breast cancer is unclear. We set out to elucidate the expression profile and function of HDGF during breast carcinogenesis. Immunoblot and immunohistochemical studies revealed elevated HDGF expression in human breast cancer cell lines and tissues. Nuclear HDGF labeling index was positively correlated with tumour grade, stage, and proliferation index, but negatively correlated with survival rate in breast cancer patients. HDGF overexpression was associated with lymph node metastasis and represented an independent prognostic factor for tumour recurrence. Gene transfer studies were performed to elucidate the influence of cellular HDGF level on the malignant behaviour and epithelial‐mesenchymal tran... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5585683 Sun, 01 Jan 2012 05:00:00 +0100 5585683 http://www.medworm.com/index.php?rid=5562668&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3987 AbstractNext generation sequencing is making sequence‐based molecular pathology and personalised oncology viable. We selected an individual initially diagnosed with conventional, but aggressive, prostate adenocarcinoma and sequenced the genome and transcriptome from primary and metastatic tissues collected prior to hormone therapy. The histology‐pathology and copy number profiles were remarkably homogeneous, yet it was possible to propose the quadrant of the prostate tumour that likely seeded the metastatic diaspora. Despite a homogenous cell type, our transcriptome analysis revealed signatures of both luminal and neuroendocrine cell types. Remarkably, the repertoire of expressed but apparently private gene fusions, including C15orf21:MYC, recapitulated this biology. We hypothesize tha... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562668 Sun, 01 Jan 2012 05:00:00 +0100 5562668 http://www.medworm.com/index.php?rid=5527630&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3978 AbstractSolid tumors are dependent on glucose, but are generally glucose‐deprived due to poor vascularization. Nevertheless cancer cells can generally survive glucose deprivation better than their normal counterparts. Thus, to render cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. We propose that lactic acidosis, a tumor microenvironment factor, may allow cancer cells to develop a resistance to glucose deprivation‐induced death, and that disruption of lactic acidosis may resume cancer cells' sensitivity to glucose depletion. Lactic acidosis, lactosis, or acidosis was generated by adding pure lactic acid, sodium lactate, or HCl to the culture medium. Cell death, cell cycle, autophagy, apoptosis and gene expression profil... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5527630 Thu, 22 Dec 2011 17:40:49 +0100 5527630 http://www.medworm.com/index.php?rid=5527633&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3979 AbstractTherapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid, vinorelbine exhibits clinical activity, however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons, however its role in regulating vinorelbine induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine induced apoptosis, as evidenced by: 1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level, 2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides, 3) dramatic downregulation of BRCA1 following selection for vinorelbine resistance, and 4) the re‐activation ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5527633 Wed, 21 Dec 2011 05:00:00 +0100 5527633 http://www.medworm.com/index.php?rid=5527632&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3976 In conclusion, TβRII plays an important but diverse role in regulating renal fibrosis and inflammation. Impaired TGF‐β/Smad3 but not the non‐canonical TGF‐β signaling pathway may be a key mechanism by which disruption of TβRII protects against renal fibrosis. In addition, deletion of TβRII also enhances NF‐κB signaling along with upregulation of renal pro‐inflammatory cytokines, which may be associated with the impairment of anti‐inflammatory properties of TGF‐β1. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5527632 Wed, 21 Dec 2011 05:00:00 +0100 5527632 http://www.medworm.com/index.php?rid=5527631&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3977 AbstractThe accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR), which involves a set of protein signalling pathways and transcription factors that re‐establish homeostasis and normal ER function, adapting cells to ER stress. If this adaptive response is insufficient, the UPR triggers an apoptotic program to eliminate irreversibly damaged cells. Recent observations suggest that ER stress plays an important role in the pathogenesis of various neurodegenerative disorders such as Alzheimer's disease, which is characterized by the deposition of amyloid‐beta (Abeta) and hyperphosphorylated tau in susceptible brain regions. Moreover, several studies demonstrate that Abeta induces UPR activation, which in ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5527631 Wed, 21 Dec 2011 05:00:00 +0100 5527631 http://www.medworm.com/index.php?rid=5516645&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3980 AbstractHigh‐grade serous ovarian carcinoma (HGSOC) is characterised by genomic instability, ubiquitous TP53 loss and frequent development of platinum resistance. Loss of homologous recombination (HR) is a mutator phenotype present in 50% of HGSOC and confers hypersensitivity to platinum treatment. We asked which other mutator phenotypes are present in HGSOC and how they drive the emergence of platinum resistance. We performed whole‐genome paired‐end sequencing on a model of two HGSOC cases, each consisting of a pair of cell lines established before and after clinical resistance emerged, to describe their structural variants (SV) and to infer their ancestral genomes as the SVs present within each pair. The first case (PEO1/PEO4), with HR deficiency, acquired translocations and small ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5516645 Mon, 19 Dec 2011 17:27:57 +0100 5516645 http://www.medworm.com/index.php?rid=5496795&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3975 AbstractWhereas naïve T cells access the lymph nodes exclusively via the high endothelial venules, their effector counterparts can also enter via the afferent lymphatics. It is unclear if such cells are confined to the lymphatic spaces during their transit through the lymph node or access the lymphocyte‐ and dendritic cell‐rich parenchyma with its potentially stimulatory environment. We used a flank HSV inoculation model that featured neuronal‐mediated movement of virus to distinct areas of skin to study the lymphatic‐mediated transit of activated T cells between different skin‐draining lymph nodes. These experiments showed that activated T cells released from the brachial lymph node, draining the primary site of inoculation, entered the downstream axillary lymph node. These act... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5496795 Tue, 13 Dec 2011 18:18:52 +0100 5496795 http://www.medworm.com/index.php?rid=5651039&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3974 AbstractOestrogen receptor‐alpha (ERα), encoded by the ESR1 gene located on 6q25, is a nuclear transcription factor. Since it was reported in 2007 that more than 20% of breast cancers show ESR1 gene amplification, there has been considerable controversy about its frequency and clinical significance. We set out to assess the frequency and levels of ESR1 amplification in breast cancers. In a total of 106 breast needle biopsy specimens examined by immunohistochemistry, 78 tumours contained more than 10% ERα‐positive cancer cells. In fluorescence in situ hybridization (FISH) analysis with an ESR1‐specific probe, variously extended ESR1 signals were found in ERα‐expressing cells. Some of these were indistinguishable from large clustered signals generally accepted to mean high‐level... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5651039 Tue, 13 Dec 2011 05:00:00 +0100 5651039 http://www.medworm.com/index.php?rid=5496796&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3974 AbstractEstrogen receptor‐alpha (ERα), encoded by the ESR1 gene located on 6q25, is a nuclear transcription factor. Since it was reported in 2007 that more than 20% of breast cancers show ESR1 gene amplification, there has been considerable controversy about its frequency and clinical significance. We set out to assess the frequency and levels of ESR1 amplification in breast cancers. In a total of 106 breast needle biopsy specimens examined by immunohistochemistry, 78 tumors contained more than 10% ERα‐positive cancer cells. In fluorescence in situ hybridization (FISH) analysis with an ESR1‐specific probe, variously extended ESR1 signals were found in ERα‐expressing cells. Some of these were indistinguishable from large clustered signals generally accepted to mean high‐level g... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5496796 Tue, 13 Dec 2011 05:00:00 +0100 5496796 http://www.medworm.com/index.php?rid=5460328&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3020 AbstractThe extracellular matrix (ECM) provides a solid scaffold and signals to cells through ECM receptors. The cell–matrix interactions are crucial for normal biological processes and when disrupted they may lead to pathological processes. In particular, the biological importance of ECM–cell membrane–cytoskeleton interactions in skeletal muscle is accentuated by the number of inherited muscle diseases caused by mutations in proteins conferring these interactions. In this review we introduce laminins, collagens, dystroglycan, integrins, dystrophin and sarcoglycans. Mutations in corresponding genes cause various forms of muscular dystrophy. The muscle disorders are presented as well as advances toward the development of treatment. Copyright © 2011 Pathological Society of Great Brita... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5460328 Thu, 01 Dec 2011 18:17:06 +0100 5460328 http://www.medworm.com/index.php?rid=5460327&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3970 AbstractIn 20‐40% of cervical intra‐epithelial neoplasia (CIN) and in 4‐8% of cervical carcinoma tissue specimens, multiple HPV genotypes have been detected. Whole tissue section (WTS) PCR does not determine how the individual types relate causally to complex and multiple CIN. Our objective was to determine whether laser capture micro‐dissection (LCM) with HPV PCR genotyping (LCM‐PCR) could accurately recover type‐specific HPV DNA from epithelial cells in individual areas of CIN and normal epithelium and whether one or more viruses are present in one lesion. For that, histologically selected samples of CIN and normal epithelium were isolated by LCM and analysed by the SPF10 PCR/LiPA25 (version 1) HPV genotyping system for 25 HPV genotypes. HPV genotypes detected in 756 areas of... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5460327 Thu, 01 Dec 2011 18:16:08 +0100 5460327 http://www.medworm.com/index.php?rid=5433471&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3969 AbstractThe unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p‐tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p‐tau, AD brains are characterized by extracellular deposits of β amyloid (Aβ). Recent in vitro studies have shown that Aβ can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) which carry mutations in the gen... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5433471 Tue, 22 Nov 2011 17:42:20 +0100 5433471 http://www.medworm.com/index.php?rid=5433474&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3964 AbstractAppreciation of the glomerular microcirculation as a specialised microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface‐anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the trans... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5433474 Mon, 21 Nov 2011 05:00:00 +0100 5433474 http://www.medworm.com/index.php?rid=5433473&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3967 AbstractIt has been well established that ovarian low‐grade and high‐grade serous carcinomas are fundamentally different types of tumours. While the molecular genetic features of ovarian high‐grade serous carcinomas are now well known, the pathogenesis of low‐grade serous carcinomas, apart from the recognition of frequent somatic mutations involving KRAS and BRAF, is largely unknown. In order to comprehensively analyze somatic mutations in low‐grade serous carcinomas, we applied exome sequencing to the DNA of eight samples of affinity‐purified low‐grade serous carcinomas. A remarkably small number of mutations were identified in seven of these tumours: a total of 70 somatic mutations in 64 genes. The eighth case displayed mixed serous and endometrioid features and a mutator p... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5433473 Mon, 21 Nov 2011 05:00:00 +0100 5433473 http://www.medworm.com/index.php?rid=5433472&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3968 AbstractChronic cardiac allograft rejection is characterized by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) causing severe long‐term complications after heart transplantation and determining allograft function and patients' prognosis. Until now, there are no sufficient preventive or therapeutic strategies. CAV and CIF are accompanied by changes in the extracellular matrix, including re‐expression of the fetal fibronectin splice variant known as ED‐A+ fibronectin. This molecule has been shown to be crucial for the development of myofibroblasts (MyoFb) as the main cell type in CIF and for the activation of vascular smooth muscle cells (VSMCs) as the main cell type in CAV. Relevant re‐expression and protein deposition of ED‐A+ fibronectin has been de... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5433472 Mon, 21 Nov 2011 05:00:00 +0100 5433472 http://www.medworm.com/index.php?rid=5411559&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3963 In conclusion, molecular screening for LS in CRC patients ≤ 70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age‐criterion (≤ 50 years) routinely used for LS‐assessment. Routine use of MSI‐testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411559 Thu, 17 Nov 2011 08:25:57 +0100 5411559 http://www.medworm.com/index.php?rid=5599897&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3963 In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599897 Mon, 14 Nov 2011 05:00:00 +0100 5599897 http://www.medworm.com/index.php?rid=5599896&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3962 In this study we show that β‐catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β‐catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene‐mediated β‐catenin inhibition within keratin 14‐expressing basal cells delayed normal airway repair while basal cell‐specific β‐catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial‐mesenchymal transition (EMT), including increased Snail transcription and reduced E‐cadherin expression. These observations are recapitulated in normal human bronchial epi... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599896 Mon, 14 Nov 2011 05:00:00 +0100 5599896 http://www.medworm.com/index.php?rid=5411563&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3959 AbstractPancreatic Ductal Adenocarcinoma (PDAC) is a major cause of cancer‐related death, largely due to metastatic disease. To better understand PDAC metastatic spread and identify novel therapeutic targets, we analysed the proteome of primary tumours and matched lymph node (LN) metastases. As frozen specimens of metastatic lesions are scarce, we examined formalin‐fixed paraffin‐embedded (FFPE) tissues. This poses technical challenges because of the cross‐linkages induced by fixation. Using laser capture microdissection (P.A.L.M system), we isolated malignant epithelia from seven FFPE primary PDAC tumours and matched LN metastases. Following dissection, samples were analysed in duplicate using Multidimensional Protein Identification Technology (MudPIT); this resulted in the identi... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411563 Mon, 14 Nov 2011 05:00:00 +0100 5411563 http://www.medworm.com/index.php?rid=5411562&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3960 AbstractEndoplasmic Reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischemia‐induced neovascularisation in type II diabetes is unknown. We studied ischemia‐induced neovascularization in the hind‐limb of 4 weeks old db‐/db‐ mice and their controls treated with or without the ER stress inhibitor (tauroursodeoxycholic acid, TUDCA, 150 mg/Kg/day) and interleukin‐1 receptor antagonist (anakinra, 0.5 µg/mouse/day) for 4 weeks. Blood pressure was similar in all groups of mice. Blood glucose, insulin levels, and body weight were reduced in db‐/db‐ mice treated with TUDCA. Increased cholesterol and reduced adiponectin in db‐/db‐ mice we... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411562 Mon, 14 Nov 2011 05:00:00 +0100 5411562 http://www.medworm.com/index.php?rid=5411561&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3961 We examined mice in which Stat3 is conditionally deleted only in the mammary epithelium. Distinct sets of genes associated with the acute phase response and innate immunity are markedly up‐regulated during first phase involution in a Stat3‐dependent manner. During second phase involution, chitinase 3‐like 1, which has been associated with wound healing and chronic inflammatory conditions, is dramatically up‐regulated by Stat3. Also at this time, the number of mammary macrophages and mast cells increases per unit area, and this increase is impaired in the absence of epithelial Stat3. Furthermore, expression of arginase‐1 and Ym1, markers of alternatively activated macrophages, is significantly decreased in the absence of Stat3, whilst iNOS, a marker associated with classically act... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411561 Mon, 14 Nov 2011 05:00:00 +0100 5411561 http://www.medworm.com/index.php?rid=5411560&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3962 In this study we show that β‐catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β‐catenin signalling is positively associated with increased disease severity, epithelial proliferation, and reduced intercellular adhesiveness. We demonstrate that transgene‐mediated β− catenin inhibition within keratin 14‐expressing basal cells delayed normal airway repair while basal cell‐specific β− catenin activation increased cell proliferation, directed differentiation, and promoted elements of early epithelial‐to‐mesenchymal transition (EMT) including increased Snail transcription and reduced E‐cadherin expression. These observations are recapitulated in normal human bronc... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411560 Mon, 14 Nov 2011 05:00:00 +0100 5411560 http://www.medworm.com/index.php?rid=5390986&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3958 AbstractCellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralised type I collagen matrix. Once metastatic niches establish in bone the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognised function of Endo180 was suppressed in osteoblasts following heterotypic direct cell‐cell contact in coculture w... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390986 Thu, 10 Nov 2011 18:38:02 +0100 5390986 http://www.medworm.com/index.php?rid=5599893&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3956 In conclusion, our results indicate that HPGD is highly expressed in metastatic and aggressive breast cancer and promotes EMT and migration in breast cancer cells. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599893 Thu, 10 Nov 2011 05:00:00 +0100 5599893 http://www.medworm.com/index.php?rid=5562675&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3957 AbstractCaveolin‐1 (Cav1) has been implicated in diverse human cancers, yet its role in hepatocellular carcinoma (HCC) tumourigenesis and metastasis remains elusive. In the current study, we aim to provide a comprehensive understanding regarding the functional role of Cav1 in HCC tumourigenesis and metastasis. Cav1 expression was examined in a panel of human HCC cell lines using western blotting analysis and quantitative RT‐PCR and human tissues by immunohistochemistry. Cav1 was not detected in normal liver cell line and all non‐tumourous liver tissues but exclusively expressed in HCC cell lines and tissues. Dramatic expression of Cav1 was found in metastatic HCC cell lines and tumours, indicating a progressive increase of Cav1 expression along disease progression. Cav1 overexpressio... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562675 Thu, 10 Nov 2011 05:00:00 +0100 5562675 http://www.medworm.com/index.php?rid=5488955&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3958 AbstractCellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralized type I collagen matrix. Once metastatic niches establish in bone, the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognized function of Endo180 was suppressed in osteoblasts following heterotypic direct cell–cell contact in co‐cultu... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5488955 Thu, 10 Nov 2011 05:00:00 +0100 5488955 http://www.medworm.com/index.php?rid=5390988&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3956 In conclusion, our results indicate that HPGD is highly expressed in metastatic and aggressive breast cancer and promotes EMT and migration in breast cancer cells. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390988 Thu, 10 Nov 2011 05:00:00 +0100 5390988 http://www.medworm.com/index.php?rid=5390987&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3957 AbstractCaveolin‐1 (Cav1) has been implicated in diverse human cancers; yet its role in hepatocellular carcinoma (HCC) tumorigenesis and metastasis remain elusive. In the current study, we aim to provide a comprehensive understanding regarding the functional role of Cav1 in HCC tumorigenesis and metastasis. Cav1 expression was examined in a panel of human HCC cell lines using western blotting analysis and quantitative RT‐PCR and human tissues by immunohistochemistry. Cav1 was not detected in normal liver cell line and all non‐tumorous liver tissues but exclusively expressed in HCC cell lines and tissues. Dramatic expression of Cav1 was found in metastatic HCC cell lines and tumors, indicating a progressive increase of Cav1 expression along disease progression. Cav1 overexpression was... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390987 Thu, 10 Nov 2011 05:00:00 +0100 5390987 http://www.medworm.com/index.php?rid=5599894&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3035 In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high‐grade serous EOC. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599894 Tue, 08 Nov 2011 05:00:00 +0100 5599894 http://www.medworm.com/index.php?rid=5390990&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3034 AbstractCPT‐11 (irinotecan), the first line chemotherapy for advanced stage colorectal cancer, remains inactive in about half of the patients (primary chemoresistance) and almost all initial responders develop secondary resistance after several courses of treatment (8 months on average). Nude mice bearing HT‐29 colon cancer xenografts were treated with CPT‐11 and/or an NF‐κB inhibitor for 2 courses. We confirm that NF‐κB inhibition potentiated CPT‐11 antitumoral effect after the first course of treatment. However, tumors grew again at the end of the second course of treatment, generating resistant tumors. We observed an increase in the basal NF‐κB activation in resistant tumors and in 2 resistant sublines obtained either from a resistant HT‐29 tumors (HT‐29R cells) or ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390990 Tue, 08 Nov 2011 05:00:00 +0100 5390990 http://www.medworm.com/index.php?rid=5390989&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3035 In conclusion, loss of MAD2 protein expression results in increased resistance to paclitaxel in EOC cells. Measuring MAD2 IHC staining intensity may predict paclitaxel responses in women presenting with high‐grade serous EOC. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390989 Tue, 08 Nov 2011 05:00:00 +0100 5390989 http://www.medworm.com/index.php?rid=5350382&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2956 (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5350382 Thu, 27 Oct 2011 05:50:56 +0100 5350382 http://www.medworm.com/index.php?rid=5350381&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2985 (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5350381 Thu, 27 Oct 2011 05:50:36 +0100 5350381 http://www.medworm.com/index.php?rid=5350379&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3033 AbstractThe lamins are major determinants of nuclear shape and chromatin organization and these features are frequently altered in prostate cancer (CaP). Human CaP cell lines frequently have nuclear lobulations which are enriched in A‐type lamins but lack B‐type lamins and have been defined as lamin B deficient microdomains (LDMDs). LDMD frequency is correlated with CaP cell line aggressiveness and increased cell motility. In addition, LNCaP cells grown in the presence of dihydrotestosterone (DHT) show an increased frequency of LDMDs. The LDMDs are enriched in activated RNA polymerase II (Pol IIo) and androgen receptor (AR) and A‐type lamins form an enlarged meshwork that appears to co‐align with chromatin fibers and AR. Furthermore, fluorescence in situ hybridization and comparati... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5350379 Thu, 27 Oct 2011 05:49:18 +0100 5350379 http://www.medworm.com/index.php?rid=5599898&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3033 AbstractThe lamins are major determinants of nuclear shape and chromatin organization and these features are frequently altered in prostate cancer (CaP). Human CaP cell lines frequently have nuclear lobulations, which are enriched in A‐type lamins but lack B‐type lamins and have been defined as lamin B‐deficient microdomains (LDMDs). LDMD frequency is correlated with CaP cell line aggressiveness and increased cell motility. In addition, LNCaP cells grown in the presence of dihydrotestosterone (DHT) show an increased frequency of LDMDs. The LDMDs are enriched in activated RNA polymerase II (Pol IIo) and androgen receptor (AR) and A‐type lamins form an enlarged meshwork that appears to co‐align with chromatin fibres and AR. Furthermore, fluorescence in situ hybridization and compar... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599898 Tue, 25 Oct 2011 04:00:00 +0100 5599898 http://www.medworm.com/index.php?rid=5488952&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3032 AbstractPapillary carcinomas are a special histological type of breast cancer and have a relatively good outcome. We characterized the genomic and phenotypic characteristics of papillary carcinomas to determine whether they would constitute an entity distinct from grade‐ and oestrogen receptor (ER)‐matched invasive ductal carcinomas of no special type (IDC‐NSTs). The phenotype of 63 papillary carcinomas of the breast and grade‐ and ER‐matched IDC‐NSTs was determined by immunohistochemistry. DNA of sufficient quality was extracted from 49 microdissected papillary carcinomas and 49 microdissected grade‐ and ER‐matched IDC‐NSTs. These samples were subjected to high‐resolution microarray‐based comparative genomic hybridization (aCGH) and Sequenom MassARRAY sequencing anal... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5488952 Tue, 25 Oct 2011 04:00:00 +0100 5488952 http://www.medworm.com/index.php?rid=5350380&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3032 AbstractPapillary carcinomas are a special histological type of breast cancer, and have a relatively good outcome. We characterised the genomic and phenotypic characteristics of papillary carcinomas, and to determine whether they would constitute an entity distinct from grade‐ and oestrogen receptor (ER)‐matched invasive ductal carcinomas of no special type (IDC‐NSTs). The phenotype of 63 papillary carcinomas of the breast and grade‐ and ER‐matched IDC‐NSTs was determined by immunohistochemistry. DNA of sufficient quality was extracted from 49 microdissected papillary carcinomas and 49 microdissected grade‐ and ER‐matched IDC‐NSTs. These samples were subjected to high‐resolution microarray‐based comparative genomic hybridisation (aCGH) and MassARRAY Sequenom sequencin... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5350380 Tue, 25 Oct 2011 04:00:00 +0100 5350380 http://www.medworm.com/index.php?rid=5338849&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2997 AbstractNasopharyngeal carcinoma (NPC) is an EBV‐associated epithelial malignancy which is prevalent in south‐east Asia and southern China. Despite the multiple genetic and epigenetic changes reported, the contribution of dysregulated signalling pathways to this distinct type of head and neck cancer is not well understood. Here we demonstrate the up‐regulation of NOTCH ligands (JAG1 or DLL4) and effector (HEY1) in the majority of EBV‐positive tumour lines and primary tumours. Among the NOTCH receptors, NOTCH3 was over‐expressed in all EBV‐positive tumour lines and 92.5% of primary tumours. Aberrant activation of NOTCH3 signalling was consistently detected in all these samples. These findings imply that NOTCH3 may play an crucial role in the development of NPC. By NOTCH3 specifi... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5338849 Wed, 19 Oct 2011 04:00:00 +0100 5338849 http://www.medworm.com/index.php?rid=5325891&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3031 AbstractCancer cell invasion into healthy tissues develops preferentially along preexisting tracks of least resistance, followed by secondary tissue remodelling and destruction. The tissue scaffolds supporting or preventing guidance of invasion vary in structure and molecular composition between organs. In brain, the guidance is provided by myelinated axons, astrocyte processes and blood vessels which are used as invasion routes by glioma cells. In the human breast, containing interstitial collagen‐rich connective tissue, disseminating breast cancer cells preferentially invade along bundled collagen fibrils and the surface of adipocytes. In both invasion types, physical guidance prompted by interfaces and space is complemented by molecular guidance. Generic mechanisms shared by most, if ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5325891 Wed, 19 Oct 2011 03:36:13 +0100 5325891 http://www.medworm.com/index.php?rid=5325892&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3030 AbstractThis 2012 Annual Review Issue of The Journal of Pathology argues strongly that cell biology, in its many disciplines, underpins the foundation of our understanding of the mechanisms of disease – the holy grail of pathology. Our increasing knowledge of the human genome will not be enough to attain this goal without parallel developments in our comprehension of the results, at the cellular level, of these genetic changes. In the end, it is cell biology and cell biologists who will deliver this mission. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5325892 Tue, 18 Oct 2011 04:00:00 +0100 5325892 http://www.medworm.com/index.php?rid=5306553&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3029 AbstractChemokines (chemo‐attractant cytokines) are a group of small proteins that act together with their cell surface receptors in development, normal physiology and immune responses, to direct cells to specific locations throughout the body. Cancer cells acquire the ability to subvert the chemokine system such that these molecules and their receptors become important regulators of cell movement into and out of the tumour microenvironment and major players in cancer biology. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306553 Wed, 12 Oct 2011 17:38:21 +0100 5306553 http://www.medworm.com/index.php?rid=5539736&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3023 In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histological diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation, whereas complete absence of staining correlates with null mutations. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5539736 Wed, 12 Oct 2011 04:00:00 +0100 5539736 http://www.medworm.com/index.php?rid=5411564&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3027 AbstractCell–cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire organisms. At the level of the individual cell, direct cell–cell adherence and communication is mediated by the intercellular junction complexes: desmosomes, adherens, tight and gap junctions. A broad spectrum of inherited, infectious and auto‐immune diseases can affect the proper function of intercellular junctions and result in either diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of diseases result from direct or indirect disruption of desmosomes—a consequence of their importance in tissue integrity, their extensive distribution, complex structure, and the wide variety of functions their components acc... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411564 Wed, 12 Oct 2011 04:00:00 +0100 5411564 http://www.medworm.com/index.php?rid=5306562&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3026 AbstractCLIP‐170 is a microtubule‐binding protein and participates in diverse microtubule‐associated cellular activities by regulating microtubule dynamics. Here we provide evidence that CLIP‐170 is a mediator of the sensitivity of the anti‐microtubule drug paclitaxel in breast cancer. In vitro cell proliferation assays reveal that CLIP‐170 expression in breast cancer cell lines correlates with their sensitivity to paclitaxel. In addition, CLIP‐170 expression in clinical samples of breast cancer correlates with the pathologic response of tumors to paclitaxel‐containing chemotherapy. Mitotic index and caspase‐3 activity analyses reveal that CLIP‐170 increases the abilities of paclitaxel to block cell cycle progression at mitosis and to induce apoptosis in breast cancer c... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306562 Wed, 12 Oct 2011 04:00:00 +0100 5306562 http://www.medworm.com/index.php?rid=5306561&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3027 AbstractCell‐cell connectivity is an absolute requirement for the correct functioning of cells, tissues and entire organisms. At the level of the individual cell, direct cell‐cell adherence and communication is mediated by the intercellular junction complexes: desmosomes, adherens‐, tight‐ and gap‐junctions. A broad spectrum of inherited, infectious and auto‐immune diseases can affect the proper function of intercellular junctions, and result in either diseases affecting specific individual tissues or widespread syndromic conditions. A particularly diverse group of diseases result from direct or indirect disruption of desmosomes – a consequence of their importance in tissue integrity, their extensive distribution, complex structure, and the wide variety of functions their com... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306561 Wed, 12 Oct 2011 04:00:00 +0100 5306561 http://www.medworm.com/index.php?rid=5306560&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3028 AbstractMitochondrial DNA defects are a relatively common cause of inherited disease and have been implicated in both ageing and cancer. Mitochondrial DNA encodes essential subunits of the mitochondrial respiratory chain and defects result in impaired oxidative phosphorylation (OXPHOS). Similar OXPHOS defects have been shown to be present in a number of neurodegenerative conditions including Parkinson's disease as well as in normal ageing human tissues. Additionally a number of tumours have been shown to contain mitochondrial DNA mutations and an altered metabolic phenotype. In this review, we outline the unique characteristics of mitochondrial genetics, before detailing important pathological features of mitochondrial DNA diseases, focusing on adult neurological disease, as well as the ro... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306560 Wed, 12 Oct 2011 04:00:00 +0100 5306560 http://www.medworm.com/index.php?rid=5306559&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3021 AbstractWith a constitutive recycling function and the capacity to digest exogenous material as well as endogenous organelles in the process of autophagy, lysosomes are at the heart of the living cell. Dynamic interactions with other cellular components ensure that the lysosomal compartment is a central point of convergence in countless diverse diseases. Inborn lysosomal (storage) diseases represent about 70 genetically distinct conditions with a combined birth frequency of about 1 in 7500. Many are associated with macromolecular storage causing physical disruption of the organelle and cognate structures; in neurons, ectopic dendritogenesis and axonal swelling due to distension with membraneous tubules and autophagic vacuoles are observed. Disordered autophagy is almost universal in lysoso... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306559 Wed, 12 Oct 2011 04:00:00 +0100 5306559 http://www.medworm.com/index.php?rid=5306558&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3023 In conclusion, the above findings support the clonal relationship of STIC and pelvic HGSC and demonstrate the utility of p53 immunostaining as a surrogate for TP53 mutation in the histologic diagnosis of STIC. In this regard, it is important to appreciate the significance of different staining patterns. Specifically, strong diffuse staining correlates with a missense mutation whereas complete absence of staining correlates with null mutations. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306558 Wed, 12 Oct 2011 04:00:00 +0100 5306558 http://www.medworm.com/index.php?rid=5306557&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3020 AbstractThe extracellular matrix provides a solid scaffold and signals to cells through extracellular matrix receptors. The cell‐matrix interactions are crucial for normal biological processes and when disrupted they may lead to pathological processes. In particular, the biological importance of extracellular matrix‐cell membrane‐cytoskeleton interactions in skeletal muscle is accentuated by the number of inherited muscle diseases caused by mutations in proteins conferring these interactions. In this review we will introduce laminins, collagens, dystroglycan, integrins, dystrophin and sarcoglycans. Mutations in corresponding genes cause various forms of muscular dystrophy. The muscle disorders will be presented as well as advances toward development of treatment. Copyright © 2011 Pa... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306557 Wed, 12 Oct 2011 04:00:00 +0100 5306557 http://www.medworm.com/index.php?rid=5306556&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3022 AbstractDeregulation of the cell cycle underlies the aberrant cell proliferation that characterises cancer and loss of cell cycle checkpoint control promotes genetic instability. During the past two decades cancer genetics has shown that hyperactivating mutations in growth signalling networks coupled to loss of function of tumour suppressor proteins drives oncogenic proliferation. Gene expression profiling of these complex and redundant mitogenic pathways to identify prognostic and predictive signatures and their therapeutic targeting, however, has proved challenging. The cell cycle machinery, which acts as an integration point for information transduced through upstream signalling networks, represents an alternative target for diagnostic and therapeutic interventions. Analysis of the DNA ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306556 Wed, 12 Oct 2011 04:00:00 +0100 5306556 http://www.medworm.com/index.php?rid=5306555&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3024 We describe their genomic and transcriptional complexity: a complexity manifest also in the diversity of scaffold structures that septins can form. Septin complexes can act to localize interacting proteins at specific intracellular locale and can also define membrane compartments by defining diffusion barriers. By such activities septins can contribute to the definition of spatial asymmetry and cell polarity and we suggest a potential role in stem cell biology. Finally, we review the evidence that septins contribute to various disease states and argue that it is a breakdown in the tight regulation of their expression (particularly of individual isoforms) and also their inherent ability to oligomerise which is pathogenic. Study of the perturbation of septin complex formation in disease will... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306555 Wed, 12 Oct 2011 04:00:00 +0100 5306555 http://www.medworm.com/index.php?rid=5306554&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3025 AbstractAutophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, the intensive scrutiny that autophagy has been subjected to at the molecular level, has also contributed to expand our understanding of the physiological role of this pathway. Added to the well‐characterized role in quality control, autophagy has proven important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodelling and in the cellular defence against extracellular insults and pathogens. It is not a surprise that in light of this growing number of physiological functions, connections between autophagic malfunctioning and human pathologies have also been strengthened. In th... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5306554 Wed, 12 Oct 2011 04:00:00 +0100 5306554 http://www.medworm.com/index.php?rid=5488954&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3015 AbstractTumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T‐ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand‐independent signalling and/or prolonging Notch1 half‐life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ‐Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine recept... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5488954 Fri, 07 Oct 2011 04:00:00 +0100 5488954 http://www.medworm.com/index.php?rid=5488953&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3016 AbstractEvidence suggests epithelial–mesenchymal transition (EMT) as one potential source of fibroblasts in idiopathic pulmonary fibrosis. To assess the contribution of alveolar epithelial cell (AEC) EMT to fibroblast accumulation in vivo following lung injury and the influence of extracellular matrix on AEC phenotype in vitro, Nkx2.1‐Cre;mT/mG mice were generated in which AECs permanently express green fluorescent protein (GFP). On days 17–21 following intratracheal bleomycin administration, ∼4% of GFP‐positive epithelial‐derived cells expressed vimentin or α‐smooth muscle actin (α‐SMA). Primary AECs from Nkx2.1‐Cre;mT/mG mice cultured on laminin‐5 or fibronectin maintained an epithelial phenotype. In contrast, on type I collagen, cells of epithelial origin displayed... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5488953 Fri, 07 Oct 2011 04:00:00 +0100 5488953 http://www.medworm.com/index.php?rid=5298489&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3011 AbstractThe proliferation of glomerular mesangial cells (GMC) and secretion of extracellular matrix (ECM) in rat Thy‐1 nephritis (Thy‐1N) resembling human mesangioproliferative glomerulonephritis (MsPGN) have been studied for many years, but the mechanisms, especially the role of signaling pathway activation and its regulation in GMC triggered by sublytic C5b‐9 complexes in Thy‐1N rats remain largely unclear. In the study, the proliferation of GMC and production of ECM as well as the role of PI3K/Akt and its regulation both in GMC induced by sublytic C5b‐9 (in vitro) and in the renal tissues of rats with Thy‐1N (in vivo) were determined, and the results revealed that GMC proliferation and ECM secretion both in vitro and in vivo were notably increased, and that PI3K/Akt1 activat... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298489 Fri, 07 Oct 2011 04:00:00 +0100 5298489 http://www.medworm.com/index.php?rid=5298488&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3012 AbstractColorectal adenomas are precursor lesions of colorectal cancer. Different biological and metabolic processes contribute to adenomagenesis. Subsequent progression to carcinoma occurs in only about 5% of the cases. Detection and removal of all adenomas would reduce CRC incidence and mortality, but at the cost of major overtreatment. Classical morphological characteristics fail to accurately discriminate between adenomas that will become malignant and those that will not. Understanding the biology of cancer development will help to better characterise adenomas at high‐risk of progression, and subsequently establish triage tests that allow to safely reserve colonoscopy only for individuals at high probability of having truly high‐risk colorectal adenomas. Screening tests based on g... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298488 Fri, 07 Oct 2011 04:00:00 +0100 5298488 http://www.medworm.com/index.php?rid=5298487&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3013 AbstractCytokinesis is the last step of cell division that physically separates the daughter cells. As such, it insures the proper inheritance of both nuclear and cytoplasmic contents. Accomplishment of cytokinesis in eukaryotes is dictated by several key events: establishment of the division plane, furrow ingression through contraction of an actomyosin ring and abscission via membrane fusion. Most mammalian somatic cells are diploid. Polyploidy can result from cytokinesis failure and may contribute to the development of pathologies such as cancer. However, polyploidy is essential for cellular differentiation and function in some contexts (e.g., hepatocytes, megakaryocytes and others). Consequently, the degree of ploidy and the achievement of cytokinesis must be tightly regulated throughou... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298487 Fri, 07 Oct 2011 04:00:00 +0100 5298487 http://www.medworm.com/index.php?rid=5298486&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3014 AbstractAccumulating evidence shows that microRNAs, functioning as either oncogenes or tumor suppressors by negatively regulating downstream target genes that are actively involved in tumor initiation and progression, may be promising biomarkers and therapy targets. Data mining through microRNA chip database indicated that let‐7c may be associated with tumor metastasis. Here, we confirmed that down‐regulation of let‐7c in primary cancer tissues was significantly associated with metastasis, advanced TNM stages, and poor survival of colorectal cancer patients. Moreover, ectopic expression of let‐7c in a highly metastatic Lovo cell line remarkably suppressed cell migration and invasion in vitro by the down‐regulation of K‐RAS, MMP11 and PBX3, as well as tumor growth and metastasis... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298486 Fri, 07 Oct 2011 04:00:00 +0100 5298486 http://www.medworm.com/index.php?rid=5298485&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3015 AbstractTumor cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T‐cell acute lymphoblastic leukemia due to the high frequency of Notch1 mutations affecting approximately 60% patients, causing ligand‐independent signalling and/or prolonging Notch1 half‐life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blasts malignant properties and localization of extramedullary infiltrations in leukemia. We inhibited the pathway through γ‐Secretase inhibitor and Notch1 RNA interference and analyzed the effect on the expression and function of chemokine receptors. Our resu... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298485 Fri, 07 Oct 2011 04:00:00 +0100 5298485 http://www.medworm.com/index.php?rid=5298484&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3016 AbstractEvidence suggests epithelial‐mesenchymal transition (EMT) as one potential source of fibroblasts in idiopathic pulmonary fibrosis. To assess the contribution of alveolar epithelial cell (AEC) EMT to fibroblast accumulation in vivo following lung injury and the influence of extracellular matrix on AEC phenotype in vitro, Nkx2.1‐Cre;mT/mG mice were generated in which AEC permanently express green fluorescent protein (GFP). On days 17‐21 following intratracheal bleomycin administration, 4% of GFP‐positive epithelial‐derived cells expressed vimentin or α‐smooth muscle actin (α‐SMA). Primary AEC from Nkx2.1‐Cre;mT/mG mice cultured on laminin‐5 or fibronectin maintained an epithelial phenotype. In contrast, on type I collagen, cells of epithelial origin displayed nucl... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298484 Fri, 07 Oct 2011 04:00:00 +0100 5298484 http://www.medworm.com/index.php?rid=5298483&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3017 In conclusion, PDAC development in KrasG12D/+;Ptf1a‐Creex1/+ mice starts from ADM and a similar process might also take place in patients with a strong family history of PDAC. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298483 Fri, 07 Oct 2011 04:00:00 +0100 5298483 http://www.medworm.com/index.php?rid=5298482&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3018 AbstractAngiogenesis, the formation of new blood vessels from pre‐existing ones, is essential for tumour development. It is initiated and regulated by growth factors, via their surface receptors, that activate several intracellular signalling pathways in endothelial cells. Cell adhesion molecules, such as integrins, also regulate angiogenesis. Despite these facts, inhibitors of endothelial cell growth factor receptors or integrins have not been as effective as initially hoped for in the long‐term inhibition of angiogenesis in cancer patients. Signalling downstream of growth factor receptors and integrins converge on the ubiquitously expressed non‐receptor tyrosine kinase Focal Adhesion Kinase (FAK). FAK is involved in endothelial cell proliferation, migration and survival, is upregul... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298482 Fri, 07 Oct 2011 04:00:00 +0100 5298482 http://www.medworm.com/index.php?rid=5298481&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3019 AbstractBile is a complex mixture that includes bile salts, the membrane phospholipid phosphatidylcholine (PC), cholesterol and various endobiotic and xenobiotic toxins each of which is secreted across the canalicular membrane of the hepatocyte by different ATP binding cassette (ABC) transporters. The bile salts are essential for the emulsification of dietary fat and lipophilic vitamins. They are synthesised from cholesterol in the hepatocyte and their secretion by the bile salt export pump (BSEP or ABCB11) drives bile flow and is the starting point for the enterohepatic cycle. The detergent nature of bile salts that is key to their physiological role also means that they are inherently cytotoxic and failure to secrete bile (intraheptic cholestasis) can precipitate severe liver disease and... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5298481 Sat, 01 Oct 2011 04:00:00 +0100 5298481 http://www.medworm.com/index.php?rid=5263368&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3010 AbstractAdvances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long‐term allograft survival. While initiating elements of anti‐allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively‐spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed Extra Domain A‐containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis, thus we hypothesized that it might als... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263368 Thu, 29 Sep 2011 18:14:10 +0100 5263368 http://www.medworm.com/index.php?rid=5496797&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3006 AbstractHypoxia is a trigger of VEGF expression, the primary cause of retinal pathologies characterized by neovascularization. During hypoxia, transcription factors such as STAT3 and HIF‐1 promote the increase in VEGF expression. Octreotide, a somatostatin receptor 2 (sst2)‐preferring agonist, reduces retinal VEGF expression and neovascularization. To investigate the intracellular pathways linking sst2 activation to the inhibition of hypoxia‐induced VEGF up‐regulation, we used pharmacological approaches and siRNA in mouse retinal explants cultured in normoxia or hypoxia. In hypoxic explants in which STAT3 or HIF‐1 was inhibited, we observed the existence of reciprocal interactions between STAT3 and HIF‐1, which synergistically induced VEGF expression. Octreotide prevented hypox... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5496797 Thu, 29 Sep 2011 04:00:00 +0100 5496797 http://www.medworm.com/index.php?rid=5263373&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3005 In conclusion, hypoxia‐induced migration of HSC/MFs involves an early, mitochondrial‐dependent, ROS‐mediated activation of ERK and JNK, followed by a delayed‐ and HIF‐1α‐dependent up‐regulation and release of VEGF. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263373 Thu, 29 Sep 2011 04:00:00 +0100 5263373 http://www.medworm.com/index.php?rid=5263372&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3006 AbstractHypoxia is a trigger of VEGF expression, primary cause of retinal pathologies characterised by neovascularisation. During hypoxia, transcription factors such as STAT3 and HIF‐1 promote the increase in VEGF expression. Octreotide, a somatostatin receptor 2 (sst2)‐preferring agonist, reduces retinal VEGF expression and neovascularisation. To investigate the intracellular pathways linking sst2 activation to the inhibition of hypoxia‐induced VEGF upregulation, we used pharmacological approaches and siRNA in mouse retinal explants cultured in normoxia or hypoxia. In hypoxic explants in which STAT3 or HIF‐1 were inhibited, we observed the existence of reciprocal interactions between STAT3 and HIF‐1, which synergistically induced VEGF expression. Octreotide prevented hypoxia‐i... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263372 Thu, 29 Sep 2011 04:00:00 +0100 5263372 http://www.medworm.com/index.php?rid=5263371&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3007 In this study, we analyzed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcome in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWS by using the Agilent Human miRNA microarray v.2 and/or qRT‐PCR. Statistical power of samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of 5 miRNAs (miR‐34a, miR‐23a, miR‐92a, miR‐490‐3p, and miR‐130b) as an independent predictor of risk to disease progression and survival. Validation analysis in the extended samples set indicated that both miR‐34a and miR490‐3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR‐34a, which appeared ass... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263371 Thu, 29 Sep 2011 04:00:00 +0100 5263371 http://www.medworm.com/index.php?rid=5263370&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3008 AbstractStomatin‐like protein 2 (STOML2), a member of the stomatin family, has been reported to be upregulated in several types of human cancers. The clinical significance and biological role of STOML2 in gliomas remain largely unknown. Here, we describe the significantly upregulated expression of STOML2 in glioma cell lines and glioma tissues at both the transcriptional and translational levels. Silencing endogenous STOML2 in glioma cells and primary glioma cells drastically reduced their migratory speed and invasive ability, associated with induction of matrix metallopeptidase 9 (MMP‐9). We also demonstrated that knockdown STOML2 significantly inhibited the transcriptional activity of NF‐κB and repressed the expression levels of NF‐κB target genes, including MMP‐9. A lucifera... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263370 Thu, 29 Sep 2011 04:00:00 +0100 5263370 http://www.medworm.com/index.php?rid=5263369&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3009 This study aimed to define the role of TLR‐2 and TLR‐9 in the modulation of small intestinal damage in a model of doxorubicin‐induced mucositis. Doxorubicin‐induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK‐3β) was assessed. Wild type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7 of original length, and increased influx of leukocytes as compared to vehicle injected mice (HS 1.33 ± 1.15). The protective effect of TLR‐2 or TLR‐9 deficiency was associated with a significant decrease of the HS a... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263369 Thu, 29 Sep 2011 04:00:00 +0100 5263369 http://www.medworm.com/index.php?rid=5433475&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3004 AbstractPrimary cilia are microtubule‐based sensory organelles that coordinate signalling pathways in cell‐cycle control, migration, differentiation and other cellular processes critical during development and for tissue homeostasis. Accordingly, defects in assembly or function of primary cilia lead to a plethora of developmental disorders and pathological conditions now known as ciliopathies. In this review, we summarize the current status of the role of primary cilia in coordinating receptor tyrosine kinase (RTK) signalling pathways. Further, we present potential mechanisms of signalling crosstalk and networking in the primary cilium and discuss how defects in ciliary RTK signalling are linked to human diseases and disorders. Copyright © 2011 Pathological Society of Great Britain an... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5433475 Wed, 28 Sep 2011 04:00:00 +0100 5433475 http://www.medworm.com/index.php?rid=5263377&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3001 AbstractThe peroxisome proliferator activated receptor γ (PPARγ) agonist, pioglitazone (PIO) exerts anti‐diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti‐obesity and anti‐diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well‐investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arre... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263377 Wed, 28 Sep 2011 04:00:00 +0100 5263377 http://www.medworm.com/index.php?rid=5263376&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3002 AbstractFanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss causing progressive bone marrow failure and sterility, diverse developmental abnormalities, and a profound predisposition to neoplasia. To date 15 genes have been indentified, biallelic disruption of any one of which, results in this clinically defined syndrome. It is now apparent that all 15 gene products act in a common process to maintain genome stability. At the molecular level, a fundamental defect in DNA repair underlies this complex phenotype. Cells derived from FA patients spontaneously accumulate broken chromos... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263376 Wed, 28 Sep 2011 04:00:00 +0100 5263376 http://www.medworm.com/index.php?rid=5263375&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3003 AbstractChondrocytes interact with their neighbours through their cartilaginous extracellular matrix. Chondrocyte‐matrix interactions compensate the lack of cell‐cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the extracellular matrix creating short and long range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell‐matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and m... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263375 Wed, 28 Sep 2011 04:00:00 +0100 5263375 http://www.medworm.com/index.php?rid=5263374&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3004 AbstractPrimary cilia are microtubule‐based sensory organelles that coordinate signaling pathways in cell cycle control, migration, differentiation and other cellular processes critical during development and for tissue homeostasis. Accordingly, defects in assembly or function of primary cilia lead to a plethora of developmental disorders and pathological conditions now known as ciliopathies. In this review, we summarize the current status of the role of primary cilia in coordinating receptor tyrosine kinase (RTK) signaling pathways. Further, we present potential mechanisms of signaling crosstalk and networking in the primary cilium and how defects in ciliary RTK signaling are linked to human diseases and disorders. Copyright © 2011 Pathological Society of Great Britain and Ireland. Pub... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263374 Wed, 28 Sep 2011 04:00:00 +0100 5263374 http://www.medworm.com/index.php?rid=5263380&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2998 AbstractChromosomal instability (CIN) has been implicated in multidrug resistance and the silencing of the ceramide transporter, CERT, promotes sensitisation to diverse cytotoxics. An improved understanding of mechanisms governing multidrug sensitisation might provide insight into pathways contributing to the death of CIN cancer cells. Using an integrative functional genomics approach, we find that CERT‐specific multidrug sensitisation is associated with enhanced autophagosome‐lysosome flux, resulting from the expression of LAMP2 following CERT silencing in colorectal and HER2+ breast cancer cell lines. Live cell microscopy analysis revealed that CERT depletion induces LAMP2‐dependent death of polyploid cells following exit from mitosis in the presence of paclitaxel. We find that CER... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263380 Mon, 26 Sep 2011 04:00:00 +0100 5263380 http://www.medworm.com/index.php?rid=5263379&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2999 AbstractNuclear lamins are intermediate filament proteins that polymerize to form the nuclear lamina on the inner aspect of the inner nuclear membrane. Long known to be essential for maintaining nuclear structure and disassembling/reassembling during mitosis in metazoans, research over the past dozen years has shown that mutations in genes encoding nuclear lamins, particularly LMNA encoding the A‐type lamins, cause a broad range of diverse diseases often referred to as laminopathies. Lamins are expressed in all mammalian somatic cells but mutations in their genes lead to relative tissue‐selective disease phenotypes in most cases. While mutations causing laminopathies have been shown to produce abnormalities in nuclear morphology, how these disease‐causing mutations or resultant alter... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263379 Mon, 26 Sep 2011 04:00:00 +0100 5263379 http://www.medworm.com/index.php?rid=5263378&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.3000 AbstractAnoikis is a programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation. It is a critical mechanism in preventing dysplastic cell growth or attachment to an inappropriate matrix. Anoikis prevents detached epithelial cells from colonizing elsewhere and is thus essential for tissue homeostasis and development. As anchorage‐independent growth and epithelial mesenchymal transition, two features associated anoikis resistance, are crucial steps during tumor progression and metastatic spreading of cancer cells, anoikis deregulation has now evoked particular attention from the scientific community. The aim of this review is to analyse the molecular mechanisms governing both anoikis and anoikis resistance, focusing on thei... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263378 Mon, 26 Sep 2011 04:00:00 +0100 5263378 http://www.medworm.com/index.php?rid=5228668&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2996 AbstractWe have previously reported that mice with muscular dystrophy, including mdx mice, develop embryonal rhabdomyosarcoma (eRMS) with a low incidence after one year of age and that almost all such tumors contain cancer‐associated p53 mutations. To further demonstrate the relevance of p53 inactivation, we created p53‐deficient mdx mice. Here we demonstrate that loss of one or both p53 (Trp53) alleles accelerates eRMS incidence in the mdx background, such that almost all Trp53‐/‐mdx animals develop eRMS by five months of age. To ascertain if increased tumor incidence was due to the regenerative microenvironment found in dystrophic skeletal muscles, we induced muscle regeneration in Trp53+/+ and Trp53‐/‐ animals using cardiotoxin (Ctx). Wild type (Trp53+/+) animals treated wit... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5228668 Mon, 19 Sep 2011 08:21:43 +0100 5228668 http://www.medworm.com/index.php?rid=5198465&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2970 AbstractIt has become increasingly clear that the four main histological subtypes of epithelial ovarian cancer (EOC), high‐grade serous, endometrioid, clear cell and mucinous, are entities with different epidemiologies, clinical presentations, responses to treatment, and ultimate outcomes. In fact, for all intents and purposes, they can be considered different diseases, their only common denominator being that they frequently involve the ovary and pelvic organs. However, clinical practice has not caught up with these insights and the treatment of EOC is that of a single disease entity. In part, this is because we lack detailed knowledge of the molecular mechanisms driving the pathogenesis of each disease, which is vital in order to develop therapeutic approaches against common driver eve... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5198465 Thu, 08 Sep 2011 04:46:10 +0100 5198465 http://www.medworm.com/index.php?rid=5198461&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2995 AbstractOligodendroglioma is characterized by unique clinical, pathological, and genetic features. Recurrent losses of chromosomes 1p and 19q are strongly associated with this brain cancer but knowledge of the identity and function of the genes affected by these alterations is limited. We performed exome sequencing on a discovery set of 16 oligodendrogliomas with 1p/19q co‐deletion to identify new molecular features at base‐pair resolution. As anticipated, there was a high rate of IDH mutations: all cases had mutations in either IDH1 (14/16) or IDH2 (2/16). In addition, we discovered somatic mutations and insertions/deletions in the CIC gene on chromosome 19q13.2 in 13/16 tumours. These discovery set mutations were validated by deep sequencing of 13 additional tumours, which revealed 7... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5198461 Thu, 08 Sep 2011 04:45:21 +0100 5198461 http://www.medworm.com/index.php?rid=5411565&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2992 AbstractFanconi anaemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukaemia and solid tumours. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumours in non‐FA patients. To study whether there is a causal relationship between FA pathway defects and tumour development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf‐deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA cross‐linking agents as manifested by G2 arrest, chromosomal aberrations, reduced survival, and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable,... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5411565 Wed, 07 Sep 2011 04:00:00 +0100 5411565 http://www.medworm.com/index.php?rid=5390991&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2995 AbstractOligodendroglioma is characterized by unique clinical, pathological, and genetic features. Recurrent losses of chromosomes 1p and 19q are strongly associated with this brain cancer but knowledge of the identity and function of the genes affected by these alterations is limited. We performed exome sequencing on a discovery set of 16 oligodendrogliomas with 1p/19q co‐deletion to identify new molecular features at base‐pair resolution. As anticipated, there was a high rate of IDH mutations: all cases had mutations in either IDH1 (14/16) or IDH2 (2/16). In addition, we discovered somatic mutations and insertions/deletions in the CIC gene on chromosome 19q13.2 in 13/16 tumours. These discovery set mutations were validated by deep sequencing of 13 additional tumours, which revealed s... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5390991 Wed, 07 Sep 2011 04:00:00 +0100 5390991 http://www.medworm.com/index.php?rid=5228669&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2992 AbstractFanconi Anemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukemia and solid tumors. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumors in non‐FA patients. To study whether there is a causal relationship between FA pathway defects and tumor development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf‐deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA crosslinking agents as manifested by G2 arrest, chromosomal aberrations, reduced survival and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable, born fol... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5228669 Wed, 07 Sep 2011 04:00:00 +0100 5228669 http://www.medworm.com/index.php?rid=5198464&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2992 AbstractFanconi Anemia (FA) is a rare recessive disorder marked by developmental abnormalities, bone marrow failure, and a high risk for the development of leukemia and solid tumors. The inactivation of FA genes, in particular FANCF, has also been documented in sporadic tumors in non‐FA patients. To study whether there is a causal relationship between FA pathway defects and tumor development, we have generated a mouse model with a targeted disruption of the FA core complex gene Fancf. Fancf‐deficient mouse embryonic fibroblasts displayed a phenotype typical for FA cells: they showed an aberrant response to DNA crosslinking agents as manifested by G2 arrest, chromosomal aberrations, reduced survival and an inability to monoubiquitinate FANCD2. Fancf homozygous mice were viable, born fol... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5198464 Tue, 06 Sep 2011 23:00:00 +0100 5198464 http://www.medworm.com/index.php?rid=5198463&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2993 AbstractSynthetic nucleic acids are commonly used laboratory tools for modulating gene expression and have the potential to be widely used in the clinic. Progress towards nucleic acid drugs, however, has been slow and many challenges remain to be overcome before their full impact on patient care can be understood. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are the two most widely used strategies for silencing gene expression. We first describe these two approaches and contrast their relative strengths and weaknesses for laboratory applications. We then review the choices faced during development of clinical candidates and the current state of clinical trials. Attitudes towards clinical development of nucleic acid silencing strategies have repeatedly swung from op... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5198463 Tue, 06 Sep 2011 23:00:00 +0100 5198463 http://www.medworm.com/index.php?rid=5198462&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2994 AbstractDiarrhoea in ulcerative colitis (UC) mainly reflects impaired colonic Na+ and water absorption. Colonocyte membrane potential, an important determinant of electrogenic Na+ absorption, is reduced in UC. Colonocyte potential is principally determined by basolateral IK (KCa3.1) channel activity. To determine whether reduced Na+ absorption in UC might be associated with decreased IK channel expression and activity, we used molecular and patch clamp recording techniques to evaluate IK channels in colon from control patients and patients with active UC. In control patients, immunolabelling revealed basolateral IK channels distributed uniformly along the surface‐crypt axis, with substantially decreased immunolabelling in patients with active UC, although IK mRNA levels measured by quant... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5198462 Tue, 06 Sep 2011 23:00:00 +0100 5198462 http://www.medworm.com/index.php?rid=5186280&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2991 This study sought to examine the effect of selective inhibition of Egr‐1 using catalytic deoxyribonucleic acid molecules (DNAzymes, DZ), delivered via the clinically relevant coronary route in a large animal model of myocardial IR. It was hypothesized that Egr‐1 inhibition with intracoronary DZ would reduce infarction size by modulating its downstream effector molecules. Egr‐1 DZs inhibited adherence of THP‐1 monocytes to IL‐1 beta activated endothelial cells in vitro and retained its catalytic activity up to 225 min after in vivo administration.In a porcine model of myocardial IR (45 min ischaemia/3 h reperfusion), DZ was taken up in the cytoplasm and nuclei of cardiomyocytes and endothelial cells in the myocardium after intracoronary delivery Egr‐1 DZs reduced infarct size an... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5186280 Wed, 31 Aug 2011 23:00:00 +0100 5186280 http://www.medworm.com/index.php?rid=5599895&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2990 In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK, and VAV1 was evaluated in non‐neoplastic gastric specimens using quantitative methylation‐specific PCR in patients with GC (n = 207) and their age‐ and gender‐matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy‐based tests (CLOtest, histology, and culture), H. pylori serology, and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS, and VAV1 but decreased methylation levels in PTPN6 (all p < 0.05); the methylation l... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5599895 Wed, 31 Aug 2011 04:00:00 +0100 5599895 http://www.medworm.com/index.php?rid=5186282&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2989 AbstractNeuropilin (NRP)‐1 is a coreceptor for vascular endothelial growth factor (VEGF). Preclinical data suggest that blockade of NRP1 suppresses tumour growth by inhibiting angiogenesis, in addition to directly inhibiting tumour cell proliferation in certain models. A humanised monoclonal antibody to NRP1 is currently being evaluated as a potential anti‐cancer therapy in clinical trials. However, the expression of NRP1 in cancer and physiological angiogenesis has yet to be systematically described. Here we characterise the in situ expression of NRP1 in human cancer and during mammalian development. A monoclonal antibody to human NRP1 was generated and validated for immunohistochemistry by western blotting, use of formalin‐fixed cell pellets transfected with NRP1, immunofluorescenc... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5186282 Tue, 30 Aug 2011 23:00:00 +0100 5186282 http://www.medworm.com/index.php?rid=5186281&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2990 In this study, we evaluated the candidate genes as markers for gastric cancer (GC) in a large Korean population. DNA methylation of PTPN6, MOS, DCC, CRK and VAV1 was evaluated in nonneoplastic gastric specimens using quantitative methylation‐specific PCR in patients with GC (n = 207) and their age‐ and gender‐matched controls (n = 207). Methylation levels in 125 GC samples were also compared. H. pylori infection status was categorized as negative, active, or past infection according to the results of endoscopy‐based tests (CLOtest, histology and culture), H. pylori serology and serum pepsinogen test. In the controls, active H. pylori infection increased methylation levels in DCC, CRK, MOS and VAV1 but decreased methylation levels in PTPN6 (all P < 0.05); the methylation levels i... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5186281 Tue, 30 Aug 2011 23:00:00 +0100 5186281 http://www.medworm.com/index.php?rid=5149066&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2988 AbstractCancer is viewed as being governed by several aberrant biological events defined by Weinberg and Hanahan as 'hallmarks'. In most human cancers the tumor suppressor p53 is mutated, leading to its malfunction and to the acquirement of oncogenic activities, termed 'gain of function'. This commentary links mutant p53 activities to the hallmarks of cancer, describing its involvement in resistance to apoptosis, genomic instability, aberrant cell cycle, invasion and metastasis, tumor microenvironment and inflammation. Recent work published in the Journal of Pathology by Acin and colleagues, summarized here, reveals an interesting mechanism by which mutant p53 accelerates mitosis entry. Collectively, the growing body of evidence relating mutant p53 and the hallmarks of cancer, reinforces t... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149066 Wed, 24 Aug 2011 20:44:20 +0100 5149066 http://www.medworm.com/index.php?rid=5325894&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2987 AbstractAcute respiratory distress syndrome (ARDS) is a devastating clinical syndrome. Angiotensin‐converting enzyme (ACE) and its effector peptide angiotensin (Ang) II have been implicated in the pathogenesis of ARDS. A counter‐regulatory enzyme of ACE, ie ACE2 that degrades Ang II to Ang‐(1–7), offers a promising novel treatment modality for this syndrome. As the involvement of ACE and ACE2 in ARDS is still unclear, this study investigated the role of these two enzymes in an animal model of ARDS. ARDS was induced in rats by intratracheal administration of LPS followed by mechanical ventilation. During ventilation, animals were treated with saline (placebo), losartan (Ang II receptor antagonist), or with a protease‐resistant, cyclic form of Ang‐(1–7) [cAng‐(1–7)]. In bro... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5325894 Thu, 18 Aug 2011 04:00:00 +0100 5325894 http://www.medworm.com/index.php?rid=5149070&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2983 In conclusion, BCL2L1 is functionally involved in several cancer‐related processes and its protein expression is associated with 20q gain. This supports a role for 20q gain‐dependent expression of BCL2L1 in colorectal adenoma‐to‐carcinoma progression. However, the absence of a direct correlation between BCL2L1 mRNA and protein expression implies that BCL2L1 protein expression is regulated at the post‐transcriptional level by a distinct factor on the 20q amplicon (e.g. ZNF217, AURKA or miRNAs). Therefore, even though BCL2L1 affects CRC biology in a 20q gain‐dependent manner, it is not likely to be a driver of chromosome 20q gain associated adenoma‐to‐carcinoma progression. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149070 Wed, 17 Aug 2011 23:00:00 +0100 5149070 http://www.medworm.com/index.php?rid=5149069&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2984 AbstractAlzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17) and Pick's disease (PiD) are commonly known as tauopathies. Neurodegeneration observed in these diseases is linked to neuronal fibrillary hyperphosphorylated tau protein inclusions. Transglutaminases (TGs) are inducible enzymes, capable of modifying conformational and/or structural properties of proteins, by inducing molecular cross‐links. Both transglutaminase 1 (TG1) and transglutaminase 2 (TG2) are abundantly expressed in brain, and are associated with fibrillary hyperphosphorylated tau protein inclusions in neurons of AD, so‐called neurofibrillary tangles (NFTs). However, other data obtained by our group suggested that tau pathology in... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149069 Wed, 17 Aug 2011 23:00:00 +0100 5149069 http://www.medworm.com/index.php?rid=5149068&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2986 AbstractRetinoid therapy is used for chemo‐prevention in immune‐suppressed patients at high risk of developing skin cancer. The retinoid signalling molecule, tripartite motif protein 16 (TRIM16), is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid‐sensitive neuroblastoma. We sought to determine the role of TRIM16 in skin squamous cell carcinoma (SCC) pathogenesis. We have shown that TRIM16 expression was markedly reduced during the histologic progression from normal skin to actinic keratosis and SCC. SCC cell lines exhibited lower cytoplasmic and nuclear TRIM16 expression compared with primary human keratinocytes (PHK) cells due to reduced TRIM16 protein stability. Overexpressed TRIM16 translocated to the nucleus, inducing growth arrest and cell differe... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149068 Wed, 17 Aug 2011 23:00:00 +0100 5149068 http://www.medworm.com/index.php?rid=5149067&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2987 AbstractAcute respiratory distress syndrome (ARDS) is a devastating clinical syndrome. Angiotensin‐converting enzyme (ACE) and its effector peptide angiotensin (Ang) II have been implicated in the pathogenesis of ARDS. A counter‐regulatory enzyme of ACE, i.e. ACE2 that degrades Ang II to Ang‐(1‐7), offers a promising novel treatment modality for this syndrome. As the involvement of ACE and ACE2 in ARDS is still unclear, this study investigated the role of these two enzymes in an animal model of ARDS. ARDS was induced in rats by intratracheal administration of LPS followed by mechanical ventilation. During ventilation animals were treated with saline (placebo), losartan (Ang II receptor antagonist), or with a protease‐resistant, cyclic form of Ang‐(1‐7) [cAng‐(1‐7)]. In br... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149067 Wed, 17 Aug 2011 23:00:00 +0100 5149067 http://www.medworm.com/index.php?rid=5121482&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2980 AbstractPremature babies are at high risk for both infantile apnea and long‐term neurobehavioral deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development and synapse formation mainly occur in the 3rd trimester of gestation and 1st postnatal year, infantile apnea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 to 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix and cerebellum, ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5121482 Fri, 12 Aug 2011 23:54:53 +0100 5121482 http://www.medworm.com/index.php?rid=5562676&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2981 In this study, we examined a wide variety of non‐neoplastic tissues, and report that co‐localized signals of PML and telomere DNA are present in endothelial, stromal, and some epithelial cells. Co‐localized signals of PML and telomere DNA showed an increased frequency in non‐neoplastic cells with DNA damage. These results suggest that a mechanism similar to that in ALT‐positive tumours also operates in non‐neoplastic cells, which may be activated by DNA damage. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5562676 Fri, 12 Aug 2011 04:00:00 +0100 5562676 http://www.medworm.com/index.php?rid=5325893&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2980 AbstractPremature babies are at high risk for both infantile apnoea and long‐term neurobehavioural deficits. Recent studies suggest that diffuse structural changes in brain white matter are a positive predictor of poor cognitive outcomes. Since oligodendrocyte maturation, myelination, axon development, and synapse formation mainly occur in the third trimester of gestation and first postnatal year, infantile apnoea could lead to and/or exaggerate white matter impairments in preterm neonates. Therefore, we investigated oligodendroglia and axon development in a neonatal mouse model of intermittent hypoxia between postnatal days 2 and 10. During critical phases of central nervous system development, intermittent hypoxia induced hypomyelination in the corpus callosum, striatum, fornix, and ce... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5325893 Fri, 12 Aug 2011 04:00:00 +0100 5325893 http://www.medworm.com/index.php?rid=5121484&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2981 In this study we examined a wide variety of non‐neoplastic tissues, and report that co‐localised signals of PML and telomere DNA are present in endothelial, stromal, and some epithelial cells. Co‐localised signals of PML and telomere DNA showed an increased frequency in non‐neoplastic cells with DNA damage. These results suggest that a mechanism similar to that in ALT positive tumours also operates in non‐neoplastic cells, which may be activated by DNA damage. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5121484 Thu, 11 Aug 2011 23:00:00 +0100 5121484 http://www.medworm.com/index.php?rid=5121483&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2982 AbstractInflammatory reactions are initiated to eliminate pathogens, but also to promote repair of damaged tissue after acute inflammation is terminated. In this regard, macrophages play a prominent role during induction as well as resolution of inflammation and injury in various organs including the kidney. The present study describes a mechanism for renal tissue regeneration after ischemia/reperfusion injury. Following injury, apoptotic cell‐derived sphingosine‐1‐phosphate (S1P) or exogenously administrated sphingosine analogue FTY720 activates macrophages to support the proliferation and healing of renal epithelium, once inflammatory conditions are terminated. Both suppression of inflammation as well as renal regeneration might require S1P receptor 3 (S1P3) signalling and downstre... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5121483 Thu, 11 Aug 2011 23:00:00 +0100 5121483 http://www.medworm.com/index.php?rid=5090261&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2979 AbstractChronic renal failure involves the progressive loss of renal parenchymal cells. For example, Alport syndrome develops from mutated type IV collagen that fosters the digestion of glomerular basement membranes and podocyte loss, followed by progressive glomerulosclerosis, i.e. Alport nephropathy. Here we show that autosomal recessive Alport nephropathy in collagen4a3‐deficient mice is associated with an increased intrarenal expression of the proapoptotic cytokine tumor necrosis factor‐alpha (TNF‐α), in glomerular cells including podocytes as well as in infiltrating leukocytes. We therefore hypothesized that TNF‐α contributes to Alport glomerulosclerosis by inducing podocyte apoptosis. To address this issue we treated 4‐week old collagen4a3‐deficient mice with either veh... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5090261 Thu, 04 Aug 2011 03:23:30 +0100 5090261 http://www.medworm.com/index.php?rid=5263382&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2979 AbstractChronic renal failure involves the progressive loss of renal parenchymal cells. For example, Alport syndrome develops from mutated type IV collagen that fosters the digestion of glomerular basement membranes and podocyte loss, followed by progressive glomerulosclerosis, ie Alport nephropathy. Here we show that autosomal recessive Alport nephropathy in collagen 4a3‐deficient mice is associated with increased intrarenal expression of the pro‐apoptotic cytokine tumour necrosis factor‐alpha (TNF‐α) in glomerular cells including podocytes as well as in infiltrating leukocytes. We therefore hypothesized that TNF‐α contributes to Alport glomerulosclerosis by inducing podocyte apoptosis. To address this issue, we treated 4‐week‐old collagen 4a3‐deficient mice with either ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263382 Wed, 03 Aug 2011 04:00:00 +0100 5263382 http://www.medworm.com/index.php?rid=5090262&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2978 AbstractInvasive lobular carcinoma (ILC) of the breast, characterized by loss of E‐cadherin expression, accounts for 5‐15% of invasive breast cancers and it is believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15‐20% risk of progression to ILC over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina mi... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5090262 Tue, 02 Aug 2011 23:00:00 +0100 5090262 http://www.medworm.com/index.php?rid=5081974&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2977 AbstractWT1 is a versatile gene that controls transitions between the mesenchymal and epithelial state of cells in a tissue‐context dependent manner. As such, WT1 is indispensable for normal development of many organs and tissues. Uncontrolled epithelial to mesenchymal transition (EMT) is a hallmark of a diverse array of pathologies and disturbance of mesenchymal to epithelial transition (MET) has been associated with a number of developmental abnormalities. It is therefore not surprising that WT1 has been linked to many of these. Here we review the role of WT1 in proper control of the mesenchymal‐epithelial balance of cells and discuss how far these roles can explain the role of WT1 in a variety of disease states. Copyright © 2011 Pathological Society of Great Britain and Ireland. Pu... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5081974 Mon, 01 Aug 2011 20:48:34 +0100 5081974 http://www.medworm.com/index.php?rid=5263381&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2977 AbstractWT1 is a versatile gene that controls transitions between the mesenchymal and epithelial state of cells in a tissue‐context dependent manner. As such, WT1 is indispensable for normal development of many organs and tissues. Uncontrolled epithelial to mesenchymal transition (EMT) is a hallmark of a diverse array of pathologies and disturbance of mesenchymal to epithelial transition (MET) has been associated with a number of developmental abnormalities. It is therefore not surprising that WT1 has been linked to many of these. Here we review the role of WT1 in proper control of the mesenchymal–epithelial balance of cells and discuss how far these roles can explain the role of WT1 in a variety of disease states. Copyright © 2011 Pathological Society of Great Britain and Ireland. Pu... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263381 Mon, 01 Aug 2011 04:00:00 +0100 5263381 http://www.medworm.com/index.php?rid=5065418&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2950 AbstractIn this issue of the Journal of Pathology, Bardella et al report a method for identifying tumours that lack fumarate hydratase. The approach they use is immunodetection of proteins that have been modified by a non‐enzymatic reaction of thiol groups in proteins with fumarate, which is termed succination. Validation included the use of mice with targeted inactivation of fumarate hydratase in the kidney, extensive studies of normal human tissues and examination of over 1000 specimens from human cancers not associated with FH mutations. Detection of protein succination is likely to provide a sensitive and specific method for pathologists to identify the small proportion of papillary renal cell carcinomas that are associated with germline mutations in the FH gene. Copyright © 2011 Pa... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065418 Wed, 27 Jul 2011 05:22:55 +0100 5065418 http://www.medworm.com/index.php?rid=5065413&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2976 This study was conducted to test the hypothesis that combinatorial assessment of these markers would provide superior prognostic information and improve their clinical utility. Tissue microarrays were used to assess the expression of Ki67 and BCL2 in 2,749 cases of invasive breast cancer. We devised a Ki67/BCL2 index representing the relative expression of each protein and assessed its association with breast cancer‐specific survival (BCSS) using a Cox proportional‐hazards model. Based on our findings, an independent cohort of 3,992 cases was used to validate the prognostic significance of the Ki67/BCL2 index. All survival analyses were conducted on complete data as well as data where missing values were resolved using multiple imputation. This study complied with reporting recommendat... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065413 Wed, 27 Jul 2011 05:22:16 +0100 5065413 http://www.medworm.com/index.php?rid=5263386&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2975 In this study, we investigated the crosstalk between T. cruzi‐induced immune activation of reactive oxygen species (ROS) and pro‐inflammatory responses, and their role in myocardial pathology. Splenocytes of infected mice (C3H/HeN) responded to Tc‐antigenic stimulus by more than a two‐fold increase in NADPH oxidase (NOX) activity, ROS generation, cytokine production (IFN‐γ > IL‐4 > TNFα > IL1‐β≈ IL6), and predominant expansion of CD4+ and CD8+ T cells. Inhibition of NOX, but not of myeloperoxidase and xanthine oxidase, controlled the ROS (>98%) and cytokine (70–89%) release by Tc‐stimulated splenocytes of infected mice. Treatment of infected mice with apocynin (NOX inhibitor) in drinking water resulted in a 50–90% decline in endogenous NOX/ROS and cytok... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263386 Tue, 26 Jul 2011 04:00:00 +0100 5263386 http://www.medworm.com/index.php?rid=5263385&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2973 AbstractEpidermolysis bullosa (EB) is a severe genetic skin fragility syndrome characterized by blister formation. The molecular basis of EB is still largely unknown and wound healing in patients suffering from EB remains a major challenge to their survival. Our previous studies have identified the actin remodelling protein Flightless I (Flii) as an important mediator of wound repair. Here we identify Flii as a novel target involved in skin blistering. Flii expression was significantly elevated in 30 patients with EB, most prominently in patients with recessive dystrophic EB (RDEB) who have defects in production of type VII collagen (ColVII). Using an autoimmune ColVII murine model of EB acquisita (EBA) and an immunocompetent‐ColVII‐hypomorphic genetic mouse model of RDEB together with... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263385 Tue, 26 Jul 2011 04:00:00 +0100 5263385 http://www.medworm.com/index.php?rid=5263384&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2976 This study was conducted to test the hypothesis that combinatorial assessment of these markers would provide superior prognostic information and improve their clinical utility. Tissue microarrays were used to assess the expression of Ki67 and BCL2 in 2749 cases of invasive breast cancer. We devised a Ki67/BCL2 index representing the relative expression of each protein and assessed its association with breast cancer‐specific survival (BCSS) using a Cox proportional‐hazards model. Based on our findings, an independent cohort of 3992 cases was used to validate the prognostic significance of the Ki67/BCL2 index. All survival analyses were conducted on complete data as well as data where missing values were resolved using multiple imputation. This study complied with reporting recommendatio... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263384 Tue, 26 Jul 2011 04:00:00 +0100 5263384 http://www.medworm.com/index.php?rid=5065417&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2972 AbstractAdenomatous Polyposis Coli (APC) mutations are found in most colorectal tumours. These mutations are almost always protein‐truncating, deleting both central domains that regulate Wnt signalling and C‐terminal domains that interact with the cytoskeleton. The importance of Wnt dysregulation for colorectal tumorigenesis is well characterised. It is, however, unclear whether loss of C‐terminal functions contributes to tumorigenesis, although this protein region has been implicated in cellular processes – including polarity, migration, mitosis and chromosomal instability (CIN) – that have been postulated as critical for the development and progression of intestinal tumours. Since almost all APC mutations in human patients disrupt both central and C‐terminal regions, we creat... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065417 Mon, 25 Jul 2011 23:00:00 +0100 5065417 http://www.medworm.com/index.php?rid=5065416&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2973 AbstractEpidermolysis bullosa (EB) is a severe genetic skin fragility syndrome characterized by blister formation. The molecular basis of EB is still largely unknown and wound healing in patients suffering from EB remains a major challenge to their survival. Our previous studies have identified the actin remodelling protein Flightless I (Flii) as an important mediator of wound repair. Here we identify Flii as a novel target involved in skin blistering. Flii expression is significantly elevated in 30 patients with EB most prominently in patients with recessive dystrophic EB (RDEB) who have defects in production of type VII collagen (ColVII). Using an autoimmune ColVII murine model of EB acquisita (EBA) and an immunocompetent‐ColVII‐hypomorphic genetic mouse model of RDEB together with m... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065416 Mon, 25 Jul 2011 23:00:00 +0100 5065416 http://www.medworm.com/index.php?rid=5065415&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2974 AbstractAdenoid cystic carcinoma (AdCC) is a rare form of triple‐negative and basal‐like breast cancer that has an indolent clinical behaviour. Four breast AdCCs were recently shown to harbour the recurrent chromosomal translocation t(6;9)(q22–23;p23–24), which leads to the formation of the MYB‐NFIB fusion gene. Our aims were i) to determine the prevalence of the MYB‐NFIB fusion in AdCCs of the breast, ii) to characterise the gene copy number aberrations found in AdCCs, and iii) to determine whether AdCCs are genomically distinct from histological grade‐matched or triple‐negative and basal‐like invasive ductal carcinomas of no special type (IDC‐NSTs). The presence of the MYB‐NFIB fusion was investigated in 13 AdCCs of the breast by fluorescence in situ hybridisation (... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065415 Mon, 25 Jul 2011 23:00:00 +0100 5065415 http://www.medworm.com/index.php?rid=5065414&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2975 In this study, we investigated the crosstalk between T. cruzi‐induced immune activation of reactive oxygen species (ROS) and proinflammatory responses, and their role in myocardial pathology. Splenocytes of infected mice (C3H/HeN) responded to Tc‐antigenic stimulus by >2‐fold increase in NADPH oxidase (NOX) activity, ROS generation, cytokine production (IFNγ>IL‐4>TNFα>IL1‐β≈︁IL6), and predominant expansion of CD4+ and CD8+ T cells. Inhibition of NOX, but not of myeloperoxidase and xanthine‐oxidase, controlled the ROS (>98%) and cytokine (70‐89%) release by Tc‐stimulated splenocytes of infected mice. Treatment of infected mice with apocynin (NOX inhibitor) in drinking water resulted in 50‐90% decline in endogenous NOX/ROS and cytokine levels, and sple... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5065414 Mon, 25 Jul 2011 23:00:00 +0100 5065414 http://www.medworm.com/index.php?rid=5043084&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2971 AbstractMutations in p53 occur in over 50% of the human head and neck squamous cell carcinomas (SCCHN). The majority of these mutations result in the expression of mutant forms of p53, rather than deletions in the p53 gene. Some p53 mutants are associated with poor prognosis in SCCHN patients. However, the molecular mechanisms that determine the poor outcome of cancers carrying p53 mutations are unknown. Here, we generated a mouse model for SCCHN and found that activation of the endogenous p53 gain‐of‐function mutation p53R172H, but not deletion of p53, cooperates with oncogenic K‐ras during SCCHN initiation, accelerates oral tumor growth and promotes progression to carcinoma. Mechanistically, expression profiling of the tumors that developed in these mice and studies using cell line... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5043084 Thu, 21 Jul 2011 17:35:44 +0100 5043084 http://www.medworm.com/index.php?rid=5043085&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2970 AbstractIt has become increasingly clear that the four main histologic subtypes of epithelial ovarian cancer (EOC), high‐grade serous, endometrioid, clear cell and mucinous, are entities with different epidemiology, clinical presentation, response to treatment and ultimate outcomes. In fact, for all intents and purposes, they can be considered different diseases; their only common denominator being that they frequently involve the ovary and pelvic organs. However, clinical practice has not caught up with these insights and the treatment of EOC is that of a single disease entity. In part, this is because we lack detailed knowledge of the molecular mechanisms driving the pathogenesis of each disease, which are vital in order to develop therapeutic approaches against common driver events. I... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5043085 Mon, 18 Jul 2011 23:00:00 +0100 5043085 http://www.medworm.com/index.php?rid=5032275&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2969 AbstractDuctal carcinoma in situ (DCIS) is a non‐obligate precursor of invasive breast cancer. The current recognition that DCIS lesions exhibit inter‐ and intra‐lesion diversity suggests that the process of evolution to invasive breast cancer is more complex than previously recognized. Here we demonstrate the reproducible growth of primary DCIS cells derived from patient's surgical and biopsy samples by the mouse intraductal (MIND) model. MIND involves injection of cells into the NOD‐SCID IL2Rgammanull (NSG) mouse mammary ducts. Twelve (8 unique and 4 repeats) DCIS and 2 atypical hyperplasia specimens, heterogeneous with respect to biomarker expression and histology, were injected into 48 mouse mammary glands and analyzed for successful xenotransplantation. Overall, 14/34 and 11/1... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5032275 Sun, 17 Jul 2011 03:15:24 +0100 5032275 http://www.medworm.com/index.php?rid=5263383&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2969 AbstractDuctal carcinoma in situ (DCIS) is a non‐obligate precursor of invasive breast cancer. The current recognition that DCIS lesions exhibit inter‐ and intra‐lesion diversity suggests that the process of evolution to invasive breast cancer is more complex than previously recognized. Here we demonstrate the reproducible growth of primary DCIS cells derived from patient's surgical and biopsy samples by the mouse intraductal (MIND) model. MIND involves injection of cells into the NOD‐SCID IL2Rgamma (NSG) mouse mammary ducts. Twelve (eight unique and four repeats) DCIS and two atypical hyperplasia specimens, heterogeneous with respect to biomarker expression and histology, were injected into 48 mouse mammary glands and analysed for successful xenotransplantation. Overall, 14/34 and... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5263383 Fri, 15 Jul 2011 04:00:00 +0100 5263383 http://www.medworm.com/index.php?rid=5149071&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2966 AbstractNotch can act as an oncogene or as a tumour suppressor and thus can either promote or inhibit tumour cell growth. To establish Notch status in Ewing's sarcoma family of tumours (ESFT), we investigated the Notch pathway by gene expression profiling meta‐analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We found that although Notch receptors were highly expressed, Notch did not appear to be active, as evidenced by the absence of Notch receptors in cell nuclei. In contrast, we show that Notch receptors known to be active in colon adenocarcinoma, hepatocarcinoma, and pancreatic carcinoma stain cell nuclei in these tumours. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149071 Thu, 14 Jul 2011 23:00:00 +0100 5149071 http://www.medworm.com/index.php?rid=5032279&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2965 AbstractStem cells accumulate mitochondrial DNA (mtDNA) mutations resulting in an observable respiratory chain defect in their progeny, allowing the mapping of stem cell fate. There is considerable uncertainty in prostate epithelial biology where both basal and luminal stem cells have been described and in this study the clonal relationships within the human prostate epithelial cell layers was explored by tracing stem cell fate. Fresh‐frozen and formalin‐fixed histologically‐benign prostate samples from 35 patients were studied using sequential cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) enzyme histochemistry and COX subunit I immuno‐fluorescence to identify areas of respiratory chain deficiency; mtDNA mutations were identified by whole mitochondrial genome sequencing ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5032279 Thu, 14 Jul 2011 23:00:00 +0100 5032279 http://www.medworm.com/index.php?rid=5032278&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2966 AbstractNotch can act as an oncogene or as a tumor suppressor and thus can either promote or inhibit tumor cell growth. To establish Notch status in Ewing's sarcoma family of tumors (ESFT), we investigated the Notch pathway by gene expression profiling meta‐analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We find that although Notch receptors were highly expressed, Notch did not appear to be active as evidenced by the absence of Notch receptors in cell nuclei. In contrast, we show that Notch receptors known to be active in colon adenocarcinoma, hepatocarcinoma, and pancreatic carcinoma stain cell nuclei in these tumors. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was ... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5032278 Thu, 14 Jul 2011 23:00:00 +0100 5032278 http://www.medworm.com/index.php?rid=5032277&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2967 AbstractNotch signalling is a highly conserved cell‐cell communication mechanism that regulates development, tissue homeostasis and repair. Within the kidney, Notch has an important function in orchestrating kidney development. Recent studies indicate that Notch plays a key role in establishing proximal epithelial fate during nephron segmentition as well as the differentiation of principal cells in the renal collecting system. Notch signalling is markedly reduced in the adult kidney, however, increased Notch signalling has been noted both in acute and chronic kidney injury. Increased glomerular epithelial Notch signaling has been associated with albuminuria and glomerulosclerosis, while tubular epithelial Notch activation caused fibrosis development most likely inducing an improper epith... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5032277 Thu, 14 Jul 2011 23:00:00 +0100 5032277 http://www.medworm.com/index.php?rid=5032276&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2968 AbstractOncostatin M receptor (OSMR) shows frequent copy‐number gain and over‐expression in advanced cervical squamous cell carcinoma (SCC). We used cell‐based in‐vitro assays, RNA‐interference and integrative gene expression profiling to investigate the functional significance of this observation. CaSki and SW756 were selected as representative cervical SCC cells that over‐expressed OSMR and ME180 and MS751 as cells that did not. The STAT‐dependent pro‐angiogenic factors VEGF‐A and ID1 were rapidly induced by OSM in CaSki/SW756 but not in ME180/MS751. However, rapid induction did occur in MS751 following forced OSMR over‐expression, while depleting OSMR in CaSki abrogated VEGF‐A expression. Conditioned medium from both CaSki and SW756 stimulated endothelial tube form... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5032276 Thu, 14 Jul 2011 23:00:00 +0100 5032276 http://www.medworm.com/index.php?rid=5012688&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2964 This study finds a new mechanism that miR‐9 utilizes to decrease E‐cadherin expression and inhibit melanoma progression. The results suggest that function of microRNAs is context and tumor type specific.Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5012688 Tue, 12 Jul 2011 14:50:39 +0100 5012688 http://www.medworm.com/index.php?rid=5149072&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2964 This study finds a new mechanism that miR‐9 utilizes to decrease E‐cadherin expression and inhibit melanoma progression. The results suggest that function of microRNAs is context and tumour type‐specific. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Source: The Journal of Pathology) The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149072 Sun, 10 Jul 2011 23:00:00 +0100 5149072 http://www.medworm.com/index.php?rid=4994937&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2963 AbstractEndometriosis is one of the most common gynecological diseases that significantly reduces life qualify of affected women and their families. Aberrant expression of cyclooxygenase‐2 (COX‐2) and thus overproduction of prostaglandin E2 (PGE2) has been shown to play critical roles in the development of this disease. However, the mechanism responsible for COX‐2 overexpression remains obscure. Here, we provide evidence for what we believe is a novel mechanism in regulating COX‐2 expression in endometriotic stromal cells. Dual specificity phosphatase‐2 (DUSP2), a nuclear phosphatase that inactivates mitogen activated protein kinase (MAPK), is markedly downregulated in stromal cells of ectopic endometriotic tissues, which results in prolonged activation of extracellular signal‐... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=4994937 Mon, 04 Jul 2011 17:16:58 +0100 4994937 http://www.medworm.com/index.php?rid=5149074&cid=s_33653_32_f&fid=33653&url=http%3A%2F%2Fdx.doi.org%2F10.1002%252Fpath.2962 AbstractKaposi's sarcoma‐associated herpesvirus (KSHV) encodes a viral interleukin 6 (vIL‐6) that mimics many activities of human IL‐6 (hIL‐6). Both vIL‐6 and hIL‐6 play important roles in stimulating the proliferation of tumours caused by KSHV. Here, we provide evidence that a miRNA pathway is involved in regulation of vIL‐6 and hIL‐6 expression through binding sites in their open reading frames (ORFs). We show a direct repression of vIL‐6 by hsa‐miR‐1293 and hIL‐6 by hsa‐miR‐608. The repression of vIL‐6 by miR‐1293 was reversed by disruption of the vIL‐6 miR‐1293 seed match through the introduction of point mutations. In addition, expression of vIL‐6 or hIL‐6 in KSHV‐infected cells could be enhanced by transfection of the respective miRNA inhibit... The Journal of Pathology journals http://www.medworm.com/rss/comments.php?id=5149074 Sun, 03 Jul 2011 23:00:00 +0100 5149074