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"Leigh, J. R. (James R.)"
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Interaction between the microbiome and TP53 in human lung cancer
Background
Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort.
Results
Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which
Acidovorax
is enriched in smokers.
Acidovorax
temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including
Acidovorax
, exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas.
Conclusions
The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.
Journal Article
Brake : seconds to live : a nation to save
Jeremy Reins wakes up in a cramped space with the only light coming from the digital numbers ticking away above his head. Confused and disoriented with no one answering his cries for help, he suddenly hears an engine rev and his predicament becomes clear: he's trapped in the trunk of a moving car. As his captors reveal themselves, Jeremy realizes he won't be set free until he gives up the whereabouts of a secret location where the U.S. President is taken in the event of a terrorist attack.
DVD
Elevated levels of OH observed in haze events during wintertime in central Beijing
Wintertime in situ measurements of OH, HO2 and RO2 radicals and OH reactivity were made in central Beijing during November and December 2016. Exceptionally elevated NO was observed on occasions, up to ∼250 ppbv. The daily maximum mixing ratios for radical species varied significantly day-to-day over the ranges 1–8×106 cm−3 (OH), 0.2–1.5×108 cm−3 (HO2) and 0.3–2.5×108 cm−3 (RO2). Averaged over the full observation period, the mean daytime peak in radicals was 2.7×106, 0.39×108 and 0.88×108 cm−3 for OH, HO2 and total RO2, respectively. The main daytime source of new radicals via initiation processes (primary production) was the photolysis of HONO (∼83 %), and the dominant termination pathways were the reactions of OH with NO and NO2, particularly under polluted haze conditions. The Master Chemical Mechanism (MCM) v3.3.1 operating within a box model was used to simulate the concentrations of OH, HO2 and RO2. The model underpredicted OH, HO2 and RO2, especially when NO mixing ratios were high (above 6 ppbv). The observation-to-model ratio of OH, HO2 and RO2 increased from ∼1 (for all radicals) at 3 ppbv of NO to a factor of ∼3, ∼20 and ∼91 for OH, HO2 and RO2, respectively, at ∼200 ppbv of NO. The significant underprediction of radical concentrations by the MCM suggests a deficiency in the representation of gas-phase chemistry at high NOx. The OH concentrations were surprisingly similar (within 20 % during the day) in and outside of haze events, despite j(O1D) decreasing by 50 % during haze periods. These observations provide strong evidence that gas-phase oxidation by OH can continue to generate secondary pollutants even under high-pollution episodes, despite the reduction in photolysis rates within haze.
Journal Article
In situ ozone production is highly sensitive to volatile organic compounds in Delhi, India
The Indian megacity of Delhi suffers from some of the poorest air quality in the world. While ambient NO2 and particulate matter (PM) concentrations have received considerable attention in the city, high ground-level ozone (O3) concentrations are an often overlooked component of pollution. O3 can lead to significant ecosystem damage and agricultural crop losses, and adversely affect human health. During October 2018, concentrations of speciated non-methane hydrocarbon volatile organic compounds (C2–C13), oxygenated volatile organic compounds (o-VOCs), NO, NO2, HONO, CO, SO2, O3, and photolysis rates, were continuously measured at an urban site in Old Delhi. These observations were used to constrain a detailed chemical box model utilising the Master Chemical Mechanism v3.3.1. VOCs and NOx (NO + NO2) were varied in the model to test their impact on local O3 production rates, P(O3), which revealed a VOC-limited chemical regime. When only NOx concentrations were reduced, a significant increase in P(O3) was observed; thus, VOC co-reduction approaches must also be considered in pollution abatement strategies. Of the VOCs examined in this work, mean morning P(O3) rates were most sensitive to monoaromatic compounds, followed by monoterpenes and alkenes, where halving their concentrations in the model led to a 15.6 %, 13.1 %, and 12.9 % reduction in P(O3), respectively. P(O3) was not sensitive to direct changes in aerosol surface area but was very sensitive to changes in photolysis rates, which may be influenced by future changes in PM concentrations. VOC and NOx concentrations were divided into emission source sectors, as described by the Emissions Database for Global Atmospheric Research (EDGAR) v5.0 Global Air Pollutant Emissions and EDGAR v4.3.2_VOC_spec inventories, allowing for the impact of individual emission sources on P(O3) to be investigated. Reducing road transport emissions only, a common strategy in air pollution abatement strategies worldwide, was found to increase P(O3), even when the source was removed in its entirety. Effective reduction in P(O3) was achieved by reducing road transport along with emissions from combustion for manufacturing and process emissions. Modelled P(O3) reduced by ∼ 20 ppb h−1 when these combined sources were halved. This study highlights the importance of reducing VOCs in parallel with NOx and PM in future pollution abatement strategies in Delhi.
Journal Article
Mechanisms of gas transfer impairment utilizing nitric oxide following severe COVID‐19 pneumonitis
Reduced carbon monoxide diffusing capacity (DLCO) is common after recovery from severe COVID‐19 pneumonitis. The extent to which this relates to alveolar membrane dysfunction as opposed to vascular injury is uncertain. Simultaneous measurement of nitric oxide diffusing capacity (DLNO) and DLCO can partition gas diffusion into its two components: alveolar–capillary membrane conductance (DmCO) and capillary blood volume (VC). We sought to evaluate DmCO and VC in the early and later recovery periods after severe COVID‐19. Patients attended for post‐COVID‐19 clinical review and lung function testing including DLNO/DLCO. Repeat testing occurred when indicated and comparisons made using t‐tests. Forty‐nine (eight female) subjects (mean ± SD age: 58 ± 13, BMI: 34 ± 8) who had severe COVID‐19 pneumonitis, WHO severity classification of 6 ± 1, and prolonged (21 ± 22 days) hospital stay, were assessed 2 months (61 ± 35 days) post discharge. DLCOadj (z‐score −1.70 ± 1.49, 25/49 < lower limit of normal [LLN]) and total lung capacity (z‐score −1.71 ± 1.30) were both reduced. DmCO and VC and were reduced to a similar extent (z‐score −1.19 ± 1.05 and −1.41 ± 1.20, p = 0.4). Seventeen (one female) patients returned for repeat testing 4 months (122 ± 61 days) post discharge. In this subgroup with more impaired lung function, DLCOadj improved but remained below LLN (z‐score −3.15 ± 0.83 vs. −2.39 ± 0.86, p = 0.01), 5/17 improved to >LNN. DmCO improved (z‐score −2.05 ± 0.89 vs. −1.41 ± 0.78, p = 0.01) but VC was unchanged (z‐score −2.51 ± 0.55 vs. −2.29 ± 0.59, p = 0.16). Alveolar membrane conductance is abnormal in the earlier recovery phase following severe COVID‐19 but significantly improves. In contrast, reduced VC persists. These data raise the possibility that persisting effects of acute vascular injury may contribute to gas diffusion impairment long after severe COVID‐19 pneumonitis. Simultaneous measurement of nitric oxide and carbon monoxide diffusing capacity (DLNO/DLCO) was used to quantify the contributions of alveolar–capillary membrane conductance and capillary blood volume (VC) to impaired gas diffusion following severe COVID‐19. At 2 months, both were reduced to a similar extent. Membrane conductance significantly improved at 4 months, however, VC remained reduced. These novel findings suggest persisting vascular injury may contribute to physiological impairment long after severe COVID‐19 pneumonitis.
Journal Article
Train Smart Study: protocol for a randomised trial investigating the role of exercise training dose on markers of brain health in sedentary middle-aged adults
IntroductionRegular aerobic exercise is associated with improved cognitive function, implicating it as a strategy to reduce dementia risk. This is reinforced by the association between greater cardiorespiratory fitness and larger brain volume, superior cognitive performance and lower dementia risk. However, the optimal aerobic exercise dose, namely the intensity and mode of delivery, to improve brain health and lower dementia risk has received less attention. We aim to determine the effect of different doses of aerobic exercise training on markers of brain health in sedentary middle-aged adults, hypothesising that high-intensity interval training (HIIT) will be more beneficial than moderate-intensity continuous training (MICT).Methods and analysisIn this two-group parallel, open-label blinded endpoint randomised trial, 70 sedentary middle-aged (45–65 years) adults will be randomly allocated to one of two 12-week aerobic exercise training interventions matched for total exercise training volume: (1) MICT (n=35) or HIIT (n=35). Participants will perform ~50 min exercise training sessions, 3 days per week, for 12 weeks. The primary outcome will be measured as between-group difference in cardiorespiratory fitness (peak oxygen uptake) change from baseline to the end of training. Secondary outcomes include between-group differences in cognitive function and ultra-high field MRI (7T) measured markers of brain health (brain blood flow, cerebrovascular function, brain volume, white matter microstructural integrity and resting state functional brain activity) changes from baseline to the end of training.Ethics and disseminationThe Victoria University Human Research Ethics Committee (VUHREC) has approved this study (HRE20178), and all protocol modifications will be communicated to the relevant parties (eg, VUHREC, trial registry). Findings from this study will be disseminated via peer-review publications, conference presentations, clinical communications and both mainstream and social media.Trial registration numberANZCTR12621000144819.
Journal Article
Observations of speciated isoprene nitrates in Beijing: implications for isoprene chemistry
Isoprene is the most important biogenic volatile organic compound in the atmosphere. Its calculated impact on ozone (O3) is critically dependent on the model isoprene oxidation chemical scheme, in particular the way the isoprene-derived organic nitrates (IN) are treated. By combining gas chromatography with mass spectrometry, we have developed a system capable of separating and unambiguously measuring individual IN isomers. In this paper we use measurements from its first field deployment, which took place in Beijing as part of the Atmospheric Pollution and Human Health in a Chinese Megacity programme, to test understanding of the isoprene chemistry as simulated in the Master Chemical Mechanism (MCM) (v.3.3.1). Seven individual isoprene nitrates were identified and quantified during the campaign: two β-hydroxy nitrates (IHN), four δ-carbonyl nitrates (ICN), and propanone nitrate. Our measurements show that in the summertime conditions experienced in Beijing the ratio of (1-OH, 2-ONO2)-IHN to (4-OH, 3-ONO2)-IHN (the numbers indicate the carbon atom in the isoprene chain to which the radical is added) increases at NO mixing ratios below 2 ppb. This provides observational field evidence of the redistribution of the peroxy radicals derived from OH oxidation of isoprene away from the kinetic ratio towards a new thermodynamic equilibrium consistent with box model calculations. The observed amounts of δ-ICN demonstrate the importance of daytime addition of NO3 to isoprene in Beijing but suggest that the predominant source of the δ-ICN in the model (reaction of NO with δ-nitrooxy peroxy radicals) may be too large. Our speciated measurements of the four δ-ICN exhibit a mean C1 : C4 isomer ratio of 1.4 and a mean trans : cis isomer ratio of 7 and provide insight into the isomeric distribution of the δ-nitrooxy peroxy radicals. Together our measurements and model results indicate that propanone nitrate was formed from the OH oxidation of δ-ICN both during the day and night, as well as from NO3 addition to propene at night. This study demonstrates the value of speciated IN measurements in testing understanding of the isoprene degradation chemistry and shows how more extensive measurements would provide greater constraints. It highlights areas of the isoprene chemistry that warrant further study, in particular the impact of NO on the formation of the IHN and the NO3-initiated isoprene degradation chemistry, as well as the need for further laboratory studies on the formation and the losses of IN, in particular via photolysis of δ-ICN and hydrolysis.
Journal Article
Author Correction: Interaction between the microbiome and TP53 in human lung cancer
Following publication of the original paper [1], the authors submitted a new Additional file 5 to replace the one containing formatting issues. The updated Additional file 5 is published in this correction.
Journal Article
The impact of GPX1 on the association of groundwater selenium and depression: a project FRONTIER study
Background
Prior animal model and human-based studies have linked selenium concentrations to decreased risk for depression; however, this work has not focused on household groundwater levels or specific depressive symptoms. The current study evaluated the link between groundwater selenium levels and depression. We also sought to determine if a functional polymorphism in the glutathione peroxidase 1 (GPX1) gene impacted this link.
Methods
We used a cross-sectional design to analyze data from 585 participants (183 men and 402 women) from Project FRONTIER, a study of rural health in West Texas. Residential selenium concentrations were estimated using Geospatial Information System (GIS) analyses. Linear regression models were created using Geriatric Depression Scale (GDS-30) total and subfactor scores as outcome variables and selenium concentrations as predictor variables. Analyses were re-run after stratification of the sample on GPX1 Pro198Leu genotype (rs1050454).
Results
Selenium levels were significantly and negatively related to all GDS and subfactor scores accounting for up to 17% of the variance beyond covariates. Selenium was most strongly protective against depression among homozygous carriers of the C allele at the Pro198Leu polymorphism of the GPX1 gene. Analyses also point towards a gene-environmental interaction between selenium exposure and GPX1 polymorphism.
Conclusion
Our results support the link between groundwater selenium levels and decreased depression symptoms. These findings also highlight the need to consider the genetics of the glutathione peroxidase system when examining this relationship, as variation in the GPX1 gene is related to depression risk and significantly influences the protective impact of selenium, which is indicative of a gene-environment interaction.
Journal Article