Reduction of double-strand DNA break repair exacerbates vascular aging.

Advanced age is the greatest risk factor for cardiovascular disease (CVD), the leading cause of death. Arterial function is impaired in advanced age which contributes to the development of CVD. One underexplored hypothesis is that DNA damage within arteries leads to this dysfunction, yet evidence demonstrating the incidence and physiological consequences of DNA damage in arteries, and in particular, in the microvasculature, in advanced age is limited. In the present study, we began by assessing the abundance of DNA damage in human and mouse lung microvascular endothelial cells and found that aging increases the percentage of cells with DNA damage. To explore the physiological consequences of increases in arterial DNA damage, we evaluated measures of endothelial function, microvascular and glycocalyx properties, and arterial stiffness in mice that were lacking or heterozygous for the double-strand DNA break repair protein ATM kinase. Surprisingly, in young mice, vascular function remained unchanged which led us to rationalize that perhaps aging is required to accumulate DNA damage. Indeed, in comparison to wild type littermate controls, mice heterozygous for ATM that were aged to ~18 mo (Old ATM +/-) displayed an accelerated vascular aging phenotype characterized by increases in arterial DNA damage, senescence signaling, and impairments in endothelium-dependent dilation due to elevated oxidative stress. Furthermore, old ATM +/- mice had reduced microvascular density and glycocalyx thickness as well as increased arterial stiffness. Collectively, these data demonstrate that DNA damage that accumulates in arteries in advanced age contributes to arterial dysfunction that is known to drive CVD.

Endothelial cell telomere dysfunction induces senescence and results in vascular and metabolic impairments.

In advanced age, increases in oxidative stress and inflammation impair endothelial function, which contributes to the development of cardiovascular disease (CVD). One plausible source of this oxidative stress and inflammation is an increase in the abundance of senescent endothelial cells. Cellular senescence is a cell cycle arrest that occurs in response to various damaging stimuli. In the present study, we tested the hypothesis that advanced age results in endothelial cell telomere dysfunction that induces senescence. In both human and mouse endothelial cells, advanced age resulted in an increased abundance of dysfunctional telomeres, characterized by activation of DNA damage signaling at telomeric DNA. To test whether this results in senescence, we selectively reduced the telomere shelterin protein telomere repeat binding factor 2 (Trf2) from endothelial cells of young mice. Trf2 reduction increased endothelial cell telomere dysfunction and resulted in cellular senescence. Furthermore, induction of endothelial cell telomere dysfunction increased inflammatory signaling and oxidative stress, resulting in impairments in endothelial function. Finally, we demonstrate that endothelial cell telomere dysfunction-induced senescence impairs glucose tolerance. This likely occurs through increases in inflammatory signaling in the liver and adipose tissue, as well as reductions in microvascular density and vasodilation to metabolic stimuli. Cumulatively, the findings of the present study identify age-related telomere dysfunction as a mechanism that leads to endothelial cell senescence. Furthermore, these data provide compelling evidence that senescent endothelial cells contribute to age-related increases in oxidative stress and inflammation that impair arterial and metabolic function.

Blood-based microRNAs as Potential Diagnostic biomarkers for Melanoma: A Meta-analysis.

INTRODUCTION: Circulating microRNAs (miRNAs) serve as noninvasive diagnostic markers in many cancers. This meta-analysis aims to evaluate the diagnostic efficacy of circulating microRNAs for melanoma. MATERIAL AND METHODS: The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and ROC curve were evaluated using the Meta-Disc V.1.4 and Comprehensive Meta-Analysis V.3.3 software packages. To investigate the heterogeneity, the I2 and Chi-square tests were used. The publishing bias was evaluated using Begg's rank correlation and Egger regression asymmetry tests. RESULTS: A total of 9 articles covering 13 studies (more than 50 miRs individually and in combination) were included, containing 1,355 participants (878 cases and 477 controls). The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR), and AUC were 0.78 (95% CI: 0.76-0.81), 0.80 (95% CI: 0.77-0.83), 4.32 (95% CI: 3.21-5.82), 0.17 (95% CI: 0.09-0.32), 28.0 (95% CI: 15.34-51.09), and 0.91, respectively. According to Begg's and Egger's tests, there was no publication bias (Begg's p = 0.160 and Egger's p = 0.289). CONCLUSION: Circulating miRNAs can serve as fair and non-invasive diagnostic biomarkers for melanoma. Additionally, specific miRNAs still need to be discovered for diagnosing melanoma.

The protective effect of curcumin on thrombin-induced hyper-permeability.

Objective: Thrombin is a proinflammatory and pro-coagulant agent which is upregulated in several human diseases. Thrombin has a critical role in promoting cell proliferation and microvascular leakage in malignant cells, resulting in cancer growth and progression. Here, we explored the potential therapeutic value of curcumin on permeability induced by thrombin in mice. Materials and Methods: To assess the activity of curcumin on thrombin-induced vascular permeability mice model, C57BL / 6 mice were randomly divided into four groups: (1) control (2) Thrombin (3) Thrombin + Curcumin and (4) Thrombin + Metformin. Thirty minutes after treatment, Evans blue was injected intravenously through the tail vein to mice. Then, animals were sacrificed and the dye was extracted from the skin tissue by incubation with formamide. Heatmap and correlation map were generated and protein-protein interaction network of the hub genes was drawn by Cytoscape software. Results: Hub DEG expression rate showed that Heat shock protein a1 (Hspa1) family (comprised of HSPa1a, b, and HSPa5), caspase 3, and minichromosome maintenance complex component 2 were overexpressed after treatment with curcumin. Functional modules of curcumin enriched through Enrich gene biological process and revealed positive association of gene expression of apoptosis process with the therapy. Curcumin was also found to reduce leucocyte migration in murine tissues. Additionally, treatment with curcumin resulted in downregulation of heat shock proteins and proinflammatory cytokines such as monocyte chemotactic protein 1, interleukin-6 and chemokine (C-X-C motif) ligand 3. Conclusion: Curcumin inhibited the proinflammatory cytokines and inflammatory HSPs in endothelial cells and reduced thrombin-induced barrier destabilization in vivo.

Can microRNAs be utilized as tumor markers for recurrence following nephrectomy in renal cell carcinoma patients? A meta-analysis provides the answer.

INTRODUCTION: Renal cell carcinoma (RCC) is an aggressive tumor. Many studies investigated microRNAs (miRs) as RCC prognostic biomarkers, often reporting inconsistent findings. We present a meta-analysis to identify if tissue-derived miRs can be used as a prognostic factor in patients after nephrectomy. METHODS: Data were obtained from PubMed, Embase, and Web of Science. The hazard ratio with 95% confidence intervals assessed the prognostic value of microRNAs. Outcomes of interest included the prognosis role of microRNAs in overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) in nephrectomy patients. RESULTS: Nine retrospective studies that evaluated microRNAs in 1,541 nephrectomy patients were collected. There were heterogeneities across studies for microRNAs in the 15 studies examining OS, RFS, and CSS (I2 = 84.51%; P < 0.01); the random-effect model was calculated (HR = 1.371; (95% CI: 0.831-2.260); P = 0.216). CONCLUSION: Our study indicated that miRNAs cannot be used as a marker for recurrence in RCC patients after nephrectomy, and researchers shouldn't make the mistake that if miRs can be used as a biomarker in RCC, they cannot be used as a marker after nephrectomy in RCC. As all of these findings were from retrospective studies, further studies are needed to verify the role of microRNAs in clinical trials.

Previous pulmonary tuberculosis enhances the risk of lung cancer: systematic reviews and meta-analysis.

PURPOSE: The possible association between history of pulmonary tuberculosis (TB) and lung cancer (LC) has attracted researchers' attention for several decades. This systematic review and meta-analysis aim to assess the association between previous pulmonary TB infection and LC risk. METHODS: A Systematic and comprehensive search was performed in the following databases: PubMed, Embase, clinical key, Web of Science and Google Scholar, in articles and abstracts published from 1987 to 2021. Thirty-two articles (involving 50,290 cases and 846,666 controls) met the inconclusive criteria. The Comprehensive Meta-Analysis version 2.2 software was used for this meta-analysis. RESULTS: The result of this meta-analysis demonstrates that pre-existing active pulmonary TB increases the risk of LC (RR = 2.170, 95% confidence interval [CI] 1.833-2.569, p < .001, I2 = 91.234%). The results showed that the risk of the history of active pulmonary TB infection in adenocarcinoma was 2.605 (95% CI 1.706-3.979, p < .001, I2 = 55.583%), in small-cell carcinoma was 2.118 (95% CI 1.544-2.905, p < .001, I2 = 0.0%), in squamous-cell carcinoma, was 3.570 (95% CI 2.661 - 4.791, p < .001, I2 = 42.695%) and 2.746 (95% CI 2.300-3.279, p < .001, I2 = 41.686%) for other histological types of LCs. According to these results, a history of active pulmonary TB increases the risk of LC. CONCLUSIONS: This study emphasizes the importance of LC screening in pulmonary TB patients even after the infection is treated. With the increased chances of LC in a patient who had a history of active pulmonary TB, there could be a need for a further follow-up period after pulmonary TB recovery.

Brain tumors and circulating micrornas: a systematic review and diagnostic meta-analysis.

PURPOSE: Brain tumors (BT) are among the most prevalent cancers in recent years. Various studies have examined the diagnostic role of microRNAs in different diseases; however, their diagnostic role in BT has not been comprehensively investigated. This meta-analysis was performed to assess microRNAs in the blood of patients with BTs accurately. METHODS: Twenty-six eligible studies were included for analysis. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under curve (AUC), Q*index, summary receiver-operating characteristic (SROC) were assessed using the Meta-Disc V.1.4 and Comprehensive Meta-Analysis V.3.3 software. RESULTS: The diagnostic accuracy of microRNA was high in identifying BT based on the pooled sensitivity 0.82 (95%CI: 0.816-0.84), specificity 0.82 (95%CI: 0.817-0.84), PLR 5.101 (95%CI: 3.99-6.51), NLR 0.187 (95%CI: 0.149-0.236), DOR 34.07 (95%CI: 22.56-51.43) as well as AUC (0.92), and Q*-index (0.86). Subgroup analyses were performed for sample types (serum/plasma), reference genes (RNU6, miR-39, and miR-24), and region to determine the diagnostic power of microRNAs in the diagnosis of BT using pooled sensitivity, specificity, PLR, NLR, AUC, and DOR. CONCLUSION: This meta-analysis suggested that circulating microRNAs might be potential markers for noninvasive early detection of BT.

Urinary Angiogenin as a Marker for Bladder Cancer: A Meta-Analysis.

AIMS: Bladder cancer (BCa) is a common cancer in North America and Europe that carries considerable morbidity and mortality. A reliable biomarker for early detection of the bladder is crucial for improving the prognosis of BCA. In this meta-analysis, we examine the diagnostic role of the angiogenin (ANG) protein in patients' urine with bladder neoplasm. METHODS: We performed a systematic literature search using ScienceDirect, Web of Science, PubMed/MEDLINE, Scopus, Google Scholar, and Embase, up to 10th October 2020 databases. Meta-Disc V.1.4 and Comprehensive Meta-Analysis V.2.2 software calculated the pooled specificity, sensitivity, area under the curve (AUC), diagnostic odds ratio (DOR), positive likelihood ratio (LR+), negative likelihood ratio (LR-), Q ∗ index, and summary receiver-operating characteristic (SROC) for the role of ANG as a urinary biomarker for BCa patients. RESULTS: Four case-control studies were included with 656 participants (417 cases and 239 controls) in this meta-analysis. The pooled sensitivity of 0.71 (95% CI: 0.66-0.75), specificity of 0.78 (95% CI: 0.73-0.81), LR+ of 3.34 (95% CI: 2.02-5.53), LR- of 0.37 (95% CI: 0.32-0.44), DOR of 9.99 (95% CI: 4.69-21.28), and AUC of 0.789 and Q ∗ index of 0.726 demonstrate acceptable diagnostic precision of ANG in identifying BCa. CONCLUSION: This meta-analysis showed that ANG could be a fair biomarker for the diagnosis of BCa patients.

Circulating miR-21 as a potential biomarker in human digestive system carcinoma: a systematic review and diagnostic meta-analysis.

Purpose: Gastrointestinal cancers (GICs) account for about a quarter of cancers. Lately, the circulating microRNAs as a non-invasive biomarker for identifying and monitoring diseases have been recognized. Several studies have examined the role of miR-21 in digestive system carcinoma. We conducted a meta-analysis to assess the diagnostic role of miR-21 in GICs.Methods: Seventeen studies involving 1700 individuals were included in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, AUC, SROC, and Q* index were calculated based on true-positive, true-negative, false-negative, and false-positive. Moreover, the subgroup analyses have been performed for miR-21 based on sample types (serum/plasma), normalized genes (U6, miR-16, and miR-39), and ethnicity.Results: The pooled sensitivity 0.722 (95% CI: 0.70-0.74), specificity 0.820 (95% CI: 0.801-0.838), PLR 4.375 (95% CI: 3.226-5.933), NLR 0.308 (95% CI: 0.239-0.398), DOR 16.06 (95% CI: 9.732-26.53) as well as AUC 0.86, and Q* index 0.79 represented the high-grade diagnostic precision of miR-21 in identifying GICs (ESCC, GC, CRC, HCC, and PC).Conclusion: This meta-analysis demonstrated that circulating miR-21 levels can be used to monitor the digestive system carcinomas. Therefore, miR-21 can be a useful biomarker of progression and fair diagnosis in GICs patients.

MicroRNA-223 in gastrointestinal cancers: A systematic review and diagnostic meta-analysis.

BACKGROUND: Several studies have been conducted on the diagnostic role of miR-223 in cancers related to the digestive system. However, the diagnostic role of this microRNA in gastrointestinal (GI) cancers has not been fully elucidated. This meta-analysis aimed to accurately assess the diagnostic role of circulating miR-223 in GI cancers. METHODS: A literature search was performed in PubMed/Medline, Science Direct, Web of Science, Google Scholar, Embase and Scopus, up to 1st May 2020 databases. Twelve studies were eligible and included in the analysis. Meta-Disc software was used to calculate the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, area under the curve (AUC) and the summary receiver operating characteristic (SROC) based on true positive, true negative, false negative and false positive for each gastrointestinal cancer separately and in total. RESULTS: Twelve case-control studies were included with 1859 participants (1080 cases and 779 controls). Pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.77 (95% CI: 0.74-0.79), 0.75 (95% CI: 0.72-0.78), 3.04 (95% CI: 2.20-4.18), 0.31 (95% CI: 0.22-0.42) and 10.77 (95% CI: 5.96-19.47), respectively. AUC was 0.83, suggesting a high-grade diagnostic precision of miR-223 in gastrointestinal cancers. Besides, subgroup analyses were performed to assess the diagnostic power of miR-223 based on the type of gastrointestinal cancer, sample type and country via calculating pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio. CONCLUSION: Our meta-analysis showed the value of circulating miR-223 levels in the early diagnosis of diverse digestive system carcinomas.

Clinical Association between Phospho-AKT Expression with Clinicopathological Characteristics of Gastrointestinal Cancer Patients: A Meta-Analysis.

Deregulation of AKT (protein kinase B) is frequently observed in human malignancies including gastrointestinal (GI) cancers. Here we have reviewed the association between AKT phosphorylation (activation) and clinical and pathological characteristics of patients with GI cancer. Articles in the EMBASE, PubMed, Cochrane Library, and Web of Science databases were searched up to July 2018. Eighteen studies comprising 1,698 patients with 5 different cancer types were included in the meta-analysis. In the pooled analysis, AKT phosphorylation was positively correlated with tumor size (r = 0.14, 95% CI: 0.06-0.22; P < 0.001), tumor grade (r = 0.08, 95% CI: 0.02-0.14; P < 0.009), tumor stage (r = 0.19, 95% CI: 0.13-0.24; P < 0.001), lymph node status (r = 0.18, 95% CI: 0.09-0.25; P < 0.001) and the presence of distant metastasis (r = 0.14, 95% CI: 0.06-0.22; P < 0.001) in the patients with GI cancer. These findings support the potential clinical value of AKT as a prognostic marker and therapeutic target in patients with GI carcinomas.

Association between genetic variants at 9p21 locus with risk of breast cancer: A systematic review and meta-analysis.

Breast cancer (BC) is the most frequent tumor in women and genetic factors are among the main risk factors contributing to this malignancy. Chromosome 9p21 contains important regulatory non-coding RNAs and is associated with multiple malignancies including BC. The current meta-analysis aimed to investigate the association between genetic variants within the 9p21 locus and risk of breast cancer. A literature search was performed using PubMed, Web of Science, Embase, MEDLINE, Scopus and Clinical key databases. Nine studies containing 23,726 subjects were eligible for the final analysis and specific odds ratios (OR) and confidence intervals (95% CI) were evaluated to assess the strength of the associations. In the pooled analysis, there was an association between the genetic variations in 9p21 locus (CDKN2A/2B) with risk of breast cancer with a standard OR of 1.22 (95% CI: 1.04-1.45, P = 0.016; random-effects model), supporting the significance of this locus as a novel risk factor for breast cancer patients. In conclusion, our results showed that 9p21 region is positively associated with risk of BC and its polymorphisms may be a candidate marker for BC susceptibility.

Angiotensin-converting enzyme gene polymorphism and digestive system cancer risk: A meta-analysis based on 9656 subjects.

The angiotensin-converting enzyme (ACE) is the major regulator of the renin-angiotensin system, and it has been reported that genetic polymorphisms at this locus are associated with risk in numerous types of human cancers. In the current meta-analysis, we aimed to evaluate the association between the ACE Gene insertion/deletion (I/D) polymorphism (DD vs II) and digestive system cancer susceptibility. A total of 19 case-control studies among 3722 patients with seven different types of cancer were included in this meta-analysis. In the pooled analysis, the relationship between the ACE I/D polymorphism and digestive system cancer risk was not statistically significant (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.68-1.29; P = 0.65; random model). Furthermore, subgroup analyses by cancer type also did not reveal an association between ACE polymorphisms and colorectal cancer (OR, 1.14; 95% CI, 0.823-1.58; P = 0.43; random effect model) and gastric cancer (OR, 0.79; 95% CI, 0.51-1.22; P = 0.28; random effect model). These findings indicate that ACE polymorphisms in the digestive tract may still affect the survival of cancer patients, and future studies into the topic of effect of ACE on cancer prognosis are warranted.

The prognostic potential of long noncoding RNA HOTAIR expression in human digestive system carcinomas: A meta-analysis.

Homeobox transcript antisense intergenic RNA (HOTAIR), one of the well-known long noncoding RNAs (lncRNAs), plays an important role in initiation and development of various tumors. Elevated level of HOTAIR is associated with metastatic behavior of primary tumor and poor outcome in several cancers. Therefore, we conducted a meta-analysis to clearly measure the prognostic impact of HOTAIR in patients with digestive system carcinomas. Fourteen studies including 2,666 patients with five different type of digestive system cancers were selected to be entered in meta-analysis. Finding demonstrated that HOTAIR overexpression could predict unfavorable outcome in digestive system carcinomas (hazard ratio [HR] = 2.4, 95% confidence interval [CI]: 2.0-2.9; p < 0.001; fixed-effect model). In stratified analysis, increased level of HOTAIR predicted poor overall survival in gastric cancer (HR = 2.1, 95% CI: 1.6-2.9; p < 0.001), colorectal cancer (HR = 4.1, 95% CI: 1.6-10.2; p = 0.002), esophageal squamous cell carcinoma (HR = 2.3, 95% CI: 1.7-3.0; p < 0.001), and hepatocellular carcinoma (HR = 3.4, 95% CI: 1.9-6.1; p < 0.001). Our meta-analysis results clearly support the prognostic value of HOTAIR to predict unfavorable prognostic outcomes in diverse digestive system carcinomas.