Up-regulation of activation-induced cytidine deaminase and its strong expression in extra- germinal centres in IgG4-related disease

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (nonspecific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD

EWSR1-ATF1融合遺伝子を持つ歯原性明細胞癌細胞株の樹立と性状解析

Objective: Clear cell odontogenic carcinoma (CCOC) is a rare malignant odontogenic tumor (MOT) characterized by sheets and lobules of vacuolated and clear cells. To understand the biology of CCOC, we established a new cell line, CCOC-T, with EWSR1-ATF1 fusion gene from a mandible tumor with distant metastasis and characterized this cell line. Materials and methods: To detect the EWSR1-ATF1 fusion gene, we used three CCOC cases, including the present case, by RT-PCR and FISH analysis. We characterized established CCOC-T cells by checking cell growth, invasion and the expression of odontogenic factors and bone-related factors. Moreover, the gene expression profile of CCOC-T cells was examined by microarray analysis. Results: Histologically, the primary tumor was comprised of cords and nests containing clear and squamoid cells separated by fibrous septa. In addition, ameloblastomatous islands with palisaded peripheral cells were observed, indicating probable odontogenic origin. This tumor expressed the fusion gene EWSR1-ATF1, which underlies the etiology of hyalinizing clear cell carcinoma (HCCC) and potentially that of CCOC. We found a breakpoint in the EWSR1-ATF1 fusion to be the same as that reported in HCCC. Established CCOC-T cells grew extremely slowly, but the cells showed highly invasive activity. Moreover, CCOC-T cells expressed bone-related molecules, odontogenic factors, and epithelial mesenchymal transition (EMT)-related molecules. Conclusion: To the best of our knowledge, this is the first report on the establishment of a CCOC cell line. CCOC-T cells serve as a useful in vitro model for understanding the pathogenesis and nature of MOT

Knockdown of legumain inhibits cleavage of annexin A2 in the mouse kidney

Legumain (EC 3.4.22.34) is an asparaginyl endopeptidase. Strong legumain activity was observed in the mouse kidney, and legumain was highly expressed in tumors. We previously reported that bovine kidney annexin A2 was co-purified with legumain and that legumain cleaved the N-terminal region of annexin A2 at an Asn residue in vitro. In this study, to determine whether annexin A2 is cleaved by legumain in vivo, siRNA-lipoplex targeting mouse legumain was injected into mouse tail veins. Mouse kidneys were then isolated and the effect of knockdown of legumain expression on annexin A2 cleavage was examined. The results showed that both legumain mRNA and protein expression levels were decreased in the siRNA-treated mouse kidneys and that legumain activity toward a synthetic substrate, Z-Ala-Ala-Asn-MCA, was decreased by about 40% in the kidney but not in the liver or spleen. Furthermore, cleavage of annexin A2 at the N-terminal region was decreased in the mouse kidney that had been treated with the legumain siRNA-lipoplex. These results suggest that legumain siRNA was delivered to the kidney by using LipoTrust and that the reduced legumain expression inhibited legumain-induced degradation of annexin A2 in vivo. (C) 2012 Elsevier Inc. All rights reserved

(8-Benzoyl-2,7-dimethoxynaphthalen-1-yl)(4-phenoxyphenyl)methanone

In the molecule of the title compound, C32H24O5, the benzoyl group and the 4-phenoxy substituted benzoyl group at the 1- and 8-positions of the naphthalene ring system are aligned almost antiparallel. The two benzene rings make a dihedral angle of 21.18&#8197;(10)&#176;, and are inclined to the naphthalene ring system by 86.53&#8197;(9) and 82.95&#8197;(8)&#176;, respectively. In the crystal, C&#8212;H...O interactions are observed involving aromatic and methoxy H atoms with ketonic carbonyl O atoms, as well as C&#8212;H...&#960; interactions between aromatic H atoms and the &#960;-systems of naphthalene and benzene rings. These interactions form a three-dimensional architecture and afford a waved alignment of the naphthalene ring systems along the c axis

Impact of health systems reform on COVID-19 control in Sierra Leone: a case study

Abstract Background There are various impacts of COVID-19 on health systems of the world. The health systems of low- and middle-income countries are less developed. Therefore, they have greater tendencies to experience challenges and vulnerabilities in COVID-19 control compared to high-income countries. It is important to contain the spread of the virus, and likewise strengthen the capacity of health systems in order for the response to be effective and swift. The experience from 2014 to 2016 Ebola outbreak in Sierra Leone served as preparation for COVID-19 outbreak. The aim of this study is to determine how control of COVID-19 outbreak in Sierra Leone was enhanced by the lessons learned from 2014 to 2016 Ebola outbreak, and health systems reform. Methods We used data from a qualitative case study conducted in four districts in Sierra Leone through key informant interviews, focus group discussions, document, and archive record reviews. A total of 32 key informant interviews and 14 focus group discussions were conducted. A thematic analysis was used to analyze the data, and all transcripts were coded and analyzed with the aid of ATLAS.ti 9 software program. Results The six themes obtained were composed of categories that connect with each other and with codes to form networks. The analysis of the responses demonstrated that “Multisectoral Leadership and Cooperation”, “Government Collaboration among International Partners”, and “Awareness in the Community” were among the key interventions used during the control of 2014–2016 Ebola virus disease outbreak, which were applied in the control of COVID-19. An infectious disease outbreak control model was proposed based on the results obtained from the analysis of the lessons learned during the Ebola virus disease outbreak, and health systems reform. Conclusions “Multisectoral Leadership and Cooperation”, “Government Collaboration among International Partners” and “Awareness in the Community” are key strategies that enhanced the control of the COVID-19 outbreak in Sierra Leone. It is recommended that they are implemented in controlling COVID-19 pandemic or any other infectious disease outbreak. The proposed model can be used in controlling infectious disease outbreaks, especially in low- and middle-income countries. Further research is needed to validate the usefulness of these interventions in overcoming an infectious disease outbreak

Galectin-2 Has Bactericidal Effects against Helicobacter pylori in a β-galactoside-Dependent Manner

Helicobacter pylori is associated with the onset of gastritis, peptic ulcers, and gastric cancer. Galectins are a family of β-galactoside-binding proteins involved in diverse biological phenomena. Galectin-2 (Gal-2), a member of the galectin family, is predominantly expressed in the gastrointestinal tract. Although some galectin family proteins are involved in immunoreaction, the role of Gal-2 against H. pylori infection remains unclear. In this study, the effects of Gal-2 on H. pylori morphology and survival were examined. Gal-2 induced H. pylori aggregation depending on β-galactoside and demonstrated a bactericidal effect. Immunohistochemical staining of the gastric tissue indicated that Gal-2 existed in the gastric mucus, as well as mucosa. These results suggested that Gal-2 plays a role in innate immunity against H. pylori infection in gastric mucus

HLA-DRB1*04:05 is involved in the development of Vogt–Koyanagi–Harada disease-like immune-related adverse events in patients receiving immune checkpoint inhibitors

Abstract Immune checkpoint inhibitors (ICIs) activate anti-tumor activity by inhibiting immune checkpoint molecules that suppress inflammatory T-cell activity. However, ICIs can initiate excessive immune responses, thereby causing immune-related adverse events (irAEs). ICI-associated uveitis (ICIU) is an irAE that affects the eyes. Although Vogt–Koyanagi–Harada disease (VKH)-like uveitis is a common form of ICIU, it is unclear which factors determine the ICIU form. We retrospectively reviewed the medical records of nine ICIU cases treated with ICIs for malignancies. We also performed HLA typing in seven cases to investigate the association between HLA and disease type. Fisher's exact test was used for the statistical analysis. Five of the ICIU cases were VKH-like ICIUs, and four were non-VKH-like ICIUs. No association was found between mean age, sex, primary disease, ICI, time to onset, and disease type. Four patients with VKH-like uveitis underwent HLA genotyping and were all positive for HLA-DRB1*04:05. All 3 patients with non-VKH-like uveitis were negative for HLA-DRB1*04:05. Statistical analysis showed that HLA-DRB1*04:05 was significantly associated with developing VKH-like ICIU (P = 0.029). In ICIU, HLA-DRB1*04:05 was associated with the pathogenesis of VKH-like uveitis, suggesting that ICI-associated VKH-like uveitis has a similar pathogenesis to VKH

Increased serum extracellular vesicle miR-144-3p and miR-486a-3p in a mouse model of adipose tissue regeneration promote hepatocyte proliferation by targeting Txnip.

Adipose-derived stem cells are expected to be applied to regenerative medicine for various incurable diseases including liver cirrhosis. Although microRNAs contained in extracellular vesicles (EV-miRNAs) have been implicated in their regenerative effects, the precise mechanism has not been fully elucidated. Tamoxifen-inducible adipocyte-specific insulin receptor knockout (iFIRKO) mice are known to exhibit acute adipose tissue regeneration with increased numbers of adipose stem and progenitor cells (ASPCs). Because adipose tissue is the major source of circulating EV-miRNAs, we investigated alterations in serum EV-miRNAs in iFIRKO mice. A comprehensive analysis using miRNA sequencing on serum EVs revealed that most EV-miRNAs were decreased due to the loss of mature adipocytes, but there were 19 EV-miRNAs that were increased in the serum of iFIRKO mice. Among them, miR-144-3p and miR-486a-3p were found to be increased in the liver as well as serum EVs. While the expression levels of pri-miR-144-3p and pri-miR-486a-3p were not increased in the liver, they were elevated in the adipose tissue, suggesting that these miRNAs may be delivered from ASPCs increased in the adipose tissue to the liver via EVs. Increased hepatocyte proliferation was observed in the liver of iFIRKO mice, and we found that both miR-144-3p and miR-486a-3p have a function to promote hepatocyte proliferation by suppressing Txnip expression as a target gene. miR-144-3p and miR-486a-3p can be candidate therapeutic tools for conditions requiring hepatocyte proliferation, such as liver cirrhosis, and our current study suggests that examining EV-miRNAs secreted in vivo may lead to the discovery of miRNAs involved in regenerative medicine that have not been identified by in vitro analysis