Tick saliva‑induced programmed death‑1 and PD‑ligand 1 and its related host immunosuppression

The tick Rhipicephalus microplus is a harmful parasite of cattle that causes considerable economic losses to the cattle breeding industry. Although R. microplus saliva (Rm-saliva) contains several immunosuppressants, any association between Rm-saliva and the expression of immunoinhibitory molecules, such as programmed death (PD)-1 and PD-ligand 1 (PD-L1), has not been described. In this study, flow cytometric analyses revealed that Rm-saliva upregulated PD-1 expression in T cells and PD-L1 expression in CD14+ and CD11c+ cells in cattle. Additionally, Rm-saliva decreased CD69 expression in T cells and Th1 cytokine production from peripheral blood mononuclear cells. Furthermore, PD-L1 blockade increased IFN-γ production in the presence of Rm-saliva, suggesting that Rm-saliva suppresses Th1 responses via the PD-1/PD-L1 pathway. To reveal the upregulation mechanism of PD-1/PD-L1 by Rm-saliva, we analyzed the function of prostaglandin E2 (PGE2), which is known as an inducer of PD-L1 expression, in Rm-saliva. We found that Rm-saliva contained a high concentration of PGE2, and PGE2 treatment induced PD-L1 expression in CD14+ cells in vitro. Immunohistochemical analyses revealed that PGE2 and PD-L1 expression was upregulated in tick-attached skin in cattle. These data suggest that PGE2 in Rm-saliva has the potential to induce the expression of immunoinhibitory molecules in host immune cells

Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2010: General view of the pathogens\u27 antibacterial susceptibility

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from patients in Japan, was conducted by Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases and Japanese Society for Clinical Microbiology in 2010.The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period from January and April 2010 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical and Laboratory Standard Institutes using maximum 45 antibacterial agents.Susceptibility testing was evaluable with 954 strains (206 Staphylococcus aureus, 189 Streptococcus pneumoniae, 4 Streptococcus pyogenes, 182 Haemophilus influenzae, 74 Moraxella catarrhalis, 139 Klebsiella pneumoniae and 160 Pseudomonas aeruginosa). Ratio of methicillin-resistant S.aureus was as high as 50.5%, and those of penicillin-intermediate and -resistant S.pneumoniae were 1.1% and 0.0%, respectively. Among H.influenzae, 17.6% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant, 33.5% to be β-lactamase-non-producing ABPC-resistant and 11.0% to be β-lactamase-producing ABPC-resistant strains. Extended spectrum β-lactamase-producing K.pneumoniae and multi-drug resistant P.aeruginosa with metallo β-lactamase were 2.9% and 0.6%, respectively.Continuous national surveillance of antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis

The difficulty to diagnose cervical cancer developing in the perinatal period with the first-trimester cytology : A retrospective study

Aim Cytological cervical cancer screening for pregnant women is routinely performed and still plays an essential role in Japan because of the considerably low rate of human pappillomavirus (HPV) vaccination. Though almost all pregnant women undergo cytological screening at their first trimester, we experienced invasive cervical cancers (ICC) diagnosed during pregnancy or postpartum period. We investigated the characteristics of perinatally diagnosed ICCs to clarify the difficulty in diagnosis during the pregnancy. Methods We retrospectively reviewed the clinical data on ICC diagnosed during pregnancy or within 1 year after delivery from 2010 to 2018 at Hokkaido University Hospital. Results We identified 18 ICC patients, and the median follow-up period was 46.5 months. Among eight patients with negative for intraepithelial lesion or malignancy (NILM), the mean duration to reach ICC diagnosis was 10.7 months, seven had stage IB1 or worse, and one was dead. On the other hand, among 10 women with abnormal cytology, the mean duration for diagnosis was 1.4 months, and 6 had stage IB1 or worse, and 1was dead. In terms of the timing of the final diagnosis, 8 were during pregnancy and 10 in the postpartum periods. Among eight pregnant patients, three resulted in a preterm delivery (33, 34, and 35 gestational weeks), and four terminated their pregnancies. One decided to continue the pregnancy until the term period. We performed conization in one patient and hysterectomy in seven. Conclusion A part of cytological examinations of pregnant women may result in presumed false-negative or underestimation, which keeps them away from the additional examination to find ICC

The Expression, Functions and Mechanisms of Circular RNAs in Gynecological Cancers

Circular RNAs (circRNAs) are covalently closed, endogenous non-coding RNAs and certain circRNAs are linked to human tumors. Owing to their circular form, circRNAs are protected from degradation by exonucleases, and therefore, they are more stable than linear RNAs. Many circRNAs have been shown to sponge microRNAs, interact with RNA-binding proteins, regulate gene transcription, and be translated into proteins. Mounting evidence suggests that circRNAs are dysregulated in cancer tissues and can mediate various signaling pathways, thus affecting tumorigenesis, metastasis, and remodeling of the tumor microenvironment. First, we review the characteristics, biogenesis, and biological functions of circRNAs, and describe various mechanistic models of circRNAs. Then, we provide a systematic overview of the functional roles of circRNAs in gynecological cancers. Finally, we describe the potential future applications of circRNAs as biomarkers for prognostic stratification and as therapeutic targets in gynecological cancers. Although the function of most circRNAs remains elusive, some individual circRNAs have biologically relevant functions in cervical cancer, ovarian cancer, and endometrial cancer. Certain circRNAs have the potential to serve as biomarkers and therapeutic targets in gynecological cancers

Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway

Background: Epithelial-to-mesenchymal transition (EMT) and aerobic glycolysis are fundamental processes implicated in cancer metastasis. Although increasing evidence demonstrates an association between EMT induction and enhanced aerobic glycolysis in human cancer, the mechanisms linking these two conditions in endometrial cancer (EC) cells remain poorly defined. Methods: We characterized the role and molecular mechanism of the glycolytic enzyme hexokinase 2 (HK2) in mediating EMT and glycolysis and investigated how long noncoding RNA DLEU2 contributes to the stimulation of EMT and glycolysis via upregulation of HK2 expression. Results: HK2 was highly expressed in EC tissues, and its expression was associated with poor overall survival. Overexpression of HK2 effectively promoted EMT phenotypes and enhanced aerobic glycolysis in EC cells via activating FAK and its downstream ERK1/2 signaling. Moreover, microRNA-455 (miR-455) served as a tumor suppressor by directly interacting with HK2 mRNA and inhibiting its expression. Furthermore, DLEU2 displayed a significantly higher expression in EC tissues, and increased DLEU2 expression was correlated with worse overall survival. DLEU2 acted as an upstream activator for HK2-induced EMT and glycolysis in EC cells through two distinct mechanisms: (i) DLEU2 induced HK2 expression by competitively binding with miR-455, and (ii) DLEU2 also interacted with EZH2 to silence a direct inhibitor of HK2, miR-181a. Conclusions: This study identified DLEU2 as an upstream activator of HK2-driven EMT and glycolysis in EC cells and provided significant mechanistic insights for the potential treatment of EC

Effects of online frame-of-reference training on assessment accuracy in the objective structured clinical examination for physical therapy students

journal articl

PD-L1 Is a Tumor Suppressor in Aggressive Endometrial Cancer Cells and Its Expression Is Regulated by miR-216a and lncRNA MEG3

Background: Poorly differentiated endometrioid adenocarcinoma and serous adenocarcinoma represent an aggressive subtype of endometrial cancer (EC). Programmed death-ligand-1 (PD-L1) was known to exhibit a tumor cell-intrinsic function in mediating immune-independent tumor progression. However, the functional relevance of tumor cell-intrinsic PD-L1 expression in aggressive EC cells and the mechanisms regulating its expression remain unknown. Methods: PD-L1 expression in 65 EC tissues and 18 normal endometrium samples was analyzed using immunohistochemical staining. The effects of PD-L1 on aggressive EC cell growth, migration and invasion were investigated by cell functional assays. Luciferase reporter assays were used to reveal the microRNA-216a (miR-216a)-dependent mechanism modulating the expression of PD-L1. Results: Positive PD-L1 expression was identified in 84% of benign cases but only in 12% of the EC samples, and the staining levels of PD-L1 in EC tissues were significantly lower than those in the normal tissues. Higher PD-L1 expression predicts favorable survival in EC. Ectopic expression of PD-L1 in aggressive EC cells results in decreased cell proliferation and the loss of mesenchymal phenotypes. Mechanistically, PD-L1 exerts the anti-tumor effects by downregulating MCL-1 expression. We found that PD-L1 levels in aggressive EC cells are regulated by miR-216a, which directly targets PD-L1. We further identified a mechanism whereby the long non-coding RNA MEG3 represses the expression of miR-216a, thereby leading to increased PD-L1 expression and significant inhibition of cell migration and invasion. Conclusion: These results reveal an unappreciated tumor cell-intrinsic role for PD-L1 as a tumor suppressor in aggressive EC cells, and identify MEG3 and miR-216a as upstream regulators of PD-L1

Critical Roles of PIWIL1 in Human Tumors : Expression, Functions, Mechanisms, and Potential Clinical Implications

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a class of small non-coding RNA molecules that are 24?31 nucleotides in length. PiRNAs are thought to bind to PIWI proteins (PIWL1-4, a subfamily of Argonaute proteins), forming piRNA/PIWI complexes that influence gene expression at the transcriptional or post-transcriptional levels. However, it has been recently reported that the interaction of PIWI proteins with piRNAs does not encompass the entire function of PIWI proteins in human tumor cells. PIWIL1 (also called HIWI) is specifically expressed in the testis but not in other normal tissues. In tumor tissues, PIWIL1 is frequently overexpressed in tumor tissues compared with normal tissues. Its high expression is closely correlated with adverse clinicopathological features and shorter patient survival. Upregulation of PIWIL1 drastically induces tumor cell proliferation, epithelial-mesenchymal transition (EMT), invasion, cancer stem-like properties, tumorigenesis, metastasis and chemoresistance, probably via piRNA-independent mechanisms. In this article, we summarize the current existing literature on PIWIL1 in human tumors, including its expression, biological functions and regulatory mechanisms, providing new insights into how the dysregulation of PIWIL1 contributes to tumor initiation, development and chemoresistance through diverse signaling pathways. We also discuss the most recent findings on the potential clinical applications of PIWIL1 in cancer diagnosis and treatment

MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1

Epithelial-mesenchymal transition (EMT) is a key process contributing to cervical cancer (CC) metastasis, and microRNAs (miRNAs) modulate the expression of genes implicated in EMT. However, the accurate role of miR-361 in CC-associated EMT and the mechanisms underlying its function in CC remains largely unknown. The functional roles of miR-361 in CC cells were explored by a series of cell functional assays. Luciferase reporter assays were used to demonstrate the potential interaction between miR-361, HSP90, and long non-coding RNA (lncRNA) NEAT1. We detected a reduction of miR-361 expression in CC tissues compared with normal tissues, and miR-361 overexpression inhibited invasion and EMT phenotypes of CC cells by directly targeting a key EMT activator HSP90. Additionally, we detected significantly higher levels of HSP90 in CC tissues compared with normal tissues, and high expression of HSP90 predicted a poorer prognosis. We further identified NEAT1 as a significantly upregulated lncRNA in CC tissues and high expression of NEAT1 was associated with worse survival in CC patients. NEAT1 directly repressed miR-361 expression and played an oncogenic role in CC cell invasion and sphere formation. Conclusions: These results demonstrated that miR-361 directly targets HSP90 to inhibit the invasion and EMT features, and NEAT1 functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMT and sphere formation in CC cells, thus providing critical insights into the molecular pathways operating in this malignancy

MicroRNA-361: A Multifaceted Player Regulating Tumor Aggressiveness and Tumor Microenvironment Formation

MicroRNA-361-5p (miR-361) expression frequently decreases or is lost in different types of cancers, and contributes to tumor suppression by repressing the expression of its target genes implicated in tumor growth, epithelial-to-mesenchymal transition (EMT), metastasis, drug resistance, glycolysis, angiogenesis, and inflammation. Here, we review the expression pattern of miR-361 in human tumors, describe the mechanisms responsible for its dysregulation, and discuss how miR-361 modulates the aggressive properties of tumor cells and alter the tumor microenvironment by acting as a novel tumor suppressor. Furthermore, we describe its potentials as a promising diagnostic or prognostic biomarker for cancers and a promising target for therapeutic development