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American Journal of Pathology

Jacquelyn O Russell, Sungjin Ko, Harvinder S Saggi, Sucha Singh, Minakshi Poddar, Donghun Shin, Satdarshan P Monga
Bromodomain and extraterminal (BET) proteins recruit key components of basic transcriptional machinery to promote gene expression. Aberrant expression and mutations in BET genes have been identified in many malignancies. Small molecule inhibitors of BET proteins like JQ1 have shown efficacy in preclinical cancer models including affecting growth of hepatocellular carcinoma. BET proteins also regulate cell proliferation in nontumor settings. We recently showed that BET proteins regulate cholangiocyte-driven liver regeneration...
March 12, 2018: American Journal of Pathology
Natalia Anahí Juiz, Irma Torrejón, Marianela Burgos, Ana María Fernanda Torres, Tomás Duffy, Nelly Melina Cayo, Anahí Tabasco, Miriam Salvo, Silvia Andrea Longhi, Alejandro Gabriel Schijman
Infection with Trypanosoma cruzi in women at reproductive age is associated with congenital transmission and adverse pregnancy outcome. The placenta is a key barrier to infection. We characterized gene expression profiles of term placental environment from T. cruzi seropositive (SP) and seronegative (SN) mothers performing RNA-seq. Nine pools of placental RNA paired samples were used: three from SN and six from SP tissues. Each pool consisted of female/male newborns and vaginal/caesarean deliveries binomials...
March 12, 2018: American Journal of Pathology
Marie Madsen, Peter Riis Hansen, Lars Bo Nielsen, Renata Martins Cardoso, Miranda van Eck, Tanja Xenia Pedersen
Psoriasis is a chronic inflammatory skin disorder associated with several comorbidities including atherosclerosis. Disease mechanisms that may affect both psoriasis and atherosclerosis include activation of T helper 1 and T helper 17 cells. Imiquimod application is an established mouse model of psoriasis-like skin inflammation. The cardiac glycoside digoxin inhibits the master transcription factor of T helper 17 differentiation, retinoid acid receptor-related orphan nuclear receptor γt, and attenuates interleukin-17-dependent pathologies in mice...
March 12, 2018: American Journal of Pathology
Morgan L Shannon, Ryann M Fame, Kevin F Chau, Neil Dani, Monica L Calicchio, Gwenaelle S Géléoc, Hart G W Lidov, Sanda Alexandrescu, Maria K Lehtinen
Choroid plexus tumors and ciliary body medulloepithelioma are predominantly pediatric neoplasms. Progress in understanding the pathogenesis of these tumors has been hindered by their rarity and lack of models that faithfully recapitulate the disease. Here, we find that endogenous c-Myc is down-regulated in the forebrain neuroepithelium, whose neural plate border domains give rise to anterior choroid plexus and ciliary body. To uncover the consequences of persistent MYC (c-Myc) expression, c-Myc expression was forced in multipotent neural precursors (Nestin-Cre:MYC), which produced a fully penetrant model of choroid plexus carcinoma and ciliary body medulloepithelioma...
March 12, 2018: American Journal of Pathology
Jungeun Yu, Stefano Zanotti, Lauren Schilling, Chris Schoenherr, Aris Economides, Archana Sanjay, Ernesto Canalis
Mice harboring Notch2 mutations replicating Hajdu Cheney syndrome (Notch2tm1.1ECan ) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2tm1.1ECan mutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional by inversion (COIN) Hajdu Cheney syndrome allele of Notch2 (Notch2[ΔPEST]COIN ) was used...
March 12, 2018: American Journal of Pathology
Adelaide Tawiah, Steve Cornick, France Moreau, Hayley Gorman, Manish Kumar, Sameer Tiwari, Kris Chadee
MUC2 mucin is a large glycoprotein produced by goblet cells that forms the protective mucus blanket overlying the intestinal epithelium as the first line of innate host defense. High MUC2 production in inflammatory bowel disease and infectious colitis depletes goblet cells and the mucus layer by an unknown mechanism. Here, we analyzed the effect of high MUC2 biosynthesis on endoplasmic reticulum (ER) stress and apoptosis in goblet cells using a high MUC2-producing human goblet cell line (HT29-H) and a HT29-H clone (HT29-L) silenced for MUC2 expression by lentivirus-mediated shRNA...
March 12, 2018: American Journal of Pathology
Martin S Taylor, Raghu R Chivukula, Laura C Myers, William R Jeck, Avinash Waghray, Purushothama R Tata, Martin K Selig, Walter J O'Donnell, Carol F Farver, B Taylor Thompson, Jayaraj Rajagopal, Richard L Kradin
Improved tools have led to a burgeoning understanding of lung regeneration in mice, but it is not yet known how these insights may be relevant to acute lung injury in humans. We report in detail two cases of fulminant idiopathic acute lung injury requiring extracorporeal membrane oxygenation in previously healthy young adults with acute respiratory distress syndrome, one of whom required lung transplantation. Biopsies showed diffuse alveolar injury with a striking paucity of alveolar epithelial regeneration, rare hyaline membranes, and diffuse contiguous airspace lining by macrophages...
February 21, 2018: American Journal of Pathology
Dörthe Masemann, Rafael Leite Dantas, Siarhei Sitnik, Tanja Schied, Carolin Nordhoff, Stephan Ludwig, Viktor Wixler
FHL2 is a multifunctional adaptor protein with fine-tuning adjustment properties. It acts as a regulator of signaling cascades but also as a cofactor of transcription and controls several anti-inflammatory immune responses. Recently, we described FHL2 as a novel regulator of influenza A virus propagation. We have shown that in vitro FHL2 restricts viral replication by accelerating the IRF-3-dependent transcription of the Ifnb1 gene. In this work, we unraveled an ambiguous role of FHL2 during influenza A virus infection in vivo...
February 17, 2018: American Journal of Pathology
Agnieszka Dzikiewicz-Krawczyk, Arjan Diepstra, Bea Rutgers, Gertrud Kortman, Debora de Jong, Jasper Koerts, Marian Bulthuis, Tineke van der Sluis, Annika Seitz, Lydia Visser, Klaas Kok, Joost Kluiver, Anke van den Berg
MicroRNAs (miRNAs) are small noncoding RNAs involved in the posttranscriptional regulation of gene expression. Deregulated miRNA levels have been linked to Burkitt lymphoma (BL) pathogenesis. To date, the number of known pathogenesis-related miRNA-target gene interactions is limited. Here, we determined for the first time the miRNA targetomes of primary BL tumors and normal B cells. AGO2-RNA immunoprecipitation (AGO2-RIP) of two frozen diagnostic BL tissue samples and three CD19+ B-cell samples isolated from routinely removed tonsils revealed distinct miRNA targetomes of BL and normal B cells...
February 16, 2018: American Journal of Pathology
Joseph X DiMario
Dystrophic skeletal muscle is characterized by fibrotic accumulation of extracellular matrix components that compromise muscle structure, function, and capacity for regeneration. Tissue fibrosis is often initiated and sustained through transforming growth factor β (TGFβ) signaling, and KLF10 is an immediate early gene that is transcriptionally activated in response to TGFβ signaling. It encodes a transcriptional regulator that mediates the effects of TGFβ signaling in a variety of cell types. This report presents results of investigation of the effects of loss of KLF10 gene expression in wild-type and dystrophic (mdx) skeletal muscle...
February 16, 2018: American Journal of Pathology
Akiko Kunita, Vanessa Baeriswyl, Claudia Meda, Erik Cabuy, Kimiko Takeshita, Enrico Giraudo, Andreas Wicki, Masashi Fukayama, Gerhard Christofori
Tumor invasion is a critical first step in the organismic dissemination of cancer cells and the formation of metastasis in distant organs, the most important prognostic factor and the actual cause of death in most of the cancer patients. We report here that the cell surface protein podoplanin (PDPN), a potent inducer of cancer cell invasion, is conspicuously expressed by the invasive front of squamous cell carcinomas (SCC) of the cervix in patients and in the transgenic HPV/E2 mouse model of cervical cancer...
February 16, 2018: American Journal of Pathology
Chih-Chia Liang, Chi-Shan Li, I-Chun Weng, Huan-Yuan Chen, Hsueh-Han Lu, Chiu-Ching Huang, Fu-Tong Liu
Impairment of the intestinal mucosal immunity significantly increases the risk of acute and chronic diseases. Immunoglobulin A (IgA) plays a major role in humoral mucosal immunity to provide protection against pathogens and toxins in the gut. Here, we investigated the role of endogenous galectin-9, a tandem repeat-type β-galactoside-binding protein, in intestinal mucosal immunity. By mucosal immunization of Lgals9-/- and littermate control mice, it was found that lack of galectin-9 impaired mucosal antigen-specific IgA response in the gut...
February 16, 2018: American Journal of Pathology
Li-Yin Hung, Taylor K Oniskey, Debasish Sen, Matthew F Krummel, Andrew E Vaughan, Noam A Cohen, De'Broski R Herbert
Trefoil factors are small secreted proteins that regulate tissue integrity and repair at mucosal surfaces, particularly in the gastrointestinal tract. However, their relative contribution(s) to controlling baseline lung function or the extent of infection-induced lung injury are unknown issues. Using irradiation bone marrow chimeras, we found that Trefoil factor 2 (TFF2) produced from both hematopoietic- and non-hematopoietic-derived cells is essential for host protection, proliferation of alveolar type 2 cells, and restoration of pulmonary gas exchange following infection with the hookworm parasite Nippostrongylus brasiliensis...
February 16, 2018: American Journal of Pathology
Paulina Cybulska, Jocelyn M Stewart, Azin Sayad, Carl Virtanen, Patricia A Shaw, Blaise Clarke, Natalie Stickle, Marcus Q Bernardini, Benjamin G Neel
High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignancy. Overall survival remains low, due to the nearly ubiquitous emergence of platinum-resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for pre-clinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment...
February 16, 2018: American Journal of Pathology
Asmita Pant, Anna K Kopeć, Kevin S Baker, Holly Cline-Fedewa, Daniel A Lawrence, James P Luyendyk
Acetaminophen (APAP)-induced liver injury in mice is associated with activation of the coagulation cascade and deposition of fibrin in liver. Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of tissue-type plasminogen activator (tPA) and plays a critical role in fibrinolysis. PAI-1 expression is increased in both experimental APAP-induced liver injury and patients with acute liver failure. Prior studies have shown that PAI-1 prevents intrahepatic hemorrhage and mortality after APAP challenge, but the downstream mechanisms are not clear...
February 16, 2018: American Journal of Pathology
Chieko Mishima, Naofumi Kagara, Jun-Ichiro Ikeda, Eiichi Morii, Tomohiro Miyake, Tomonori Tanei, Yasuto Naoi, Masafumi Shimoda, Kenzo Shimazu, Seung Jin Kim, Shinzaburo Noguchi
The pathological feature of intraductal papillomas is defined as a papillary structure composed of a fibrovascular stromal core lined by luminal epithelial cells and myoepithelial cells. We used droplet digital PCR for the mutational analysis of AKT1 (E17K) and PIK3CA (H1047R, E542K, and E545K) in 60 papillomas. AKT1 and PIK3CA mutations were detected in 12 (20%) and 17 (28%) of the papillomas, respectively. In five tumors harboring mutations, mutational analysis of AKT1 or PIK3CA was performed separately using luminal epithelial cells and myoepithelial cells sorted using anti-CK19 antibody and anti-SMA antibody...
February 15, 2018: American Journal of Pathology
Toshiaki Totoki, Corina N D' Alessandro-Gabazza, Masaaki Toda, Prince Baffour Tonto, Atsuro Takeshita, Taro Yasuma, Kota Nishihama, Motoh Iwasa, Noriyuki Horiki, Yoshiyuki Takei, Esteban C Gabazza
Protein S is a vitamin K-dependent glycoprotein produced mainly in the liver with anticoagulant, anti-inflammatory, immune-modulatory, and anti-apoptotic properties. Protein S exacerbates acute liver injury by prolonging the survival of liver immune cells. However, the effect of protein S on chronic liver injury and fibrosis is unknown. Here we investigated whether human protein S can affect chronic liver injury and fibrosis. Liver injury/fibrosis was induced by carbon tetrachloride injection in mice overexpressing human protein S and in wild-type mice...
February 15, 2018: American Journal of Pathology
Anna Löfdahl, Christina Wenglén, Kristina Rydell-Törmänen, Gunilla Westergren-Thorsson, Anna-Karin Larsson-Callerfelt
Serotonin (5-hydroxytryptamine, 5-HT) is associated with several chronic pulmonary diseases, recognizing 5-HT2 receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT2 receptors, especially, 5-HT2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pre-treated with 5-HT2B receptor antagonists; EXT5, EXT9, RS127445, and PRX08066, as well as ketanserin (5-HT2A/2C receptor antagonist) (1 μM, 10 μM), prior to addition of cumulative concentrations of 5-HT to induce bronchoconstriction...
February 15, 2018: American Journal of Pathology
Cameron A Schmidt, Adam J Amorese, Terence E Ryan, Emma J Goldberg, Michael D Tarpey, Thomas D Green, Reema R Karnekar, Dean J Yamaguchi, Espen E Spangenburg, Joseph M McClung
Limited efficacy of clinical interventions for peripheral arterial disease (PAD) necessitates a better understanding of the environmental and genetic determinants of tissue pathology. Existing research has largely ignored the early skeletal muscle injury response during hindlimb ischemia (HLI). We compared the hindlimb muscle response, following six hours of ischemia, in two mouse strains that differ dramatically in their post-ischemic extended recovery: C57BL/6J and BALB/cJ. Perfusion, measured by laser Doppler and normalized to the control limb, differed only slightly between strains following HLI (<12% across all measures)...
February 15, 2018: American Journal of Pathology
Lyne Gagnon, Martin Leduc, Jean-Francois Thibodeau, Ming-Zhi Zhang, Brigitte Grouix, Francois Sarra-Bournet, William Gagnon, Kathy Hince, Mikaël Tremblay, Lilianne Geerts, Christopher R J Kennedy, Richard L Hébert, Alex Gutsol, Chet E Holterman, Eldjonai Kamto, Liette Gervais, Jugurtha Ouboudinar, Jonathan Richard, Alexandra Felton, Alexandre Laverdure, Jean-Christophe Simard, Sylvie Létourneau, Marie-Pier Cloutier, Francois A Leblond, Shaun D Abbott, Christopher Penney, Jean-Simon Duceppe, Boulos Zacharie, Jocelyn Dupuis, Angelino Calderone, Quang Trinh Nguyen, Raymond C Harris, Pierre Laurin
Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors...
February 15, 2018: American Journal of Pathology
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