Search

Background: Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) suffer from a high burden of pulmonary diseases, even after accounting for their smoking status. Cytotoxic CD8 T-cells are likely implicated in this phenomenon and may act as a double-edged sword. While being essential in viral infection control, their hyperactivation can also contribute to lung mucosal tissue damage. The effects of HIV and smoking on pulmonary mucosal CD8 T-cell dynamics has been a neglected area of research, which we address herein. Methods: Bronchoalveolar lavage (BAL) fluid were obtained from ART-treated PLWH (median duration of supressed viral load: 9 years; smokers: n = 14; non-smokers: n = 21) and HIV-uninfected controls (smokers: n = 11; non-smokers: n = 20) without any respiratory symptoms or active infection. Lymphocytes were isolated and CD8 T-cell subsets and homing markers were characterized by multiparametric flow cytometry. Results: Both smoking and HIV infection were independently associated with a significant increase in frequencies of total pulmonary mucosal CD8 T-cell. BAL CD8 T-cells were primarily CD69 + expressing CD103 and/or CD49a, at least one of the two granzymes (GzmA/GzmB), and little Perforin. Higher expression levels of CD103, CD69, and GzmB were observed in smokers versus non-smokers. The ex vivo phenotype of GzmA + and GzmB + cells revealed increased expression of CD103 and CXCR6 in smokers, while PLWH displayed elevated levels of CX3CR1 compared to controls. Conclusion: Smoking and HIV could promote cytotoxic CD8 T-cell retention in small airways through different mechanisms. Smoking likely increases recruitment and retention of GzmB + CD8 Trm via CXCR6 and CD103. Heightened CX3CR1 expression could be associated with CD8 non-Trm recruitment from the periphery in PLWH. [ABSTRACT FROM AUTHOR]

Background: Sepsis remains a growing global health concern with soaring mortality and no direct anti-sepsis drug. Although smoking has distinct deleterious effects on chronic inflammatory illnesses and can impair immune function, a comprehensive analysis of the connection between sepsis and smoking is lacking. Methods: This large-scale longitudinal cohort study retrospectively assessed adults aged ≥ 20 years who underwent national health checkups under the Korean National Health Insurance Service between January and December 2009 (N = 4,234,415) and were followed up for 10 years. Sepsis was identified based on the International Classification of Diseases, 10th Revision codes, and smoking status, including accumulated amount, was collected through a self-administered questionnaire. The Cox proportional hazard regression model was used, adjusting for age, sex, household income, body mass index, drinking, exercise, diabetes, hypertension, dyslipidemia, and chronic renal disease. Results: After excluding cases with sepsis occurring before follow-up or after ≤ 1 year of follow-up, 3,881,958 participants, including non-smokers (N = 2,342,841), former smokers (N = 539,850), and active smokers (N = 999,267), were included. Compared to non-smokers, all active smokers (adjust hazard ratio: 1.41, 95% confidence interval 1.38–1.44) and former smokers (1.10, 1.07–1.14) with ≥ 20 pack-years exhibited a significantly higher risk of sepsis (p < 0.001). Smoking of ≥ 30 pack-years in former and active smokers groups significantly increased sepsis incidence (adjust hazard ratio [95% confidence interval] 1.34 [1.31–1.38], p < 0.001). Conclusions: Smoking is closely associated with the incidence of sepsis. Smoking cessation may help in the primary prevention of sepsis. [ABSTRACT FROM AUTHOR]

As humans age, their memory T cell compartment expands due to the lifelong exposure to antigens. This expansion is characterized by terminally differentiated CD8+ T cells (Temra), which possess NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by the sporadic reactivation of cytomegalovirus (CMV), yet their epigenomic patterns and cellular heterogeneity remain understudied. To address this gap, we correlated their gene expression profiles with chromatin openness and conducted single-cell transcriptome analysis, comparing them to other CD8+ subsets and CMV-responses. We confirmed that Temra cells exhibit high expression of genes associated with cytotoxicity and lower expression of costimulatory and chemokine genes. The data revealed that CMV-responsive CD8+ T cells (Tcmv) were predominantly derived from a mixed population of Temra and memory cells (Tcm/em) and shared their transcriptomic profiles. Using ATAC-seq analysis, we identified 1449 differentially accessible chromatin regions between CD8+ Temra and Tcm/em cells, of which only 127 sites gained chromatin accessibility in Temra cells. We further identified 51 gene loci, including costimulatory CD27, CD28, and ICOS genes, whose chromatin accessibility correlated with their gene expression. The differential chromatin regions Tcm/em cells were enriched in motifs that bind multiple transcriptional activators, such as Jun/Fos, NFkappaB, and STAT, whereas the open regions in Temra cells mainly contained binding sites of T-box transcription factors. Our single-cell analysis of CD8+CCR7loCD45RAhi sorted Temra population showed several subsets of Temra and NKT-like cells and CMC1+ Temra populations in older individuals that were shifted towards decreased cytotoxicity. Among CD8+CCR7loCD45RAhi sorted cells, we found a decreased proportion of IL7R+ Tcm/em-like and MAIT cells in individuals with high levels of CMV antibodies (CMVhi). These results shed new light on the molecular and cellular heterogeneity of CD8+ Temra cells and their relationship to aging and CMV infection. [ABSTRACT FROM AUTHOR]

BACKGROUND: The prenatal environment influences lifetime health; epigenetic mechanisms likely predominate. In 2016, the first international consortium paper on cigarette smoking during pregnancy and offspring DNA methylation identified extensive, reproducible exposure signals. This finding raised expectations for epigenome-wide association studies (EWAS) of other exposures. OBJECTIVE: We review the current state-of-the-science for DNA methylation associations across prenatal exposures in humans and provide future recommendations. METHODS: We reviewed 134 prenatal environmental EWAS of DNA methylation in newborns, focusing on 51 epidemiological studies with meta-analysis or replication testing. Exposures spanned cigarette smoking, alcohol consumption, air pollution, dietary factors, psychosocial stress, metals, other chemicals, and other exogenous factors. Of the reproducible DNA methylation signatures, we examined implementation as exposure biomarkers. RESULTS: Only 19 (14%) of these prenatal EWAS were conducted in cohorts of 1,000 or more individuals, reflecting the still early stage of the field. To date, the largest perinatal EWAS sample size was 6,685 participants. For comparison, the most recent genome-wide association study for birth weight included more than 300,000 individuals. Replication, at some level, was successful with exposures to cigarette smoking, folate, dietary glycemic index, particulate matter with aerodynamic diameter <10 μm and <2.5 μm, nitrogen dioxide, mercury, cadmium, arsenic, electronic waste, PFAS, and DDT. Reproducible effects of a more limited set of prenatal exposures (smoking, folate) enabled robust methylation biomarker creation. DISCUSSION: Current evidence demonstrates the scientific premise for reproducible DNA methylation exposure signatures. Better powered EWAS could identify signatures across many exposures and enable comprehensive biomarker development. Whether methylation biomarkers of exposures themselves cause health effects remains unclear. We expect that larger EWAS with enhanced coverage of epigenome and exposome, along with improved single-cell technologies and evolving methods for integrative multi-omics analyses and causal inference, will expand mechanistic understanding of causal links between environmental exposures, the epigenome, and health outcomes throughout the life course. [ABSTRACT FROM AUTHOR]

Introduction: Immunotherapies have improved the prognosis of many cancer patients including patients with advanced melanoma. Immune checkpoint receptors including CTLA-4 and PD-1 have been established as main therapeutic targets for immunotherapy of melanoma. Although monotherapy is effective in melanoma patients, a dual therapy approach has been shown to be most effective. Dual checkpoint blockade, however, increases substantially the risk for immune-related adverse events (irAEs). Methods: In this study, we characterized peripheral immune cell subsets in patients with anti-PD-1 monotherapy and with dual immune receptors blockade targeting PD-1 and CTLA-4. Results: We found differences in peripheral T cells between patients who developed severe immune-related side effects and patients with mild irAEs. We identified several mainly changes in CD8+ T cell subsets in patients with severe irAE under dual PD-1 and CTLA-4 blockade. Discussion: This work suggests that peripheral immune cell dynamics could be associated with severe immune-related side effects in patients receiving immune checkpoint inhibitors. These changes could be used as future biomarkers in early diagnosis of irAEs. [ABSTRACT FROM AUTHOR]

Objective: This study sought to explain results of the Water Up!@Home randomised controlled trial where low-income parents were randomised to receive an educational intervention +a low-cost water filter pitcher or only the filter. Parents in both groups had reported statistically significant reductions in sugar-sweetened beverages (SSB) and increases in water intake post-intervention.Design: Qualitative explanatory in-depth interviews analysed thematically and deductively.Setting: Washington, DC metropolitan area, USA.Participants: Low-income Latino parents of infants/toddlers who had participated in the Water Up! @Home randomised controlled trial.Results: The filter-stimulated water consumption in both groups by (1) increasing parents' perception of water safety; (2) acting as a cue to action to drink water; (3) improving the flavour of water (which was linked to perceptions of safety) and (4) increasing the perception that this option was more economical than purchasing bottled water. Safe and palatable drinking water was more accessible and freely available in their homes; participants felt they did not need to ration their water consumption as before. Only intervention participants were able to describe a reduction in SSB intake and described strategies, skills and knowledge gained to reduce SSB intake. Among the comparison group, there was no thematic consensus about changes in SSB or any strategies or skills to reduce SSB intake.Conclusions: A low-cost water filter facilitated water consumption, which actively (or passively for comparison group) displaced SSB consumption. The findings have implications for understanding and addressing the role of water security on SSB consumption. [ABSTRACT FROM AUTHOR]

Rejection is still a critical barrier to the long-term survival of graft after liver transplantation, requiring clinicians to unveil the underlying mechanism of liver transplant rejection. The cellular diversity and the interplay between immune cells in the liver graft microenvironment remain unclear. Herein, we performed single-cell RNA sequencing analysis to delineate the landscape of immune cells heterogeneity in liver transplantation. T cells, NK cells, B cells, and myeloid cell subsets in human liver and blood were enriched to characterize their tissue distribution, gene expression, and functional modules. The proportion of CCR6+CD4+ T cells increased within an allograft, suggesting that there are more memory CD4+ T cells after transplantation, in parallel with exhausted CTLA4+CD8+ T and actively proliferating MKI67+CD8+ T cells increased significantly, where they manifested heterogeneity, distinct function, and homeostatic proliferation. Remarkably, the changes of CD1c+ DC, CADM+ DC, MDSC, and FOLR3+ Kupffer cells increase significantly, but the proportion of CD163+ Kupffer, APOE+ Kupffer, and GZMA+ Kupffer decreased. Furthermore, we identified LDLR as a novel marker of activated MDSC to prevent liver transplant rejection. Intriguingly, a subset of CD4+CD8+FOXP3+ T cells included in CTLA4+CD8+ T cells was first detected in human liver transplantation. Furthermore, intercellular communication and gene regulatory analysis implicated the LDLR+ MDSC and CTLA4+CD8+ T cells interact through TIGIT-NECTIN2 signaling pathway. Taken together, these findings have gained novel mechanistic insights for understanding the immune landscape in liver transplantation, and it outlines the characteristics of immune cells and provides potential therapeutic targets in liver transplant rejection. [ABSTRACT FROM AUTHOR]

Background: Bronchopulmonary dysplasia (BPD) is a lung disease in premature infants caused by therapeutic oxygen supplemental and characterized by impaired pulmonary development which persists into later life. While advances in neonatal care have improved survival rates of premature infants, cases of BPD have been increasing with limited therapeutic options for prevention and treatment. This study was designed to explore the relationship between gestational age (GA), birth weight, and estimated blood cell-type composition in premature infants and to elucidate early epigenetic biomarkers associated with BPD. Methods: Cord blood DNA from preterm neonates that went on to develop BPD (n = 14) or not (non-BPD, n = 93) was applied to Illumina 450 K methylation arrays. Blood cell-type compositions were estimated using DNA methylation profiles. Multivariable robust regression analysis elucidated CpGs associated with BPD risk. cDNA microarray analysis of cord blood RNA identified differentially expressed genes in neonates who later developed BPD. Results: The development of BPD and the need for oxygen supplementation were strongly associated with GA (BPD, p < 1.0E−04; O2 supplementation, p < 1.0E−09) and birth weight (BPD, p < 1.0E−02; O2 supplementation, p < 1.0E−07). The estimated nucleated red blood cell (NRBC) percent was negatively associated with birth weight and GA, positively associated with hypomethylation of the tobacco smoke exposure biomarker cg05575921, and high-NRBC blood samples displayed a hypomethylation profile. Epigenome-wide association study (EWAS) identified 38 (Bonferroni) and 275 (false discovery rate 1%) differentially methylated CpGs associated with BPD. BPD-associated CpGs in cord blood were enriched for lung maturation and hematopoiesis pathways. Stochastic epigenetic mutation burden at birth was significantly elevated among those who developed BPD (adjusted p = 0.02). Transcriptome changes in cord blood cells reflected cell cycle, development, and pulmonary disorder events in BPD. Conclusions: While results must be interpreted with caution because of the small size of this study, NRBC content strongly impacted DNA methylation profiles in preterm cord blood and EWAS analysis revealed potential insights into biological pathways involved in BPD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Childcare settings are important environments for influencing child eating and physical activity (PA). Family childcare homes (FCCH) care for many children of low-income and diverse racial/ethnic backgrounds who are at greater risk for poor diet quality, low PA, and obesity, but few interventions have targeted this setting. The aim of this study was to assess the efficacy of a multicomponent intervention conducted in FCCH on the diet quality and PA of 2–5 year old children in their care. Trial design: Cluster randomized trial. Methods: The cluster-randomized trial, Healthy Start/Comienzos Sanos (2015–2019) evaluated an 8-month nutrition and PA intervention that included four components: (1) monthly telephone calls from a support coach using brief motivational interviewing, (2) tailored reports, newsletters and videos, (3) group support meetings, and (4) active play toys. After completing baseline measurement, FCCH were randomized into intervention or comparison groups in matched pairs. Both groups received the same intervention components but on different topics (intervention: nutrition/PA vs. comparison: reading readiness/literacy). Evaluation staff were blinded to group assignment. Child primary outcome measures collected at baseline and 8-months included: 1) Healthy Eating Index (HEI-2015) scores calculated from diet observation, and 2) accelerometer measurement of PA. Process measures were collected from field data and provider surveys. Generalized Estimating Equation Models assessed changes in HEI-2015 scores and PA over time by experimental condition. Results: Ethnically diverse FCCH providers (n = 119) and 2-to-5-year-old children in their care (n = 377) were included in the final analysis. Process evaluation showed high participation in all intervention components except for group meetings. Compared to children in comparison group FCCH, children in intervention FCCH increased total HEI-2015 scores by 7.2 points (p <.001) including improvement in component scores for vegetables (0.84 points, p =.025) and added sugar (0.94 points, p =.025). For PA, compared to children in the comparison group, children in intervention FCCH decreased sedentary time by 5.7% (p =.021). Conclusions: The multicomponent Healthy Start intervention was effective in improving diet quality and sedentary behavior of children in FCCH, which demonstrates the promise of obesity prevention interventions in this setting. Future research could include enhancing the Healthy Start intervention to strengthen the PA component, considering virtual peer support, and determining how to best translate and disseminate the intervention into FCCH nationally. Trial registration: National Institutes of Health, NCT02452645. Registered 5 May 2015. [ABSTRACT FROM AUTHOR]

The adaptive immune system has the enormous challenge to protect the host through the generation and differentiation of pathogen‐specific short‐lived effector T cells while in parallel developing long‐lived memory cells to control future encounters with the same pathogen. A complex regulatory network is needed to preserve a population of naïve cells over lifetime that exhibit sufficient diversity of antigen receptors to respond to new antigens, while also sustaining immune memory. In parallel, cells need to maintain their proliferative potential and the plasticity to differentiate into different functional lineages. Initial signs of waning immune competence emerge after 50 years of age, with increasing clinical relevance in the 7th–10th decade of life. Morbidity and mortality from infections increase, as drastically exemplified by the current COVID‐19 pandemic. Many vaccines, such as for the influenza virus, are poorly effective to generate protective immunity in older individuals. Age‐associated changes occur at the level of the T‐cell population as well as the functionality of its cellular constituents. The system highly relies on the self‐renewal of naïve and memory T cells, which is robust but eventually fails. Genetic and epigenetic modifications contribute to functional differences in responsiveness and differentiation potential. To some extent, these changes arise from defective maintenance; to some, they represent successful, but not universally beneficial adaptations to the aging host. Interventions that can compensate for the age‐related defects and improve immune responses in older adults are increasingly within reach. [ABSTRACT FROM AUTHOR]

DNA methylation is highly sensitive to in utero perturbations and has an established role in both embryonic development and regulation of gene expression. The foetal genetic component has been previously shown to contribute significantly to the timing of birth, yet little is known about the identity and behaviour of individual genes. The aim of this study was to test the extent genome-wide DNA methylation levels in umbilical cord blood were associated with gestational age at birth (GA). Findings were validated in an independent sample and evidence for the regulation of gene expression was evaluated for cis gene relationships in specimens with multi-omic data. Genome-wide DNA methylation, measured by the Illumina Infinium Human Methylation 450 K BeadChip, was associated with GA for 2,372 CpG probes (5% FDR) in both the Pregnancy, Race, Environment, Genes (PREG) and Newborn Epigenetic Study (NEST) cohorts. Significant probes mapped to 1,640 characterized genes and an association with nearby gene expression measures obtained by the Affymetrix HG-133A microarray was found for 11 genes. Differentially methylated positions were enriched for actively transcribed and enhancer chromatin states, were predominately located outside of CpG islands, and mapped to genes enriched for inflammation and innate immunity ontologies. In both PREG and NEST, the first principal component derived from these probes explained approximately one-half (58.1% and 47.8%, respectively) of the variation in GA. Gene pathways identified are consistent with the hypothesis of pathogen detection and response by the immune system to elicit premature labour as a consequence of unscheduled inflammation. [ABSTRACT FROM AUTHOR]

Background: Early detection is essential to improve the survival and life quality of lung cancer (LC) patients. Changes of peripheral blood DNA methylation could be associated with malignancy but were mostly studied in Caucasians. Methods: Here, in a Chinese population, we performed mass spectrometry assays to investigate the association between very early stage LC and methylation levels of RAPSN in the peripheral blood by a case–control cohort using of 221 LC patients (93.2% LC at stage I) and 285 unrelated cancer free control individuals. Results: The odds ratios (ORs) of all CpG sites were evaluated for their risk to LC using inter-quartile analyses by logistic regression. In general, we observed an association between very early LC and decreased methylation of RAPSN_CpG_1.15 and RAPSN_CpG_3.4 (referring to Q4, OR range from 1.64 to 1.81, p< 0.05). Stratified by gender, while hypomethylation of RAPSN_CpG_1.15, RAPSN_CpG_3.4 and RAPSN_CpG_7.14 were associated with LC in males (referring to Q4, ORs range from 1.94 to 2.31, p< 0.05), RAPSN_CpG_2 and RAPSN_CpG_5 showed significantly lower methylation in female LC patients comparing to controls (referring to Q4, ORs range from 2.49 to 3.60, p< 0.05). The risk of RAPSN hypomethylation to LC was enhanced by aging, and typically for people older than 55 years (referring to Q4, ORs range from 2.17 to 3.61 in six out of all 10 analyzed CpG groups, p< 0.05). Conclusion: Our study reveals an association between RAPSN hypomethylation in peripheral blood and LC and suggests the occurrence of altered blood-based methylation at the early stage of cancer. [ABSTRACT FROM AUTHOR]

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications. [ABSTRACT FROM AUTHOR]