CD4+CCR8+ Tregs in ovarian cancer: a potential effector Tregs for immune regulation.

BACKGROUND: Tregs are key drivers of immunosuppression in solid tumors. As an important chemokine receptor on Tregs, the regulatory effect of CCR8 on tumor immunity has received more and more attention. However, the current research on CCR8 in the immune microenvironment of ovarian cancer has not been clear. METHODS: Bioinformatics analysis was used to compare the transcriptome differences between CD4+ T cells in the peripheral circulation and infiltrated in ovarian tumor tissues. RT-PCR was used to detect the expression levels of chemokine receptor-related differential genes on CD4+ T cells in peripheral blood and ovarian tumor tissues. Multiparameter flow cytometry was used to detect the proportion and phenotypic characteristics of CD4+CCR8+ Tregs and CD4+CCR8- Tregs in different sample types. The expression level of CCR8 ligands was detected at multiple levels. To explore the important role of CCR8-CCL1 and CCR8-CCL18 axis in the migration and invasion of CD4+CCR8+ Tregs into ovarian tumor tissues by establishing a chemotaxis system in vitro. RESULTS: In this study, significantly different gene expression profiles were found between peripheral circulating CD4+ T cells and infiltrating CD4+ T cells in ovarian tumor tissues, in which chemokine-chemokine receptor signaling pathway was significantly enriched in all three groups of differential genes. The expression level of CCR8 in infiltrating CD4+ T cells of ovarian cancer tissue was significantly higher than that in peripheral blood of healthy controls and ovarian cancer patients, and high expression of CCR8 was significantly correlated with advanced tumor stage and poor differentiation. CD4+CCR8+ Tregs are the main type of infiltrating CD4+ Tregs in ovarian tumor tissues, which have stronger immunosuppressive phenotypes, secrete more inhibitory cytokines and have stronger proliferation ability. The ligands CCL1 and CCL18 corresponding to CCR8 were significantly overexpressed in ovarian tumor tissues, and the CCR8-CCL1 and CCR8-CCL18 axis played a key role in the migration and infiltration of CD4+CCR8+ Tregs into ovarian tumor tissues. CONCLUSIONS: The results of this study may help to understand the phenotypic characteristics and recruitment process of Tregs in the tumor, and provide new ideas for improving the immunosuppressive status of the ovarian cancer microenvironment.

Prognostic Factors and a Predictive Nomogram of Cancer-Specific Survival of Epithelial Ovarian Cancer Patients with Pelvic Exenteration Treatment.

Objective: The aim of this study was to explore prognostic factors, develop and internally validate a prognostic nomogram model, and predict the cancer-specific survival (CCS) of epithelial ovarian cancer (EOC) patients with pelvic exenteration (PE) treatment. Methods: A total of 454 EOC patients from the Surveillance, Epidemiology, and End Results (SEER) database were collected according to the inclusion criteria and randomly divided into the training (n = 317) and validation (n = 137) cohorts. Prognostic factors of EOC patients with PE treatment were explored by univariate and multivariate stepwise Cox regression analyses. A predictive nomogram was constructed based on selected risk factors. The predictive power of the constructed nomogram was assessed by the time-dependent receiver operating characteristic (ROC) curve. Kaplan-Meier (KM) curve stratified by patients' nomoscore was also plotted to assess the risk stratification of the established nomogram. In internal validation, the C index, calibration curve, and decision curve analysis (DCA) were employed to assess the discrimination, calibration, and clinical utility of the models, respectively. Results: In the training cohort, age, histological type, Federation of Gynecology and Obstetrics (FIGO) stage, number of examined lymph nodes, and number of positive lymph nodes were found to be independent prognostic factors of postoperative CSS. A practical nomogram model of EOC patients with PE treatment was constructed based on these selected risk factors. Time-dependent ROC curves and KM curves showed the superior predictive capability and excellent clinical stratification of the nomogram in both training and validation cohorts. In the internal validation, the C index, calibration plots, and DCA in the training and validation cohorts confirmed that the nomogram presents a high level of prediction accuracy and clinical applicability. Conclusion: Our nomogram exhibited satisfactory survival prediction and prognostic discrimination. It is a user-friendly tool with high clinical pragmatism for estimating prognosis and guiding the long-term management of EOC patients with PE treatment.

Microarray bioinformatics in cancer- a review.

Bioinformatics is one of the newest fields of biological research, and should be viewed broadly as the use of mathematical, statistical, and computational methods for the processing and analysis of biological data. Over the last decade, the rapid growth of information and technology in both "genomics" and "omics" eras has been overwhelming for the laboratory scientists to process experimental results. Traditional gene-by-gene approaches in research are insufficient to meet the growth and demand of biological research in understanding the true biology. The massive amounts of data generated by new technologies as genomic sequencing and microarray chips make the management of data and the integration of multiple platforms of high importance; this is then followed by data analysis and interpretation to achieve biological understanding and therapeutic progress. Global views of analyzing the magnitude of information are necessary and traditional approaches to lab work have steadily been changing towards a bioinformatics era. Research is moving from being restricted to a laboratory environment to working with computers in a "virtual lab" environment. The present review article shall put light on this emerging field and its applicability towards cancer research.

Hypoxia Affects Autophagy in Human Umbilical Vein Endothelial Cells via the IRE1 Unfolded Protein Response.

OBJECTIVE: The purpose of this study was to investigate the role of the unfolded protein response, specifically the inositol-requiring enzyme 1 (IRE1) signaling pathway, in hypoxia-induced autophagy in human umbilical venous endothelial cells (HUVECs). METHODS: The expression of IRE1 and autophagy relative protein in HUVECs with hypoxia was explored by Western blotting, qRT-PCR and confocal microscopy. Further, we evaluated the biological effects of HUVECs by tube formation assay and wound healing assay in vitro. Finally, we examined the function of IRE1 in local blood vessels through animal models. RESULTS: Hypoxia activated the IRE1 signaling pathway and induced autophagy in a time-dependent manner in HUVECs and further influenced the biological effects of HUVECs. Intraperitoneal injection of IRE1 inhibitors inhibited local vascular autophagy levels and lipid accumulation in model animals. CONCLUSION: Hypoxia can induce autophagy and activate the IRE1 signaling pathway in HUVECs and the IRE1 signaling pathway is involved in autophagy in hypoxic conditions.

Identification of HMOX1 as a Critical Ferroptosis-Related Gene in Atherosclerosis.

Ferroptosis is a novel form of programmed iron-dependent cell death. The ferroptosis-related genes (FRGs) have been recognized as biomarkers for cancers. Increasing evidence has indicated that ferroptosis is involved in the process of atherosclerosis. However, the potential FRGs used for the diagnosis, prognosis and therapy for atherosclerosis are still unclear. We aimed to identify the ferroptosis-related differentially expressed genes (DEGs) of atherosclerosis. We downloaded the mRNA-sequencing data of patients with atherosclerosis from the Gene Expression Omnibus (GEO) database. HMOX1 was identified as an essential ferroptosis-related DEG by bioinformatic analysis of the GSE28829 and GSE43292 datasets. The pro-ferroptotic effect of HMOX1 was validated through cell experiments. Then we conducted a single-gene analysis of HMOX1 and found that high-expression of HMOX1 in atherosclerotic plaques was accompanied by matrix metalloproteinases (MMPs) producing and M0 macrophages infiltration. Taken together, our present study suggested HMOX1 as a potential diagnostic biomarker for atherosclerosis and provided more evidence about the vital role of ferroptosis in atherosclerosis progression.

miR-145-5p affects autophagy by targeting CaMKIIδ in atherosclerosis.

BACKGROUND: Atherosclerosis (AS) is a chronic progressive inflammatory disease involving many cells. miR-145-5p mediates the biological phenotypes of human aortic vascular smooth muscle cells (HAVSMCs) and influences the progression of AS, but the potential mechanism needs further study. METHODS: Total RNA was extracted from patient plasma and arteries to determine the expression of miR-145-5p. The CaMKIIδ pathway and genes were predicted as the target of miR-145-5p by bioinformatics approaches. The interaction between miR-145-5p and CaMKIIδ was confirmed by RT-qPCR and Dual Luciferase Reporter Assay System. Western blot analysis, immunofluorescence staining, transmission electron microscopy (TEM) and protein tracing on HAVSMCs transduced with mCherry-GFP-LC3 lentiviral vectors to determine the mechanism by which miR-145-5p affects the atherosclerotic disease process. RESULTS: The expression of miR-145-5p was downregulated in blood and arteries specimens of patients with coronary stenosis. Correspondingly, CaMKIIδ was upregulated and miR-145-5p was downregulated in hypoxic HAVSMCs. CaMKIIδ was predicted and confirmed as a downstream target of miR-145-5p. In addition, CaMKIIδ induced the upregulation of autophagy-related proteins by activating the AMPK/mTOR/ULK1 signalling pathway. Moreover, we confirmed that miR-145-5p inhibits CaMKIIδ expression by binding to a specific sequence in the CaMKIIδ 3' UTR and affects autophagy. Crucially, CaMKIIδ was promoted by the downregulation of miR-145-5p and then activating autophagy in HAVSMCs through the AMPK/mTOR/ULK1 signalling pathway to affect the AS progress. CONCLUSIONS: miR-145-5p regulates CaMKIIδ, leading to altered autophagy in HAVSMCs. This alteration plays an important role in AS progression.

Cellular immunotherapy of cancer: an overview and future directions.

The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor-associated immune suppression.

Epidemiological aspects of heart diseases.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Coronary heart disease (CHD) is the main cause of mortality in heart patients following stroke, rheumatic heart disease and myocardial infarctions. Approximately 80% of individuals succumb to CVDs, due to poor living conditions in low and middle income families and malnutrition. Infectious diseases, human immunodeficiency, tuberculosis, malaria, high blood pressure or hypertension, obesity and overweight, and nutritional disorders including smoking, excessive alcohol consumption, high salt and sugar intake, as well as other factors are responsible for CVDs and CHDs in young as well as elderly individuals. The focus of the present review are recent epidemiological aspects of CVD and CHD as well as the usefulness of a Mediterranean diet for heart patients and the prevention of heart diseases.

Effects of the short-term application of pantoprazole combined with aspirin and clopidogrel in the treatment of acute STEMI.

The aim of the present study was to determine the effects of the short-term application of pantoprazole on the co-treatment of acute ST-segment elevation myocardial infarction (STEMI) with aspirin and clopidogrel. A total of 207 acute patients showing primary symptoms of STEMI, who received successful emergent percutaneous coronary intervention treatment during hospitalization were randomly divided into two groups. In the test group proton pump inhibitors (PPIs), the patients were treated with a combination of aspirin and clopidogrel and pantoprazole, while those in the control group were treated only with aspirin and clopidogrel. Gastrointestinal bleeding events and major adverse cardiac events (MACEs) were observed in the two groups. Gastrointestinal bleeding events of the two groups mostly occurred within the first week of hospitalization, although the incidence in the PPIs group was significantly higher than that in the control group (p<0.05). However, no significant difference was observed for the incidence of MACEs between the two groups (p>0.05). In conclusion, the results of the present study have shown that the short-term application of pantoprazole combined with aspirin and clopidogrel does not increase the incidence of MACEs in patients with acute STEMI, reduces the risk of gastrointestinal bleeding, and is thus worth promoting clinically, particularly for high-risk groups.

Process Reengineering for Quality Improvement in ICU Based on Taylor's Management Theory.

Using methods including questionnaire-based surveys and control analysis, we analyzed the improvements in the efficiency of ICU rescue, service quality, and patients' satisfaction, in Xuzhou Central Hospital after the implementation of fine management, with an attempt to further introduce the concept of fine management and implement the brand construction. Originating in Taylor's "Theory of Scientific Management" (1982), fine management uses programmed, standardized, digitalized, and informational approaches to ensure each unit of an organization is running with great accuracy, high efficiency, strong coordination, and at sustained duration (Wang et al., Fine Management, 2007). The nature of fine management is a process that breaks up the strategy and goal, and executes it. Strategic planning takes place at every part of the process. Fine management demonstrates that everybody has a role to play in the management process, every area must be examined through the management process, and everything has to be managed (Zhang et al., The Experience of Hospital Nursing Precise Management, 2006). In other words, this kind of management theory demands all people to be involved in the entire process (Liu and Chen, Med Inf, 2007). As public hospital reform is becoming more widespread, it becomes imperative to "build a unified and efficient public hospital management system" and "improve the quality of medical services" (Guidelines on the Pilot Reform of Public Hospitals, 2010). The execution of fine management is of importance in optimizing the medical process, improving medical services and building a prestigious hospital brand.

Improving the Management of Appointment Registration and Exploring an Innovative Medical Service.

Improving levels of healthcare service to enhance patient care are not only what patients' demands of medical staff, but also what the medical staff demands of the hospital managers. The practical experiences of Xuzhou Central Hospital have proved that a carefully designed hospital culture helps to mobilize the enthusiasm of medical staff, improve patient satisfaction, and lead to an increase in the pace of a hospital's integrated development.

Epidemiological Perspectives of Diabetes.

The global statistics of diabetes mellitus in year 2013 indicated, about 382 million people had this disease worldwide, with type 2 diabetes making up about 90 % of the cases. This is equal to 8.3 % of the adult population with equal rates in both women and men. In year 2012 and 2013 diabetes resulted in mortality of 1.5-5.1 million people per year, making it the 8th leading cause of death in the world. It is predicted that by year 2035 about 592 million people will die of diabetes. The economic cost of diabetes seems to have increased worldwide. An average age of onset of diabetes is 42.5 years and could be due to consumption of high sugar and high-calorie diet, low physical activity, genetic susceptibility, and lifestyle. Approximately 8 % children and about 26 % young adults have diabetes mellitus in the world. The results of epidemiological study of type 1 diabetes mellitus (T1D) are presented by demographic, geographic, biologic, cultural, and other factors in human populations. The prevalence of T1D has been increased by 2-5 % worldwide and its prevalence is approximately one in 300 in US by 18 years of age. The epidemiological studies are important to study the role, causes, clinical care, prevention, and treatment of type1 diabetes in pregnant women and their children before and after birth. In this article, causes, diagnosis, symptoms, treatment and medications, and epidemiology of diabetes will be described.

Breast Cancer: Epidemiology and Etiology.

Breast cancer, the most frequently occurring cancer in women, is a major public health problem, with 1,384,155 estimated new cases worldwide with nearly 459,000 related deaths. Breast cancer is highly heterogeneous in its pathological characteristics, some cases showing slow growth with excellent prognosis, while others being aggressive tumors. Current predictions and statistics suggest that both worldwide incidence of breast cancer and related mortality are on the rise. According to 2012 GLOBOCAN statistics, nearly 1.7 million women were diagnosed with breast cancer with 522,000 related deaths-an increase in breast cancer incidence and related mortality by nearly 18 % from 2008. According to American Cancer Society, one in eight women in the United States will develop breast cancer in her lifetime. It has been predicted that the worldwide incidence of female breast cancer will reach approximately 3.2 million new cases per year by 2050. These numbers reflect the magnitude of breast cancer incidence, its effect on society worldwide and the need for urgency for preventive and treatment measures. While technological advances in medical sciences and health care have made it possible to detect the disease early and to start the treatment early on to prevent the progress of the disease into a metastatic state, there are several unanswered questions with regard to the molecular mechanisms that underlie the aggressiveness of certain forms of this disease. Epidemiological studies suggest that addressing socio economical issues is utmost important, so that all women have equal access to medical care from screening to advanced treatment, and only such decisive action can help reduce the worldwide burden of breast cancer.