Showing papers in "Disease Markers in 2019"

Combined Diagnostic Efficacy of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Mean Platelet Volume (MPV) as Biomarkers of Systemic Inflammation in the Diagnosis of Colorectal Cancer

Abstract: Background Systemic inflammation in colorectal cancer (CRC) may be reflected by neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV). This study was designed to investigate the efficiency of preoperative NLR, PLR, and MVP as a tool for the assessment of tumor characteristics in newly diagnosed patients with CRC. Patients and methods For 300 patients and 300 healthy volunteers, complete blood counts with automated differential counts were performed. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count; PLR was calculated by dividing the absolute platelet count by the absolute lymphocyte count. The diagnostic performance of NLR, PLR, and MVP was estimated by ROC curve. Results ROC curve analysis showed high diagnostic efficacy of NLR and PLR in CRC patients with cut-off values of 2.15 (AUC = 0.790, 95% CI 0.736-0.884, Se = 74.1%, and Sp = 73%) and 123 (AUC = 0.846, 95% CI 0.801-0.891, Se = 73.5%, and Sp = 80%) compared to healthy controls, respectively. The diagnostic efficacy of three combined markers was superior compared with individual markers (AUC = 0.904, 95% CI 0.812-0.989, Se = 96%, and Sp = 70%). Conclusion NRL, PLR, and MPV may be useful markers in diagnostic and early recognition of different stages of CRC; additionally combined all together have stronger diagnostic efficacy.

The Triglyceride-Glucose Index Predicts Coronary Artery Disease Severity and Cardiovascular Outcomes in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome.

Abstract: Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is the leading cause of morbidity and mortality from cardiovascular disease worldwide. Several recent studies have shown the relationship between the triglyceride-glucose (TyG) index and vascular disease; however, the role of the TyG index in NSTE-ACS has not been extensively assessed. Thus, we aimed to investigate the association of the TyG index with cardiovascular risk factors and outcomes in NSTE-ACS. Overall, 438 patients with NSTE-ACS were enrolled to examine the association of the TyG index with the SYNTAX score and major adverse cardiovascular events (MACEs). The TyG index was calculated as ln (fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2). The severity of coronary lesions was quantified by the SYNTAX score. MACEs included cardiac death, nonfatal myocardial infarction, target vessel revascularization, congestive heart failure, and nonfatal stroke. All the patients underwent a 12-month follow-up for MACEs after admission. Multivariate regression analysis identified metabolic risk factors as independent parameters correlated with the TyG index. The prevalence of glucose metabolism disorder, metabolic syndrome, and MACEs increased with increasing TyG index. The TyG index showed a strong diagnostic performance for cardiovascular risk factors and was independently associated with the SYNTAX score (OR 6.055, 95% CI 2.915-12.579, P < 0.001). The risk of MACEs (12.8% and 22.8% for the low TyG index and high TyG index groups, respectively; adjusted HR = 1.791, 95% CI 1.045-3.068, P = 0.034) significantly increased in the high TyG index group as compared with the low TyG index group. The multivariate Cox regression analysis further revealed that the TyG index was an independent predictor of MACEs (HR 1.878, 95% CI 1.130-3.121, P = 0.015). In conclusion, the TyG index might be an independent predictor of coronary artery disease severity and cardiovascular outcomes in NSTE-ACS.

Efficiency of CAR-T Therapy for Treatment of Solid Tumor in Clinical Trials: A Meta-Analysis

Abstract: Background. Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success among hematologic tumors, but its role in treating solid tumors is still unclear. Methods. A comprehensive search of electronic databases up to June 1, 2018, was carried out by two independent reviewers. We included studies which focused on the association between CAR-T cell therapy and patient response rate and survival time in solid tumors. Results. 22 studies with 262 patients were included in our meta-analysis. The overall pooled response rate of CAR-T cell therapy was 9% (95% confidence interval (CI): 4-16%). Subgroup analysis (analyses) demonstrated that CAR-T therapy could perform its best therapeutic effect on neuroblastoma, while barely works among gastrointestinal malignancies. Moreover, the treatment efficacy was not significantly impacted by different treatment strategies (lymphodepletion before T cell infusion, transfection method, cell culture duration, persistence of CAR-T cells, transfection efficacy, total cell dose, and administration of IL-2). Only T cell culture duration was associated with better clinical prognosis. Conclusions. Although CAR-T cell therapy did not have satisfactory responses in solid tumors, researchers were still holding an optimistic attitude towards its future efficacy with more modifications of its structure.

Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism.

Abstract: The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn’s disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.

Clinical Significance of Preoperative Serum CEA, CA125, and CA19-9 Levels in Predicting the Resectability of Cholangiocarcinoma.

Abstract: To explore the clinical significance of preoperative serum CEA, CA125, and CA19-9 levels in predicting the resectability of cholangiocarcinoma. Patients with cholangiocarcinoma diagnosed by radiologic examination and admitted to the Second Affiliated Hospital of Harbin Medical University from September 1, 2011, to November 30, 2017, were retrospectively included. The relationship between the preoperative serum CEA, CA125, and CA19-9 levels and the resectability of cholangiocarcinoma was analyzed by receiver operating characteristic (ROC) curve, as well as the best cut-off point. A total of 112 met the inclusion criteria. In 50 patients with radical surgeries, the levels of preoperative serums CEA, CA125, and CA19-9 were 5.0 ± 13.9 ng/mL, 15.3 ± 11.8 U/mL, and 257.5 ± 325.6 U/mL, respectively, which were lower than those in patients with unresectable tumor. Based on the ROC curve, the ideal CA19-9 cut-off value was determined to be 1064.1 U/mL in prediction of resectability, with a sensitivity of 53.2%, a specificity of 94.0%, and the area under the ROC curve of 0.73 ( ). The cut-off value of CA125 was 17.8 U/mL with a sensitivity of 72.6%, a specificity of 78.0%, and the area under the ROC curve of 0.81 ( ). The cut-off value of CEA was 2.6 ng/mL with a sensitivity of 79.0%, a specificity of 48.0%, and the area under the ROC curve of 0.66 ( ). In addition to this, we found that using the combination of three tumor markers could improve the value in predicting resectability of cholangiocarcinoma. In summary, this study suggested that the preoperative serum CEA, CA125, and CA19-9 levels can help predict the resectability of cholangiocarcinoma.

The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis.

Abstract: CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.

Molecular Biomarkers Related to Oral Carcinoma: Clinical Trial Outcome Evaluation in a Literature Review.

Abstract: Backgrounds. The objective of the present research was to systematically revise the international literature about the genetic biomarkers related to oral cancer (OC) evaluating the recent findings in clinical studies. Methods. A comprehensive review of the current literature was conducted according to the PRISMA guidelines by accessing the NCBI PubMed database. The authors conducted the search of articles in the English language published from 2008 to 2018. The present systematic review included only papers with significant results about correlation between wound healing, genetic alteration, and OC. Prognostic capacity of genetic markers was not evaluated in vivo. Results. The first analysis with filters recorded about 1884 published papers. Beyond reading and consideration of suitability, only 20 and then 8 papers, with case report exclusion, were recorded for the revision. Conclusion. All the researches recorded the proteomic and genetic alterations in OC human biopsy cells. The gene modification level in the different studies, compared with samples of healthy tissues, has always been statistically significant, but it is not possible to associate publications with each other because each job is based on the measurement of different biomarkers and gene targets. Further investigations should be required in order to state scientific evidence about a clear advantage of using these biomarkers for diagnostic purpose.

Biomarkers for Alzheimer's Disease in Saliva: A Systematic Review.

Abstract: Background. The histopathological changes of Alzheimer’s disease (AD) are detectable decades prior to its clinical expression. However, there is a need for an early, inexpensive, noninvasive diagnostic biomarker to detect specific Alzheimer pathology. Recently developed neuroimaging biomarkers show promising results, but these methods are expensive and cause radiation. Furthermore, the analysis of cerebrospinal fluid (CSF) biomarkers requires an invasive lumbar puncture. Saliva is an easily obtained body fluid, and a stable saliva biomarker would therefore be a promising candidate for a future method for diagnosing AD. The purpose of this systematic review was to investigate studies of biomarkers in saliva samples for the diagnosis of AD. Methods. The included articles were identified through a literature search in PubMed and Google Scholar for all articles until November 1st, 2018, and furthermore, all reference lists of included articles were reviewed by hand. We included articles written in English investigating saliva from patients with AD and a control group. Results. A total of 65 studies were identified, whereof 16 studies met the inclusion criteria and were included in the systematic review. A plethora of different biomarkers were investigated, and ten out of the sixteen studies showed a statistical significance in biomarkers between patients with AD and healthy, elderly controls, among these biomarkers for specific AD pathology (amyloid beta 1-42 (Aβ42) and tau). Conclusion. Aβ42 and tau seem to be worthy candidates for future salivary biomarkers for AD, but other biomarkers such as lactoferrin and selected metabolites also have potential. More studies must be carried out with larger sample sizes and a standardization of the sampling and processing method. Factors such as diurnal variation, AD patients’ decreased ability of oral self-care, and salivary flowrates must be taken into consideration.

Role of Circular RNAs in Preeclampsia

Abstract: Circular RNAs (circRNAs) are noncoding RNAs characterized by circular covalently closed structures, which are generated by back-splicing. circRNA is more stable and conserved than linear RNA and exists in various organisms. Preeclampsia (PE), a common hypertensive disorder of pregnancy, has a profound impact on maternal and neonatal mortality and morbidity. Recent studies demonstrated that circRNAs were differentially expressed in PE maternal-fetal interface compared with those in the control and might mediate pathological processes in pregnancy complications. However, the mechanisms of action of circRNAs in PE are still unclear. Here, we provide a comprehensive review on the current state of knowledge on circRNAs associated with PE. We summarize the known expression profiles of circRNAs and discuss their potential application as biomarkers of PE. The possible mechanisms underlying circRNA dysregulation in the etiology of PE are also explored.

Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer.

Abstract: TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.

A New Approach for the Diagnosis of Systemic and Oral Diseases Based on Salivary Biomolecules.

Abstract: Early diagnosis represents the target of contemporary medicine and has an important role in the prognosis and further treatment. Saliva is a biofluid that generated a high interest among researchers due to its multiple advantages over other body fluids. The multitude of components that can act as biomarkers influenced the existing technologies to develop protocols that could allow saliva to become the new noninvasive diagnostic method. Saliva as a diagnostic tool can bring substantial addition to the diagnostic armamentarium, providing important information about oral and general health. The diagnostic applications of saliva extended and had a rapid evolution due to the advancement in salivaomics. The present review summarizes the latest researches in saliva-related studies and explores the information and correlations that saliva can offer regarding the systemic and oral diseases, highlighting its great potential of diagnosis. It is expected that in the future specific guidelines and results regarding the salivary diagnostics are to be available, together with high-sensitivity and specificity tests for multiple systemic and oral diseases.

Prognostic Biomarkers of Sarcoidosis: A Comparative Study of Serum Chitotriosidase, ACE, Lysozyme, and KL-6

Abstract: Purpose. Sarcoidosis is a systemic granulomatous disease with unknown etiology. Many clinical presentations have been reported, and acute disease needs to be distinguished from subacute and chronic disease. The unpredictable clinical course of the disease prompted us to evaluate the clinical utility of biomarker serum detection in sarcoidosis follow-up. Methods. Serum concentrations of chitotriosidase, ACE, KL-6, and lysozyme were analyzed by different methods in a population of 74 sarcoidosis patients (46 on steroid therapy at sampling) regularly monitored at Siena Sarcoidosis Regional Referral Centre and in a group of controls with the aim of comparing their contribution to clinical management of sarcoidosis patients. Results. KL-6 concentrations were significantly elevated in sarcoidosis patients with lung fibrosis and were significantly correlated with DLco and CPI score, while chitotriosidase was significantly higher in patients with extrapulmonary localizations. With a cut-off value of 303.5 IU/ml, KL-6 showed the best sensitivity (78%), while chitotriosidase reported the best specificity (85%) among the biomarkers. Conclusions. KL-6 is a reliable biomarker of fibrotic lung involvement in sarcoidosis patients. Among biomarkers, KL-6 showed the best sensitivity and serum chitotriosidase the best specificity, even in patients on chronic steroid therapy, and seemed to correlate with extrapulmonary localizations.

General Decrease of Taste Sensitivity Is Related to Increase of BMI: A Simple Method to Monitor Eating Behavior

Abstract: Background and Objectives. The present study was conducted to evaluate the relationship between taste identification ability and body mass index (BMI) by studying the response to the administration of different taste stimuli to both sides of the tongue in three different groups of subjects. Subjects and Methods. Thirty healthy normal-weight volunteers, 19 healthy overweight subjects, and 22 obese subjects were enrolled. For each subject, the lateralization Oldfield score, body weight, height, and blood pressure were determined. The taste test is based on filter paper strips soaked with 4 taste stimuli presented at different concentrations to evoke 4 basic taste qualities (salty, sour, sweet, and bitter); pure rapeseed oil and water were also administered to evoke fat and neutral taste qualities. The stimuli were applied to each side of the protruded tongue. Subjects were asked to identify the taste from a list of eight descriptions according to a multiple choice paradigm. Results. The results showed a general lowering of taste sensitivity with the increase of BMI, except for the taste of fat with rapeseed oil as the stimulus. Other variables affecting taste sensitivity are age (negative association), gender (women generally show higher sensitivity), and taste stimuli concentration (positive association). Conclusions. Our findings could provide important insights into how new therapies could be designed for weight loss and long-term weight maintenance and how diets could be planned combining the correct caloric and nutritional supply with individual taste preferences.

Metabolomics Analysis in Serum from Patients with Colorectal Polyp and Colorectal Cancer by 1H-NMR Spectrometry.

Abstract: Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Colorectal adenomatous polyps are at high risk for the development of CRC. In this report, we described the metabolic changes in the sera from patients with colorectal polyps and CRC by using the NMR-based metabolomics. 110 serum samples were collected from patients and healthy controls, including 40 CRC patients, 32 colorectal polyp patients, and 38 healthy controls. The metabolic profiles and differential metabolites of sera were analyzed by multivariate statistical analysis (MSA), including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) methods. A total of 23 differential metabolites were identified from MSA. According to the pathway analysis and multivariate ROC curve-based exploratory analysis by using the relative concentrations of differential metabolites, we found abnormal metabolic pathways and potential biomarkers involved with the colorectal polyp and CRC. The results showed that the pyruvate metabolism and glycerolipid metabolism were activated in colorectal polyps. And the glycolysis and glycine, serine, and threonine metabolism were activated in CRC. The changed metabolism may promote cellular proliferation. In addition, we found that the rates of acetate/glycerol and lactate/citrate could be the potential biomarkers in colorectal polyp and CRC, respectively. The application of 1H-NMR metabolomics analysis in serum has interesting potential as a new detection and diagnostic tool for early diagnosis of CRC.

Geriatric Nutritional Risk Index Predicts Adverse Outcomes in Human Malignancy: A Meta-Analysis.

Abstract: Background Geriatric Nutritional Risk Index (GNRI) has been widely used to assess the nutritional status in a variety of human pathological conditions, but the prognostic value of the GNRI in malignancies has not been evinced. Methods Relevant studies updated on Jul 27, 2019, were retrieved in available databases, including PubMed, Web of Science, Cochrane library, Chinese CNKI, and Chinese Wan-fang. Hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled by using STATA 14. Results A total of 15 studies involving 8,046 subjects were included in this meta-analysis. Meta-analysis results evinced that low GNRI was associated with poor OS (HR = 1.95, 95% CI: 1.49-2.56, p ≤ 0.001), poor CSS (HR = 1.81, 95% CI: 1.49-2.19, p ≤ 0.001), poor DFS (HR = 1.67, 95% CI: 1.28-2.17, p ≤ 0.001), and poor PFS (HR = 1.68, 95% CI: 1.28-2.21, p ≤ 0.001), and the correlation of GNRI with OS was not changed when stratified by possible confounding factors, suggesting that malignancy patients with low GNRI would suffer from reduced survival rate and increased recurrence rate. Moreover, low GNRI was also associated with postoperative complications in malignancies. Conclusions In summary, GNRI is associated poor prognosis in human malignancies, and GNRI should be used as a predictive indicator of adverse outcomes during malignancy treatment.

TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration

Abstract: Increasing evidence suggests that pathogenic mechanisms underlying neurodegeneration are strongly linked with neuroinflammatory responses. Tyro3, Axl, and Mertk (TAM receptors) constitute a subgroup of the receptor tyrosine kinase family, cell surface receptors which transmit signals from the extracellular space to the cytoplasm and nucleus. TAM receptors and the corresponding ligands, Growth Arrest Specific 6 and Protein S, are expressed in different tissues, including the nervous system, playing complex roles in tissue repair, inflammation and cell survival, proliferation, and migration. In the nervous system, TAM receptor signalling modulates neurogenesis and neuronal migration, synaptic plasticity, microglial activation, phagocytosis, myelination, and peripheral nerve repair, resulting in potential interest in neuroinflammatory and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Multiple Sclerosis. In Alzheimer and Parkinson diseases, a role of TAM receptors in neuronal survival and pathological protein aggregate clearance has been suggested, while in Multiple Sclerosis TAM receptors are involved in myelination and demyelination processes. To better clarify roles and pathways involving TAM receptors may have important therapeutic implications, given the fine modulation of multiple molecular processes which could be reached. In this review, we summarise the roles of TAM receptors in the central nervous system, focusing on the regulation of immune responses and microglial activities and analysing in vitro and in vivo studies regarding TAM signalling involvement in neurodegeneration.

KIF20A Affects the Prognosis of Bladder Cancer by Promoting the Proliferation and Metastasis of Bladder Cancer Cells.

Abstract: Objective. To investigate the expression of kinesin family member 20A (KIF20A) in bladder cancer, the effect of KIF20A on the proliferation and metastasis of bladder cancer cells, and the effect of KIF20A expression on the prognosis of bladder cancer patients. Methods. Bladder cancer tissue and its adjacent tissues were collected from tumour patients. The mRNA and protein expression levels of KIF20A in the tissue samples were detected by qRT-PCR and western blot. Immunohistochemical (IHC) staining was used to identify the expression and distribution of KIF20A proteins in the tissue samples. The relationship between the KIF20A expression and the clinical pathology of bladder cancer was analysed. The effect of the differential expression of KIF20A on the prognosis of patients with bladder cancer was analysed by the TCGA database. The plasmid was transfected into the bladder cell lines T24 and 5637 to construct two stable cell lines with knocked down KIF20A. The effect of KIF20A expression on the proliferation and invasion of T24 and 5637 bladder cells was explored in vitro using the abovementioned stable cell lines. The effect of the KIF20A expression on the proliferation of bladder cancer cells was evaluated by a mouse xenograft model. Results. The expression of KIF20A was significantly higher in the bladder cancer tissues than in the adjacent control tissues. The expression of KIF20A was significantly associated with the degree of pathological differentiation of bladder cancer. Patients with a higher expression of KIF20A had a higher tumour grade and a more advanced stage. The mean survival of patients with a high KIF20A expression was significantly lower than the mean survival of patients with a low KIF20A expression. The in vitro experiments demonstrated that the knockdown of KIF20A significantly inhibited T24 and 5637 cell proliferation and invasion. The in vivo experiments showed that the knockdown of KIF20A significantly inhibited the proliferation of the bladder tumours. Conclusion. KIF20A promotes the proliferation and metastasis of bladder cancer cells. Bladder cancer patients with a high KIF20A expression have a worse tumour differentiation and a poor prognosis. KIF20A may become an independent factor that affects the prognosis of bladder cancer patients and a therapeutic target for bladder cancer.

Association of Single-Nucleotide Polymorphism REX1 rs6815391, OCT4 rs13409 or rs3130932, and CTBP2 rs3740535 with Primary Lung Cancer Susceptibility: A Case-Control Study in a Chinese Population

Abstract: The purpose of the current study is to explore the contribution of single-nucleotide polymorphisms (SNPs) of REX1 rs6815391, OCT4 rs13409 or rs3130932, and CTBP2 rs3740535 to the risk of lung cancer. A questionnaire survey was used to obtain basic information of the included subjects. A case control study was performed in 1121 patients and 1121 controls. All subjects were subjected to blood sampling for genomic DNA extraction and genotyping of the cancer stem cell-associated gene SNPs, including REX1 rs6815391, OCT4 rs13409 or rs3130932, and CTBP2 rs3740535 by real-time PCR. The association with the risk of primary lung cancer and interaction with environmental factors were assessed using unconditional logistic regression for the odds ratios and corresponding 95% confidence intervals. The genotype frequency distribution of OCT4 rs13409 loci was statistically significant, but there was no significant difference in the rest of the loci between lung cancer patients and healthy controls. The OCT4 gene was also related with lung cancer susceptibility in the genetic model after adjusting for lung cancer-related factors. Despite the presence of the dominant or recessive model, the four loci polymorphisms were associated with pollution near the place of residence, house type, worse ventilation situation, smoking, passive smoking, cooking oil fumes (COF), and family history of cancer, which increased the risk of lung cancer. Nonmarried status, , COF, smoking, passive smoking, family history of cancer, and history of lung disease were independent risk factors of lung cancer susceptibility. Additionally, college degree or above, no pollution near the place of residence, protective genotype 1 or 2, and well ventilation can reduce the occurrence of lung cancer. There is an interaction between the four loci and environmental factors, and OCT4 rs13409 is a risk factor of primary lung cancer.

Identification of METTL14 in Kidney Renal Clear Cell Carcinoma Using Bioinformatics Analysis.

Abstract: The kidney renal clear cell carcinoma (KIRC) with poor prognosis is the main histological subtype of the renal cell carcinoma, accounting for 80–90% of patients. Currently, the N6-methyladenosine (m6A) epitranscriptional modification draws much attention. The m6A RNA modification, the most plentiful internal modification of mRNAs and noncoding RNAs in the majority of eukaryotes, regulates mRNAs at different levels and is involved in disease occurrence and progression. The GTExPortal and TCGAportal were applied to investigate the METTL14 mRNA expression in different tissues and KIRC stages. The Human Protein Atlas was used to verify the location of METTL14 in KIRC tissues. The main microRNAs (miRNAs) related to KIRC were analyzed using OncoLnc and starBase, while corresponding circular RNAs (circRNAs) interacting with miRNAs were predicted via circBank; then, the METTL14-miRNA-circRNA interaction network was established. The level of methyltransferase-like 14 (METTL14) mRNA was significantly lower in KIRC tissues compared with normal kidney tissues, which was relative to clinical and pathological stages. circRNAs may regulate METTL14 mRNA as miRNAs sponge to affect the KIRC progression. METTL14 mRNA is likely to regulate PTEN mRNA expression via changing its m6A RNA modification level. METTL14 mRNA expression negatively correlated with the KIRC stages and positively correlated with KIRC patients’ overall survival, which has great potential to serve as a clinical biomarker in KIRC.

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction.

Abstract: Left ventricular diastolic dysfunction (LVDD) is an important precursor to many different cardiovascular diseases. Diastolic abnormalities have been studied extensively in the past decade, and it has been confirmed that one of the mechanisms leading to heart failure is a chronic, low-grade inflammatory reaction. The triggers are classical cardiovascular risk factors, grouped under the name of metabolic syndrome (MetS), or other systemic diseases that have an inflammatory substrate such as chronic obstructive pulmonary disease. The triggers could induce myocardial apoptosis and reduce ventricular wall compliance through the release of cytokines by multiple pathways such as (1) immune reaction, (2) prolonged cell hypoxemia, or (3) excessive activation of neuroendocrine and autonomic nerve function disorder. The systemic proinflammatory state causes coronary microvascular endothelial inflammation which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes favoring hypertrophy development and increases resting tension. So far, it has been found that inflammatory cytokines associated with the heart failure mechanism include TNF-α, IL-6, IL-8, IL-10, IL-1α, IL-1β, IL-2, TGF-β, and IFN-γ. Some of them could be used as diagnosis biomarkers. The present review aims at discussing the inflammatory mechanisms behind diastolic dysfunction and their triggering conditions, cytokines, and possible future inflammatory biomarkers useful for diagnosis.

KIF23 Promotes Gastric Cancer by Stimulating Cell Proliferation.

Abstract: Gastric cancer (GC) is one of the most aggressive malignant tumors with low early diagnosis and high metastasis. Despite progress in treatment, to combat this disease, a better understanding of the underlying mechanisms and novel therapeutic targets is needed. KIF23, which belongs to the KIF family, plays a vital role in various cell processes, such as cytoplasm separation and axon elongation. Nowadays, KIF23 has been found to be highly expressed in multiple tumor tissues and cells, suggesting a potential link between KIF23 and tumorigenesis. Herein, we reported that KIF23 expression was correlated with poor prognosis of gastric cancer and found an association between KIF23 and pTNM stage. An in vitro assay proved that the proliferation of gastric cancer cells was significantly inhibited, which is caused by KIF23 depletion. Additionally, knockdown of KIF23 resulted in a marked inhibition of cell proliferation of gastric cancer in mice, with significant downregulation of Ki67 and PCNA expression. In conclusion, these data indicate that KIF23 is a potential therapeutic target for gastric cancer treatment.

Effects of Angiopoietin-Like 3 on Triglyceride Regulation, Glucose Homeostasis, and Diabetes

Abstract: Angiopoietin-like 3 (ANGPTL3) is a regulator of plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL). ANGPTL3 is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain, which forms a complex with ANGPTL8 orchestrating LPL inhibition. ANGPTL3-4-8 mouse model studies indicate that these three ANGPTL family members play a significant role in partitioning the circulating TRG to specific tissues according to nutritional states. Recent data indicate a positive correlation of ANGPTL3 with plasma glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in insulin-resistant states. The aim of this review is to critically present the metabolic effects of ANGPTL3, focusing on the possible mechanisms involved in the dysregulation of carbohydrate homeostasis by this protein. Heterozygous and homozygous carriers of ANGPTL3 loss-of-function mutations have reduced risk for type 2 diabetes mellitus. Suggested mechanisms for the implication of ANGPTL3 in carbohydrate metabolism include the (i) increment of free fatty acids (FFAs) owing to the enhancement of lipolysis in adipose tissue, which can induce peripheral as well as hepatic insulin resistance; (ii) promotion of FFA flux to white adipose tissue during feeding, leading to the attenuation of de novo lipogenesis and decreased glucose uptake and insulin sensitivity; (iii) induction of hypothalamic LPL activity in mice, which is highly expressed throughout the brain and is associated with enhanced brain lipid sensing, reduction of food intake, and inhibition of glucose production (however, the effects of ANGPTL3 on hypothalamic LPL in humans need more clarification); and (iv) upregulation of ANGPTL4 expression (owing to the plasma FFA increase), which possibly enhances insulin resistance due to the selective inhibition of LPL in white adipose tissue leading to ectopic lipid accumulation and insulin resistance. Future trials will reveal if ANGPTL3 inhibition could be considered an alternative therapeutic target for dyslipidemia and dysglycemia.

Serum Exosomal miRNAs Are Associated with Active Pulmonary Tuberculosis.

Abstract: Introduction. Tuberculosis (TB) remains a major threat to human health. Due to the limited accuracy of the current TB diagnostic tests, it is critical to determine novel biomarkers for this disease. Circulating exosomes have been used as diagnostic biomarkers in various diseases. Objective of the Study. In this pilot study, we examined the expression of miRNAs as biomarker candidates for the diagnosis of TB infection. Methods. Serum-derived exosomes were isolated from TB patients and matched control subjects. The expression of miR-484, miR-425, and miR-96 was examined by RT-PCR methods. Results. The expression of miR-484, miR-425, and miR-96 were significantly increased in serum of TB patients which correlated with the TB infection level. A receiver operating characteristic (ROC) curve analysis showed the diagnostic potency of each individual serum exosomal miRNA with an area under the curve for miR-484 ( ), 0.66 for miR-425 ( ), and 0.62 for miR-96 ( ). Conclusion. These results demonstrate that exosomal miRNAs have diagnostic potential in active tuberculosis. The diagnostic power may be improved when combined with conventional diagnostic markers.

Metformin Use and Lung Cancer Risk in Diabetic Patients: A Systematic Review and Meta-Analysis.

Abstract: Background Antidiabetic medications (ADMs) can alter the risk of different types of cancer, but the relationship between lung cancer incidence and metformin remains controversial. Our aim was to quantitatively estimate the relationship between incidences of lung cancer and metformin in patients with diabetes in this meta-analysis. Methods We performed a search in PubMed, Embase, ISI Web of Science, and Cochrane Library until September 20, 2017. The odds ratio (OR), relative risk (RR) or hazard ratio (HR), and 95% confidence interval (95% CI) were estimated using the random-effect model. The Newcastle-Ottawa Scale (NOS) was used to assess the study quality. Results A total of 13 studies (10 cohort studies and 3 case-control studies) were included in the meta-analysis. Compared to nonmetformin users, metformin probably decreased lung cancer incidence in diabetic patients (RR = 0.89; 95% CI, 0.83-0.96; P = 0.002) with significant heterogeneity (Q = 35.47, I2 = 66%, P = 0.0004). Subgroup analysis showed that cohort studies (RR = 0.91; 95% CI, 0.85-0.98; P = 0.008), location in Europe (RR = 0.90; 95% CI, 0.86-0.94; P < 0.0001), the control drug of the sulfonylurea group (RR = 0.91; 95% CI, 0.86-0.96; P = 0.001), and adjusting for smoking (RR = 0.86; 95% CI, 0.75-1.00; P = 0.05) may be related to lower lung cancer risk. No significant publication bias was detected using a funnel plot. Conclusion Metformin use was related to a lower lung cancer risk in diabetic patients compared to nonusers, but this result was retrieved from observational studies and our findings need more well-designed RCTs to confirm the association.

Preoperative Anemia or Low Hemoglobin Predicts Poor Prognosis in Gastric Cancer Patients: A Meta-Analysis.

Abstract: Background. The prognostic value of preoperative anemia in gastric cancer remains unclear. Therefore, the purpose of the present study is to evaluate the prognostic value of preoperative anemia in gastric cancer. Methods. We searched Embase and PubMed databases for relevant studies from inception to March 2018. The prognostic value of preoperative anemia in gastric cancer was determined by calculating the hazard ratio (HR) and the corresponding 95% confidence interval (CI) as effect measures. A random effect model was used in cases in which there was significant heterogeneity; otherwise, a fixed effect model was used. Statistical analyses were performed using Stata software. Results. Seventeen studies involving 13,154 gastric cancer patients were included. The estimated rate of preoperative anemia was 36% (-44%). The overall survival of preoperative anemia was poor (,-1.45). Moreover, disease-free survival was significantly lower in patients with preoperative anemia compared with those without this condition (,-2.32). These findings were corroborated by the results of subgroup analyses. Conclusions. The results indicate that preoperative anemia predicts poor prognosis in gastric cancer, including overall survival and disease-free survival. Therefore, preoperative anemia may be a convenient and cost-effective blood-derived prognostic marker for gastric cancer.

Presence of Circulating miR-145, miR-155, and miR-382 in Exosomes Isolated from Serum of Breast Cancer Patients and Healthy Donors

Abstract: miR-145, miR-155, and miR-382 have been proposed as noninvasive biomarkers to distinguish breast cancer patients from healthy individuals. However, it is unknown if these three miRNAs are secreted by exosomes. Thus, we hypothesized that miR-145, miR-155, and miR-382 in breast cancer patients are present in exosomes. We isolated exosomes from serum of breast cancer patients and healthy donors, then we characterized them according to their shape, size, and exosome markers by scanning electron microscopy, atomic force microscopy, nanoparticle tracking analysis (NTA), and Western blot and determined the exosome concentration in all samples by NTA. Later, exosomal small RNA extraction was done to determine the expression levels of miR-145, miR-155, and miR-382 by qRT-PCR. We observed a round shape of exosomes with a mean size of 119.84 nm in breast cancer patients and 115.4 nm in healthy donors. All exosomes present the proteins CD63, Alix, Tsg, CD9, and CD81 commonly used as markers. Moreover, we found a significantly high concentration of exosomes in breast cancer patients with stages I, III, and IV compared to healthy donors. We detected miR-145, miR-155, and miR-382 in the exosomes isolated from serum of breast cancer patients and healthy donors. Our results show that the exosomes isolated from the serum of breast cancer patients and healthy donors contains miR-145, miR-155, and miR-382 but not in a selective manner in breast cancer patients. Moreover, our data support the association between exosome concentration and the presence of breast cancer, opening the possibility to study how miRNAs packaged into exosomes play a role in BC progression.

Genome-Wide Plasma Cell-Free DNA Methylation Profiling Identifies Potential Biomarkers for Lung Cancer.

Abstract: As a noninvasive blood testing, the detection of cell-free DNA (cfDNA) methylation in plasma has raised an increasing interest due to diagnostic applications. Although extensively used in cfDNA methylation analysis, bisulfite sequencing is less cost-effective. In this study, we investigated the cfDNA methylation patterns in lung cancer patients by MeDIP-seq. Compared with the healthy individuals, 330 differentially methylated regions (DMRs) at gene promoters were identified in lung cancer patients with 33 hypermethylated and 297 hypomethylated regions, respectively. Moreover, these hypermethylated genes were validated with the publicly available DNA methylation data, yielding a set of ten significant differentially methylated genes in lung cancer, including B3GAT2, BCAR1, HLF, HOPX, HOXD11, MIR1203, MYL9, SLC9A3R2, SYT5, and VTRNA1-3. Our study demonstrated MeDIP-seq could be effectively used for cfDNA methylation profiling and identified a set of potential biomarker genes with clinical application for lung cancer.

Prognostic Value of BIRC5 in Lung Adenocarcinoma Lacking EGFR, KRAS, and ALK Mutations by Integrated Bioinformatics Analysis.

Abstract: Objective This study was aimed at investigating the prognostic significance of Baculoviral IAP repeat containing 5 (BIRC5) in lung adenocarcinoma (LAD) lacking EGFR, KRAS, and ALK mutations (triple-negative (TN) adenocarcinomas). Methods The gene expression profiles were obtained from Gene Expression Omnibus (GEO). The identification of the differentially expressed genes (DEGs) was performed by GeneSpring GX. Gene set enrichment analysis (GSEA) was used to execute gene ontology function and pathway enrichment analysis. The protein interaction network was constructed by Cytoscape. The hub genes were extracted by MCODE and cytoHubba plugin from the network. Then, using BIRC5 as a candidate, the prognostic value in LAD and TN adenocarcinomas was verified by the Kaplan-Meier plotter and The Cancer Genome Atlas (TCGA) database, respectively. Finally, the mechanism of BIRC5 was predicted by a coexpressed network and enrichment analysis. Results A total of 38 upregulated genes and 121 downregulated genes were identified. 9 hub genes were extracted. Among them, the mRNA expression of 5 genes, namely, BIRC5, MCM4, CDC20, KIAA0101, and TRIP13, were significantly upregulated among TN adenocarcinomas (all P < 0.05). Notably, only the overexpression of BIRC5 was associated with unfavorable overall survival (OS) in TN adenocarcinomas (log rank P = 0.0037). TN adenocarcinoma patients in the BIRC5 high-expression group suffered from a significantly high risk of distant metastasis (P = 0.046), advanced N stage (P = 0.033), and tumor-bearing (P = 0.031) and deceased status (P = 0.003). The mechanism of BIRC5 and coexpressed genes may be linked closely with the cell cycle. Conclusion Overexpressed in tumors, BIRC5 is associated with unfavorable overall survival in TN adenocarcinomas. BIRC5 is a potential predictor and therapeutic target in TN adenocarcinomas.

Oxidative Stress in Animal Models of Acute and Chronic Renal Failure

Abstract: Introduction. Kidney disease is a worldwide health and economic burden, with rising prevalence. The search for biomarkers for earlier and more effective disease screening and monitoring is needed. Oxidative stress has been linked to both, acute kidney injury (AKI) and chronic kidney disease (CKD). The aim of our study was to investigate whether the concentrations of systemic markers of oxidative stress and antioxidant status are affected by AKI and CKD, and to identify potential biomarkers. Methods. In adult male Wistar rats, AKI was induced by bilateral nephrectomy, and CKD was induced by 5/6 nephrectomy. Blood was collected 48 hours after surgery in AKI and 6 months after surgery in CKD. Advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGEs), fructosamine, total antioxidant capacity (TAC), and ferric reducing antioxidant power (FRAP) were measured. Results. Impaired renal function was confirmed by high concentrations of plasma creatinine and urea in AKI and CKD animals. AOPP and fructosamine were higher by 100% and 54% in AKI, respectively, and by 100% and 199% in CKD, respectively, when compared to corresponding control groups. Similarly, there was approximately a twofold increase in AGEs (by 92%) and TAC (by 102%) during AKI. In CKD, concentrations of FRAP, as an antioxidative status marker, were doubled (by 107%) when compared to the control group, but concentration of TAC, another marker of antioxidative status, did not differ between the groups. Conclusions. AKI and CKD led to increased systemic oxidative stress. AOPP and fructosamine could be considered potential biomarkers for both, acute and chronic kidney damage. On the other hand, AGEs, TAC, and FRAP seem to be disease specific, which could help to differentiate between acute and chronic kidney injuries. However, this needs further validation in clinical studies.

Serum Vascular Endothelial Growth Factor Levels Correlate with Severity of Retinopathy in Diabetic Patients: A Systematic Review and Meta-Analysis.

Abstract: Background. Investigations regarding serum and plasma vascular endothelial growth factor (VEGF) levels in patients with diabetic retinopathy (DR) are conflicting. This meta-analysis is aimed at determining whether serum and plasma VEGF levels are associated with DR and its severity in diabetic patients. Methods. PubMed and EMBASE were used to search for published studies, and serum and plasma VEGF levels were compared among DR, nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), and nondiabetic retinopathy (NDR) patients. Standardized mean differences (SMD) and 95% confidence interval (CI) were pooled using a random effects model. Results. A total of 29 studies comprising 1805 DR (or NPDR or PDR) patients and 1699 NDR patients were included. ELISA was used to evaluate serum or plasma VEGF levels in all except for two studies included in this meta-analysis. Overall, serum VEGF levels were significantly higher in DR patients (SMD: 0.74, 95% CI: 0.44-1.03) than those in NDR patients, while plasma VEGF levels were not in the comparison (SMD: 0.40, 95% CI: −0.13-0.92). Similarly, NPDR (SMD: 0.51, 95% CI: 0.22-0.80) and PDR (SMD: 1.32, 95% CI: 0.79-1.85) patients had higher serum VEGF levels compared with NDR patients, but the difference was not significant in plasma samples (SMD: 0.24, 95% CI: −0.47-0.95; SMD: 0.37, 95% CI: −0.30-1.05). In addition, serum VEGF levels were higher in PDR patients than those in NPDR patients (SMD: 0.87, 95% CI: 0.41-1.33), but plasma VEGF levels were not (SMD: −0.00, 95% CI: −0.31-0.31). The subgroup and metaregression analysis revealed that the study location, study design, and publication year of a study have certain influence on heterogeneity between studies in serum or plasma samples. Conclusions. VEGF levels in the serum instead of those in the plasma correlate to the presence and severity of DR in diabetic patients. Further large-scale studies are required to confirm these findings.