Potential Biological Pathways Research Articles

Integrating Bioinformatics and Drug Sensitivity Analyses to Identify Molecular Characteristics Associated with Targeting Necroptosis in Breast Cancer and their Clinical Prognostic Significance.

Breast cancer accounts for over 1.8 million new cases worldwide annually, and prompt diagnosis and treatment are imperative to prevent mortality. Necroptosis, a form of programmed cell death, is thought to be a critical pathway for cancer cell apoptosis, yet, its relationship with breast cancer progression and molecular mechanisms remains largely unexplored. Our study aims to investigate the molecular characteristics and clinical prognostic value of necroptosis-related genes in breast cancer using a comprehensive approach that involves integrated bioinformatics analysis along with drug sensitivity assessment. Transcriptional, clinical, and tumor mutation burden (TMB) data related to breast cancer from the TCGA and GEO databases were integrated, and the necroptosis gene set was downloaded from the GSEA website for analysis. The screening conditions were set as adjusted p < 0.05 and |log2FC(fold change)| > 0.585 to screen for differential expression genes related to breast cancer necroptosis. Survival prognosis analysis was conducted on breast cancer necroptosis genes. Further analysis was conducted on prognosis-related necroptosis genes, including immune infiltration analysis and GO/KEGG enrichment analysis, to explore the potential biological functions and signaling pathway mechanisms of breast cancer necroptosis genes. Drug sensitivity screening was conducted on the prognosis-related necroptosis to identify potential drugs that target the promotion of necroptosis gene expression, and ultimately, single-gene analysis was performed on the core target genes obtained. Through integrated bioinformatics analysis, 29 differentially expressed mRNAs related to BRCA-Necroptosis were identified, including 18 upregulated mRNAs and 11 downregulated mRNAs. In addition, single-factor analysis of differential genes showed that the expression of HSPA4, PLK1, TNFRSF1B, FLT3, and LEF1 was closely related to BRCA survival prognosis. Based on the expression of these genes, a breast cancer prognosis model was constructed, and it was found that the area under the curve (AUC) of the curve of the risk genes for necroptosis was the largest, indicating that these genes have a certain clinical predictive significance for the occurrence and prognosis of BRCA. Additionally, there were significant differences in clinical characteristics of BRCA patients with different necroptosis gene expressions. Furthermore, GSVA and immune infiltration analysis revealed that Necroptosis-DEGs mainly affect the occurrence and progression of BRCA by participating in immune functions such as APC co-inhibition, APC costimulation, CCR, checkpoint, as well as infiltrating immune cells such as B cells naive, plasma cells, and T cells CD8. Moreover, the necroptosis gene group column chart indicated a 1-year survival rate of 0.979, a 3-year survival rate of 0.883, and a 5-year survival rate of 0.774. The necroptosis gene group and column chart are important indicators for evaluating BRCA prognosis. Finally, drug sensitivity screening of BRCA-Necroptosis genes showed that compounds such as A- 770041, AC220, AP-24534, Bexarotene, and BMS-509744 have certain effects as potential targeted drugs for the treatment of BRCA necroptosis genes. Necroptosis genes are implicated in the pathogenesis and progression of breast cancer and are thought to impact the prognosis and response to drug treatments in individuals with BRCA. Consequently, understanding the role of these genes in breast cancer may aid in identifying more precise and efficacious therapeutic targets.

Targeted Regulation of Osteoblasts and Osteoclasts in Osteosarcoma Patients by CSF3R Receptor Inhibition of Osteolysis Caused by Tumor Inflammation Based on Transcriptional Spectrum Analysis and Drug Library Screening.

Osteosarcoma (OS) is a common primary malignant bone tumor that mainly occurs in children and adolescents. The use of IL-8 inhibitor compounds has been reported in patents, which can be used to treat and/or prevent osteosarcoma, but the pathogenesis of osteosarcoma remains to be investigated. At present, osteoblasts and osteoclasts play an important role in the occurrence and development of OS. However, the relationship between osteoblasts and osteoclasts in the specific participation mechanism and inflammatory response of OS patients has not been further studied. The transcriptome, clinical data, and other data related to OS were downloaded from the GEO database to analyze them with 200 known inflammatory response genes. We set the screening conditions as p < 0.05 and | log2FC| > 0.50, screened the differentially expressed genes (DEGs) related to OS, tested the correlation coefficient between the OS INF gene and clinical risk, and analyzed the survival prognosis. We further enriched and analyzed the DEGs and inflammatory response genes of OS with GO/KEGG to explore the potential biological function and signal pathway mechanism of OS inflammatory response genes. Moreover, the virtual screening of drug sensitivity of OS based on the FDA drug library was also carried out to explore potential therapeutic drugs targeted to regulate OS osteogenesis and osteoclast inflammation, and finally, the molecular dynamics simulation verification of OS core protein and potential drugs was carried out to explore the binding stability and mechanism between potential drugs and core protein. Through differential analysis of GSE39058, GSE36001, GSE87624, and three other data sets closely related to OS osteoblasts and osteoclasts, we found that there was one upregulated gene (CADM1) and one down-regulated gene (PHF15) related to OS. In addition, GSEA enrichment analysis of the DEGs of OS showed that it was mainly involved in the progress of OS through biological functions, such as oxidative photosynthesis, acute junction, and epithelial-mesenchymal transition. The enrichment analysis of OS DEGs revealed that they mainly affect the occurrence and progress of OS by participating in the regulation of the actin skeleton, PI3K Akt signal pathway, complement and coagulation cascade. According to the expression of CSF3R in OS patients, a risk coefficient model and a diagnostic model were established. It was found that the more significant the difference in the CSF3R gene in OS patients, the greater the risk coefficient of disease (p < 0.05). The AUC under the curve of the CSF3R gene was greater than 0.65, which had a good diagnostic significance for OS. The above results showed that the prognosis risk gene CSF3R related to OS inflammation was closely related to the survival status of OS patients. Finally, through the virtual screening of the ZINC drug library and molecular dynamics simulation, it was found that the docking model formed by the core protein CSF3R and the compounds, Leucovorin and Methotrexate, were the most stable, which revealed that the compounds Leucovorin and Methotrexate might play a role in the treatment of OS by combining with the inflammatory response related factor CSF3R of OS. CSF3R participates in the occurrence and development of OS bone destruction by regulating the inflammatory response of osteoblasts and osteoclasts and can affect the survival prognosis of OS patients.

Unraveling the heart-brain axis: shared genetic mechanisms in cardiovascular diseases and Schizophrenia

The comorbidity between cardiovascular diseases (CVD) and schizophrenia (SCZ) has attracted widespread attention from researchers, with shared genetic causes potentially providing important insights into their association. This study conducted a comprehensive analysis of genetic data from 17 types of CVD and SCZ using genome-wide multi-trait association studies (GWAS), employing statistical methods such as LDSC, MTAG, LAVA, and bidirectional Mendelian randomization to explore global and local genetic correlations and identify pleiotropic single nucleotide variants (SNVs). The analysis revealed a significant genetic correlation between CVD and SCZ, identifying 842 potential pleiotropic single nucleotide variants (SNVs) and multiple associated biological pathways. Notably, genes such as TRIM27, CENPM, and MYH7B played critical roles in the shared genetic variations of both types of diseases. This study reveals the complex genetic relationship between CVD and SCZ, highlighting potential shared biological mechanisms involving immune responses, metabolic factors, and neurodevelopmental processes, thereby providing new directions for future interventions and treatments.

A glutamine metabolish-associated prognostic model to predict prognosis and therapeutic responses of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) ranks among the most lethal malignancies around the world. However, the current management strategies for predicting prognosis in HCC patients remain unreliable. Our study developed a robust prognostic model based on glutamine metabolism associated-genes (GMAGs), utilizing data from The Cancer Genome Atlas database. The prognostic values of model were validated through the databases of the Gene Expression Omnibus and International Cancer Genome Consortium via Kaplan‒Meier curves and receiver operating characteristic (ROC). The potential biological pathways associated with prognostic risk were investigated through different enrichment analysis, and Gene variation analysis. The correlation between prognostic model and therapeutic responses were analyzed. Quantitative real-time PCR (qRT-PCR) and cellular experiments were measured to analyze the GMAGs. Consequently, a prognostic model was constructed of 4 GMAGs (RRM1, RRM2, G6PD, and GPX7) through least absolute shrinkage and selection operator (LASSO) regression analysis. The Kaplan‒Meier curves and ROC curves showed a reliable predictive capacity of prognosis for HCC patients (p < 0.05). The enrichment analyses revealed a multitude of biological pathways that are significantly associated with cancer. Patients with high prognostic risk might be sensitive to immunotherapy (p < 0.05). The results of qRT-PCR revealed that all 4 GMAGs exhibited significantly higher expression levels in HCC samples compared to normal samples (p < 0.05). Moreover, the knockdown of RRM1 suppresses the progression of HCC cells. In this study, we developed a robust prognostic model for predicting the prognosis of HCC patients based on GMAGs, and identified RRM1 as a potential therapeutic target for HCC.

Shared genetic architecture between COVID-19 and irritable bowel syndrome: a large-scale genome-wide cross-trait analysis.

It has been reported that COVID-19 patients have an increased risk of developing IBS; however, the underlying genetic mechanisms of these associations remain largely unknown. The aim of this study was to investigate potential shared SNPs, genes, proteins, and biological pathways between COVID-19 and IBS by assessing pairwise genetic correlations and cross-trait genetic analysis. We assessed the genetic correlation between three COVID-19 phenotypes and IBS using linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) methods. Two different sources of IBS data were combined using METAL, and the Multi-trait analysis of GWAS (MTAG) method was applied for multi-trait analysis to enhance statistical robustness and discover new genetic associations. Independent risk loci were examined using genome-wide complex trait analysis (GCTA)-conditional and joint analysis (COJO), multi-marker analysis of genomic annotation (MAGMA), and functional mapping and annotation (FUMA), integrating various QTL information and methods to further identify risk genes and proteins. Gene set variation analysis (GSVA) was employed to compute pleiotropic gene scores, and combined with immune infiltration algorithms, IBS patients were categorized into high and low immune infiltration groups. We found a positive genetic correlation between COVID-19 infection, COVID-19 hospitalization, and IBS. Subsequent multi-trait analysis identified nine significantly associated genomic loci. Among these, eight genetic variants were closely related to the comorbidity of IBS and COVID-19. The study also highlighted four genes and 231 proteins associated with the susceptibility to IBS identified through various analytical strategies and a stratification approach for IBS risk populations. Our study reveals a shared genetic architecture between these two diseases, providing new insights into potential biological mechanisms and laying the groundwork for more effective interventions.

The unrevealed links: periodontal health, human milk composition, and infant gut microbiome dynamics.

This review aims to identify the mechanistic relationships related to periodontal diseases and its possible association with changes in human milk composition and the composition and function of infants' gut microbiome. Maternal health conditions, especially inflammatory, are associated with altered human milk composition. It is not known whether maternal oral inflammatory diseases, including periodontal diseases, deleteriously affect human milk composition. A narrative review was conducted according to SANRA, the Scale for the Assessment of Narrative Review Articles, guidelines. PubMed, Google Scholar, and Cochrane database of systematic reviews were searched from September 2019 up to December 2023 using keywords such as breast/human milk, maternal health/infections, and periodontal diseases. Reference lists of relevant articles were also screened. Our primary outcome of interest was human milk composition (i.e., any changes in macronutrients, immunological components, etc.). Secondary outcomes included changes in human milk microbiome and subsequent changes in the infant gut microbiome. Outcomes were synthesized using a narrative approach where the existing evidence and current literature were summarized. No risk of bias assessment of the studies was performed in this review. The search yielded no studies investigating the relationship between periodontal diseases in nursing mothers and changes in human milk composition. However, a dose-response relationship exists between the severity of periodontal diseases and the risk of adverse pregnancy outcomes such as preterm birth. Mastitis and diabetes affected milk lipids. Immunoglobulin A (sIgA) was increased in mastitis, whereas reduced concentrations were reported in diabetes. Potential biological pathways through which periodontal diseases can negatively affect human milk composition include the systemic dissemination of inflammatory cytokines like IL-6, PGE2, and tumor necrosis factor (TNF)-β that can be up-regulated by bacterial by-products. This biological plausibility needs to be investigated, given the potentially negative impact on the quality of human milk that could be caused by periodontal inflammation.

Effect of the Intake of Solid Block Dairy Products Like Cheese on Serum Uric Acid in Children: A Preliminary Mechanistic Investigation.

This study aimed to investigate the relationship between the intake of solid block dairy products like cheese and serum uric acid levels, along with its potential physiological mechanisms. Data for our study were obtained from the Chinese Children and Lactating Women Nutrition and Health Surveillance. Generalized linear models and restricted cubic splines were employed to analyze the relationship between the intake of solid block dairy products like cheese and serum uric acid levels. Two-sample Mendelian randomization (TSMR) analysis was conducted to infer causality, based on a large sample size and robust methodology. Gene Ontology (GO) enrichment analysis was also performed to identify potential biological pathways. Among all types of dairy products, a significant negative association with serum uric acid levels was observed only for the intake of solid block dairy products like cheese, regardless of covariate adjustment (β = -0.182, p < 0.001). TSMR results supported a negative causal relationship between cheese intake and serum uric acid levels (β = -0.103, 95% CI: -0.149 to -0.057; p = 0.002). The JAK-STAT signaling pathway and autophagy regulation were identified as potential physiological mechanisms underlying this relationship. The intake of solid block dairy products like cheese was found to result in decreased levels of serum uric acid, with potential mechanisms involving the JAK-STAT signaling pathway and the regulation of autophagy.

Sex Differences in Protein Biomarkers and Measures of Fat Distribution.

Sex differences in obesity and fat distribution may in part explain differences in cardiovascular risk in men versus women. We sought to examine sex differences in the associations of obesity and adiposity measures with cardiovascular disease-related protein biomarkers. In a cross-sectional observational cohort study, we examined whether the association of obesity (body mass index [BMI] and waist circumference) and adiposity measures (visceral adipose tissue) with biomarkers demonstrates effect modification by sex using multiplicative interaction terms in multivariable linear regression models. Among 3143 participants (mean age, 50 years; 49% women), sex modified the association of BMI, waist circumference, and visceral adipose tissue with cardiovascular disease-related protein biomarkers (7 for BMI, 3 for waist circumference, and 23 for visceral adipose tissue, false discovery rate [FDR]-qint<0.05 for all). For example, higher BMI was associated with lower α1-microglobulin levels in men but not in women (ß, -0.113; SE, 0.028; P<0.001 in men versus ß, -0.007; SE, 0.024; P=0.78 in women). By contrast, higher BMI was associated with higher adipsin levels in men and women, but the association was more pronounced in women (ß, 0.287; SE, 0.023; P<0.001 in women versus ß, 0.189; SE, 0.026; P<0.001 in men). The associations of higher visceral adipose tissue with biomarkers representing adiposity, inflammation, and fibrosis were more pronounced in women versus men. We found that sex modified the associations of obesity and adipose traits with cardiovascular risk ascertained by cardiovascular disease-related biomarkers including markers of adiposity, inflammation, and fibrosis. These findings highlight potential biological pathways that may underlie some of the observed differences in obesity-related cardiovascular disease between women and men.

THE ROLE OF PHYSICAL ACTIVITY IN IMPROVING THE QUALITY OF SLEEP OF PATIENTS WITH VARIOUS SLEEP DISORDERS

Sleep is an important human behavior and difficulties with sleep are closely related to health, potentially leading to the development of diseases and a reduced quality of life. Sleep disorders cover a wide range of problems associated with mental health disorders, such as anxiety and depression, and contribute to an increased tendency to become overweight or obese. In addition, sleep difficulties can lead to more serious sleep disorders, such as problems with sleep maintenance, poor sleep efficiency, and reduced daytime attention. The purpose of the study is to highlight the role of physical activity in improving the quality of sleep in patients with various sleep disorders. Materials and methods. To better understand the impact of physical activity on sleep quality and its positive effect on sleep onset and duration, a search of scientific literature was conducted between 2019 and 2024 in the PubMed, Scopus, Web of Science, and Google Scholar databases using the terms “exercise,” “sleep,” “quality of life,” “insomnia,” and “activity.” The search resulted in the selection of publications that examined the relationship between daily sleep and physical activity and will be discussed in this review. Results. The study identified potential biological pathways that explain the possible interactions between sleep and physical activity in the short and long term. Acute or repetitive physical activity increases total sleep time by reducing insulin resistance and the concentration of inflammatory markers, better regulation of circadian rhythm, and the release of brain-derived neurotrophic factor. In turn, sleep deprivation can alter physical performance or contribute to fatigue during physical activity by increasing cortisol concentrations, decreasing growth hormone and prolactin concentrations, and stimulating inflammatory markers. Scientific studies have established the beneficial effects of physical activity in alleviating sleep problems. Numerous studies show that moderate to vigorous physical activity has a positive effect on sleep quality. Physical activity has pluripotential beneficial effects on bodily functions. These benefits include a reduction in the incidence of cardiovascular disease, coronary heart disease, hypertension, type 2 diabetes, and death. In addition to these effects, physical activity has a significant beneficial effect on the onset, duration, and quality of sleep, which complements its beneficial effects. In contrast, lack of sleep is associated with an increased incidence of cardiovascular complications and death. In this regard, physical activity serves as a non-pharmacological means of improving sleep, especially in older people who often have difficulty falling asleep. Regarding the time of exercise and its effect on sleep, there was no difference between morning and evening exercise in terms of sleep onset and quality. In addition, the multifaceted benefits of physical activity go beyond improving sleep to contribute to overall well-being and longevity, offering a comprehensive health solution that is comparatively better than alternative treatments. Conclusions. Based on the research presented here, it can be concluded that the scientific literature has identified an improvement in sleep quality after physical activity, and empirical evidence confirms its positive impact, regardless of type or intensity. Increased physical activity was found to be associated with improved total sleep duration, reduced sleep latency, and improved sleep efficiency. Exercise can improve sleep by reducing sleep latency and increasing slow wave sleep.

The Role of Connexin26 and Connexin30 in the Mouse Cochlea of Noise-Induced Hearing Loss.

We aimed to explore the role of connexin26 (Cx26) and connexin30 (Cx30) in the cochlea in noise-induced permanent threshold shifts (PTS) and temporary threshold shift (TTS). Prospective, controlled. Laboratory. A mouse model of noise-induced PTS and TTS was constructed. Western blots were used to detect the expression of Cx26 and Cx30 in the cochlea. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to assess the potential biological pathways. Both the expression of Cx26 and Cx30 showed a trend of first rising and then falling in noise-induced PTS. The expression of Cx26 increased greatly in the 24 hours noise exposure (P < .05) and reached the highest level in the 4 hours after noise exposure (P < .05), then decreased gradually and returned to the control level on the seventh day after the noise exposure, when compared with the control group. The expression of Cx30 showed a similar trend in noise-induced PTS. However, both the expression of Cx26 and Cx30 showed a trend of first falling and then rising in noise induced TTS. The expression of Cx26/Cx30 reached its lowest level in the 4 hours after noise exposure (P < .05), and then increased to the control level on the second day after noise exposure (P > .05), compared with the control group. The first KEGG and GO pathway may be related with oxidative phosphorylation. Cx26 and Cx30 may have an effect in noise induced PTS and TTS. Future studies are needed to confirm the results.

Development of biomarker signatures associated with anoikis to predict prognosis in patients with esophageal cancer: An observational study.

Anoikis, a form of programmed cell death linked to cancer, has garnered significant research attention. Esophageal cancer (ESCA) ranks among the most prevalent malignant tumors and represents a major global health concern. To ascertain whether anoikis-related genes (ARGs) can accurately predict ESCA prognosis, we evaluated the predictive value and molecular mechanisms of ARGs in ESCA and constructed an optimal model for prognostic prediction. Using the Cancer Genome Atlas (TCGA)-ESCA database, we identified ARGs with differences in ESCA. ARG signatures were generated using Cox regression. A predictive nomogram model was developed to forecast ARG signatures and patient outcomes in ESCA. Gene set enrichment analysis (GSEA) was employed to uncover potential biological pathways associated with ARG signatures. Estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) and cell-type identification by estimating relative subsets of RNA transcripts analyses were used to assess differences in the immune microenvironment of the ARG signature model. Based on ARGs, the patients with ESCA were divided into high and low groups, and the sensitivity of patients to drugs in the database of genomics of drug sensitivity in cancer was analyzed. Finally, the correlation between drug sensitivity and risk score was then evaluated based on the ARG signatures. Prognostic relevance was significantly linked to the ARG profiles of 5 genes: MYB binding protein 1a (MYBBP1A), plasminogen activator, urokinase (PLAU), budding uninhibited by benzimidazoles 3, HOX transcript antisense RNA, and euchromatic histone-lysine methyltransferase 2 (EHMT2). Using the risk score as an independent prognostic factor combined with clinicopathological features, the nomogram accurately predicted the overall survival (OS) of individual patients with ESCA. Gene ontology (GO) enrichment analysis indicated that the primary molecular roles included histone methyltransferase function, binding to C2H2 zinc finger domains, and histone-lysine N-methyltransferase activity. GSEA revealed that the high-risk cohort was connected to cytokine-cytokine receptor interaction, graft-versus-host disease, and hematopoietic cell lineage, whereas the low-risk cohort was related to arachidonic acid metabolism, drug metabolism via cytochrome P450 and fatty acid metabolism. Drug sensitivity tests showed that 16 drugs were positively correlated, and 3 drugs were negatively correlated with ARG characteristic scores. Our study developed 5 ARG signatures as biomarkers for patients with ESCA, providing an important reference for the individualized treatment of this disease.

Proteome- and Transcriptome-Wide Genetic Analysis Identifies Biological Pathways and Candidate Drug Targets for Preeclampsia.

Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1 [sulfotransferase 1A1], SH2B3 [SH2B adapter protein 3], SERPINE2 [serpin family E member 2], RGS18 [regulator of G-protein signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [methionyl aminopeptidase 1], MANEA [mannosidase endo-alpha], jun-D [JunD proto-oncogene], GDF15 [growth differentiation factor 15], FGL1 [fibrinogen like 1], FGF5 [fibroblast growth factor 5], FES [FES proto-oncogene], APOBR [apolipoprotein B receptor], ANP [natriuretic peptide A], ALDH-E2 [aldehyde dehydrogenase 2 family member], ADAMTS13 [ADAM metallopeptidase with thrombospondin type 1 motif 13], and 3MG [N-methylpurine DNA glycosylase]), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.

Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility.

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.

Abstract A048: Association between ambient particulate matter and colorectal cancer incidence: The Multiethnic Cohort Study

Abstract Background: Growing evidence suggests that air pollution may be a risk factor for colorectal cancer (CRC). We examined the association between ambient particulate matter (PM) exposure and CRC risk within the Multiethnic Cohort Study (MEC), representing the first study to include a large sample of racial and ethnic minoritized populations. Methods: The MEC is a prospective study that recruited, from 1993 through 1996, men and women ages 45-75 years largely from five racial and ethnic groups (African American, Japanese American, Latino, Native Hawaiian, and Non-Hispanic White) living in Hawai‘i and California. This study included 98,675 California MEC participants, residing predominately in Los Angeles County. Satellite-based PM2.5 (PM with an aerodynamic diameter &amp;lt;2.5μm) exposures were estimated from a published spatiotemporal model. Kriging interpolation was used to estimate PM10 (PM &amp;lt;10μm) exposures using routine air monitoring data from the US Environmental Protection Agency. Time-varying PM exposures were assessed from time of recruitment through 12/31/2018. Incident invasive CRC cases were identified via linkage with the California Cancer Registry (n=3,217). Cox proportional hazards models were used to examine the association between PM and CRC risk using age as the time metric, with strata defined by age at cohort entry and race and ethnicity, and adjusting for demographic and lifestyle factors. Heterogeneity of the PM-CRC association was assessed by sex, race and ethnicity, and CRC subsite (right colon, left colon, rectum). Results: Risk of CRC increased with PM2.5 (per 10μg/m3 hazard ratio [HR] 1.13, 95% confidence interval [CI] 0.96-1.33) with a larger HR observed among females (HR 1.29, 95% CI 1.03-1.62) than males (HR 0.96, 95% CI 0.76-1.22) (Pheterogeneity=0.24). CRC risk was positively associated with PM2.5 across race and ethnicity (except for African American participants) with the largest HR observed among Latino participants (HR 1.47, 95% CI 1.03-2.08) (Pheterogeneity=0.20). There was no statistically significant heterogeneity of PM2.5 effect by tumor subsite (Pheterogeneity=0.07); although larger HRs were seen for left colon (HR 1.52, 95% CI 1.08- 2.14) and rectal cancers (HR 1.54, 95% CI 1.05-2.25) than right colon cancers (HR 1.09, 95% CI 0.88-1.35). PM10 was not associated with CRC risk (per 10 μg/m3; HR 1.02, 95% CI 0.93-1.22) with no evidence of heterogeneity in associations by sex or race and ethnicity (respective Pheterogeneity 0.75, 0.44). Although HRs for PM10 appeared to differ by CRC subsite (Pheterogeneity=0.03), the 95% CI of these HRs included the null (right HR 0.95, 95% CI 0.84-1.06; left HR 1.13, 95% CI 0.95-1.35; rectal HR 1.18, 95% CI 0.97-1.43). Conclusions: Preliminary findings suggest that PM2.5 exposure is associated with CRC risk with larger associations in females and, possibly, for left colon and rectal cancer. Additional studies are needed to confirm these findings and evaluate the potential biological pathways underlying these associations. Citation Format: Ugonna Ihenacho, Chiuchen Tseng, Jun Wu, Scott Fruin, Timothy V. Larson, Salma Shariff-Marco, Loïc Le Marchand, Daniel O. Stram, Lynne R. Wilkens, Christopher A. Haiman, Beate Ritz, Iona Cheng, Anna H. Wu. Association between ambient particulate matter and colorectal cancer incidence: The Multiethnic Cohort Study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A048.

Longitudinal associations between microRNAs and weight in the diabetes prevention program.

Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.

TESC overexpression mitigates amyloid-β-induced hippocampal atrophy and memory decline

Background and objectivesGenome-wide association studies (GWASs) have identified numerous candidate genes for human brain-imaging phenotypes; however, the biological relevance of many of these genes remains unconfirmed. This study aimed to investigate the causal relationships among tescalcin (TESC) (a GWAS-indicated gene), hippocampal volume, Alzheimer’s disease (AD), and the underlying biological mechanisms. MethodsHuman transcriptional data were analyzed to confirm relative TESC expression in the hippocampus. In cell experiments, RNA-seq analysis was used to identify the potential biological pathways for TESC overexpression, and immunofluorescence imaging and cell viability assays were used to evaluate the effect of TESC overexpression on neuronal structure and survival. In animal experiments, the effects of TESC overexpression on hippocampal volume and cognitive function in normal mice and amyloid-β (Aβ)-induced AD mice were investigated by 9.4 T magnetic resonance imaging and behavioral tests. Underlying mechanisms were further assessed via western blotting and electrophysiological recordings. ResultsHuman transcriptional data demonstrated that TESC is primarily expressed in the hippocampus and neurons. TESC overexpression enhanced the viability of HT22 cells and reduced Aβ-induced cell death. In mouse models, Tesc-overexpressing mice revealed increased hippocampal volume, likely owing to enhanced cell viability and long-term potentiation (LTP), and reducing apoptotic- and oxidation-induced hippocampal damage. TESC overexpression could significantly mitigate Aβ-induced hippocampal atrophy and memory impairment, potentially by reducing Aβ-induced neuronal apoptosis and LTP weakening. ConclusionThis study exemplifies the translation of GWAS findings into actionable biological knowledge and suggests that upregulation of TESC may offer a promising therapeutic strategy for AD.

Neuro-endocrine-immune network mechanism of acupuncture for post-stroke depression

The nervous, endocrine and immune systems are interconnected through neurotransmitters, endocrine hormones and cytokines, forming a neuro-endocrine-immune (NEI) network that outputs effect information to target organs in a multi-level and multi-system manner. The effects of acupuncture can be amplified through the NEI network, causing local microenvironment responses at acupoints to treat post-stroke depression (PSD). This paper systematically elucidates the mechanisms of acupuncture treatment for PSD from three aspects: nervous, endocrine and immune, and reveals the potential mechanisms and biological pathways of acupuncture treatment for PSD from an overall perspective based on the NEI network, aiming to provide a reliable theoretical basis for fundamental research on acupuncture treatment for PSD.

The influence of Helicobacter pylori infection on acute coronary syndrome and lipid metabolism in the Chinese ethnicity.

Acute coronary syndrome (ACS) patients frequently present a relatively high prevalence of Helicobacter pylori (H. pylori) infection. H. pylori was previously hypothesized to induce ACS through the regulation of lipid levels. However, the risk of H. pylori-induced ACS varies significantly among different ethnic groups, and the associations between H. pylori and lipid parameters remain unclear. This study aimed to systematically assess the risk of ACS in Chinese populations with H. pylori infection while also evaluating the effects of H. pylori on lipid parameters. A hospital-based case-control study involving 280 participants was conducted. Immunoblotting was used for the detection and genotyping of H. pylori. The associations between H. pylori and ACS, as well as lipid parameters, were analyzed via the chi-square test and a multiple logistic regression model. H. pylori infection significantly increased the risk of ACS among all participants (adjusted odds ratio (OR) = 4.04, 95% confidence interval (CI): 1.76-9.25, P < 0.05), with no associations with virulence factors (cytotoxin-associated gene A (CagA) or vacuole toxin geneA (VacA)). Subgroup analysis revealed a significant increase in the risk of ACS among the elderly population aged 56-64 years with H. pylori infection. Additionally, a substantial association was observed between H. pylori and acute myocardial infarction (AMI). No significant differences were found in lipid parameters, including low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and the LDL/HDL ratio, between individuals positive and negative for H. pylori infection. Similar results were observed between the ACS group and the control group. Our study has demonstrated for the first time that H. pylori does not significantly impact lipid metabolism but increases the risk of ACS fourfold in the Chinese population (OR = 4.04, 95% CI: 1.76-9.25). Furthermore, the virulence factors of H. pylori (CagA and VacA) may not be involved in the mechanisms by which they promote the development of ACS. This finding provides additional evidence for the association between H. pylori and ACS among different ethnic groups and refutes the biological mechanism by which H. pylori affects ACS through lipid metabolism regulation. Regular screening for H. pylori and eradication treatment in elderly individuals and those at high risk for ACS may be effective measures for reducing the incidence of ACS. Future research should include multicenter randomized controlled trials and explore host genetics and the effects of H. pylori on the gut microbiota as potential biological pathways linking H. pylori and ACS.

Associations of hair cortisol levels with violence, poor mental health, and harmful alcohol and other substance use among female sex workers in Nairobi, Kenya

Violence, poor mental health, and harmful substance use are commonly experienced by female sex workers (FSWs) in sub-Saharan Africa, all of which are associated with increased HIV susceptibility. We aimed to investigate the associations between violence, poor mental health and harmful alcohol/substance use with hair cortisol concentration (HCC) levels as a potential biological pathway linking the experiences of these stressors and HIV vulnerability. We used the baseline data of the Maisha Fiti study of FSWs in Nairobi, Kenya. Participants reported recent violence, poor mental health, and harmful alcohol/substance use. Hair samples proximal to the scalp were collected to measure cortisol levels determined by ELISA. We analysed the data of 425 HIV-negative respondents who provided at least 2 cm of hair sample. The prevalence of recent violence was 89.3% (physical 54.6%; sexual 49.4%; emotional 77.0% and financial 66.5%), and 29.1% had been arrested due to sex work. 23.7% of participants reported moderate/severe depression, 11.6% moderate/severe anxiety, 13.5% PTSD and 10.8% recent suicidal thoughts and/or attempts. About half of the participants (48.8%) reported recent harmful alcohol and/or other substance use. In multivariable linear regression analyses, both physical and/or sexual violence (adjusted geometric mean ratio (aGMR) = 1.28; 95% CI 1.01–1.62) and harmful alcohol and/or other substance use (aGMR = 1.31; 95% CI 1.03–1.65) were positively and independently associated with increased HCC levels. Findings suggest a role of violence and substance use in elevated HCC levels, which could increase HIV risk due to cortisol-related T cell activation. However, longitudinal and mechanistic studies are needed to confirm this hypothesis.

Resting-State Brain Function Alteration in Colorectal Cancer Patients.

To investigate the abnormal pattern of altered functional activity in the brain and the neuroimaging mechanisms underlying the cognitive impairment of patients with colorectal cancer (CRC) via resting-state functional magnetic resonance imaging (rs-fMRI). CRC patients (n = 56) and healthy controls (HCs) (n = 50) were studied. The participants underwent rs-fMRI scans and the Montreal Cognitive Assessment (MoCA). The amplitude of low-frequency fluctuations (ALFF), degree centrality (DC), regional homogeneity (ReHo), and MoCA scores, were calculated for participants. The scores of executives, visuospatial, memory, language and attention were lower in CRC patients. ReHo and ALFF values in the left postcentral gyrus, ReHo values in the right postcentral gyrus, ALFF and DC values in the left middle occipital gyrus, ReHo and DC values in the right lingual gyrus, DC values in the right angular gyrus and precuneus, and ALFF values in the left middle temporal gyrus decreased conspicuously in the CRC patients. CRC patients have abnormal resting state function, mainly in the brain areas involved in cognitive function. The overlapping brain regions with abnormal functional indicators are in the middle occipital gyrus, postcentral gyrus, and lingual gyrus. This study reveals the potential biological pathways involved in brain impairment and neurocognitive decline in patients with CRC.