Cardiovascular disease therapeutics via engineered oral microbiota: Applications and perspective.

Engineering bacteria are considered as a potential treatment for cardiovascular diseases and related risk factors. Oral bacteria are closely related to the occurrence and development of cardiovascular diseases, and their engineering has broad prospects and potential in the treatment of cardiovascular diseases. Oral pathogenic bacteria undergo protein and genetic engineering, including the incorporation of exogenous plasmids to yield therapeutic effects; genetically engineered oral probiotics can be harnessed to secrete cytokines and reactive oxygen species, offering novel therapeutic avenues for cardiovascular diseases.

Identification and Validation of a Cancer-Testis Antigen-Related Signature to Predict the Prognosis in Stomach Adenocarcinoma.

Background: Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate in the pathogenesis and development of multiple cancers and are aberrantly overexpressed in various types of cancer. This study aimed to develop a CTA-related gene signature (CTARSig) to predict prognosis in STAD patients and explore its underlying mechanisms. Methods: We performed differential and prognostic analyses of CTA-related genes and constructed a CTA-related signature (CTARSig) along with a novel nomogram to predict the prognosis of patients with STAD based on the Cox and The Least Absolute Shrinkage and Selection Operator. CTARSig was further validated in an external cohort (GSE84437). Additionally, univariate and multivariate Cox regression, as well as receiver operating characteristic (ROC) analyses, were performed to assess the CTARSig systematically. Single-sample gene set enrichment analysis and ESTIMATE were used to characterise the Tumor Immune Microenvironment (TIME) in patients with STAD. Furthermore, Gene Set Variation Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology analyses revealed the biological functions and signalling pathways associated with CTARSig. Finally, the human gastric cancer cell lines, HCG-27 and AGS, were used for in vitro and in vivo experiments, respectively, to further validate the role of ELOVL4. Results: Eleven CTA-related genes were identified to construct the CTARSig. Kaplan-Meier curves, independent prognostic analysis, and ROC curves revealed that CTARSig could better predict survival in patients with STAD. Moreover, in our study, we demonstrated that ELOVL4 is upregulated in gastric cancer tissues and that its high expression is associated with poor survival. Additionally, in vitro and in vivo experiments demonstrated that ELOVL4 promotes the metastatic and invasive potential of STAD cells, suggesting it may be a potential therapeutic target for STAD. Conclusion: In this study, a novel signature associated with CTAs was constructed for STAD, which may be a good predictor of patient prognosis. Thus, ELOVL4 may be a potential therapeutic target for gastric cancer. This study provides new insights into the potential roles of CTAs in gastric cancer.

Association of cerebral palsy with autism spectrum disorder and attention-deficit/hyperactivity disorder in children: a large-scale nationwide population-based study.

OBJECTIVE: To examine the association of cerebral palsy with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), providing evidence for interdisciplinary medical service for children with cerebral palsy. DESIGN: A large-scale nationwide population-based study. SETTING: The National Health Interview Survey (NHIS). PATIENTS: 177 899 children aged 3-17 years among NHIS participants from 1997 to 2003 and 2008 to 2018. RESULTS: Among the 177 899 children included in this analysis, 602 (0.33%) had cerebral palsy, 1997 (1.16%) had ASD, and 13 697 (7.91%) had ADHD. Compared with children without cerebral palsy, children with cerebral palsy had a higher prevalence of ASD (6.09% vs 1.15%; p<0.001) and ADHD (15.91% vs 7.89%; p<0.001). After adjustment for age, sex, race/ethnicity, family highest education level, family income level and geographical region, the OR among children with cerebral palsy, compared with children without cerebral palsy, was 5.07 (95% CI 3.25 to 7.91) for ASD (p<0.001) and 1.95 (95% CI 1.43 to 2.66) for ADHD (p<0.001). Furthermore, the association of cerebral palsy with ASD and ADHD remained significant in all subgroups stratified by age, sex and race. CONCLUSION: In a large, nationally representative sample of US children, this study shows that children with cerebral palsy are at an increased risk of ASD and ADHD.

Using machine learning methods to analyze the association between urinary polycyclic aromatic hydrocarbons and chronic bowel disorders in American adults.

The etiology of chronic bowel disorders is multifaceted, with environmental exposure to harmful substances potentially playing a significant role in their pathogenesis. However, research on the correlation between polycyclic aromatic hydrocarbons (PAHs) and chronic bowel disorders remains limited. Using data from the National Health and Nutrition Examination Survey (NHANES) conducted in 2009-2010, we investigated the relationship between 9 PAHs and chronic diarrhea and constipation in U.S. adults. We employed unsupervised methods such as clustering and Principal Component Analysis (PCA) to identify participants with similar exposure patterns. Additionally, we used supervised learning techniques, namely weighted quantile sum (WQS) and Bayesian kernel machine (BKMR) regressions, to assess the association between PAHs and the occurrence of chronic diarrhea and chronic constipation. PCA identified three principal components in the unsupervised analysis, explaining 86.5% of the total PAH variability. The first component displayed a mild association with chronic diarrhea, but no correlation with chronic constipation. Participants were divided into three clusters via K-means clustering, based on PAH concentrations. Clusters with higher PAH exposure demonstrated an increased odds ratio for chronic diarrhea, but no meaningful connection with chronic constipation. In the supervised analysis, the WQS regression underscored a positive relationship between the PAH mixture and chronic diarrhea, with three PAHs significantly impacting the mixture effect. The mixture index showed no correlation with chronic constipation. BKMR analysis illustrated a positive trend in the impact of four specific PAHs on chronic diarrhea, given other metabolites were fixed at their 50th percentiles. Our results suggest a clear association between higher PAH exposure and an increased risk of chronic diarrhea, but not chronic constipation. It also underscores the potential role of specific PAHs in contributing to the risk of chronic diarrhea.

The cancer/testis antigen HORMAD1 promotes gastric cancer progression by activating the NF-κB signaling pathway and inducing epithelial-mesenchymal transition.

OBJECTIVES: HORMAD1 is a cancer/testis antigen (CTAs) that regulates DNA homologous recombination, mismatch repair, and other tumor characteristics. However, its role and regulatory mechanisms in gastric cancer remain unclear. METHODS: We performed transcriptomic profiling on seven gastric cancers and paired tissues; HORMAD1 was significantly upregulated in gastric cancer samples and was related to poor prognosis survival. Furthermore, cancer pathway microarray, bioinformatic analysis, western blot, and immunochemistry assay demonstrated that HORMAD1 affected the NF-κB signaling pathway. RESULTS: In vitro and vivo studies confirmed that HORMAD1 knockdown inhibited cell growth and invasion, whereas overexpression reversed these effects. Mechanistically, HORMAD1 regulates the epithelial-mesenchymal transition process (EMT) via the NF-κB pathway by increasing the phosphorylation levels of NF-κB (p-65) and Iκκ-ß. Downstream target genes of the NF-κB signaling pathway, such as c-Myc, CyclinD1, may be involved in HORMAD1-induced tumorigenesis in gastric cancer (GC). CONCLUSIONS: HORMAD1 plays an important role in gastric cancer progression and could be a promising prognostic biomarker and therapeutic target.

The indicative role of inflammatory index in the progression of periodontal attachment loss.

OBJECTIVE: To explore the forewarning immunological indicators during periodontal attachment loss progression in American adults. METHODS: A total of 5744 participants with periodontal attachment loss were enrolled from the National Health and Nutrition Examination Surveys (NHANES) 2009-2014. In which, dependent variable was the counts of teeth with severe attachment loss (depth of periodontal probing was above 5 mm). Independent variables were circulatory immunological indexes, including counts of white blood cells (WBC), Lymphocytes, Monocytes, Neutrophils, Eosinophils, and Basophils. The association among variables was examined using multivariable linear regression models, fitting with smoothing curves, and generalizing additive models. RESULTS: Based on the indicators of 5744 subjects, we found that severe attachment loss tended to occur in the elderly or males and was accompanied by higher WBC, Monocytes, and Neutrophils, as well as lower poverty-income ratio and educational qualification. WBC (above the inflection point: 6200 cells/µL) and Neutrophils (above the inflection point: 3300 cells/µL) counts were positively associated with attachment loss progression in each multivariable linear regression model. On subgroup analyses, stratified by sex and race, the positive correlation of WBC or Neutrophils with severe attachment loss was stable in both men and women, as well as in all races except blacks (WBC ß = - 0.0576, 95% CI - 0.1945 to 0.0793, Neutrophils ß = - 0.0527, 95% CI - 0.2285 to 0.1231). CONCLUSION: Increasing WBC (above 6200 cells/µL) and Neutrophils (above 3300 cells/µL) counts were risk indicators of severe periodontal attachment loss among all races, except in blacks.

Using three statistical methods to analyze the association between aldehyde exposure and markers of inflammation and oxidative stress.

BACKGROUND: Exposure to aldehydes has been linked to adverse health outcomes such as inflammation and oxidative stress, but research on the effects of these compounds is limited. This study is aimed at assessing the association between aldehyde exposure and markers of inflammation and oxidative stress. METHODS: The study used data from the NHANES 2013-2014 survey (n = 766) and employed multivariate linear models to investigate the relationship between aldehyde compounds and various markers of inflammation (alkaline phosphatase (ALP) level, absolute neutrophil count (ANC), and lymphocyte count) and oxidative stress (bilirubin, albumin, and iron levels) while controlling for other relevant factors. In addition to generalized linear regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) analyses were applied to examine the single or overall effect of aldehyde compounds on the outcomes. RESULTS: In the multivariate linear regression model, each 1 standard deviation (SD) change in propanaldehyde and butyraldehyde was significantly associated with increases in serum iron levels (beta and 95% confidence interval, 3.25 (0.24, 6.27) and 8.40 (0.97, 15.83), respectively) and the lymphocyte count (0.10 (0.04, 0.16) and 0.18 (0.03, 0.34), respectively). In the WQS regression model, a significant association was discovered between the WQS index and both the albumin and iron levels. Furthermore, the results of the BKMR analysis showed that the overall impact of aldehyde compounds was significantly and positively correlated with the lymphocyte count, as well as the levels of albumin and iron, suggesting that these compounds may contribute to increased oxidative stress. CONCLUSIONS: This study reveals the close association between single or overall aldehyde compounds and markers of chronic inflammation and oxidative stress, which has essential guiding value for exploring the impact of environmental pollutants on population health.

Myoglobin and left ventricular ejection fraction as predictive markers for death in children with fulminant myocarditis.

Background: Fulminant myocarditis (FM) is an inflammatory process of the myocardium and an important cause of cardiac dysfunction in children; it is characterized by rapid onset, acute progression, and high mortality. The study sought to describe the clinical characteristics and prognostic factors in children with FM. Methods: The study population consists of 37 consecutive patients admitted from May 2014 to December 2021 with a diagnosis of FM. According to the prognosis of children with FM during hospitalization, they were divided into "survival" group (25 cases) and "death" group (12 cases). A multivariate logistic regression analysis was performed to identify the independent predictors of in-hospital mortality in the patients, and receiver operating characteristic (ROC) curve was used to explore the predictive value of related factors. Results: The 37 children with FM had an average age of 8.35 ± 4.36 years old. Twenty-five of the patients survived and 12 died. Twenty-five of the children were discharged from the hospital after a series of active rescue treatments such as nutritional myocardial drugs, high-dose intravenous immunoglobulin (IVIG), glucocorticoids (GCs), temporary pacemaker (TP), extracorporeal membrane oxygenation (ECMO), and continuous renal replacement therapy (CRRT).Twelve of the children were classified into the death group because the resuscitation failed. The levels of procalcitonin (PCT), creatine kinase (CK), and myoglobin (MYO) in the death group were all higher than in the survival group (all P < 0.05), and the left ventricular ejection fraction (LVEF) in the death group was significantly lower than in the survival group (P = 0.002). The binary logistic regression analysis revealed that MYO [OR:1.006; 95%CI:(1-1.012); P = 0.045] and LVEF [OR: 0.876; 95% CI: (0.785-0.978); P = 0.019] were independent predictors of FM. ROC curve analysis showed that the area under ROC curve (AUC) of MYO and LVEF was [AUC:0.957; 95%CI:0.897~1] and [AUC:0.836; 95%CI:0.668~1], and the area under the combined ROC curve for MYO + LVEF was significantly higher than that for MYO or LVEF alone (P < 0.05), indicating that the MYO + LVEF combined diagnosis had a higher predictive value for FM. Conclusion: The levels of MYO and LVEF can be markers for prognosis of FM and can effectively evaluate the disease severity. Their combination can improve forecast accuracy; thus, the detection of the above-mentioned indexes possesses a higher value for clinical applications.

Additional Adverse Perinatal Outcomes With No Effect on Neonatal Mortality and Birth Defects in Pregnancies Conceived by Assisted Reproductive Technology.

Background: Pregnancy outcomes and perinatal diseases of children conceived by assisted reproductive technology (ART) and spontaneous conception (SC) are still unclear. We sought to compare the effects of ART and SC on adverse neonatal outcomes. Methods: We included 5,913 neonates admitted to the neonatal intensive care unit (NICU) of the First Affiliated Hospital of the University of Science and Technology of China between January 2017 and December 2020. There were 1,112 (18.8%) ART pregnancies and 4,801 (81.2%) SC pregnancies. Data on maternal characteristics, comorbidities during pregnancy, and neonatal outcomes were collected and analyzed. Logistic regression models estimated the odds ratios (ORs) and 99% CIs of neonatal outcomes according to ART pregnancy. Neonatal outcomes primarily included neonatal respiratory distress syndrome (NRDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neonatal anemia, birth defects, and mortality. Results: Among 5,913 neonates, 485 (8.2%) had NRDS, 165 (2.8%) had BPD, 113 (1.9%) had ROP, 602 (10.2%) had neonatal anemia, and 1,112 (18.8%) were ART infants. The incidence of pregnancy-related complications, such as gestational diabetes mellitus (GDM), gestational hypothyroidism, and rheumatic immune diseases, in mothers receiving ART, was higher than that in the SC group. On multivariate analysis, ART was independently associated with NRDS (OR = 1.46; 95% CI, 1.11-1.93; p = 0.008) and ROP (OR = 1.79; 95% CI, 1.06-3.05; p = 0.031). Moreover, the association persisted after adjustment for maternal age, history of cesarean section, preconception factors, and pregnancy complications. For BPD (OR = 1.44; 95% CI, 0.91-2.27; p = 0.117) and neonatal anemia (OR = 1.12; 95% CI, 0.87-1.45; p = 0.373), the associations were attenuated substantially when adjusting for pregnancy complications. ART was associated with neither birth defects (OR = 0.98; 95% CI, 0.77-1.25; p = 0.889) nor mortality (OR = 0.98; 95% CI, 0.51-1.91; p = 0.961). Conclusion: ART was independently associated with adverse neonatal outcomes, including NRDS and ROP. Therefore, women who conceive by ART must improve their perinatal health and management of pregnancy-related comorbidities to enhance the quality of life of their offspring.

Serum vitamin E concentration is negatively associated with body mass index change in girls not boys during adolescence.

BACKGROUND: Vitamin E is the most abundant lipid-soluble antioxidants present in plasma; however, the relationship between serum vitamin E and change in body mass index (BMI)-for-age Z scores in adolescents has not been well described. METHODS: This study is a cross-sectional study. Data were analyzed from 4014 adolescents who participated in the National Health and Nutrition Examination Survey. The nutritional status was calculated by BMI Z scores and was classified into normal weight, overweight, and obese. Multivariable-adjusted logistic regression was used to examine the association between serum vitamin E levels with overweight/obesity. Besides, the interaction effects between potential confounders and vitamin E on obesity were further evaluated. RESULTS: After adjusting potential confounders, serum vitamin E levels were negatively associated with overweight/obesity in girls but not in boys. Per standard deviation increment in vitamin E concentrations was associated with a 92% decreased risk of obesity in females. Besides, lower quartiles of serum vitamin E were associated with a higher risk of overweight/obesity in girls. Moreover, the inverse association between serum vitamin E levels and obesity was also found in most subgroups through subgroup analysis. CONCLUSIONS: Our study supports the negative association between serum vitamin E levels and overweight/obesity in adolescents. A higher serum vitamin E level may be associated with a reduced probability of obesity in girls, but not in boys.

In vitro Assessment of Myocardial Protection following Hypothermia-Preconditioning in a Human Cardiac Myocytes Model.

Ischemia/reperfusion-derived myocardial dysfunction is a common clinical scenario in patients after cardiac surgery. In particular, the sensitivity of cardiomyocytes to ischemic injury is higher than that of other cell populations. At present, hypothermia affords considerable protection against an expected ischemic insult. However, investigations into complex hypothermia-induced molecular changes remain limited. Therefore, it is essential to identify a culture condition similar to in vivo conditions that can induce damage similar to that observed in the clinical condition in a reproducible manner. To mimic ischemia-like conditions in vitro, the cells in these models were treated by oxygen/glucose deprivation (OGD). In addition, we applied a standard time-temperature protocol used during cardiac surgery. Furthermore, we propose an approach to use a simple but comprehensive method for the quantitative analysis of myocardial injury. Apoptosis and expression levels of apoptosis-associated proteins were assessed by flow cytometry and using an ELISA kit. In this model, we tested a hypothesis regarding the effects of different temperature conditions on cardiomyocyte apoptosis in vitro. The reliability of this model depends on strict temperature control, controllable experimental procedures, and stable experimental results. Additionally, this model can be used to study the molecular mechanism of hypothermic cardioprotection, which may have important implications for the development of complementary therapies for use with hypothermia.

The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES.

Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration.

MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in the hyperhomocysteinemia, which is a risk factor related to the occurrence of congenital heart defect (CHD). However, the association between MTHFR polymorphism and CHD has been inconclusive. METHODS: We conducted an updated meta-analysis to provide comprehensive evidence on the role of MTHFR A1298C polymorphism in CHD. Databases were searched and a total of 16 studies containing 2207 cases and 2364 controls were included. RESULTS: We detected that a significant association was found in the recessive model (CC vs. AA + AC: OR = 1.38, 95% CI: 1.10-1.73) for the overall population. Subgroup analysis showed that associations were found in patients without Down Syndrome in genetic models for CC vs. AA (OR = 1.47, 95% CI: 1.01-2.14), CC vs. AC (OR = 1.29, 95% CI: 1.00-1.66) and recessive model (OR = 1.44, 95% CI: 1.14-1.82). We conducted a meta-regression analysis, Galbraith plots and a sensitivity analysis to assess the sources of heterogeneity. CONCLUSIONS: In summary, our present meta-analysis supports the MTHFR 1298C allele as a risk factor for CHD. However, further studies should be conducted to investigate the correlation of plasma homocysteine levels, enzyme activity, and periconceptional folic acid supplementation with the risk of CHD.

Brain Development and Akt Signaling: the Crossroads of Signaling Pathway and Neurodevelopmental Diseases.

Neurodevelopmental biology, coupled with the application of advanced histological, imaging, molecular, cellular, biochemical, and genetic approaches, has provided new insights into these intricate genetic, cellular, and molecular events. During telencephalic development, specific neural progenitor cells (NPCs) proliferate, differentiate into numerous cell types, migrate to their apposite positions, and form an integrated circuitry. Critical disturbance to this dynamic process via genetic and environmental risk can cause neurological disorders and disability. The phosphatidylinositol-3-OH kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling cascade contributes to mediate various cellular processes, including cell proliferation and growth, and nutrient uptake. In light of its critical function, dysregulation of this node has been regarded as a root cause of several neurodevelopmental diseases, such as megalencephaly ("big brain"), microcephaly ("small brain"), autism spectrum disorders, intellectual disability, schizophrenia, and epilepsy. In this review, particular emphasis will be given to the PI3K-Akt-mTOR signaling pathway and their paramount importance in neurodevelopment of the cerebral neocortex, because of its critical roles in complex cognition, emotional regulation, language, and behaviors.