A substantial proportion of disease risk for common complex disorders is attributable to environmental exposures and pollutants. An appreciation of how environmental pollutants act on our cells to ...produce deleterious health effects has led to advances in our understanding of the molecular mechanisms underlying the pathogenesis of chronic diseases, including cancer and cardiovascular, neurodegenerative and respiratory diseases. Here, we discuss emerging research on the interplay of environmental pollutants with the human genome and epigenome. We review evidence showing the environmental impact on gene expression through epigenetic modifications, including DNA methylation, histone modification and non-coding RNAs. We also highlight recent studies that evaluate recently discovered molecular processes through which the environment can exert its effects, including extracellular vesicles, the epitranscriptome and the mitochondrial genome. Finally, we discuss current challenges when studying the exposome - the cumulative measure of environmental influences over the lifespan - and its integration into future environmental health research.
CD24Fc: an emerging COVID-19 therapy Eckhardt, Christina M; O'Donnell, Max R
The Lancet infectious diseases,
05/2022, Volume:
22, Issue:
5
Journal Article
Peer reviewed
Open access
The primary endpoint was time to clinical improvement, defined as time elapsed between a baseline National Institute of Allergy and Infectious Diseases 8-point ordinal scale (NIAID-OS) score of 2–4 ...and a score of 5 or higher or hospital discharge.2 Among all 234 participants who were randomly assigned to a treatment group (of whom 62% were male and 38% female, 47% were non-Hispanic White, and median age was 59 years IQR 48–68), time to clinical improvement was accelerated among participants who received CD24Fc (median 6·0 days) compared with those who received placebo (10·5 days) over the 28-day study period (hazard ratio HR 1·40, 95% CI 1·02–1·92). ...CD24Fc infusion was compared with an outdated standard of care that included a combination of experimental corticosteroids, remdesivir, and convalescent plasma given at the discretion of the treating physician. Since the enrolment period ended, trials have shown that convalescent plasma was not associated with reduced time to clinical improvement,6 and IL-6 receptor antagonists have emerged as an important part of the COVID-19 treatment framework.5 A key component of clinical trial design is ensuring the control group reflects the current standard of care. Participants with an NIAID-OS score of 2 or 3 appeared to derive minimal benefit from CD24Fc treatment, although larger studies are required to evaluate the effectiveness of CD24Fc in subgroups defined by severity of illness.
Purpose of Review
Inhaled environmental exposures cause over 12 million deaths per year worldwide. Despite localized efforts to reduce environmental exposures, tobacco smoking and air pollution ...remain the urgent public health challenges that are contributing to the growing prevalence of respiratory diseases. The purpose of this review is to describe the mechanisms through which inhaled environmental exposures accelerate lung aging and cause overt lung disease.
Recent Findings
Environmental exposures related to fossil fuel and tobacco combustion and occupational exposures related to silica and coal mining generate oxidative stress and inflammation in the lungs. Sustained oxidative stress causes DNA damage, epigenetic instability, mitochondrial dysfunction, and cell cycle arrest in key progenitor cells in the lung. As a result, critical repair mechanisms are impaired, leading to premature destruction of the lung parenchyma.
Summary
Inhaled environmental exposures accelerate lung aging by injuring the lungs and damaging the cells responsible for wound healing. Interventions that minimize exposure to noxious antigens are critical to improve lung health, and novel research is required to expand our knowledge of therapies that may slow or prevent premature lung aging.
Unsupervised machine learning methods are important analytical tools that can facilitate the analysis and interpretation of high-dimensional data. Unsupervised machine learning methods identify ...latent patterns and hidden structures in high-dimensional data and can help simplify complex datasets. This article provides an overview of key unsupervised machine learning techniques including K-means clustering, hierarchical clustering, principal component analysis, and factor analysis. With a deeper understanding of these analytical tools, unsupervised machine learning methods can be incorporated into health sciences research to identify novel risk factors, improve prevention strategies, and facilitate delivery of personalized therapies and targeted patient care.
Level of evidence:
I
Although convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.
We conducted a ...randomized, double-blind, placebo-controlled trial among adults hospitalized with severe and critical COVID-19 at five sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized in a 2:1 ratio to receive a single transfusion of either convalescent plasma or placebo (normal control plasma). The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.
Of 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to normal control plasma. At 28 days, no significant improvement in clinical status was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval (CI) 0.83-2.68, p=0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 12.6% versus 18/73 24.6%, OR 0.44, 95% CI 0.22-0.91, p=0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.
In adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in clinical status at day 28. However, a significant improvement in mortality was observed, which warrants further evaluation.
ClinicalTrials.gov, NCT04359810FUNDING. Amazon Foundation. Skoll Foundation.
We present a novel concept for the in situ control of site-selectivity of catalytic acetylations of partially protected sugars using light as external stimulus and oligopeptide catalysts equipped ...with an azobenzene moiety. The isomerizable azobenzene-peptide backbone defines the size and shape of the catalytic pocket, while the π-methyl-l-histidine (Pmh) moiety transfers the electrophile. Photoisomerization of the E- to the Z-azobenzene catalyst (monitored via NMR) with an LED (λ = 365 nm) drastically changes the chemical environment around the catalytically active Pmh moiety, so that the light-induced change in the catalyst shape alters site-selectivity. As a proof of principle, we employed (4,6-O-benzylidene)methyl-α-d-pyranosides, which provide a change in regioselectivity from 2:1 (E) to 1:5 (Z) for the monoacetylated products at room temperature. The validity of this new catalyst-design concept is further demonstrated with the regioselective acetylation of the natural product quercetin. In situ irradiation NMR spectroscopy was used to quantify photostationary states under continuous irradiation with UV light.
The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and ...molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer.
Purpose of Review
Environmental pollutants contribute to the pathogenesis of numerous diseases including chronic cardiovascular, respiratory, and neurodegenerative diseases, among others. Emerging ...evidence suggests that extracellular vesicles (EVs) may mediate the association of environmental exposures with chronic diseases. The purpose of this review is to describe the impact of common environmental exposures on EVs and their role in linking environmental pollutants to the pathogenesis of chronic systemic diseases.
Recent Findings
Common environmental pollutants including particulate matter, tobacco smoke, and chemical pollutants trigger the release of EVs from multiple systems in the body. Existing research has focused primarily on air pollutants, which alter EV production and release in the lungs and systemic circulation. Air pollutants also impact the selective loading of EV cargo including microRNA and proteins, which modify the cellular function in recipient cells. As a result, pollutant-induced EVs often contribute to a pro-inflammatory and pro-thrombotic milieu, which increases the risk of pollutant-related diseases including obstructive lung diseases, cardiovascular disease, neurodegenerative diseases, and lung cancer.
Summary
Common environmental exposures are associated with multifaceted changes in EVs that lead to functional alterations in recipient cells and contribute to the pathogenesis of chronic systemic diseases. EVs may represent emerging targets for the prevention and treatment of diseases that stem from environmental exposures. However, novel research is required to expand our knowledge of the biological action of EV cargo, elucidate determinants of EV release, and fully understand the impact of environmental pollutants on human health.
Shortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown.
What is the clinical impact of TL testing on the ...management of ILD?
Patients were evaluated in the Columbia University ILD clinic and underwent CLIA-certified TL testing by flow cytometry and fluorescence in-situ hybridization (FlowFISH) as part of clinical management. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared against research qPCR TL measurement.
A total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR 2.00, 95% CI 1.27, 3.32). TL testing led to clinical management changes for 35 (32%) patients, most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n=34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 (29%) patients. Inclusion of TL testing below the 1st percentile helped reclassify 8 of 9 variants of uncertain significance (VUS) into actionable findings. The qPCR test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays.
Incorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.
Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of ...early lung injury.
Evaluate associations of plasma EV-miRNAs with lung function.
The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study).
In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted
value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity.
Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.
PDF
