Evidence strongly supports that access to specialty gastroenterology or hepatology care in cirrhosis is associated with higher adherence to guideline‐recommended care and improves clinical outcomes. ...Presently, only about one half of acute care hospitalizations for cirrhosis‐related complications result in inpatient specialty care, and the current hepatology workforce cannot meet the demand of patients with liver disease nationwide, particularly in less densely populated areas and in community‐based practices not affiliated with academic centers. Telemedicine, defined as the delivery of health care services at a distance using electronic means for diagnosis and treatment, holds tremendous promise to increase access to broadly specialty care. The technology is cheap and easy to use, although it is presently limited in scale by interstate licensing restrictions and reimbursement barriers. The outbreak of severe acute respiratory syndrome coronavirus 2 and coronavirus disease 2019 has, in the short term, accelerated the growth of telemedicine delivery as a public health and social distancing measure. Herein, we examine whether this public health crisis can accelerate the national conversation about broader adoption of telemedicine for routine medical care in non‐crisis situations, using a case series from our telehepatology program as a pragmatic example.
The transcription factor c-MYC is stabilized and activated by phosphorylation at serine 62 (S62) in breast cancer. Protein phosphatase 2A (PP2A) is a critical negative regulator of c-MYC through its ...ability to dephosphorylate S62. By inactivating c-MYC and other key signaling pathways, PP2A plays an important tumor suppressor function. Two endogenous inhibitors of PP2A, I2PP2A, Inhibitor-2 of PP2A (SET oncoprotein) and cancerous inhibitor of PP2A (CIP2A), inactivate PP2A and are overexpressed in several tumor types. Here we show that SET is overexpressed in about 50–60% and CIP2A in about 90% of breast cancers. Knockdown of SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells in vitro or in vivo with OP449, a novel SET antagonist, also decreases the tumorigenic potential of breast cancer cells and induces apoptosis. We show that this is, at least in part, due to decreased S62 phosphorylation of c-MYC and reduced c-MYC activity and target gene expression. Because of the ubiquitous expression and tumor suppressor activity of PP2A in cells, as well as the critical role of c-MYC in human cancer, we propose that activation of PP2A (here accomplished through antagonizing endogenous inhibitors) could be a novel antitumor strategy to posttranslationally target c-MYC in breast cancer.
We investigated variations in the relative sensitivity of surface ozone formation in summer to precursor species concentrations of volatile organic compounds (VOCs) and nitrogen oxides (NOx) as ...inferred from the ratio of the tropospheric columns of formaldehyde to nitrogen dioxide (the "Ratio") from the Aura Ozone Monitoring Instrument (OMI). Our modeling study suggests that ozone formation decreases with reductions in VOCs at Ratios less than 1 and NOx at Ratios greater than 2; both NOx and VOC reductions may decrease ozone formation for Ratios between 1 and 2. Using this criteria. the OMI data indicate that ozone formation became: 1. more sensitive to NOx over most of the United States from 2005 to 2007 because of the substantial decrease in NOx emissions, primarily from stationary sources, and the concomitant decrease in the tropospheric column of NO2. and 2. more sensitive to NOx with increasing temperature, in part because emissions of highly reactive, biogenic isoprene increase with temperature, thus increasing the total VOC reactivity. In cities with relatively low isoprene emissions (e.g .. Chicago). the data clearly indicate that ozone formation became more sensitive to NOx from 2005 to 2007. In cities with relatively high isoprene emissions (e.g ., Atlanta), we found that the increase in the Ratio due to decreasing NOx emissions was not obvious as this signal was convolved with variations in the Ratio associated with the temperature dependence of isoprene emissions and, consequently, the formaldehyde concentration.
Urban heat island (UHI) effects can strengthen heat waves and air pollution episodes. In this study, the dampening impact of urban trees on the UHI during an extreme heat wave in the Washington, ...D.C., and Baltimore, Maryland, metropolitan area is examined by incorporating trees, soil, and grass into the coupled Weather Research and Forecasting model and an urban canopy model (WRF-UCM). By parameterizing the effects of these natural surfaces alongside roadways and buildings, the modified WRF-UCM is used to investigate how urban trees, soil, and grass dampen the UHI. The modified model was run with 50% tree cover over urban roads and a 10% decrease in the width of urban streets to make space for soil and grass alongside the roads and buildings. Results show that, averaged over all urban areas, the added vegetation decreases surface air temperature in urban street canyons by 4.1 K and road-surface and building-wall temperatures by 15.4 and 8.9 K, respectively, as a result of tree shading and evapotranspiration. These temperature changes propagate downwind and alter the temperature gradient associated with the Chesapeake Bay breeze and, therefore, alter the strength of the bay breeze. The impact of building height on the UHI shows that decreasing commercial building heights by 8 m and residential building heights by 2.5 m results in up to 0.4-K higher daytime surface and near-surface air temperatures because of less building shading and up to 1.2-K lower nighttime temperatures because of less longwave radiative trapping in urban street canyons.
WRF‐Chem simulations were performed for the March 2005 East Asian Studies of Tropospheric Aerosols: an International Regional Experiment (EAST‐AIRE) Intensive Observation Campaign (IOC) to ...investigate the direct effects of aerosols on surface radiation and air quality. Domain‐wide, WRF‐Chem showed a decrease of 20 W/m2 in surface shortwave (SW) radiation due to the aerosol direct effect (ADE), consistent with observational studies. The ADE caused 24 h surface PM2.5 (particulate matter with diameter < 2.5 µm) concentrations to increase in eastern China (4.4%), southern China (10%), western China (2.3%), and the Sichuan Basin (9.6%), due to different aerosol compositions in these four regions. Conversely, surface 1 h maximum ozone was reduced by 2.3% domain‐wide and up to 12% in eastern China because less radiation reached the surface. We also investigated the impact of reducing SO2 and black carbon (BC) emissions by 80% on aerosol amounts via two sensitivity simulations. Reducing SO2 decreased surface PM2.5 concentrations in the Sichuan Basin and southern China by 5.4% and decreased ozone by up to 6 ppbv in the Sichuan Basin and Southern China. Reducing BC emissions decreased PM2.5 by 3% in eastern China and the Sichuan Basin but increased surface ozone by up to 3.6 ppbv in eastern China and the Sichuan Basin. This study indicates that the benefits of reducing PM2.5 associated with reducing absorbing aerosols may be partially offset by increases in ozone at least for a scenario when NOx and VOC emissions are unchanged.
Key Points
Modeled shortwave radiation at the surface over East Asia decreases by 20 W m‐2 due to the aerosol direct effect
The aerosol direct effect causes modeled PM2.5 concentrations over East Asia to increase and ozone amounts to decrease
PM2.5 air quality benefits in East Asia associated with reducing absorbing aerosols may be partially offset by increases in ozone
A three‐dimensional (3‐D) cloud‐scale chemical transport model that includes a parameterized source of lightning NOx on the basis of observed flash rates has been used to simulate six midlatitude and ...subtropical thunderstorms observed during four field projects. Production per intracloud (PIC) and cloud‐to‐ground (PCG) flash is estimated by assuming various values of PIC and PCG for each storm and determining which production scenario yields NOx mixing ratios that compare most favorably with in‐cloud aircraft observations. We obtain a mean PCG value of 500 moles NO (7 kg N) per flash. The results of this analysis also suggest that on average, PIC may be nearly equal to PCG, which is contrary to the common assumption that intracloud flashes are significantly less productive of NO than are cloud‐to‐ground flashes. This study also presents vertical profiles of the mass of lightning NOx after convection based on 3‐D cloud‐scale model simulations. The results suggest that following convection, a large percentage of lightning NOx remains in the middle and upper troposphere where it originated, while only a small percentage is found near the surface. The results of this work differ from profiles calculated from 2‐D cloud‐scale model simulations with a simpler lightning parameterization that were peaked near the surface and in the upper troposphere (referred to as a “C‐shaped” profile). The new model results (a backward C‐shaped profile) suggest that chemical transport models that assume a C‐shaped vertical profile of lightning NOx mass may place too much mass near the surface and too little in the middle troposphere.
Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of ...good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease.
The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer.
In cancer, kinases are often activated and phosphatases suppressed, leading to aberrant activation of signaling pathways driving cellular proliferation, survival, and therapeutic resistance. Although ...pancreatic ductal adenocarcinoma (PDA) has historically been refractory to kinase inhibition, therapeutic activation of phosphatases is emerging as a promising strategy to restore balance to these hyperactive signaling cascades. In this study, we hypothesized that phosphatase activation combined with kinase inhibition could deplete oncogenic survival signals to reduce tumor growth. We screened PDA cell lines for kinase inhibitors that could synergize with activation of protein phosphatase 2A (PP2A), a tumor suppressor phosphatase, and determined that activation of PP2A and inhibition of mTOR synergistically increase apoptosis and reduce oncogenic phenotypes
and
. This combination treatment resulted in suppression of AKT/mTOR signaling coupled with reduced expression of c-MYC, an oncoprotein implicated in tumor progression and therapeutic resistance. Forced expression of c-MYC or loss of PP2A B56α, the specific PP2A subunit shown to negatively regulate c-MYC, increased resistance to mTOR inhibition. Conversely, decreased c-MYC expression increased the sensitivity of PDA cells to mTOR inhibition. Together, these studies demonstrate that combined targeting of PP2A and mTOR suppresses proliferative signaling and induces cell death and implicates this combination as a promising therapeutic strategy for patients with PDA. SIGNIFICANCE: These findings present a combinatorial strategy targeting serine/threonine protein phosphatase PP2A and mTOR in PDA, a cancer for which there are currently no targeted therapeutic options.
http://cancerres.aacrjournals.org/content/canres/79/1/209/F1.large.jpg.
The sensitivity of tropical tropospheric composition to the source strength of nitrogen oxides (NOx) produced by lightning (LNOx) is analyzed for September through November 2007 using the NASA GEOS‐5 ...model constrained by MERRA fields, with full GMI stratospheric‐tropospheric chemistry and an LNOx algorithm that is appropriate for use in a climate modeling setting; satellite retrievals from OMI, TES, and OMI/MLS; and in situ measurements from SHADOZ ozonesondes. Global mean LNOx production rates of 0 to 492 mol NO flash−1 and the subsequent responses of NOx, ozone (O3), hydroxyl radical (OH), nitric acid (HNO3), peroxyacetyl nitrate (PAN), and NOy (NOx + HNO3 + PAN) are investigated. The radiative implications associated with LNOx‐induced changes in tropospheric O3 are assessed. Increasing the LNOx production rate by a factor of 4 (from 123 to 492 mol flash−1) leads to tropical upper tropospheric enhancements of greater than 100% in NOx, OH, HNO3, and PAN. This increase in LNOx production also leads to O3 enhancements of up to 60%, which subsequently yields a factor‐of‐three increase in the mean net radiative flux at the tropopause. An LNOx source of 246 mol flash−1 agrees reasonably well with measurements, with an approximate factor‐of‐two uncertainty due to the short length of the study, inconsistencies in the observational data sets, and systematic biases in modeled LNOx production. Further research into the regional dependencies of lightning flash rates and LNOx production per flash, along with improvements in satellite retrievals, should help resolve the discrepancies that currently exist between the model and observations.
Key Points
An LNOx parameterization is implemented for use in a climate modeling setting
An LNOx source of 246 mol flash−1 agrees reasonably well with observations
Quadrupling the LNOx source yields a factor‐of‐three increase in net radiative flux
Over the past four decades, policy-led reductions in anthropogenic emissions have improved air quality over the Baltimore-Washington region (BWR). Most of the improvements in meeting the ozone air ...quality metrics (NAAQS) did not occur until the early 2000s despite large reductions in ozone precursors (NOx, CO, and volatile organic compounds (VOCs)) in the prior decades. We use observations of ozone and ozone precursors from satellites, ground-based sites, and the 2011 DISCOVER-AQ aircraft campaign in Maryland to illustrate how ozone chemistry in the BWR evolved between 1972 and 2019. Analysis of weekday vs weekend probability of ozone exceedance indicates the BWR transitioned to the NOx-limited regime by 2000–2003. A data-constrained box model agrees with this transition period and illustrates the key roles of reduced emissions of formaldehyde (HCHO), aromatics, and other VOCs since 1996, which reduced the peak of ozone production at the time of the transition and likely prevented the BWR from experiencing worsening surface air quality as the region transitioned to NOx-limited chemistry. Analysis of satellite observations of tropospheric column HCHO to NO2 analyzed using a new approach for evaluation of chemical regimes derived from DISCOVER-AQ data also provide a consistent depiction of the timing of the transition period that we infer from ground-based observations and the box model. Finally, despite significant improvements in air quality over the past two decades, the BWR still has not met the EPA standard for surface ozone. With predominantly NOx-limited ozone chemistry over the BWR, continued decreases in emission of NOx will slow the rate of ozone production and help improve air quality. We highlight emissions of NO2 from the diesel truck fleet as a worthwhile focus for future policy because emissions from this source appear to influence day-of-week variations in observed NO2, with an accompanying effect on ozone.
•O3 in BWR had a nonlinear response to NOx reductions but are now sensitive to NOx.•Diesel trucks in BWR are a major contributor to weekly trends in NOx and likely O3.•VOC reductions had a major contribution to decreases in PO3 at Essex, MD until 2004.•Both O3 chemical regimes were observed over BWR for HCHO/NO2 ratios between 1.2 and 2.2
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