[Infiltrated T Cells Induce the Accumulation of Myeloid-derived Suppressor Cells in Tumor Microenvironment].

OBJECTIVE: To determine the role of infiltrated T cells in the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor microenvironment. METHODS: T-cell-deficient nude mice models were established using BALB/c mice. Growth of tumors was compared between those with and without adoptive transfer of T cells. Pathological changes of the tumors were examined with HE histological analysis. The levels of MDSCs were detected with flow cytometry (FACS). RESULTS: Tumor growth was promoted in T-cell-deficient nude mice, which was accompanied with lower levels of MDSCs compared with BALB/c mice (P < 0.05). T cell transfer increased the level of MDSCs significantly (P < 0.05). T cells depletion decreased the level of MDSCs (P < 0.05). CONCLUSION: Infiltrated T cells induce the accumulation of MDSCs in tumor microenvironment, and influence tumor growth.

PDCD6 Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis through the AKT/GSK3ß/ß-catenin Pathway.

Objective: Programmed cell death 6 (PDCD6), a Ca 2+-binding protein, has been reported to be aberrantly expressed in all kinds of tumors. The aim of this study was to explore the role and mechanism of PDCD6 in hepatocellular carcinomas (HCCs). Methods: The expression levels of PDCD6 in liver cancer patients and HCC cell lines were analyzed using bioinformatics and Western blotting. Cell viability and metastasis were determined by methylthiazol tetrazolium (MTT) and transwell assays, respectively. And Western blotting was used to test related biomarkers and molecular pathway factors in HCC cell lines. LY294002, a PI3K inhibitor inhibiting AKT, was used to suppress the AKT/GSK3ß/ß-catenin pathway to help evaluate the role of this pathway in the HCC carcinogenesis associated with PDCD6. Results: The analysis of The Cancer Genome Atlas Database suggested that high PDCD6 expression levels were relevant to liver cancer progression. This was consistent with our finding of higher levels of PDCD6 expression in HCC cell lines than in normal hepatocyte cell lines. The results of MTT, transwell migration, and Western blotting assays revealed that overexpression of PDCD6 positively regulated HCC cell proliferation, migration, and invasion. Conversely, the upregulation of PDCD6 expression in the presence of an AKT inhibitor inhibited HCC cell proliferation, migration, and invasion. In addition, PDCD6 promoted HCC cell migration and invasion by epithelial-mesenchymal transition. The mechanistic investigation proved that PDCD6 acted as a tumor promoter in HCC through the AKT/GSK3ß/ß-catenin pathway, increasing the expression of transcription factors and cellular proliferation and metastasis. Conclusion: PDCD6 has a tumor stimulative role in HCC mediated by AKT/GSK3ß/ß-catenin signaling and might be a potential target for HCC progression.

Cognitive engagement of nursing undergraduates in blended learning: A parallel mixed method study.

BACKGROUND: Blended learning is being integrated into undergraduate nursing education at all levels and from all directions. Cognitive engagement is not only an embodiment and guarantee of students' engagement into the curriculum from a cognitive level, deep engagement and high-level thinking, but also an important indicator of whether students are effectively engaged in the blended learning curricula. However, no studies have been seen to investigate the cognitive engagement of nursing undergraduates in the blended learning curricula and its influential factors. OBJECTIVES: To explore nursing undergraduates' cognitive engagement during the blended learning curricula and its influential factors. DESIGN: A convergent parallel mixed-methods was used. Data were collected between November 2021 and May 2022, inclusive. SETTINGS AND PARTICIPANTS: The study was carried out in the nursing school at a university in China. Participants including students undertaking entry to the blended learning curricula. METHODS: In the quantitative component (n = 142), participants' cognitive engagement was investigated and factors associated with it were examined using univariate analysis, correlation analysis and multiple regression analysis. During this period, personal, semi-structured interviews were conducted with a subset of these participants (n = 15) to understand participants' cognitive engagement experiences. RESULTS: The cognitive engagement of nursing undergraduates was at a moderate level and the cognitive engagement experiences were reflected in the four themes of Reconstitution, Connection, Elaboration and Retention. The influential factors of cognitive engagement were learning activities (ß = 0.226, p = 0.004), autonomy (ß = 0.158, p = 0.047), academic self-efficacy (ß = 0.311, p < 0.001, ß = 0.271, p < 0.001) and social interaction (ß = 0.358, p < 0.001). CONCLUSIONS: The cognitive engagement of nursing undergraduates in the blended learning curricula needs to be improved. To maximize promote cognitive engagement of nursing undergraduates in the blended learning curricula, educators should design diverse learning activities, engage in high quality social interactions with students, and maximize students' autonomy and self-efficacy.

The effectiveness of auricular acupressure on pain management during labor: A systematic review and meta-analysis of randomized controlled trials.

AIM: This meta-analysis aimed to systematically evaluate the effectiveness of auricular acupressure on pain management during labor. METHODS: Six English and three Chinese electronic databases were comprehensively searched from inception to 6 November 2021. The PRISMA checklist was followed. The methodological quality of the included studies was assessed with the Cochrane Collaboration Bias Risk Assessment Tool. The meta-analysis was performed using Review Manager 5.3 software. Heterogeneity between studies was calculated using I2 . RESULTS: Five studies comprising 312 participants were included. The labor pain scores of the auricular acupressure group were significantly lower than those of the usual care group at cervix dilations of 6, 8, and 10 cm, with mean differences (95% confidence intervals) of -1.05 (-1.41, -0.69), -1.44 (-2.07, -0.82), and -1.96 (-3.30, -0.61), respectively. Auricular acupressure can thus effectively improve the labor pain perception at cervix dilations of 6, 8, and 10 cm. Moreover, auricular acupressure shortened the active phase, and had the trend of shortening the second and third stages of labor. There was no evidence that auricular acupressure had an effect on the rate of cesarean section or the 1 and 5 min Apgar scores. CONCLUSION: Effective labor pain relief, better labor pain perception, and the lack of adverse effects support the use of auricular acupressure. More high-quality and rigorous trials are needed to verify our findings before we can make strong recommendations.

Phosphatidylserine released from apoptotic cells in tumor induces M2-like macrophage polarization through the PSR-STAT3-JMJD3 axis.

BACKGROUND: Understanding how the tumor microenvironment is shaped by various factors is important for the development of new therapeutic strategies. Tumor cells often undergo spontaneous apoptotic cell death in tumor microenvironment, these apoptotic cells are histologically co-localized with immunosuppressive macrophages. However, the mechanism by which tumor cell apoptosis modulates macrophage polarization is not fully understood. In this study, we aimed to explore the tumor promoting effects of apoptotic tumor cells and the signal pathways involved. METHODS: Apoptotic cells and macrophages in tumors were detected by immunohistochemical staining. Morphological analysis was performed with Giemsa staining. Lipids generated from apoptotic cells were detected by liquid chromatography-mass spectrometry. Phosphatidylserine-containing liposomes were prepared to mimic apoptotic cells. The expression of protein was determined by real-time PCR, immunohistochemistry enzyme-linked immunosorbent assay and Western blotting. Mouse malignant ascites and subcutaneous tumor models were designed for in vivo analysis. Transgenic mice with specific genes knocked out and inhibitors specific to certain proteins were used for the mechanistic studies. RESULTS: The location and the number of apoptotic cells were correlated with that of macrophages in several types of carcinomas. Phosphatidylserine, a lipid molecule generated in apoptotic cells, induced polarization and accumulation of M2-like macrophages in vivo and in vitro. Moreover, sustained administration of phosphoserine promoted tumor growth in the malignant ascites and subcutaneous tumor models. Further analyses suggested that phosphoserine induced a M2-like phenotype in macrophages, which was related to the activation of phosphoserine receptors including T-cell immunoglobin mucin 4 (TIM4) and the FAK-SRC-STAT3 signaling pathway as well as elevated the expression of the histone demethylase Jumonji domain-containing protein 3 (JMJD3). Administration of specific inhibitors of these pathways could reduce tumor progression. CONCLUSIONS: This study suggest that apoptotic cell-generated phosphoserine might be a notable signal for immunosuppressive macrophages in tumors, and the related pathways might be potential therapeutic targets for cancer therapy.

FAM225A promotes sorafenib resistance in hepatocarcinoma cells through modulating miR-130a-5p-CCNG1 interaction network.

Chemotherapy resistance is still a key hurdle in current hepatocellular carcinoma (HCC) treatment. Therefore, clarifying the molecular mechanisms contributing to this acquired resistance is urgent for the effective treatment of liver cancer. In this research, we observed that lncRNA FAM225A expression is dramatically upregulated not only in hepatocellular carcinoma tissues and cell lines but also in sorafenib-resistant HepG2/SOR cells. Moreover, FAM225A knockdown significantly weakened HepG2/SOR cells resistance to sorafenib treatment by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Similar results were obtained from the tumor xenograft model in mice. Further mechanistic researches revealed that the direct interaction between FAM225A and miR-130a-5p, while miR-130a-5p negatively modulated CCNG1 expression by targeting 3'UTR of CCNG1. MiR-130a-5p inhibition or CCNG1 overexpression could partially offset FAM225A knockdown-induced increased viability of HepG2/SOR cells in response to sorafenib challenge. Collectively, our findings provide evidence that FAM225A/miR-130a-5p/CCNG1 interaction network regulates the resistance of HCC cells to sorafenib treatment and could supply a possible strategy for restoring sorafenib sensitivity in HCC therapy.

A folate receptor-targeted lipoplex delivering interleukin-15 gene for colon cancer immunotherapy.

Interleukin-15 has been implicated as a promising cytokine for cancer immunotherapy, while folate receptor α (FRα) has been shown to be a potentially useful target for colon cancer therapy. Herein, we developed F-PLP/pIL15, a FRα-targeted lipoplex loading recombinant interleukin-15 plasmid (pIL15) and studied its antitumor effects in vivo using a CT26 colon cancer mouse model. Compared with control (normal saline) treatment, F-PLP/pIL15 significantly suppressed tumor growth in regard to tumor weight (P < 0.001) and reduced tumor nodule formation (P < 0.001). Moreover, when compared to other lipoplex-treated mice, F-PLP/pIL15-treated mice showed higher levels of IL15 secreted in the serum (P < 0.001) and ascites (P < 0.01). These results suggested that the targeted delivery of IL15 gene might be associated with its in vivo antitumor effects, which include inducing tumor cell apoptosis, inhibiting tumor proliferation and promoting the activation of immune cells such as T cells and natural killer cells. Furthermore, hematoxylin and eosin staining of vital organs following F-PLP/pIL15 treatment showed no detectable toxicity, thus indicating that intraperitoneal administration may be a viable route of delivery. Overall, these results suggest that F-PLP/pIL15 may serve as a potential targeting preparation for colon cancer therapy.

Ovarian cancer treatment with a tumor-targeting and gene expression-controllable lipoplex.

Overexpression of folate receptor alpha (FRα) and high telomerase activity are considered to be the characteristics of ovarian cancers. In this study, we developed FRα-targeted lipoplexes loaded with an hTERT promoter-regulated plasmid that encodes a matrix protein (MP) of the vesicular stomatitis virus, F-LP/pMP(2.5), for application in ovarian cancer treatment. We first characterized the pharmaceutical properties of F-LP/pMP(2.5). The efficient expression of the MP-driven hTERT promoter in SKOV-3 cells was determined after an in-vitro transfection assay, which was significantly increased compared with a non-modified LP/pMP(2.5) group. F-LP/pMP(2.5) treatment significantly inhibited the growth of tumors and extended the survival of mice in a SKOV-3 tumor model compared with other groups. Such an anti-tumor effect was due to the increased expression of MP in tumor tissue, which led to the induction of tumor cell apoptosis, inhibition of tumor cell proliferation and suppression of tumor angiogenesis. Furthermore, a preliminary safety evaluation demonstrated a good safety profile of F-LP/pMP(2.5) as a gene therapy agent. Therefore, FRα-targeted lipoplexes with therapeutic gene expression regulated by an hTERT promoter might be a promising gene therapy agent and a potential translational candidate for the clinical treatment of ovarian cancer.

Treatment of dextran sodium sulfate-induced experimental colitis by adoptive transfer of peritoneal cells.

The adoptive transfer of the natural regulatory B cells and macrophages should be a useful treatment for inflammation and autoimmune disease. However, it is usually difficult to isolate these cells from the tissues and expand them. Here, we investigated the feasibility of adoptively transferring peritoneal cells (PCs) as a treatment for DSS-induced colitis. We found that peritoneal cavity can provide an easily accessible site for harvesting enough number of PCs, namely, two-dose PCs for the treatment from a mouse in one operation. Adoptive therapy of these cells from healthy mice or those with disease is effectively in reducing the disease activity score. The natural B cells and macrophages of the infused PCs can selectively migrate to lesion sites and regulate the expression of Stat3, NF-κB, Smad3 and Smad7. Additionally, PCs exert dual activity of IL-10 and TGF-ß secreted spontaneously by both peritoneal B cells and macrophages, which in turn enhance the induction of regulatory B cells and Macrophages in microenvironment of inflammation. Moreover, PCs can re-establish immunological tolerance in the OVA-immunized mice. Thus, our findings provide a new strategy for colitis therapy and could be of importance in additional exploration of other inflammation and autoimmune diseases therapy.

Gene therapy with beta-defensin 2 induces antitumor immunity and enhances local antitumor effects.

Beta-defensins, small antimicrobial peptides, are involved in host immune responses to tumors. In this study, we used beta-defensin 2 (BD2) to explore the possible role of beta-defensins in cancer gene therapy. A recombinant plasmid expressing a secretable form of BD2 was constructed. The biological activities of BD2 in immature dendritic cells (iDCs) were tested in vitro and in vivo. The antitumor effects were investigated in three established tumor models. The secreted BD2 was detected and exhibited chemotactic activity in iDCs both in vitro and in vivo. Recruitment and activation of iDCs in tumor niches resulted in significant tumor growth inhibition. Adoptive transfer of splenocytes and depletion of immune cell subsets revealed that CD8(+) T lymphocyte responses mediated the increased tumor inhibition. Furthermore, we also found that chemotactic and maturation-inducing activities in iDCs in tumor milieu contributed to enhanced local antitumor effects. Our study indicates that gene therapy with BD2 can mediate specific antitumor immunity and augment local antitumor effects. Our study also suggested that beta-defensins may merit further exploration for cancer immunotherapy as promising immunogenes.

Prognostic role of microRNA-21 in non-small cell lung cancer: a meta-analysis.

INTRODUCTION: Many studies have reported that microRNA-21 (miR-21) mihght predict the survival outcome in non-small cell lung cancers (NSCLCs) but the opposite opinion has also been expressed. The aim of this study was to summarize the evidence for a prognostic role of miR-21. MATERIALS AND METHODS: All the eligible studies was searched by Medline and EMBASE and patients' clinical characteristics and survival outcome were extracted. Then a meta-analysis was performed to clarify the prognostic role of the miR-21 expression in different subgroups. RESULTS: A total of 8 eligible articles were yielded covering survival outcomes or clinical characteristics. The combined hazard ratio (HR) and 95% confidence interval (95% CI) for overall survival (OS) was 2.19 [0.76, 6.30], while the combined HR (95% CI) of Asian group for OS had a significant result, 5.49 [2.46, 12.27]. The combined HR (95% CI) for recurrence free survival or disease free survival (RFS/DFS) was 2.31 [1.52, 3.49]. Odds ratios (ORs) showed that the miR-21 expression was associated with lymph node status and histological type. CONCLUSION: miR-21 expression could predict the prognostic outcome of NSCLC in Asians, despite some deficiencies in the study data.