Common Biological Pathways Research Articles

Association Between Speech Reception Threshold in Noise and Multimorbidity: The UK Biobank Study.

To investigate the association between hearing function, as approached with the functional auditory capacity, and multimorbidity. Cross-sectional study. The UK Biobank was established from 2006 to 2010 in the United Kingdom. This cross-sectional analysis included 165,524 participants who provided baseline information on hearing function. Functional auditory capacity was measured with a digit triplet test. Three categories were defined according to the speech reception threshold in noise (SRTn): normal (SRTn < -5.5 dB signal-to-noise ratio [SNR]), insufficient (SRTn ≥ -5.5 to ≤ -3.5 dB SNR) and poor hearing function (SRTn > -3.5 dB SNR). To define multimorbidity, 9 chronic diseases were considered, including chronic obstructive pulmonary disease, dementia, Parkinson's disease, stroke, cancer, depression, osteoarthritis, coronary heart disease, and diabetes; multimorbidity was defined as the coexistence of 2 or more in the same individual. Analyses were conducted using logistic models adjusted for relevant confounders. Among the study participants, 54.5% were women, and the mean (range) age was 56.7 (39-72) years. The prevalence of insufficient and poor hearing function and multimorbidity was 13% and 13.2%, respectively. In comparison with having a normal SRTn, the odds ratio (95% confidence interval) of multimorbidity associated with insufficient SRTn was 1.13 (1.08-1.18), and with poor SRTn was 1.25 (1.14-1.37). Insufficient and poor hearing function was associated with multimorbidity. This association suggests common biological pathways for many of the considered morbidities.

Prenatal air pollution, maternal immune activation, and autism spectrum disorder

BackgroundAutism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter < 2.5 µm (PM2.5) and maternal immune activation (MIA) conditions. Because these exposures may share common biological effect pathways, we hypothesized that synergistic associations of prenatal air pollution and MIA-related conditions would increase ASD risk in children. ObjectivesThis study examined interactions between MIA-related conditions and prenatal PM2.5 or major PM2.5 components on ASD risk. MethodsIn a population-based pregnancy cohort of children born between 2001 and 2014 in Southern California, 318,751 mother–child pairs were followed through electronic medical records (EMR); 4,559 children were diagnosed with ASD before age 5. Four broad categories of MIA-related conditions were classified, including infection, hypertension, maternal asthma, and autoimmune conditions. Average exposures to PM2.5 and four PM2.5 components, black carbon (BC), organic matter (OM), nitrate (NO3–), and sulfate (SO42-), were estimated at maternal residential addresses during pregnancy. We estimated the ASD risk associated with MIA-related conditions, air pollution, and their interactions, using Cox regression models to adjust for covariates. ResultsASD risk was associated with MIA-related conditions [infection (hazard ratio 1.11; 95% confidence interval 1.05–1.18), hypertension (1.30; 1.19–1.42), maternal asthma (1.22; 1.08–1.38), autoimmune disease (1.19; 1.09–1.30)], with higher pregnancy PM2.5 [1.07; 1.03–1.12 per interquartile (3.73 μg/m3) increase] and with all four PM2.5 components. However, there were no interactions of each category of MIA-related conditions with PM2.5 or its components on either multiplicative or additive scales. ConclusionsMIA-related conditions and pregnancy PM2.5 were independently associations with ASD risk. There were no statistically significant interactions of MIA conditions and prenatal PM2.5 exposure with ASD risk.

The role of cytokines and Indolamine-2.3 dioxygenase in experiencing a psycho-neurological symptom cluster in hematological cancer patients: IL-1alpha, IL-1beta, IL-4, IL-6, TNF-alpha, kynurenine, and tryptophan

ObjectiveThis study examined (a) whether there are a subgroup of cancer patients experiencing the selected psycho-neurological symptoms as a cluster (depression, cognitive impairment, fatigue, sleep disturbance, and pain); (b) whether demographic and clinical characteristics and pro-inflammatory cytokines (IL-1α, IL-1β, IL-4, IL-6, TNF-alpha) are associated with subgroup membership; and (c) whether the activity of indolamine-2.3 dioxygenase(IDO) is associated with pro-inflammatory cytokine activity and psycho-neurological symptom cluster experience. MethodsThis was a prospective cohort study where 149 hematologic patients were recruited from a university hospital and 65 healthy volunteers provided control data. Latent profile analyses were conducted to identify subgroups at two time points: the last day of chemotherapy and 1 week after chemotherapy completion. Influencing factors of subgroup membership were examined by logistic regression. ResultsA substantial number of patients (33%, 34% at each time point) experienced the selected psycho-neurological symptoms as a cluster. Older age and elevated IL-1α and IL-6 were associated with experiencing the psycho-neurological symptom cluster. IDO activity was higher in the patients experiencing psycho-neurological symptom cluster; and was positively associated with IL-6. Symptom severity, IL-1α, IL-6, and IDO activity were all significantly higher in cancer patients than in the healthy controls. The findings were preserved across time points. ConclusionsThe activation of pro-inflammatory cytokines and their cross-talk with IDO may be a common biological mechanism, underlying a psycho-neurological symptom cluster experience. The novel approaches for symptom assessment and management can be developed by assessing multiple psycho-neurological symptoms as a cluster and by targeting their common biological pathway.

Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-analysis.

Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy. We searched articles until January 25, 2022, in MEDLINE, Embase, PsycInfo, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker's pooled standardized mean difference (SMD) and 95% CI. Molecular interaction network and enrichment analyses were conducted in Cytoscape (PROSPERO CRD42021297110). We included 22 studies with 1,499 cases with post-brain injury epilepsy and 7,929 controls without post-brain injury epilepsy. Forty-five biomarkers in the blood or CSF were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most of the biomarkers (28/45) were investigated in single studies; only 9 provided validation data, and studies used variable definitions for early-onset and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in 4 studies were significantly higher in patients with poststroke epilepsy (PSE) than those without PSE (SMD 0.44; CI 0.19-0.69). From individual studies, 15 biomarkers in the blood and 7 in the CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (interleukin [IL]-6, IL-1β]) were predominantly inflammation related. We cannot yet recommend using the reported biomarkers for designing antiepileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Although our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual's genetic susceptibilities might contribute to his/her risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted.

Plasma proteome of growing tumors

Early detection of cancer is vital for the best chance of successful treatment, but half of all cancers are diagnosed at an advanced stage. A simple and reliable blood screening test applied routinely would therefore address a major unmet medical need. To gain insight into the value of protein biomarkers in early detection and stratification of cancer we determined the time course of changes in the plasma proteome of mice carrying transplanted human lung, breast, colon, or ovarian tumors. For protein measurements we used an aptamer-based assay which simultaneously measures ~ 5000 proteins. Along with tumor lineage-specific biomarkers, we also found 15 markers shared among all cancer types that included the energy metabolism enzymes glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phophate isomerase and dihydrolipoyl dehydrogenase as well as several important biomarkers for maintaining protein, lipid, nucleotide, or carbohydrate balance such as tryptophanyl t-RNA synthetase and nucleoside diphosphate kinase. Using significantly altered proteins in the tumor bearing mice, we developed models to stratify tumor types and to estimate the minimum detectable tumor volume. Finally, we identified significantly enriched common and unique biological pathways among the eight tumor cell lines tested.

Clinical and Biological Predictors of Cancer Incidence and Mortality in Patients with Stable Coronary Artery Disease.

Clinical and epidemiological evidence has recently revealed a link between coronary artery disease (CAD) and cancer. Shared risk factors and common biological pathways are probably involved in both pathological conditions. The aim of this paper was to evaluate whether and which conventional risk factors and novel circulating biomarkers could predict cancer incidence and death in patients with CAD. The study included 750 CAD patients, who underwent blood sampling for the evaluation of systemic inflammatory indexes (NLR and SII) and specific biomarkers of oxidative damage (leukocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)). Study participants were followed up for a mean of 5.4 ± 1.2 years. Sixty-seven patients (8.9%) developed cancer during the follow-up time, and nineteen (2.5%) died of cancer. Cox multivariable analysis revealed that age (HR = 1.071; 95% CI: 1.034-1.109; p < 0.001), smoking habit (HR = 1.994; 95% CI: 1.140-3.488; p = 0.016), obesity (HR = 1.708; 95% CI: 1.022-2.854; p = 0.041) and SII (HR = 1.002; 95% CI: 1.001-1.003; p = 0.045) were associated with cancer incidence, while only age (HR = 1.132; 95% CI: 1.052-1.219; p = 0.001) was a predictor of cancer death. Patients with lung and gastrointestinal cancers had significantly higher median mtDNAcn levels than those without cancer. Our study suggests that aggressive risk factor modification and suppression of chronic inflammation may be essential to preventing cancer in CAD patients.

Schizophrenia and the COVID-19 pandemic: A narrative review from the biomedical perspective.

The outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in 2020 caused a rapid worsening of global mental health. Patients with severe mental disorders, including schizophrenia, are at higher risk of being infected. The neuroinvasive potential of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed. The aim of this article was to present a narrative and comprehensive review of multidimensional associations between schizophrenia and COVID-19 with special emphasis on common biological pathways. Online searches were performed in the PubMed database and covered the publication period until September 17, 2022. Search terms included "psychosis", "schizophrenia", "inflammation" and "COVID-19". Viewed as a neuroinflammatory state, schizophrenia shares several neurobiological mechanisms with the COVID-19. Environmental stress, common comorbidities of schizophrenia and adverse effects of antipsychotic treatment are associated with the higher severity and mortality of the COVID-19. Additionally, more frequent relapses of psychosis have been observed, and might be related to lower treatment adherence. In the context of clinical manifestation, higher level of negative symptoms has been identified among patients with schizophrenia during the pandemic. Improvements in mental health care policy and treatment adjustment are necessary to protect people with schizophrenia who are the population that is particularly vulnerable to the consequences of the COVID-19 pandemic. Future research will show if prenatal infection with the SARS-CoV-2 increases a risk of psychosis.

Identifying hub genes and common biological pathways between COVID-19 and benign prostatic hyperplasia by machine learning algorithms.

COVID-19, a serious respiratory disease that has the potential to affect numerous organs, is a serious threat to the health of people around the world. The objective of this article is to investigate the potential biological targets and mechanisms by which SARS-CoV-2 affects benign prostatic hyperplasia (BPH) and related symptoms. We downloaded the COVID-19 datasets (GSE157103 and GSE166253) and the BPH datasets (GSE7307 and GSE132714) from the Gene Expression Omnibus (GEO) database. In GSE157103 and GSE7307, differentially expressed genes (DEGs) were found using the "Limma" package, and the intersection was utilized to obtain common DEGs. Further analyses followed, including those using Protein-Protein Interaction (PPI), Gene Ontology (GO) function enrichment analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Potential hub genes were screened using three machine learning methods, and they were later verified using GSE132714 and GSE166253. The CIBERSORT analysis and the identification of transcription factors, miRNAs, and drugs as candidates were among the subsequent analyses. We identified 97 common DEGs from GSE157103 and GSE7307. According to the GO and KEGG analyses, the primary gene enrichment pathways were immune-related pathways. Machine learning methods were used to identify five hub genes (BIRC5, DNAJC4, DTL, LILRB2, and NDC80). They had good diagnostic properties in the training sets and were validated in the validation sets. According to CIBERSORT analysis, hub genes were closely related to CD4 memory activated of T cells, T cells regulatory and NK cells activated. The top 10 drug candidates (lucanthone, phytoestrogens, etoposide, dasatinib, piroxicam, pyrvinium, rapamycin, niclosamide, genistein, and testosterone) will also be evaluated by the P value, which is expected to be helpful for the treatment of COVID-19-infected patients with BPH. Our findings reveal common signaling pathways, possible biological targets, and promising small molecule drugs for BPH and COVID-19. This is crucial to understand the potential common pathogenic and susceptibility pathways between them.

The Impact of Abstinence on Serum Leptin Levels and on the Nutritional Profile of Alcoholics

Introduction: Alcohol use disorder (AUD) is associated with changes in metabolism and in the nutritional profile. Food-seeking behaviors and psychoactive substances share common biological pathways that activate the reward system and leptin is a modulator of this system. Objective: To measure serum leptin levels and nutritional status of individuals with before their detoxification and then 15 days later. Methods: In total, 38 men diagnosed with AUD and admitted to a detoxification unit were analyzed. Serum leptin levels, Body Mass Index (BMI), Waist Circumference (WC) and body composition were assessed by Bioelectrical Impedance Analysis (BIA) once within the first 48 hours of hospital admission and again 15 days after the first assessment. Results: Weight, BMI and WC increased significantly during detoxing (p&lt;0.001), but body fat and leptin levels percentages remained similar. At admission, leptin levels were positively correlated with body fat (0.607), WC (0.696), and BMI (0.357). After 15 days, only leptin and BMI were significantly correlated (0.462). Conclusion: Our results reinforce the relationship between leptin and nutritional parameters related to body weight. It is essential to educate about nutrition and to encourage healthy eating behaviors so individuals with AUD can reduce weight gain during the recovery period.

Hierarchical association of COPD to principal genetic components of biological systems.

Many disease-causing genetic variants converge on common biological functions and pathways. Precisely how to incorporate pathway knowledge in genetic association studies is not yet clear, however. Previous approaches employ a two-step approach, in which a regular association test is first performed to identify variants associated with the disease phenotype, followed by a test for functional enrichment within the genes implicated by those variants. Here we introduce a concise one-step approach, Hierarchical Genetic Analysis (Higana), which directly computes phenotype associations against each function in the large hierarchy of biological functions documented by the Gene Ontology. Using this approach, we identify risk genes and functions for Chronic Obstructive Pulmonary Disease (COPD), highlighting microtubule transport, muscle adaptation, and nicotine receptor signaling pathways. Microtubule transport has not been previously linked to COPD, as it integrates genetic variants spread over numerous genes. All associations validate strongly in a second COPD cohort.

Transcriptome alterations and therapeutic drugs in different organs after spinal cord injury based on integrated bioinformatic analysis

ObjectiveTo identify transcriptomic alterations and therapeutic drugs in different organs after spinal cord injury via comprehensive bioinformatics analyses. MethodsRNA-sequencing data of the soleus muscle, bladder, liver, raphe, and sensorimotor cortex areas in various rat spinal cord injury models were obtained from the Gene Expression Omnibus database for bioinformatics analysis. Then, the common pathways and biological pathway changes in multiple organs were identified. ResultsBy comparing the enrichment results of differentially expressed genes, inflammatory response and lipid metabolism were found to be significantly altered in multiple organs. The MAPK signaling pathway was a key pathway in the abovementioned biological processes. In addition, autonomous repair was observed in each organ. Finally, pharmacological analysis showed that coenzyme A might be an effective drug. ConclusionCoenzyme A is a candidate treatment drug for spinal cord injury. Hence, in addition to the current mechanisms targeted by anti-inflammatory approaches, lipid metabolism can also be a treatment target for spinal cord injury.

Common Clinical and Molecular Pathways between Migraine and Sarcoidosis.

Migraine and sarcoidosis are two distinct medical conditions that may have some common biological and clinical pathways. Sarcoidosis is a chronic granulomatous disease characterized by the formation of granulomas in various organs, including the lungs, skin, cardiovascular system, lymph nodes, and brain. Migraine is a common comorbidity in sarcoidosis patients and a common neurological disorder characterized by recurrent headaches that can be accompanied by other symptoms, such as nausea, vomiting, and sensitivity to light and sound. There have been several reports of individuals with neurosarcoidosis experiencing migraines, though the exact relationship between the two disorders is not well understood. Both conditions have been associated with inflammation and the activation of the immune system. In sarcoidosis, the formation of granulomas is thought to be an immune response to the presence of an unknown antigen. Similarly, the pain and other symptoms associated with migraines are thought to be caused by inflammation in the brain and the surrounding blood vessels. There is also evidence to suggest an interplay of environmental and genetic factors playing a role in both conditions, but evidence is inconsistent with the hypothesis of shared genetic susceptibility. This review aims to illustrate common clinical and biological pathways between migraine and sarcoidosis, including inflammation and dysregulation of the immune system, with a focus on the cumulative burden of concurrent disorders and therapeutic implications.

Biomarkers as prognostic determinants of epilepsy after post-acute central nervous system insults: a systematic review and meta-analysis (P3-5.017)

<h3>Objective:</h3> To conduct a systematic review of biofluid biomarkers to test their association with the risk of post-CNS insult epilepsy. <h3>Background:</h3> It remains unknown if there are shared common biological pathways of an epileptogenic mechanism associated with a range of cerebral insults i.e., stroke, traumatic brain injury, and infections; and if certain biological markers could predict the risk of post-CNS insult epilepsy. <h3>Design/Methods:</h3> We searched articles until January 25, 2022, in PubMed, Embase, PsycINFO, Google Scholar, and Web of Science. The primary outcome was the difference in mean biomarker levels in patients with post-CNS insult epilepsy compared to patients without post-CNS insult epilepsy. We used the modified quality score based on the Reporting Recommendations for Tumor Marker Prognostic Studies for risk of bias assessment. For each biomarker, the level difference was calculated using the pooled standardized mean difference (SMD) and 95% confidence intervals (CI). (PROSPERO CRD42021297110) <h3>Results:</h3> We included 22 studies of 1499 cases with post-CNS insult epilepsy and 7929 controls with no post-CNS insult epilepsy. They investigated 47 biomarkers in blood or cerebrospinal fluid (CSF). Of 22 studies, 21 had moderate-to-high risk of bias. A meta-analysis was possible for only 19 biomarkers. Only blood glucose levels in four studies were significantly higher in patients with post-stroke epilepsy (PSE) than in patients without PSE (SMD 0.44; CI 0.19 to 0.69). From individual studies, 15 biomarkers in blood and seven in CSF were significantly associated with post-CNS insult epilepsy. <h3>Conclusions:</h3> While several biomarkers were found to be associated with epilepsy due to CNS insults, we do not recommend using the reported biomarkers for use in clinical settings or clinical trials. A significant limitation of these studies is that they included fewer patients with CNS insults who developed post-cerebral insult epilepsy. Collaborative efforts to promote biomarker discovery are therefore warranted. <b>Disclosure:</b> Mr. Misra has nothing to disclose. Ms. Khan has nothing to disclose. The institution of Dr. Lam has received research support from NIH. Dr. Mazumder has nothing to disclose. Ms. Eldem has nothing to disclose. Dr. Gururangan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ceribell Inc. Dr. Gururangan has stock in Ceribell Inc. The institution of Dr. Gururangan has received research support from NIH-NINDS. The institution of Dr. Gururangan has received research support from Leon Levy Foundation. Dr. Hickman has nothing to disclose. Dr. Goswami has nothing to disclose. Mrs. Funaro has nothing to disclose. The institution of Joan Montaner has received research support from spanish govt. Joan Montaner has received intellectual property interests from a discovery or technology relating to health care. Dr. Quinn has nothing to disclose. Dr. Liebeskind has received research support from Cerenovus. Dr. Liebeskind has received research support from Genentech . Dr. Liebeskind has received research support from Medtronic. Dr. Liebeskind has received research support from Stryker. Dr. Mishra has nothing to disclose.

Genetic Associations Between Stress-Related Disorders and Autoimmune Disease.

Objective: Emerging evidence supports a bidirectional phenotypic association between stress-related disorders and autoimmune disease. However, the biological underpinnings remain unclear. Here, the authors examined whether and how shared genetics contribute to the observed phenotypic associations. Methods: Based on data from 4,123,631 individuals identified from Swedish nationwide registers, familial coaggregation of stress-related disorders (any disorder or posttraumatic stress disorder [PTSD]) and autoimmune disease were initially estimated in seven cohorts with different degrees of kinship. Polygenic risk score (PRS) analyses were then performed with individual-level genotyping data from 376,871 participants in the UK Biobank study. Finally, genetic correlation analyses and enrichment analyses were performed with genome-wide association study (GWAS) summary statistics. Results: Familial coaggregation analyses revealed decreasing odds of concurrence of stress-related disorders and autoimmune disease with descending kinship or genetic relatedness between pairs of relatives; adjusted odds ratios were 1.51 (95% CI=1.09–2.07), 1.28 (95% CI=0.97–1.68), 1.16 (95% CI=1.14–1.18), and 1.01 (95% CI=0.98–1.03) for monozygotic twins, dizygotic twins, full siblings, and half cousins, respectively. Statistically significant positive associations were observed between PRSs of stress-related disorders and autoimmune disease, as well as between PRSs of autoimmune disease and stress-related disorders. GWAS summary statistics revealed a genetic correlation of 0.26 (95% CI=0.14–0.38) between these two phenotypes and identified 10 common genes and five shared functional modules, including one module related to G-protein–coupled receptor pathways. Similar analyses performed for PTSD and specific autoimmune diseases (e.g., autoimmune thyroid disease) largely recapitulated the results of the main analyses. Conclusions: This study demonstrated familial coaggregation, genetic correlation, and common biological pathways between stress-related disorders and autoimmune disease.

Transcriptomic analysis reveals shared gene signatures and molecular mechanisms between obesity and periodontitis.

Both obesity (OB) and periodontitis (PD) are chronic non-communicable diseases, and numerous epidemiological studies have demonstrated the association between these two diseases. However, the molecular mechanisms that could explain the association between OB and PD are largely unclear. This study aims to investigate the common gene signatures and biological pathways in OB and PD through bioinformatics analysis of publicly available transcriptome datasets. The RNA expression profile datasets of OB (GSE104815) and PD (GSE106090) were used as training data, and GSE152991 and GSE16134 as validation data. After screening for differentially expressed genes (DEGs) shared by OB and PD, gene enrichment analysis, protein-protein interaction (PPI) network construction, GeneMANIA analysis, immune infiltration analysis and gene set enrichment analysis (GSEA) were performed. In addition, receiver operating characteristic (ROC) curves were used to assess the predictive accuracy of the hub gene. Finally, we constructed the hub gene-associated TF-miRNA-mRNA regulatory network. We identified a total of 147 DEGs shared by OB and PD (38 down-regulated and 109 up-regulated). Functional analysis showed that these genes were mainly enriched in immune-related pathways such as B cell receptor signalling, leukocyte migration and cellular defence responses. 14 hub genes (FGR, MNDA, NCF2, FYB1, EVI2B, LY86, IGSF6, CTSS, CXCR4, LCK, FCN1, CXCL2, P2RY13, MMP7) showed high sensitivity and specificity in the ROC curve analysis. The results of immune infiltration analysis showed that immune cells such as macrophages, activated CD4 T cells and immune B cells were present at high infiltration levels in both OB and PD samples.The results of GeneMANIA analysis and GSEA analysis suggested that five key genes (FGR, LCK, FYB1, LY86 and P2RY13) may be strongly associated with macrophages. Finally, we constructed a TF-miRNA-mRNA regulatory network consisting of 233 transcription factors (TFs), 8 miRNAs and 14 mRNAs based on the validated information obtained from the database. Five key genes (FGR, LCK, FYB1, LY86, P2RY13) may be important biomarkers of OB and PD. These genes may play an important role in the pathogenesis of OB and PD by affecting macrophage activity and participating in immune regulation and inflammatory responses.

Six immune-related promising biomarkers may promote hepatocellular carcinoma prognosis: a bioinformatics analysis and experimental validation

BackgroundAbnormal miRNA and mRNA expression and dysregulated immune microenvironment have been found to frequently induce the progression of hepatocellular carcinoma (HCC) in recent reports. In particular, the immune-related competing endogenous RNAs (ceRNA) mechanism plays a crucial role in HCC progression. However, the underlying mechanisms remain unclear.MethodsDifferentially expressed immune-related genes were obtained from the Immport, GEO, and TCGA databases. The mRNA and protein expression levels in HCC tissues and adjacent normal tissues were confirmed, and we further investigated the methylation levels of these biomarkers to explore their function. Then, the TIMER and TISCH databases were used to assess the relationship between immune infiltration and hub genes. Survival analysis and univariate and multivariate Cox models were used to evaluate the association between hub genes and HCC diagnosis. Hub gene expression was experimentally validated in six HCC cell lines and 15 HCC samples using qRT-PCR and immunohistochemistry. The hub genes were uploaded to DSigDB for drug prediction enrichment analysis.ResultsWe identified that patients with abnormal miRNAs (hsa-miR-125b-5p and hsa-miR-21-5p) and their targeted genes (NTF3, PSMD14, CD320, and SORT1) had a worse prognosis. Methylation analysis of miRNA-targeted genes suggested that alteration of methylation levels is also a factor in the induction of tumorigenesis. We also found that the development of HCC progression caused by miRNA-mRNA interactions may be closely correlated with the infiltration of immunocytes. Moreover, the GSEA, GO, and KEGG analysis suggested that several common immune-related biological processes and pathways were related to miRNA-targeted genes. The results of qRT-PCR, immunohistochemistry, and western blotting were consistent with our bioinformatics results, suggesting that abnormal miRNAs and their targeted genes may affect HCC progression.ConclusionsBriefly, our study systematically describes the mechanisms of miRNA-mRNA interactions in HCC and predicts promising biomarkers that are associated with immune filtration for HCC progression.

Multi-omics integration to identify the genetic expression and protein signature of dilated and ischemic cardiomyopathy.

Heart failure (HF) is a complex clinical syndrome leading to high morbidity. In this study, we aimed to identify the gene expression and protein signature of HF main causes, namely dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM). Omics data were accessed through GEO repository for transcriptomic and PRIDE repository for proteomic datasets. Sets of differentially expressed genes and proteins comprising DCM (DiSig) and ICM (IsSig) signatures were analyzed by a multilayered bioinformatics approach. Enrichment analysis via the Gene Ontology was performed through the Metascape platform to explore biological pathways. Protein-protein interaction networks were analyzed via STRING db and Network Analyst. Intersection of transcriptomic and proteomic analysis showed 10 differentially expressed genes/proteins in DiSig (AEBP1, CA3, HBA2, HBB, HSPA2, MYH6, SERPINA3, SOD3, THBS4, UCHL1) and 15 differentially expressed genes/proteins in IsSig (AEBP1, APOA1, BGN, CA3, CFH, COL14A1, HBA2, HBB, HSPA2, LTBP2, LUM, MFAP4, SOD3, THBS4, UCHL1). Common and distinct biological pathways between DiSig and IsSig were retrieved, allowing for their molecular characterization. Extracellular matrix organization, cellular response to stress and transforming growth factor-beta were common between two subphenotypes. Muscle tissue development was dysregulated solely in DiSig, while immune cells activation and migration in IsSig. Our bioinformatics approach sheds light on the molecular background of HF etiopathology showing molecular similarities as well as distinct expression differences between DCM and ICM. DiSig and IsSig encompass an array of "cross-validated" genes at both transcriptomic and proteomic level, which can serve as novel pharmacological targets and possible diagnostic biomarkers.

Gene set enrichment analysis indicates convergence in the mTOR signalling pathway between syndromic and non-syndromic autism

Autism is a developmental disorder that affects around 62.1 million people globally. Estimates of its prevalence have been on the rise. Recent research suggests that in the United States alone, the cost of caring for individuals with autism could reach $461 billion by 2025, including medical expenses. Autism results from a combination of genetic and environmental factors, and molecular diagnosis can often be challenging. Therefore, there is a need for more reliable biomarkers to assist in clinical evaluation. Here, we employed a bioinformatics technique, Gene Set Enrichment Analysis (GSEA), that allows for the evaluation of whether specific genes associated with autism are related to common biological pathways and particular molecular processes using data extracted from genetic biobanks. Thus, it was possible to validate 910 genes related to autism by means of GSEA. The generated data indicated genetic convergence in a molecular pathway, suggesting that the disordered activation of the RAS-MAPK and PI3K-AKT signaling cascades converges in the mTOR pathway. Cell typification in silico indicated high expression in striated neurons, type D1 (p=5,947e-04) and type D2 (p=1,292e-05). In conclusion, our molecular pathway data can be used to assess, using computer modeling, whether new drug candidates for treating autism interact with proteins involved in the mTOR pathway, thus optimizing the screening of new drugs. In addition, with the evidence of such biomarkers and the development of easily accessible laboratory tests, in the future, the early clinical diagnosis of autism could be significantly improved.

CXCR4 as possible druggable target linking inflammatory bowel disease and Parkinson's disease.

Parkinson's disease (PD) is a chronic, progressive, and second most prevalent neurological disorder affecting the motor system. It has been found that people suffering with inflammatory bowel disease (IBD) are at 22% more risk for PD. In the current study, we have established a molecular link between gut and brain. The microarray gene expression datasets of Homo sapiens were obtained from Gene Expression Omnibus Database. Major genes involved in gut-brain connection were found to be CXCR4, LRRK2, APOE, SNCA, IL6, HIF-1α, ABCA1 etc. The common biological pathways linking both the pathologies were found to be HIF-signaling, cytokines interactions, JAK-STAT pathway, cholesterol metabolism, apoptosis and CXCR4 signaling which modulates the synaptic function and neuronal survival in the mature brain. It is known that flavonoid-rich foods throughout life hold the potential to limit the inflammation, neurodegeneration and, to prevent the age-dependent cognitive impairment. Therefore, the potential receptor, CXCR4 was used further for docking with twenty-seven phytochemicals from 5 different classes of Flavonoids found in several dietary items. Docking studies of the top scoring compounds were compared with a known inhibitor (BPRCX807) of receptor CXCR4 (IC50 = 40.4 ± 8.0nM). The study indicates that Flavan-3-ol families of flavonoids are the best fit and finest dietary supplements for improving brain health. Hence the food items like Pistachio nuts, hazelnuts, Green Tea, walnuts, etc. should be incorporated more in the diet of healthy people as well as in IBD and PD patients to prevent inflammation in gut and brain damage from oxidative stress.

Abstract A046: Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells

Abstract Leukemia inhibitory factor receptor (LIFR) signals through signal transducer and activator of transcription 3 (STAT3), a transcription factor that is associated with poor prognosis due to its overexpression and/or hyperactivity in 40% of breast cancer cases. LIFR has been defined as either a promoter or suppressor of metastasis in mammary carcinoma, and recently we have shown that its expression is significantly upregulated following loss of the RNA-binding protein heterogenous nuclear ribonucleoprotein E1 (hnRNP E1, “E1”). We have further shown that E1 is a regulator of the epithelial-to-mesenchymal transition (EMT) and of differentiation in mammary epithelium. Mechanistically, E1 acts as a tumor suppressor by binding to and inhibiting translation of mRNAs involved in EMT and cellular self-renewal, including the cytokine FAM3C. We have demonstrated that FAM3C binds to LIFR in the extracellular space and activates STAT3. Herein, we characterize induction of LIFR expression in response to FAM3C/LIFR signaling, and show that E1 upregulates LIFR transcription through FAM3C, involving initiation at the LIFR promoter locus. Induction of LIFR expression in mammary epithelial cells has been shown to be associated with tumor initiation, breast cancer stem cells, and metastasis. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with FAM3C/LIFR interaction. Comparison between RNA-sequencing data from our mouse model of mammary carcinoma and human mammary carcinoma cell lines reveals common biological pathways and potential therapeutic targets. Future directions will be aimed at investigating the effect of modulation of LIFR expression during tumor dissemination in vivo. Citation Format: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe. Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A046.