Utility of gastric biopsy in diagnosing IgG4‐related gastrointestinal disease

The utility of gastric biopsy for diagnosing immunoglobulin (Ig)G4‐related gastrointestinal disease (IgG4‐GID) remains unclear. Bottom‐heavy plasmacytosis (BHP) is a distinct feature of IgG4‐GID. To clarify the feasibility of using gastric biopsies to diagnose BHP in IgG4‐GID, we analyzed the histological features and immunostaining of gastric biopsy specimens from 31 known IgG4‐related disease (IgG4‐RD) patients and we assessed the presence of BHP in 1696 consecutive routine gastric biopsies. Cases with both >10 IgG4‐positive plasma cells per high‐power field and an IgG4/IgG‐positive ratio >40% were defined as IgG4‐high. Ten of the 31 IgG4‐RD patients were concluded to have IgG4‐GID, in which IgG4‐positive plasma cells were notably detected at the deeper part of the mucosa. Six cases displayed BHP whereas the remaining four cases showed transmural infiltration with concomitant Helicobacter pylori‐associated gastritis. In addition to BHP, we identified two unique histologic features for IgG4‐GID: plasmacytic aggregation in the muscularis mucosae and permeative plasmacytic infiltration between fundic glands in the non‐atrophic mucosa. Six of the routine cases (0.35%) displayed BHP, including a case with IgG4‐RD. IgG4‐GID can be suspected by the presence of gastric biopsy specimens with characteristic histological features. Such cases are recommended to undergo further examinations to determine whether IgG4‐RD is present

Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas

細胞老化による発がん抑制作用を個体レベルで解明 --細胞老化の仕組みを利用した新たながん治療法開発に向けて--. 京都大学プレスリリース. 2019-09-11.Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development

Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice

<div><p>Background</p><p>Acute respiratory distress syndrome (ARDS) is a severe and life-threatening acute lung injury (ALI) that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK) pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred)-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK)-MAPK pathway, in lipopolysaccharide (LPS)-induced acute lung inflammation.</p><p>Methods</p><p>Wild-type (WT) mice and <i>Spred-2^−/−</i> mice were exposed to intratracheal LPS (50 µg in 50 µL PBS) to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For <i>ex</i><i>vivo</i> experiments, alveolar macrophages were harvested from untreated WT and <i>Spred-2^−/−</i> mice and stimulated with LPS. In <i>in</i><i>vitro</i> experiments, specific knock down of <i>Spred-2</i> by siRNA or overexpression of <i>Spred-2</i> by transfection with a plasmid encoding the <i>Spred-2</i> sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells.</p><p>Results</p><p>LPS-induced acute lung inflammation was significantly exacerbated in <i>Spred-2^−/−</i> mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in <i>Spred-2^−/−</i> mice. Specific knock down of <i>Spred-2</i> augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas <i>Spred-2</i> overexpression decreased this response in RAW264.7 cells.</p><p>Conclusions</p><p>The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls the development of LPS-induced lung inflammation by negatively regulating the ERK-MAPK pathway. Thus, Spred-2 may represent a therapeutic target for the treatment of ALI.</p></div

U0126 inhibits the enhanced lung inflammation in Spred-2^−/− mice.

<p>We treated <i>Spred-2^−/−</i> mice intranasally with 20 µL of 5 mM U0126 (n = 6) or DMSO vehicle control (n = 5) before LPS administration (50 µg in 50 µL). At 24 hours after LPS administration, mice were killed. (A) The number of infiltrating leukocytes in BAL fluids was counted. #<i>P</i><0.01, vs. WT mice. (B) Representative images of lung sections are shown (original magnification 200×). (C) TNF-α, CXCL2, CCL2 and IL-10 levels in BAL fluids were measured by ELISA. Dotted lines indicate the levels in BAL fluids from PBS-treated control mice. #<i>P</i><0.01, ¶<i>P</i><0.001, vs. WT control.</p