Episodic wintertime particle pollution by ammonium nitrate is an important air quality concern across the Midwest U.S. Understanding and accurately forecasting PM2.5 episodes are complicated by ...multiple pathways for aerosol nitrate formation, each with uncertain rate parameters. Here, the Community Multiscale Air Quality model (CMAQ) simulated regional atmospheric nitrate budgets during the 2009 LADCO Winter Nitrate Study, using integrated process rate (IPR) and integrated reaction rate (IRR) tools to quantify relevant processes. Total nitrate production contributing to PM2.5 episodes is a regional phenomenon, with peak production over the Ohio River Valley and southern Great Lakes. Total nitrate production in the lower troposphere is attributed to three pathways, with 57% from heterogeneous conversion of N2O5, 28% from the reaction of OH and NO2, and 15% from homogeneous conversion of N2O5. TNO3 formation rates varied day‐to‐day and on synoptic timescales. Rate‐limited production does not follow urban‐rural gradients and NOx emissions due, to counterbalancing of urban enhancement in daytime HNO3 production with nocturnal reductions. Concentrations of HNO3 and N2O5 and nighttime TNO3 formation rates have maxima aloft (100–500 m), leading to net total nitrate vertical flux during episodes, with substantial vertical gradients in nitrate partitioning. Uncertainties in all three pathways are relevant to wintertime aerosol modeling and highlight the importance of interacting transport and chemistry processes during ammonium nitrate episodes, as well as the need for additional constraint on the system through field and laboratory experiments.
Key Points
Regional HNO3 production is dominated by nocturnal conversion of N2O5Heterogeneous and homogeneous HNO3 production maxima at boundary layer topTotal nitrate production during episodes highest over Great Lakes and Ohio Valley
Highlights • β-catenin localization in hepatocellular carcinoma tissue array is characterized. • Glutamine synthetase correlates with nuclear β-catenin localization in HCC. • Nuclear β-catenin in HCC ...correlates with decreased intratumoral fibrosis. • Mice expressing normal or mutant-β-catenin show equal fibrosis and HCC after TAA. • Lack of β-catenin in HCC correlates with absence of inflammation and fibrosis.
Objective: Altered cognitive function has been associated with breast cancer treatment, particularly adjuvant chemotherapy, but the underlying neuropsychological mechanisms are not yet understood. ...Recent research indicates that compromised attention and working memory can exist before adjuvant treatment, implicating psychological distress, such as worry, as a possible contributor to observed alterations in cognitive function. We hypothesized that worry associated with breast cancer diagnosis might influence neurocognitive responses before any adjuvant therapy. Design: Fifty women, 25 due to receive chemotherapy and 25 due to receive radiation therapy, participated in the study. Women performed a verbal working memory task during functional magnetic resonance imaging scanning to assess neurocognitive responses before any adjuvant treatment and to test the relationship of such responses with self-reports of worry. Results: Although prechemotherapy participants showed significantly higher levels of worry compared with preradiation participants, higher worry, across both groups, was related to altered brain function. Specifically, increased worry was associated with reduced demand-related deactivation in default-mode regions, such as the precuneus/posterior cingulate. Reduced demand-related deactivation was critically related to worse behavioral performance, which was partially mediated by worry. Conclusion: Worry appears to be a significant contributor to neurocognitive dysfunction independent of adjuvant treatment for breast cancer. These results suggest that alterations in cognitive function may develop before any chemotherapy treatment and that worry about cancer diagnosis may contribute to reports of "chemo brain" during treatment. Psychological interventions aimed at mitigating worry may help to alleviate cognitive dysfunction associated with life-threatening illness such as breast cancer.
Chronic nitrogen (N) and (or) sulfur (S) deposition to boreal forests in the Athabasca oil sands region (AOSR) in Alberta, Canada, has been caused by oil sands mining and extraction/upgrading ...activities. It is important that we understand the response of microbial community function to chronic N and S deposition as microbial populations mediate soil carbon (C) and N cycles and affect ecosystem resilience. To evaluate the impact of N and (or) S deposition on soil microbial community functions, we conducted a simulated N and S deposition experiment in a boreal mixedwood forest with the following four treatments: control (CK), N addition (+N, 30 kg N·haâ»Â¹ as NHâNOâ), S addition (+S, 30 kg S·haâ»Â¹ as NaSOâ), and N plus S addition (+NS, 30 kg N·haâ»Â¹ + 30 kg S·haâ»Â¹), from 2006 to 2010. Nitrogen and (or) S deposition did not change soil organic carbon, total N, dissolved organic C and N, or soil microbial biomass C and N. Soil microbial community-level physiological profiles, however, were strongly affected by 5 years of N and (or) S addition. Soil β-glucosidase activity in the +NS treatment was greater than that in the +S treatment, and S addition decreased soil arylsulfatase; however, urease and dehydrogenase activities were not affected by the simulated N and (or) S deposition. Our data suggested that N and (or) S deposition strongly affected soil microbial community functions and enzymatic activities without changing soil microbial biomass in the studied boreal forest.
The relationship between allergic and eosinophilic inflammation, either systemic or local, in allergic diseases remains unclear.
We performed combined genome-wide association study (GWAS) and ...epigenome-wide (EWAS) for atopy and tissue eosinophilia to identify both genetic and epigenetic signatures between systemic and local allergic inflammation, and to capture global patterns of gene regulation.
We included 126 subjects for atopy analysis and 147 for tissue eosinophilia analysis, as well as 18 normal nasal tissue samples. We identified differentially methylated positions (DMPs) and genes associated with atopy and tissue eosinophilia. Furthermore, we performed mendelian randomization analysis and penalized regression along with replication in an independent cohort.
EWAS identified genes, including Musashi RNA binding protein 2 (MSI2), associated with atopy, which contained enriched DMPs that genetically affect atopy. A direct association was observed between MSI2 single-nucleotide polymorphisms and atopy, as was a causal effect of changes in MSI2 expression and methylation on atopy, which was replicated in a Costa Rican population. Regarding tissue eosinophilia, EWAS identified genes with enriched DMPs directly contributing to tissue eosinophilia at the gene level, including CAMK1D. The gene ontology terms of the identified genes for both phenotypes encompassed immune-related terms.
EWAS combined with GWAS identified novel candidate genes, especially the methylation of MSI2, contributing to systemic allergic inflammation. Certain genes displayed a greater association with either systemic or local allergic inflammation; however, it is expected that a harmonized effect of these genes influences immune responses.
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Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide ...association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
While metals have been implicated in the pathophysiology of Parkinson's disease (PD), the clinical evidence is scarce. Further, the contribution of metals for the risk or clinical presentation of PD ...remains to be explored.
To investigate the associations between the level of metals in blood serum and PD risk or clinical presentation, including sex-related differences, we studied 325 PD patients and age- and sex-matched 304 controls. We collected clinical data of the PD patients, including age at onset, PD duration, levodopa-equivalent dose (LED), Hoehn and Yahr stage (H-Y stage), presence of motor fluctuation, levodopa-induced dyskinesia (LID), freezing of gait, hallucination, and Mini-Mental State Examination (MMSE) score. Iron, copper, and zinc levels in serum were assayed by inductively coupled plasma mass spectrometry. Statistical analyses were performed to determine the sex-related differences in metal levels.
Among the three metal elements tested, serum copper levels showed significant correlations with PD risk or clinical presentation. Higher copper levels were associated with a decreased PD risk. Higher copper or lower iron levels were associated with the risk of LID in women. Serum copper levels were negatively correlated with MMSE scores in PD patients.
This clinical study suggests significant associations between serum metal levels and PD risk or essential clinical features, demonstrating the possible roles of metals in PD pathogenesis or symptom development.
•Clinical evidence on the implication of metal in Parkinson's disease (PD) is rare.•Higher copper level in serum is associated with a decreased PD risk.•Higher copper or lower iron is associated with levodopa-induced dyskinesia in women.•Serum copper level is negatively correlated with MMSE scores in PD patients.•There are associations between serum metals and PD risk or clinical presentation.
Several phase II/III trials of anti-insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies (mAbs) have shown limited efficacy. The mechanisms of resistance to IGF-1R mAb-based therapies ...and clinically applicable strategies for overcoming drug resistance are still undefined.
IGF-1R mAb cixutumumab efficacy, alone or in combination with Src inhibitors, was evaluated in 10 human head and neck squamous cell carcinoma (HNSCC) and six non-small cell lung cancer (NSCLC) cell lines in vitro in two- or three-dimensional culture systems and in vivo in cell line- or patient-derived xenograft tumors in athymic nude mice (n = 6-9 per group). Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were determined by Western or ligand blotting, immunoprecipitation, immunofluorescence, and cell adhesion analyses and enzyme-linked immunosorbent assay. Data were analyzed by the two-sided Student t test or one-way analysis of variance.
Integrin β3-Src signaling cascade was activated by IGF-1 in HNSCC and NSCLC cells, when IGF-1 binding to IGF-1R was hampered by cixutumumab, resulting in Akt activation and cixutumumab resistance. Targeting integrin β3 or Src enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines and patient-derived tumors in vitro and in vivo. Mean tumor volume of mice cotreated with cixutumumab and integrin β3 siRNA was 133.7 mm(3) (95% confidence interval CI = 57.6 to 209.8 mm(3)) compared with those treated with cixutumumab (1472.5 mm(3); 95% CI = 1150.7 to 1794.3 mm(3); P < .001) or integrin β3 siRNA (903.2 mm(3); 95% CI = 636.1 to 1170.3 mm(3); P < .001) alone.
Increased Src activation through integrin ανβ3 confers considerable resistance against anti-IGF-1R mAb-based therapies in HNSCC and NSCLC cells. Dual targeting of the IGF-1R pathway and collateral integrin β3-Src signaling module may override this resistance.
With growing demands for metals and diminishing global reserves of high-grade ores, it is becoming increasingly important to develop suitable metal extraction methods for processing low-grade ...materials. Bioleaching is an energy- and environmentally attractive process for the processing of copper and other sulfidic ores. Acidithiobacillus ferrooxidans, a commonly observed member of the acidophilic bioleaching consortia, derives energy from the oxidation of iron and reduced sulfur compounds. The licanantase protein is a major component of secretome of sulfur-grown Acidithiobacillus spp. Here we report the effect of the genetic overexpression of the endogenous licanantase in A. ferrooxidans on the bioleaching of three different copper sulfide minerals: chalcocite, covellite, and chalcopyrite. Significantly improved cell attachment occurred with increased extracellular polymeric substance secretion, and enhanced biofilm formation was observed for the engineered cells with all three minerals as compared to the results with the wild type cells. However, the bioleaching efficiencies of these minerals were affected differently, where improved copper solubilization was observed for the leaching of chalcocite and covellite but no difference was observed for chalcopyrite. We propose that this observation results from the enhanced Fe3+ chelating capability of the engineered licanantase-rich biofilms. The overexpression of licanantase in bioleaching microbes may be an attractive approach for enhancing the bioleaching of some low-grade copper and other ores.
Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a ...poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.
This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.
Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio HR, 0.71 95% CI, 0.57 to 0.89;
= .003) and durvalumab + olaparib arms (HR, 0.55 95% CI, 0.43 to 0.69;
< .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR durvalumab
control, 0.42 95% CI, 0.22 to 0.80; HR durvalumab + olaparib
control, 0.41 95% CI, 0.21 to 0.75) and pMMR subgroups (HR durvalumab
control, 0.77 95% CI, 0.60 to 0.97; HR durvalumab + olaparib
control 0.57; 95% CI, 0.44 to 0.73); and in PD-L1-positive subgroups (HR durvalumab
control, 0.63 95% CI, 0.48 to 0.83; HR durvalumab + olaparib
control, 0.42 95% CI, 0.31 to 0.57). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab
control: HR, 0.77 95% CI, 0.56 to 1.07;
= .120; durvalumab + olaparib
control: HR, 0.59 95% CI, 0.42 to 0.83;
= .003). The safety profiles of the experimental arms were generally consistent with individual agents.
Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.
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