Simulated sensitivity of secondary organic aerosol in the South Coast Air Basin of California to nitrogen oxides and other chemical parameters

<p>Sensitivity of secondary organic aerosol (SOA) concentrations in the South Coast Air Basin (SoCAB) of California to nitrogen oxide (NO_x) emission is simulated using gas-phase chemistry and gas-particle partitioning modules. These modules are implemented into a three-dimensional air quality model applied for high-pollution summer meteorology and 2008 emissions. To test sensitivity, NO_x emissions in all locations and at all times are scaled by factors ranging from 0.1 to 10.0 in separate model runs. The basin-wide average SOA concentration exhibits a ‘turnover’ NO_x emission multiplicative factor, above and below which the average SOA concentration decreases. For the entire SoCAB, this critical NO_x emission factor is ∼0.3; while the magnitude of SOA concentrations changes with time, this peak value (∼0.2–0.3) appears to be relatively independent of the hour of the simulated day. When considering individual locations within the SoCAB, this peak factor shows a slightly broader range. Projected emissions for 2023 indicate a decrease in basin-average SOA concentration; the response at individual locations, however, can be either positive or negative, indicating the need for location-specific considerations. Ensembles of module simulations based on parameter values selected using efficient sampling techniques (Latin Hypercube method) are used to identify parameters to which SOA predictions are significantly sensitive. Total SOA predictions are most sensitive (in no particular order) to concentrations of O₃, unsaturated species formed from the gas-phase oxidation of monoaromatic compounds, and substituted products from long-chain alkane oxidation. Secondary inorganic aerosol species, likely through influencing aerosol liquid water, control at least partially the formation of SOA upwind. In addition, the rate at which unsaturated bicyclic oxidation products of monoaromatic compounds are oxidized by hydroxyl radical impacts significantly SOA prediction. These findings emphasize the need for consideration of long-chain alkanes and monoaromatic species when designing emission control strategies.</p> <p>© 2018 American Association for Aerosol Research</p

Disparities in air quality downscaler model uncertainty across socioeconomic and demographic indicators in North Carolina.

Studies increasingly use output from the Environmental Protection Agency's Fused Air Quality Surface Downscaler ('downscaler') model, which provides spatial predictions of daily concentrations of fine particulate matter (PM2.5) and ozone (O3) at the census tract level, to study the health and societal impacts of exposure to air pollution. Downscaler outputs have been used to show that lower income and higher minority neighborhoods are exposed to higher levels of PM2.5 and lower levels of O3. However, the uncertainty of the downscaler estimates remains poorly characterized, and it is not known if all subpopulations are benefiting equally from reliable predictions. We examined how the percent errors (PEs) of daily concentrations of PM2.5 and O3 between 2002 and 2016 at the 2010 census tract centroids across North Carolina were associated with measures of racial and educational isolation, neighborhood disadvantage, and urbanicity. Results suggest that there were socioeconomic and demographic disparities in surface concentrations of PM2.5 and O3, as well as their prediction uncertainties. Neighborhoods characterized by less reliable downscaler predictions (i.e., higher PEPM2.5 and PEO3) exhibited greater levels of aerial deprivation as well as educational isolation, and were often non-urban areas (i.e., suburban, or rural). Between 2002 and 2016, predicted PM2.5 and O3 levels decreased and O3 predictions became more reliable. However, the predictive uncertainty for PM2.5 has increased since 2010. Substantial spatial variability was observed in the temporal changes in the predictive uncertainties; educational isolation and neighborhood deprivation levels were associated with smaller increases in predictive uncertainty of PM2.5. In contrast, racial isolation was associated with a greater decline in the reliability of PM2.5 predictions between 2002 and 2016; it was associated with a greater improvement in the predictive reliability of O3 within the same time frame

Nanoparticle Delivered Vascular Disrupting Agents (VDAs): Use of TNF-Alpha Conjugated Gold Nanoparticles for Multimodal Cancer Therapy

Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1–2 h followed by a dramatic 80% drop in perfusion 2–6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted manner. We anticipate our work to direct investigations into more potent tumor vasculature specific combinations of VDAs and nanoparticles with the goal of transitioning optimal regimens into clinical trials

Galectin-1-based tumour-targeting for gold nanostructure-mediated photothermal therapy

<p><b>Purpose:</b> To demonstrate delivery of Au nanocages to cells using the galectin-1 binding peptide anginex (Ax) and to demonstrate the value of this targeting for selective <i>in vitro</i> photothermal cell killing.</p> <p><b>Materials and methods:</b> Au nanocages were synthesised, coated with polydopamine (PDA), and conjugated with Ax. Tumour and endothelial cell viability was measured with and without laser irradiation. Photoacoustic (PA) mapping and PA flow cytometry were used to confirm cell targeting <i>in vitro</i> and in tissue slices <i>ex vivo</i>.</p> <p><b>Results:</b> Cell viability was maintained at ≥50% at 100 pM suggesting low toxicity of the nanocage alone. Combining the targeted construct (25 pM) with low power 808 nm laser irradiation for 10–20 min (a duration previously shown to induce rapid and sustained heating of Au nanocages [AuNC] in solution), resulted in over 50% killing of endothelial and tumour cells. In contrast, the untargeted construct combined with laser irradiation resulted in negligible cell killing. We estimate approximately 6 × 10⁴ peptides were conjugated to each nanocage, which also resulted in inhibition of cell migration. Binding of the targeted nanocage reached a plateau after three hours, and cell association was 20-fold higher than non-targeted nanocages both <i>in vitro</i> and <i>ex vivo</i> on tumour tissue slices. A threefold increase in tumour accumulation was observed in preliminary <i>in vivo</i> studies.</p> <p><b>Conclusions:</b> These studies demonstrate Ax’s potential as an effective targeting agent for Au-based theranostics to tumour and endothelial cells, enabling photothermal killing. This platform further suggests potential for multimodal <i>in vivo</i> therapy via next-generation drug-loaded nanocages.</p

High-frequency ultrasound imaging of targeted-microbubbles detects tumor vessel hypoxia.

<p>Representative image and quantified data of anti-pimonidazole labeled microbubbles (MBα-pimo) bound in perfused hypoxic tumor vasculature without pimonidazole injection <b>(A)</b>, and with pimonidazole injection <b>(B)</b> in 4T1 tumor bearing mice. Top image shows the signal before the burst sequence and the bottom image shows after the burst sequence <b>(A, B)</b>. <b>(C)</b> Quantified data of different experimental conditions using targeting and non-targeting microbubbles (as indicated). <b>D)</b> Summary of quantitated data statistically analyzed represented as mean ± SEM, ^#p < 0.05, versus non-targeting MB, MBα-pimo without pimonidazole injection, and MBα-pimo in muscle tissue (ANOVA post-hoc Holm-Sidak).</p

3D modeling of MBα-pimo distribution in mammary gland carcinoma.

<p><b>A)</b> Single slice images taken from a 3D imaging sequence in B-mode <i>(left)</i>. Single slice images taken from a 3D imaging sequence depicting the differential targeted expression (d.T.E) <i>(right)</i>. <b>B)</b> Three-dimensional contrast projection of 3D stack image data from hypoxia targeted, MBα-pimo, contrast signal collected in a rear-limb 4T1 tumor. Images (0.152mm/slice) generated using Visualsonics imaging system and post-processed using the Huygens essential software.</p

Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia

<div><p>Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be ‘created’ on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions.</p></div

Vascular hypoxia in murine breast carcinomas and normal tissue.

<p>Immunofluorescence analysis of hypoxemia in 4T1 mammary gland carcinoma. <b>(A)</b>, 4T1 tumor tissue is stained for tumor vessels (CD31; red). (<b>B)</b> Tumor hypoxia (pimonidazole; green) is co-localized (white) in relation to microvasculature in 4T1 tumor tissue <b>(C)</b>. Quantification of overall tumor vessels <b>(D)</b>, hypoxia <b>(E)</b>, and hypoxic tumor vessels <b>(F)</b> in 4T1, SCK and MMTV-Wnt-1 carcinomas. Immunofluorescence analysis of vasculature (CD31; red) and hypoxia (pimonidazole; green) in non-diseased kidney <b>(G)</b>, spleen <b>(H)</b> and liver <b>(I)</b> indicates a lack of global and vessel hypoxia in normal tissue.</p

Pimonidazole targeting microbubbles.

<p><b>(A)</b> A graphic representation of the microbubbles and conditions used. <i>Left</i>, unlabeled microbubbles (MB); middle, pimonidazole-targeting MB (MBα-pimo); and <i>right</i>, MBα-pimo without pimonidazole present in the circulation. <b>(B)</b> MBα-pimo binds hypoxic 2H11 endothelial cells only in the presence of pimonidazole. MBα-pimo does not bind endothelial cells (<i>left</i>), unless pimonidazole is added (<i>middle</i>). (<i>right</i>), MBα-pimo binding to the cell surface of hypoxic endothelial cells, magnification 40X.</p

Schematic of anti-pimonidazole targeted-microbubbles (MBα-pimo) with ultrasound imaging for detection of vascular hypoxia.

<p><b>(A)</b> Illustration showing the differential distribution of MBα-pimo in well-oxygenated tumor endothelium (red) compared to hypoxic tumor endothelium (blue) during imaging and intervention by ultrasound. <b>(B)</b> Representative quantification graphic of MBα-pimo where the binding occurs over a 5 minute window after IV injection followed by a data collection period of contrast signal, a single ultrasound pulse to burst bound and free MBα-pimo, and a final data collection during the immediate reperfusion window. Subsequently, the difference in signal from the steady state prior to microbubble burst (‘pre’) and following burst (‘post’) can be calculated. This differential targeted expression (d.T.E.; linear, a.u.) represents the relative amount of bound MBα-pimo and indirectly indicates the location and amount of vascular hypoxia within the tumor (x-axis scale not linear).</p