TracMyAir smartphone application for modeling exposures to PM and ozone - Integration with air quality networks and location-activity sensors.

Epidemiologic studies of ambient fine particulate matter (PM) and ozone (O) often use outdoor concentrations from central-site monitors or air quality model estimates as exposure surrogates, which can result in exposure errors. We previously developed an exposure model called TracMyAir, which is an iPhone application that determines seven tiers of individual-level exposure metrics for ambient PM and O using outdoor concentrations, home building characteristics, weather, time-activities. The exposure metrics with increasing information needs and complexity include: outdoor concentration (C, Tier 1), building infiltration factor (F, Tier 2), indoor concentration (C, Tier 3), time spent in microenvironments (ME) (T, Tier 4), personal exposure factor (F, Tier 5), exposure (E, Tier 6), and inhaled dose (D, Tier 7).

Encountering Prescribed Fire: Characterizing the Intersection of Prescribed Fire and Wildfire in the CONUS.

Prescribed fire is applied across the United States as a fuel treatment to manage the impact of wildfires and restore ecosystems. While the recent application of prescribed fire has largely been confined to the southeastern US, the increase in catastrophic wildfires has accelerated the growth of prescribed fire more broadly. To effectively achieve wildfire risk reduction benefits, which includes reducing the amount of smoke emitted, the area treated by prescribed fire must come into contact with a subsequent wildfire.

2004-2017 Geospatial dataset of wild and prescribed fire activity over the conterminous United States.

Wildland fire activity is provided in a geospatial database of polygons over the conterminous United States for the 2004 through 2017 time period. The location, timing, and size of the fires are derived from a fusion of wildland fire activity from a consistent set of national ground reports, satellite, and geospatial fire data. A combination of information from the underlying data sources and a regional climatological approach is used to differentiate prescribed fire from unplanned wildfire.

A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer.

Background: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent.

Patients And Methods: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone).

A phase 2 study of AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

Background: Inhibition of the adenosine 2A receptor (AR) diminishes the immunosuppressive effects of adenosine and may complement immune-targeting drugs. This phase 2 study evaluated the AR antagonist AZD4635 in combination with durvalumab or oleclumab in patients with metastatic castration-resistant prostate cancer.

Methods: Patients with histologically/cytologically confirmed disease progressing within 6 months on ≥ 2 therapy lines were randomly assigned to either Module 1 (AZD4635 + durvalumab) or Module 2 (AZD4635 + oleclumab).

The HTAP_v3 emission mosaic: merging regional and global monthly emissions (2000-2018) to support air quality modelling and policies.

This study, performed under the umbrella of the Task Force on Hemispheric Transport of Air Pollution (TF-HTAP), responds to the global and regional atmospheric modelling community's need of a mosaic emission inventory of air pollutants that conforms to specific requirements: global coverage, long time series, spatially distributed emissions with high time resolution, and a high sectoral resolution. The mosaic approach of integrating official regional emission inventories based on locally reported data, with a global inventory based on a globally consistent methodology, allows modellers to perform simulations of high scientific quality while also ensuring that the results remain relevant to policymakers. HTAP_v3, an ad hoc global mosaic of anthropogenic inventories, has been developed by integrating official inventories over specific areas (North America, Europe, Asia including Japan and South Korea) with the independent Emissions Database for Global Atmospheric Research (EDGAR) inventory for the remaining world regions.

Comprehensive clinical pharmacology characterization of AZD4635 in healthy participants to support dosing considerations.

Aims: Two phase 1 studies characterized the oral bioavailability of AZD4635 (potential anticancer therapy) and factors that may influence its pharmacokinetics (PKs; food, smoking, proton-pump inhibitors [PPIs] and CYP1A2 inhibitors) to support continued clinical development of AZD4635.

Methods: Study 1 (comparative PK study; nonsmokers) consists of Part A and Part B. Participants (fasted) in Part A were administered 50 mg of AZD4635 either as nanosuspension or capsule.

2002-2017 anthropogenic emissions data for air quality modeling over the United States.

The United States Environmental Protection Agency (US EPA) has developed a set of annual North American emissions data for multiple air pollutants across 18 broad source categories for 2002 through 2017. The sixteen new annual emissions inventories were developed using consistent input data and methods across all years. When a consistent method or tool was not available for a source category, emissions were estimated by scaling data from the EPA's 2017 National Emissions Inventory with scaling factors based on activity data and/or emissions control information.

Phase Ia/b, Open-Label, Multicenter Study of AZD4635 (an Adenosine A2A Receptor Antagonist) as Monotherapy or Combined with Durvalumab, in Patients with Solid Tumors.

Purpose: To evaluate AZD4635, an adenosine A2A receptor antagonist, as monotherapy or in combination with durvalumab in patients with advanced solid tumors.

Patients And Methods: In phase Ia (dose escalation), patients had relapsed/refractory solid tumors; in phase Ib (dose expansion), patients had checkpoint inhibitor-naïve metastatic castration-resistant prostate cancer (mCRPC) or colorectal carcinoma, non-small cell lung cancer with prior anti-PD-1/PD-L1 exposure, or other solid tumors (checkpoint-naïve or prior anti-PD-1/PD-L1 exposure). Patients received AZD4635 monotherapy (75-200 mg once daily or 125 mg twice daily) or in combination with durvalumab (AZD4635 75 or 100 mg once daily).

Performance Evaluation of the Meteorology and Air Quality Conditions From Multiscale WRF-CMAQ Simulations for the Long Island Sound Tropospheric Ozone Study (LISTOS).

The Long Island Sound (LIS) Tropospheric Ozone Study was a multi-agency collaborative field campaign conducted during the summer of 2018 to improve the understanding of ozone chemistry and transport from New York City to areas downstream, especially the LIS and adjacent Connecticut coastline. Measurements made during this campaign were leveraged to test and evaluate the coupled WRF-CMAQ model at 12 km, 4 and 1.33 km horizontal grid spacing.

An evaluation of empirical and statistically based smoke plume injection height parametrisations used within air quality models.

Air quality models are used to assess the impact of smoke from wildland fires, both prescribed and natural, on ambient air quality and human health. However, the accuracy of these models is limited by uncertainties in the parametrisation of smoke plume injection height (PIH) and its vertical distribution. We compared PIH estimates from the plume rise method (Briggs) in the Community Multiscale Air Quality (CMAQ) modelling system with observations from the 2013 California Rim Fire and 2017 prescribed burns in Kansas.

The Community Multiscale Air Quality (CMAQ) model versions 5.3 and 5.3.1: system updates and evaluation.

The Community Multiscale Air Quality (CMAQ) model version 5.3 (CMAQ53), released to the public in August 2019 and followed by version 5.3.

The Detailed Emissions Scaling, Isolation, and Diagnostic (DESID) module in the Community Multiscale Air Quality (CMAQ) modeling system version 5.3.2.

Air quality modeling for research and regulatory applications often involves executing many emissions sensitivity cases to quantify impacts of hypothetical scenarios, estimate source contributions, or quantify uncertainties. Despite the prevalence of this task, conventional approaches for perturbing emissions in chemical transport models like the Community Multiscale Air Quality (CMAQ) model require extensive offline creation and finalization of alternative emissions input files. This workflow is often time-consuming, error-prone, inconsistent among model users, difficult to document, and dependent on increased hard disk resources.

Evaluation of Combination Strategies for the AR Inhibitor AZD4635 Across Tumor Microenvironment Conditions a Systems Pharmacology Model.

Background: Adenosine receptor type 2 (AR) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying, mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy.

Methods: The model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by AR or PD-L1, as well as other immunosuppressive mechanisms; 3) AR and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb.

Combining Matching and Synthetic Control to Trade off Biases from Extrapolation and Interpolation.

The synthetic control (SC) method is widely used in comparative case studies to adjust for differences in pre-treatment characteristics. SC limits extrapolation bias at the potential expense of interpolation bias, whereas traditional matching estimators have the opposite properties. This complementarity motives us to propose a matching and synthetic control (or MASC) estimator as a model averaging estimator that combines the standard SC and matching estimators.

Impact of wildfire on particulate matter in the southeastern United States in November 2016.

In November 2016, a large area of wildfire occurred in the southeastern United States, concomitant with the occurrence of severe drought during the same period. Whereas the previous studies on biomass burning over this region mainly focused on the prescribed fire, this study investigated the impact of wildfire using the two-way-coupled Weather Research and Forecasting model and Community Multiscale Air Quality model. Two episodic wildfire burning events (November 6 to 9 and November 13 to 16, 2016) were selected, and the mean contribution to fine particulate matter (PM) in the southeastern United States from wildfires reached 9.

Significant ground-level ozone attributed to lightning-induced nitrogen oxides during summertime over the Mountain West States.

Using lightning flash data from the National Lightning Detection Network with an updated lightning nitrogen oxides (NO) emission estimation algorithm in the Community Multiscale Air Quality (CMAQ) model, we estimate the hourly variations in lightning NO emissions for the summer of 2011 and simulate its impact on distributions of tropospheric ozone (O) across the continental United States. We find that typical summer-time lightning activity across the U.S.

Adenosine Signaling Is Prognostic for Cancer Outcome and Has Predictive Utility for Immunotherapeutic Response.

Purpose: There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is critical to understand the potential for these molecules. However, it is challenging to measure tumor adenosine levels at scale, thus novel, clinically tractable biomarkers are needed.

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution.

Reflecting on progress since the 2005 NARSTO emissions inventory report.

Emission inventories are the foundation for cost-effective air quality management activities. In 2005, a report by the public/private partnership North American Research Strategy for Tropospheric Ozone (NARSTO) evaluated the strengths and weaknesses of North American emissions inventories and made recommendations for improving their effectiveness. This paper reviews the recommendation areas and briefly discusses what has been addressed, what remains unchanged, and new questions that have arisen.

Impacts of different characterizations of large-scale background on simulated regional-scale ozone over the continental United States.

This study analyzes simulated regional-scale ozone burdens both near the surface and aloft, estimates process contributions to these burdens, and calculates the sensitivity of the simulated regional-scale ozone burden to several key model inputs with a particular emphasis on boundary conditions derived from hemispheric or global-scale models. The Community Multiscale Air Quality (CMAQ) model simulations supporting this analysis were performed over the continental US for the year 2010 within the context of the Air Quality Model Evaluation International Initiative (AQMEII) and Task Force on Hemispheric Transport of Air Pollution (TF-HTAP) activities. CMAQ process analysis (PA) results highlight the dominant role of horizontal and vertical advection on the ozone burden in the mid-to-upper troposphere and lower stratosphere.

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease.

MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia.

In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells.

Modeling crop residue burning experiments to evaluate smoke emissions and plume transport.

Crop residue burning is a common land management practice that results in emissions of a variety of pollutants with negative health impacts. Modeling systems are used to estimate air quality impacts of crop residue burning to support retrospective regulatory assessments and also for forecasting purposes. Ground and airborne measurements from a recent field experiment in the Pacific Northwest focused on cropland residue burning was used to evaluate model performance in capturing surface and aloft impacts from the burning events.