Molecular Biomarkers in Glioblastoma: A Systematic Review and Meta-Analysis

Background: Glioblastoma (GBM) is a highly aggressive cancer with poor prognosis that needs better treatment modalities. Moreover, there is a lack of reliable biomarkers to predict the response and outcome of current or newly designed therapies. While several molecular markers have been proposed as potential biomarkers for GBM, their uptake into clinical settings is slow and impeded by marker heterogeneity. Detailed assessment of prognostic and predictive value for biomarkers in well-defined clinical trial settings, if available, is scattered throughout the literature. Here we conducted a systematic review and meta-analysis to evaluate the prognostic and predictive significance of clinically relevant molecular biomarkers in GBM patients. Material and methods: A comprehensive literature search was conducted to retrieve publications from 3 databases (Pubmed, Cochrane and Embase) from January 2010 to December 2021, using specific terms. The combined hazard ratios (HR) and confidence intervals (95% CI) were used to evaluate the association of biomarkers with overall survival (OS) in GBM patients. Results: Twenty-six out of 1831 screened articles were included in this review. Nineteen articles were included in the meta-analyses, and 7 articles were quantitatively summarised. Fourteen studies with 1231 GBM patients showed a significant association of MGMT methylation with better OS with the pooled HR of 1.66 (95% CI 1.32–2.09, p < 0.0001, random effect). Five studies including 541 GBM patients analysed for the prognostic significance of IDH1 mutation showed significantly better OS in patients with IDH1 mutation with a pooled HR of 2.37 (95% CI 1.81–3.12; p < 0.00001]. Meta-analysis performed on 5 studies including 575 GBM patients presenting with either amplification or high expression of EGFR gene did not reveal any prognostic significance with a pooled HR of 1.31 (95% CI 0.96–1.79; p = 0.08). Conclusions: MGMT promoter methylation and IDH1 mutation are significantly associated with better OS in GBM patients. No significant associations were found between EGFR amplification or overexpression with OS.     

A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the ABCB1, IL-10, ITPA, MIF, and TNF genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.     

Cervicovaginal Microbiota Composition in Chlamydia trachomatis Infection: A Systematic Review and Meta-Analysis

In healthy women, the cervicovaginal microbiota is characterized by the predominance of Lactobacillus spp., whereas the overgrowth of anaerobic bacteria leads to dysbiosis, known to increase the risk of acquiring genital infections like Chlamydia trachomatis. In the last decade, a growing body of research has investigated the composition of the cervicovaginal microbiota associated with chlamydial infection via 16s rDNA sequencing, with contrasting results. A systematic review and a meta-analysis, performed on the alpha-diversity indices, were conducted to summarize the scientific evidence on the cervicovaginal microbiota composition in C. trachomatis infection. Databases PubMed, Scopus and Web of Science were searched with the following strategy: “Chlamydia trachomatis” AND “micro*”. The diversity indices considered for the meta-analysis were Operational Taxonomic Unit (OTU) number, Chao1, phylogenetic diversity whole tree, Shannon’s, Pielou’s and Simpson’s diversity indexes. The search yielded 425 abstracts for initial review, of which 16 met the inclusion criteria. The results suggested that the cervicovaginal microbiota in C. trachomatis-positive women was characterized by Lactobacillus iners dominance, or by a diverse mix of facultative or strict anaerobes. The meta-analysis, instead, did not show any difference in the microbial biodiversity between Chlamydia-positive and healthy women. Additional research is clearly required to deepen our knowledge on the interplay between the resident microflora and C. trachomatis in the genital microenvironment.     

Donor Heart Preservation with Hydrogen Sulfide: A Systematic Review and Meta-Analysis

Preclinical studies have shown that postconditioning with hydrogen sulfide (H₂S) exerts cardioprotective effects against myocardial ischemia-reperfusion injury (IRI). The aim of this study was to appraise the current evidence of the cardioprotective effects of H₂S against IRI in order to explore the future implementation of H₂S in clinical cardiac transplantation. The current literature on H₂S postconditioning in the setting of global myocardial ischemia was systematically reviewed and analyzed, performing meta-analyses. A literature search of the electronic databases Medline, Embase and Cinahl identified 1835 studies that were subjected to our pre-defined inclusion criteria. Sixteen studies were considered eligible for inclusion. Postconditioning with H₂S showed significant robust effects with regard to limiting infarct size (standardized mean difference (SMD) = −4.12, 95% CI [−5.53–−2.71], p < 0.00001). Furthermore, H₂S postconditioning consistently resulted in a significantly lower release of cardiac injury markers, lower levels of oxidative stress and improved cardiac function. Postconditioning with slow-releasing H₂S donors offers a valuable opportunity for novel therapies within cardiac preservation for transplantation. Before clinical implication, studies evaluating the long-term effects of H₂S treatment and effects of H₂S treatment in large animal studies are warranted.     

Early Pregnancy Biomarkers in Pre-Eclampsia: A Systematic Review and Meta-Analysis

Pre-eclampsia (PE) complicates 2%–8% of all pregnancies and is an important cause of perinatal morbidity and mortality worldwide. In order to reduce these complications and to develop possible treatment modalities, it is important to identify women at risk of developing PE. The use of biomarkers in early pregnancy would allow appropriate stratification into high and low risk pregnancies for the purpose of defining surveillance in pregnancy and to administer interventions. We used formal methods for a systematic review and meta-analyses to assess the accuracy of all biomarkers that have been evaluated so far during the first and early second trimester of pregnancy to predict PE. We found low predictive values using individual biomarkers which included a disintegrin and metalloprotease 12 (ADAM-12), inhibin-A, pregnancy associated plasma protein A (PAPP-A), placental growth factor (PlGF) and placental protein 13 (PP-13). The pooled sensitivity of all single biomarkers was 0.40 (95% CI 0.39–0.41) at a false positive rate of 10%. The area under the Summary of Receiver Operating Characteristics Curve (SROC) was 0.786 (SE 0.02). When a combination model was used, the predictive value improved to an area under the SROC of 0.893 (SE 0.03). In conclusion, although there are multiple potential biomarkers for PE their efficacy has been inconsistent and comparisons are difficult because of heterogeneity between different studies. Therefore, there is an urgent need for high quality, large-scale multicentre research in biomarkers for PE so that the best predictive marker(s) can be identified in order to improve the management of women destined to develop PE.     

Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis

Renal fibrosis (RF) constitutes the common end-point of all kinds of chronic kidney disease (CKD), regardless of the initial cause of disease. The aim of the present study was to identify the key players of fibrosis in the context of diabetic nephropathy (DN). A systematic review and meta-analysis of all available genetic association studies regarding the genes that are included in signaling pathways related to RF were performed. The evaluated studies were published in English and they were included in PubMed and the GWAS Catalog. After an extensive literature review and search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, eight signaling pathways related to RF were selected and all available genetic association studies of these genes were meta-analyzed. ACE, AGT, EDN1, EPO, FLT4, GREM1, IL1B, IL6, IL10, IL12RB1, NOS3, TGFB1, IGF2/INS/TH cluster, and VEGFA were highlighted as the key genetic components driving the fibrosis process in DN. The present systematic review and meta-analysis indicate, as key players of fibrosis in DN, sixteen genes. However, the results should be interpreted with caution because the number of studies was relatively small.     

The Protective Effects of the Autophagic and Lysosomal Machinery in Vascular and Valvular Calcification: A Systematic Review

Background: Autophagy is a highly conserved catabolic homeostatic process, crucial for cell survival. It has been shown that autophagy can modulate different cardiovascular pathologies, including vascular calcification (VCN). Objective: To assess how modulation of autophagy, either through induction or inhibition, affects vascular and valvular calcification and to determine the therapeutic applicability of inducing autophagy. Data sources: A systematic review of English language articles using MEDLINE/PubMed, Web of Science (WoS) and the Cochrane library. The search terms included autophagy, autolysosome, mitophagy, endoplasmic reticulum (ER)-phagy, lysosomal, calcification and calcinosis. Study characteristics: Thirty-seven articles were selected based on pre-defined eligibility criteria. Thirty-three studies (89%) studied vascular smooth muscle cell (VSMC) calcification of which 27 (82%) studies investigated autophagy and six (18%) studies lysosomal function in VCN. Four studies (11%) studied aortic valve calcification (AVCN). Thirty-four studies were published in the time period 2015–2020 (92%). Conclusion: There is compelling evidence that both autophagy and lysosomal function are critical regulators of VCN, which opens new perspectives for treatment strategies. However, there are still challenges to overcome, such as the development of more selective pharmacological agents and standardization of methods to measure autophagic flux.     

Meta-Analysis of miR-146a Polymorphisms Association with Coronary Artery Diseases and Ischemic Stroke

Coronary artery disease (CAD) and ischemic stroke (IS) are manifestations of atherosclerosis, with a high death rate. miR-146a is a microRNA that participates in the progress of CAD and IS. A single nucleotide polymorphism (SNP) in the precursor of miR-146a, rs2910164, was found to be associated with the risks of CAD and IS. However, the results were inconsistent and inconclusive. A meta-analysis was performed to assess the relationship of rs2910164 and CAD as well as IS susceptibility. The database Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) were searched for related studies. Crude odds ratios with 95% confidence intervals were used to investigate the strength of the association by random- or fixed-effect model. A total of eight studies, with 3138 cases and 3097 controls were identified for the meta-analysis. The results shows that rs2910164 is associated with the risk of CAD significantly in allelic model (OR = 0.86), homozygous model (OR = 0.70), heterozygous model (OR = 0.80) and dominant model (OR = 0.76). The subjects carrying the GG genotype, GG + GC genotype or G allele are at lower risks of CAD. For the susceptibility of IS, there are no significant associations between rs2910164 and total studies. However, in subgroup analysis by sample size and ethnicity, the GG, GG + GC and G allele of rs2910164 are found to be associated with higher risks of IS in large sample size group and in Koreans, under homozygous and dominant models. In conclusion, the current meta-analysis suggests lower risks of CAD for GG, GG + GC genotype and G allele of rs2910164, while rs2910164 is not associated with the risk of IS. Thus rs2910164 might be recommended as a predictor for susceptibility of CAD, but not IS.     

Diagnostic Value of Salivary miRNA in Head and Neck Squamous Cell Cancer: Systematic Review and Meta-Analysis

Several studies have highlighted the diagnostic potential of salivary microRNA (miRNA) in head and neck squamous cell cancer (HNSCC). The purpose of this meta-analysis was to summarize published studies and evaluate the diagnostic accuracy of salivary miRNA in HNSCC detection. In this meta-analysis, we systematically searched PubMed, EMBASE, and Cochrane Library databases for studies on miRNA and HNSCC diagnosis. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with a summary receiver-operating characteristic curve were calculated using a bivariate random-effect meta-analysis model. Furthermore, subgroup analyses were conducted to explore the main sources of heterogeneity. Seventeen studies from ten articles, including 23 miRNA and a total of 759 subjects, were included in this meta-analysis. The pooled sensitivity and specificity of salivary miRNA in the diagnosis of HNSCC were 0.697 (95% CI: 0.644–0.744) and 0.868 (95% CI: 0.811–0.910), respectively. The overall area under the curve was 0.803 with a DOR of 12.915 (95% CI: 9.512–17.534). Salivary miRNAs are a promising non-invasive diagnostic biomarker with moderate accuracy for HNSCC. These results must be verified by large-scale prospective studies.     

Hallmarks of Cancer Expression in Oral Lichen Planus: A Scoping Review of Systematic Reviews and Meta-Analyses

Oral lichen planus (OLP) is a common chronic inflammatory disease of unknown etiology and likely autoimmune nature that is currently considered an oral potentially malignant disorder, implying that patients suffering from this process are at risk of developing oral cancer in their lifetime. The molecular alterations that develop in OLP and that make the affected oral epithelium predisposed to malignancy are unknown, although, as in other autoimmune diseases (ulcerative colitis, primary biliary cirrhosis, etc.), they may be linked to oncogenesis-promoting effects mediated by the inflammatory infiltrate. So far there is no in-depth knowledge on how these hallmarks of cancer are established in the cells of the oral epithelium affected by OLP. In this scoping review of systematic reviews and meta-analyses the state of evidence based knowledge in this field is presented, to point out gaps of evidence and to indicate future lines of research. MEDLINE, Embase, Cochrane Library and Dare were searched for secondary-level studies published before October 2022. The results identified 20 systematic reviews and meta-analyses critically appraising the hallmarks tumor-promoting inflammation (n = 17, 85%), sustaining proliferative signaling (n = 2, 10%), and evading growth suppressors (n = 1, 5%). No evidence was found for the other hallmarks of cancer in OLP. In conclusion, OLP malignization hypothetically derives from the aggressions of the inflammatory infiltrate and a particular type of epithelial response based on increased epithelial proliferation, evasion of growth-suppressive signals and lack of apoptosis. Future evidence-based research is required to support this hypothesis.     

A Review of the Effect of Diet on Cardiovascular Calcification

Cardiovascular (CV) calcification is known as sub-clinical atherosclerosis and is recognised as a predictor of CV events and mortality. As yet there is no treatment for CV calcification and conventional CV risk factors are not consistently correlated, leaving clinicians uncertain as to optimum management for these patients. For this reason, a review of studies investigating diet and serum levels of macro- and micronutrients was carried out. Although there were few human studies of macronutrients, nevertheless transfats and simple sugars should be avoided, while long chain ω-3 fats from oily fish may be protective. Among the micronutrients, an intake of 800 μg/day calcium was beneficial in those without renal disease or hyperparathyroidism, while inorganic phosphorus from food preservatives and colas may induce calcification. A high intake of magnesium (≥380 mg/day) and phylloquinone (500 μg/day) proved protective, as did a serum 25(OH)D concentration of ≥75 nmol/L. Although oxidative damage appears to be a cause of CV calcification, the antioxidant vitamins proved to be largely ineffective, while supplementation of α-tocopherol may induce calcification. Nevertheless other antioxidant compounds (epigallocatechin gallate from green tea and resveratrol from red wine) were protective. Finally, a homocysteine concentration >12 µmol/L was predictive of CV calcification, although a plasma folate concentration of >39.4 nmol/L could both lower homocysteine and protect against calcification. In terms of a dietary programme, these recommendations indicate avoiding sugar and the transfats and preservatives found in processed foods and drinks and adopting a diet high in oily fish and vegetables. The micronutrients magnesium and vitamin K may be worthy of further investigation as a treatment option for CV calcification.     

Janus Kinase Inhibitors Improve Disease Activity and Patient-Reported Outcomes in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of 24,135 Patients

Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.     

Biomarkers of Genotoxicity in Medical Workers Exposed to Low-Dose Ionizing Radiation: Systematic Review and Meta-Analyses

Medical staff represent the largest group of workers occupationally exposed to ionizing radiation (IR). Chronic exposure to low-dose IR may result in DNA damage and genotoxicity associated with increased risk of cancer. This review aims to identify the genotoxicity biomarkers that are the most elevated in IR-exposed vs. unexposed health workers. A systematic review of the literature was performed to retrieve relevant studies with various biomarkers of genotoxicity. Subsequent meta-analyses produced a pooled effect size for several endpoints. The search procedure yielded 65 studies. Chromosome aberrations (CA) and micronuclei (MN) frequencies were significantly different between IR-exposed and unexposed workers (θ_pooled = 3.19, 95% CI 1.46–4.93; and θ_pooled = 1.41, 95% CI 0.97–1.86, for total aberrant cells and MN frequencies, respectively), which was not the case for ring chromosomes and nucleoplasmic bridges. Although less frequently used, stable translocations, sister chromatid exchanges (SCE) and comet assay endpoints were also statistically different between IR-exposed and unexposed workers. This review confirms the relevance of CA and MN as genotoxicity biomarkers that are consistently elevated in IR-exposed vs. unexposed workers. Other endpoints are strong candidates but require further studies to validate their usefulness. The integration of the identified biomarkers in future prospective epidemiological studies is encouraged.     

Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review

Takotsubo syndrome (TTS), recognized as stress’s cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.     

Coronary Artery Ectasia: Review of the Non-Atherosclerotic Molecular and Pathophysiologic Concepts

Coronary artery ectasia (CAE) is frequently encountered in clinical practice, conjointly with atherosclerotic CAD (CAD). Given the overlapping cardiovascular risk factors for patients with concomitant CAE and atherosclerotic CAD, a common underlying pathophysiology is often postulated. However, coronary artery ectasia may arise independently, as isolated (pure) CAE, thereby raising suspicions of an alternative mechanism. Herein, we review the existing evidence for the pathophysiology of CAE in order to help direct management strategies towards enhanced detection and treatment.     

Endothelial Nitric Oxide Synthase (eNOS) 4b/a Gene Polymorphisms and Coronary Artery Disease: Evidence from a Meta-Analysis

A variety of studies have suggested that the 4b/a polymorphism in the endothelial nitric oxide synthase (eNOS) was associated with coronary artery disease (CAD) risk. However, the data remain conflicting. The aim of the present meta-analysis was to estimate the overall association between risk of CAD and eNOS 4b/a polymorphism. Case-control, cohort or cross-sectional studies evaluating the association between eNOS 4b/a polymorphism and CAD susceptibility were systematically identified in PubMed up to 31 October 2013. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated to assess the association in overall and subgroup analyses. A total of 10,617 cases and 8302 controls from 37 studies were included in the study. The results of overall analysis revealed significant positive associations between CAD risk and eNOS 4b/a polymorphism in homozygote comparisons (OR = 1.47, 95% CI = 1.16–1.87), heterozygote comparisons (OR = 1.14, 95% CI = 1.02–1.27) and dominant models (OR = 1.18, 95% CI = 1.06–1.33). In subgroup analyses, similar associations were identified in African individuals, as determined using population-based source subgroups and noted in small-and-moderate sample size subgroups (case sample size or control sample size <500). The current meta-analysis revealed that eNOS 4b/a polymorphisms could be a risk factor for developing CAD, particularly in African populations and population-based subgroups.     

The Diagnostic Performance of Ultrasonography in the Evaluation of Extrathyroidal Extension in Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

Extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) is an indication of disease progression and can influence treatment aggressiveness. This meta-analysis assesses the diagnostic accuracy of ultrasonography (US) in detecting ETE. A systematic review and meta-analysis were performed by searching PubMed, Embase, and Cochrane for studies published up to April 2022. The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated. The areas under the curve (AUC) for summary receiver operating curves were compared. A total of 11 studies analyzed ETE in 3795 patients with PTC. The sensitivity of ETE detection was 76% (95%CI = 74–78%). The specificity of ETE detection was 51% (95%CI = 49–54%). The DOR of detecting ETE by US was 5.32 (95%CI = 2.54–11.14). The AUC of ETE detection was determined to be 0.6874 ± 0.0841. We report an up-to-date analysis elucidating the diagnostic accuracy of ETE detection by US. Our work suggests the diagnostic accuracy of US in detecting ETE is adequate. Considering the importance of ETE detection on preoperative assessment, ancillary studies such as adjunct imaging studies and genetic testing should be considered.     

Long-Term Efficacy of Intranasal Esketamine in Treatment-Resistant Major Depression: A Systematic Review

Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.     

Association between Phosphatase Related Gene Variants and Coronary Artery Disease: Case-Control Study and Meta-Analysis

Recent studies showed that the serum alkaline phosphatase is an independent predictor of the coronary artery disease (CAD). In this work, we aimed to summarize the association between three phosphatase related single nucleotide polymorphisms (rs12526453, rs11066301 and rs3828329) and the risk of CAD in Han Chinese. Our results showed that the rs3828329 of the ACP1 gene was closely related to the risk of CAD in Han Chinese (OR = 1.45, p = 0.0006). This significant association of rs3828329 with CAD was only found in the females (Additive model: OR = 1.80, p = 0.001; dominant model: OR = 1.69, p = 0.03; recessive model: OR = 1.96, p = 0.0008). Moreover, rs3828329 was likely to exert its effect in females aged 65 years and older (OR = 2.27, p = 0.001). Further meta-analyses showed that the rs12526453 of PHACTR11 gene (OR = 1.14, p < 0.0001, random-effect method) and the rs11066301 of PTPN11 gene (OR = 1.15, p < 0.0001, fixed-effects method) were associated with CAD risk in multiple populations. Our results showed that the polymorphisms rs12526453 and rs11066301 are significantly associated with the CAD risk in multiple populations. The rs3828329 of ACP1 gene is also a risk factor of CAD in Han Chinese females aged 65 years and older.     

CTLA4-Linked Autoimmunity in the Pathogenesis of Endometriosis and Related Infertility: A Systematic Review

Several studies, although with conflicting results, have sought to determine the concentration of soluble CTLA4 antigens in peripheral blood plasma and peritoneal fluid in patients with endometriosis-related infertility. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) through a search of the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library, Health Technology Assessment Database and Web of Science, and Clinical Trials research register. We included observational or prospective human and animal studies with any features related to endometriosis and/or infertility studies involving CTLA4-related pathogenesis published in English. The results of studies in which the size and characteristics of the observed groups were not stated were excluded. From the initial pool of 73 publications identified and screened, we finally included 5 articles to summarize the most recent knowledge about CTLA4-linked autoimmunity in the pathogenesis of endometriosis and related infertility. Evidence from clinical studies shows that CTLA4-based autoimmunity is involved in the maintenance of chronic inflammation in the peritoneal environment, with pre-clinical evidence of anti-CTLA antibodies as a potential novel target therapy for endometriosis. However, CTLA4 gene analyses do not support findings of CTLA4-linked autoimmunity as a primary determinant of the pathogenesis of endometriosis. These findings underlie the role of complex interactions within the family of immune checkpoint molecules involved. Further studies are needed to investigate the clinical relevance of anti-CTLA target therapy, taking into account the potential adverse events and repercussions of novel immunologic therapy modalities. However, with the general scarcity of studies investigating this topic, the clinical importance of CTLA4 autoimmunity still remains unclear.