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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 577 records · Page 32
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

E6D25E, HPV16 Asian variant shows specific proteomic pattern correlating in cells transformation and suppressive innate immune response

HPV16 Asian variant (HPV16As) containing E6D25E oncogene, is commonly associated with cervical cancers of Asian populations. To explore a mechanism of E6D25E oncoprotein in carcinogenesis, we compared protein profiles in human keratinocytes expressing E6D25E with E6 of HPV16 prototype (E6Pro). A human cervical keratinocyte cell line, HCK1T, was transduced with retroviruses containing E6D25E or E6Pro genes. Biological properties of E6D25E or E6Pro transduced HCK1T cells were characterized. Protein profiles of the transduced HCK1T cells were analyzed using 2D-PAGE and characterized by mass spectrometry and western blotting. Reactomes of modulated proteins were analyzed by using the Reactome Knowledgebase. The E6D25E and E6Pro oncoproteins were comparable for their abilities to degrade p53 and suppress the induction of p21, and induce cell proliferation. Interestingly, the protein profiles of the HCK1T cells transduced with E6D25E showed specific proteomic patterns different from those with E6Pro. Among altered proteins, more than 1.5-fold up- or down- regulation was observed in E6D25E-expressing cells for gp96 and keratin7 which involved in activation of TLR signaling and transformation of squamocolumnar junction cells, respectively. This report describes new cellular proteins specifically targeted by E6D25E oncoprotein that may contribute to impair immune response against viral infection and cell transformation associated with oncogenic property of HPV16As variant. - Highlights: • E6D25E HPV16 specifically modulates protein profile of human keratinocytes. • E6D25E HPV16 modulates protein profile which involves in TLR signalling and transformation of squamocolumnar junction cells. • E6D25E oncoprotein may correlate to impair of immune response against viral infection and cells transformation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Structural basis for multi-specific peptide recognition by the anti-IDH1/2 monoclonal antibody, MsMab-1

A point mutation in isocitrate dehydrogenase 1 (IDH1) and IDH2 is directly linked to the pathogenesis of certain types of tumors. To detect this mutation, several antibodies that can distinguish between mutant and wild-type enzymes have been established. One of which, MsMab-1, has a unique multi-specific character against several types of mutated IDH1/2. This promiscuous character is in remarkable contrast to the highly specific antigen recognition typically observed with a monoclonal antibody. We solved the crystal structure of MsMab-1 Fab fragment in complex with either IDH1 or IDH2-derived peptides. Based on the structure, it became clear that the peptide-binding pocket of the antibody is highly complementary to the core determinant shared between the IDH1 and IDH2, while leaving just enough space for the side chain of the pathogenic but not the wild-type amino acids located in the mutation position. Clarification of the molecular basis for the peculiar binding characteristics of MsMab-1 in atomic detail will help facilitating its diagnostic application, and may be used to develop better diagnostic reagents through structure-guided protein engineering. - Highlights: • Mutations of IDH1 and IDH2 correlates with the pathogeny of a part of brain tumor. • A monoclonal antibody MsMab-1 recognizes several mutated sequences of IDH1 and IDH2. • MsMab-1 has high potential in diagnostic applications for brain tumors. • Crystal structures reveal the molecular basis of the multi-specificity of MsMab-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Site-specific aptamer inhibitors of Thermus RNA polymerase

Highlights: • ssDNA aptamers recognize specific epitopes of Thermus aquaticus core RNA polymerase. • Aptamers sense RNA polymerase interactions with transcription factors and antibiotics. • Aptamers inhibit transcriptional activity of the RNA polymerase core enzyme. Bacterial RNA polymerase (RNAP) is an RNA-synthesizing molecular machine and a target for antibiotics. In transcription, RNAP can interact with DNA sequence-specifically, during promoter recognition by the σ-containing holoenzyme, or nonspecifically, during productive RNA elongation by the core RNAP. We describe high-affinity single-stranded DNA aptamers that are specifically recognized by the core RNAP from Thermus aquaticus. The aptamers interact with distinct epitopes inside the RNAP main channel, including the rifamycin pocket, and sense the binding of other RNAP ligands such as rifamycin and the σ{sup A} subunit. The aptamers inhibit RNAP activity and can thus be used for functional studies of transcription and development of novel RNAP inhibitors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Specificity and utility of SubB2M, a new N-glycolylneuraminic acid lectin

Highlights: • SubB2M showed improved specificity and recognition for Neu5Gc containing glycans in a Neu5Ac/Neu5Gc glycan array and by surface plasmon resonance. • Far-western blot analysis showed that SubB2M preferentially binds to serum glycoproteins from bovine over human. • SubB2M detected Neu5Gc-glycoproteins spiked into normal human serum with greater sensitivity than SubB and anti-Neu5Gc IgY. • SubB2M will be a useful tool for the testing of serum and other bodily fluids for cancer diagnosis and prognosis. The B subunit of the subtilase cytotoxin (SubB) recognises N-glycolylneuraminic acid (Neu5Gc) containing glycans, the most prominent form of aberrant glycosylation in human cancers. We have previously engineered SubB by construction of a SubB{sub ΔS106/ΔT107} mutant (SubB2M) for greater specificity and enhanced recognition of Neu5Gc containing glycans. In this study, we further explore the utility of SubB2M as a Neu5Gc lectin by showing its improved specificity and recognition for Neu5Gc containing glycans over the wild-type SubB protein and an anti-Neu5Gc IgY antibody in a N-acetylneuraminic acid (Neu5Ac)/Neu5Gc glycan array and by surface plasmon resonance. Far-western blot analysis showed that SubB2M preferentially binds to bovine serum glycoproteins over human serum glycoproteins. SubB2M was also able to detect Neu5Gc containing bovine glycoproteins spiked into normal human serum with greater sensitivity than the wild-type SubB and the anti-Neu5Gc IgY antibody. These results suggest that SubB2M will be a useful tool for the testing of serum and other bodily fluids for cancer diagnosis and prognosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

The N-terminal domain of gastrulation brain homeobox 2 (Gbx2) is required for iridophore specification in zebrafish

Highlights: • Iridophore formation is suppressed by gbx2 knockdown in zebrafish. • gbx2 is expressed in neural crest cells and iridophores during development. • gbx2 knockdown leads to apoptosis of neural crest cells. • The N-terminal domain of Gbx2 rescues the phenotype of gbx2 knockdown. Although body color pattern formation by pigment cells plays critical roles in animals, pigment cell specification has not yet been fully elucidated. In zebrafish, there are three chromatophores: melanophore, iridophore, and xanthophore, that are derived from neural crest cells (NCCs). A recent study has reported the differentially expressed genes between melanophores and iridophores. Based on transcriptome data, we identified that Gbx2 is required for iridophore specification during development. In support of this, iridophore formation is suppressed by gbx2 knockdown by morpholino antisense oligonucleotide, at 72 h post fertilization (hpf) in zebrafish. Moreover, gbx2 is expressed in sox10-expressing NCCs and guanine crystal plates-containing iridophores during development at 24 and 48 hpf, respectively. In gbx2 knockdown zebrafish embryos, apoptosis of sox10-expressing NCCs was detected at 24 hpf without any effect on the formation of melanophores and xanthophores at 48 hpf. We further observed that the N-terminal domain of Gbx2 is able to rescue the iridophore formation defect caused by gbx2 knockdown. Our study provides insights into the requirement of N-terminal domain of Gbx2 for iridophore specification in zebrafish.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Evolution of archaeal Rib7 and eubacterial RibG reductases in riboflavin biosynthesis: Substrate specificity and cofactor preference

Highlights: • The first archaeal dimeric structures of Methanosarcina mazei Rib7 are reported. • Our studies show the divergences between archaeal and eubacterial Rib7 reductases. • Asp33 together with Arg36, had been evolved to ensure the substrate specificity. • Unexpectedly, an endogenous NADPH cofactor is observed in M. mazei Rib7. • The endogenous NADPH greatly enhances the structural stability of archaeal Rib7. Archaeal/fungal Rib7 and eubacterial RibG possess a reductase domain for ribosyl reduction in the second and third steps, respectively, of riboflavin biosynthesis. These enzymes are specific for an amino and a carbonyl group of the pyrimidine ring, respectively. Here, several crystal structures of Methanosarcina mazei Rib7 are reported at 2.27–1.95 Å resolution, which are the first archaeal dimeric Rib7 structures. Mutational analysis displayed that no detectable activity was observed for the Bacillus subtilis RibG K151A, K151D, and K151E mutants, and the M. mazei Rib7 D33N, D33K, and E156Q variants, while 0.1–0.6% of the activity was detected for the M. mazei Rib7 N9A, S29A, D33A, and D57N variants. Our results suggest that Lys151 in B. subtilis RibG, while Asp33 together with Arg36 in M. mazei Rib7, ensure the specific substrate recognition. Unexpectedly, an endogenous NADPH cofactor is observed in M. mazei Rib7, in which the 2′-phosphate group interacts with Ser88, and Arg91. Replacement of Ser88 with glutamate eliminates the endogenous NADPH binding and switches preference to NADH. The lower melting temperature of ∼10 °C for the S88E and R91A mutants suggests that nature had evolved a tightly bound NADPH to greatly enhance the structural stability of archaeal Rib7.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Differential expression of cyclosporine A-Induced calcineurin isoform-specific matrix metalloproteinase 9 (MMP-9) in renal fibroblasts

Highlights: • Regulation of CsA-induced MMP-9 production and activity in renal fibroblasts is CnA isoform specific. • The CnAβ isoform is associated with enhanced secreted MMP-9 while the CnAα isoform is associated with significantly low levels of secreted MMP-9. • CsA-mediated induction of MMP-9 secretion in renal fibroblasts may be regulated by cross-talk between CnAβ isoform and the TGF-β/Smad3 pathway. • Intracellular MMP-9 expression in CnAβ{sup −/−} renal fibroblasts is enhanced by CsA. Long-term treatment with the potent immunosuppressive drug cyclosporine A (CsA) results in chronic nephrotoxicity. Its immunosuppressive properties are due to the inhibition of the calcium- and calmodulin-dependent phosphatase protein calcineurin A (CnA) which has three catalytic isoforms. Of those, the CnAα and β isoforms are ubiquitously expressed, particularly in the kidney. Additionally, chronic nephrotoxicity has been associated with an imbalance of extracellular matrix (ECM) synthesis and degradation resulting in an accumulation of ECM molecules. This study evaluates whether the expressions of matrix metalloproteinases (MMP-2 and MMP-9) induced by CsA are calcineurin isoform specific. Wild-type (WT), CnAα knockout (CnAα{sup −/−}) and CnAβ knockout (CnAβ{sup −/−}) kidney fibroblast cell lines (an in vitro innovative tool that was previously created in our lab) were treated with CsA at 10 ng/ml for 48 h. ELISA analysis demonstrated that the CsA-induced secretion profile of MMP-9 was highest in CnAα{sup −/−} cells and lowest in CnAβ{sup −/−} cells vs. WT cells. In contrast, CsA did not induce an increase in MMP-2 protein levels in WT, CnAα{sup −/−} nor CnAβ{sup −/−} renal fibroblasts. These results indicate that MMP-9 secretion is CnA-isoform specific, i.e. the CnAβ isoform contributes to the CsA-induced upregulation of MMP-9 while the CnAα does not. As such, understanding the role of calcineurin A isoforms in the regulation of the homeostasis of ECM degradation in the kidney after long-term CsA treatment needs to be further investigated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Autoimmune sialadenitis is associated with the upregulation of chemokine/chemokine receptor pairs in T cell-specific TRAF6-deficient mice

Sialadenitis is an inflammatory condition affecting the salivary glands including the parotid, submandibular, and sublingual glands. There are several different types of sialadenitis, each with different sites of predilection. However, the pathogenic mechanism underlying the tissue specificity of sialadenitis is largely unknown. TRAF6 is a cytoplasmic adaptor protein that is necessary for the activation of dendritic cells in response to Toll-like receptor ligands, thereby regulating innate immune responses. We previously demonstrated that T cell-specific TRAF6-deficient mice (TRAF6ΔT mice) spontaneously develop systemic inflammatory disease. Here, we show that salivary secretion is reduced in TRAF6ΔT mice due to sialadenitis that occurs in the parotid and submandibular glands, but not the sublingual glands. Consistent with pathological findings, both CD4{sup +} and CD8{sup +} T cells predominantly infiltrated the submandibular glands; however, sublingual infiltration was rare in TRAF6ΔT mice. The TH1 cytokine IFN-γ, the TH1 cell attractant chemokine CCL2, and its cognate receptor CCR2 were upregulated concomitantly in both the submandibular and sublingual glands. Interestingly, the TH17 cell attractant chemokine CCL20 and its cognate receptor CCR6 were selectively increased in the submandibular glands, but not in the sublingual glands of TRAF6ΔT mice. Thus, the expression of TRAF6 in T cells might be implicated in tissue-specific sialadenitis by regulating the chemokine-chemokine receptor system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Structural basis for specific calcium binding by the polycystic-kidney-disease domain of Vibrio anguillarum protease Epp

Highlights: • Crystal structure of the first PKD domain of Vibrio anguillarum Epp is determined. • Epp-PKD1 contains a pentagonal-bipyramidal Ca{sup 2+}-binding site. • Specific binding to Ca{sup 2+} increases conformational stability of Epp-PKD1. • Epp-PKD1 differs in the oligomeric state and Ca{sup 2+} coordination from the homologous PrtV-PKD1. Extracellular proteases are often produced as pre-pro-enzyme and then undergo multiple processing steps to mature into the active form. The protease Epp, a virulent factor of Vibrio anguillarum, belongs to this family. Its maturation might be regulated by Ca{sup 2+} via its polycystic kidney disease (PKD) domain, but the molecular mechanism is unknown. Herein, we report the crystal structure of the first PKD domain from V. anguillarum Epp (Epp-PKD1) and its specific Ca{sup 2+}-binding capacity. Epp-PKD1 exists as a monomer, consisting of seven β-strands which form two β-sheets stacking with each other. One Ca{sup 2+} is bound by the residues Asn3, Gln4, Asp27, Asp29, Asp68 and a water molecule with a pentagonal bipyramidal geometry. Incubating the apo Epp-PKD1 with Ca{sup 2+} but not Mg{sup 2+}, Mn{sup 2+}, or Zn{sup 2+}, enhances the thermal and chemical stability of Epp-PKD1, indicating its specific binding to Ca{sup 2+}. Epp-PKD1 shares high similarity in both sequence and overall structure with that of Vibrio cholerae PrtV, a homologous protease of Epp, however, they differ in the oligomeric state and local structure at the Ca{sup 2+}-binding site, suggesting maturation of PrtV and Epp might be differently regulated by Ca{sup 2+}. Likely, proteases may take advantage of the structural diversity in PKD domains to tune their Ca{sup 2+}-regulated maturation process.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

IL-36α is involved in hapten-specific T-cell induction, but not local inflammation, during contact hypersensitivity

Highlights: • IL-36α was detected in the skin of psoriatic dermatitis, but not contact dermatitis. • IL-36α is not essential for dendritic cell migration. • IL-36α is involved in hapten-specific T-cell induction and activation. • IL-36α is not essential for induction of the inflammation of contact dermatitis. Levels of IL36α are known to be increased in specimens from patients with atopic dermatitis and psoriasis. In addition, it has been reported that IL-36α is crucial for development of imiquimod-induced psoriatic dermatitis in mice. On the other hand, the role of IL-36α in induction of allergic contact dermatitis/contact hypersensitivity (ACD/CHS) is poorly understood. We found that IL-36α was produced in keratinocytes of mice during imiquimod-induced psoriatic dermatitis, but it was hardly detectable in the skin of mice during either fluorescein isothiocyanate (FITC)- or 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced CHS. Although IL-36α can enhance activation of dendritic cells (DCs) and T cells, in CHS, IL-36α was not essential for DC migration from the skin to draining LNs, but it was required for induction or activation of hapten-specific T cells such as Th/Tc1 or Th17 cells. However, local inflammation, assessed by measurement of ear skin thickness, was comparable between wild-type and IL-36α-deficient mice during both FITC- and DNFB-induced CHS. These observations indicate that IL-36α is involved in induction and/or activation of hapten-specific T-cell subsets in the sensitization phase of CHS, but not essential for induction of local inflammation in the elicitation phase.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Detection of N-glycolylneuraminic acid biomarkers in sera from patients with ovarian cancer using an engineered N-glycolylneuraminic acid-specific lectin SubB2M

Highlights: • N-glycolylneuraminic acid (Neu5Gc) has been proposed as cancer biomarker. • A Neu5Gc-specific lectin, SubB2M, was used to detect Neu5Gc in patient sera. • Serum from ovarian cancer patients has significantly elevated Neu5Gc levels. • Late stage ovarian cancer patients have uniformly elevated levels of Neu5Gc-glycans. N-glycolylneuraminic acid (Neu5Gc)-containing glycans are a prominent form of aberrant glycosylation found in human tumor cells and have been proposed as cancer biomarkers. The B subunit of the subtilase cytotoxin (SubB) produced by Shiga toxigenic Escherichia coli recognises Neu5Gc containing glycans. We have previously engineered this lectin, SubB2M, for greater specificity and enhanced recognition of Neu5Gc-containing glycans. Here we further explore the utility of SubB2M to detect Neu5Gc tumor biomarkers in sera from patients with ovarian cancer. Using surface plasmon resonance (SPR) we show that SubB2M can detect the established ovarian cancer biomarker, CA125, in a highly sensitive and specific fashion in the context of human serum. These studies established conditions for screening serum samples from patients with ovarian cancer for Neu5Gc glycans. We found that serum from patients with all stages of ovarian cancer had significantly elevated mean levels of Neu5Gc glycans compared to normal controls. Serum from patients with late stage disease (stages IIIC, IV) had uniformly elevated levels of Neu5Gc glycans. Detection of Neu5Gc-glycans using SubB2M has the potential to be used as a diagnostic ovarian cancer biomarker, as well as a tool for monitoring treatment and disease progression in late stage disease.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Evolution of DNA Specificity in a Transcription Factor Family Produced a New Gene Regulatory Module

Complex gene regulatory networks require transcription factors (TFs) to bind distinct DNA sequences. To understand how novel TF specificity evolves, we combined phylogenetic, biochemical, and biophysical approaches to interrogate how DNA recognition diversified in the steroid hormone receptor (SR) family. After duplication of the ancestral SR, three mutations in one copy radically weakened binding to the ancestral estrogen response element (ERE) and improved binding to a new set of DNA sequences (steroid response elements, SREs). They did so by establishing unfavorable interactions with ERE and abolishing unfavorable interactions with SRE; also required were numerous permissive substitutions, which nonspecifically improved cooperativity and affinity of DNA binding. Furthermore, our findings indicate that negative determinants of binding play key roles in TFs’ DNA selectivity and—with our prior work on the evolution of SR ligand specificity during the same interval—show how a specific new gene regulatory module evolved without interfering with the integrity of the ancestral module.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Application-specific optimal model weighting of global climate models: A red tide example

Global climate models (GCMs) and Earth system models (ESMs) provide many climate services with environmental relevance. The High Resolution Model Inter-comparison Project (HighResMIP) of the Coupled Model Intercomparison Project Phase 6 (CMIP6) provides model runs of GCMs and ESMs to address regional phenomena. Developing a parsimonious ensemble of CMIP6 requires multiple ensemble methods such as independent-model subset selection, prescreening-based subset selection, and model weighting. The work presented here focuses on application-specific optimal model weighting, with prescreening-based subset selection. As such, independent ensemble members are categorized, selected, and weighted based on their ability to reproduce physically-interpretable features of interest that are problem-specific. We discuss the strengths and caveats of optimal model weighting using a case study of red tide prediction in the Gulf of Mexico along the West Florida Shelf. Red tide is a common name of specific harmful algal blooms that occur worldwide, causing adverse socioeconomic and environmental impacts. Our results indicate the importance of prescreening-based subset selection as optimal model weighting can underplay robust ensemble members by optimizing error cancellation. Prescreening-based subset selection also provides insights about the validity of the model weights. By illustrating the caveats of using non-representative models when optimal model weighting is used, the findings and discussion of this study are pertinent to many other climate services.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2026

Bridging semantics, control specifications and assessment: A library for scalable demand flexibility controls

There is growing recognition that Demand Flexibility (DF) can play a major role in enhancing grid reliability, with building control applications emerging as key enablers for DF. However, the traditional approach to deploying new control applications in buildings, including those for DF, remains largely manual and tailored to individual buildings, making it difficult to scale. While research efforts have explored semantics-driven portability, DF controls specification, and assessment approaches, these initiatives are fragmented and limited in scope. This paper proposes a novel methodology, grounded in design science research, to integrate these elements and create a comprehensive DF controls library for both industry and academia. This approach is applied to develop the Demand FLEXibility controls LIBrary using Semantics (DFLEXLIBS), an extensible open-source library that provides DF controls for HVAC systems in Python. DFLEXLIBS enables portable, easy-to-deploy controls that abstract building-specific data points, facilitating assessment across diverse buildings. DFLEXLIBS features nine different control applications, and it is successfully implemented and tested across four virtual and two real buildings, bridging the gap between semantics-driven portability, DF controls specification, and rigorous performance assessment. Its benefits are measured by a reusability ratio greater than 90% and a functional overlap ratio of around 70% for the most common functions used in the library, significantly reducing time for deploying new controls.

Controls library↗
DOE OSTI2025

An open control sequence specification to scale building demand flexibility via analytics software

For over two decades, researchers and practitioners have showcased the ability of large commercial buildings to provide grid services by shedding or shifting load. Various utility demand response (DR) and virtual power plant (VPP) programs throughout the United States are presently utilizing these demand-side resources. However, growth of these programs have been limited, in part due to the high cost necessary to integrate the DR control strategies into the building automation system (BAS). Implementing these strategies involves adjusting control sequences, necessitating dozens of hours of customized programming per building, limiting their adoption to large organizations and progressive owners. Recent efforts by researchers and industry have demonstrated the capability of energy management and information systems (EMIS), originally designed for fault detection and diagnostics, to interface with existing BAS and perform supervisory control to optimize building operations. While these approaches are quickly being adopted by industry, demand flexibility (DF) control strategies remain limited in product offerings. One of the challenges is the lack of documented best-practice DF sequences, despite the rich literature on field implementations. This paper develops a new open-specification for a zone-based temperature adjustment shed strategy for commercial building HVAC systems, describing the specification’s implementation in two EMIS tools in both experimental and field settings. Both implementations successfully reduced electric load by at least 40% on average during the called event, while maintaining temperature limits. This study’s detailed process from specification to deployment shows the potential for scalability as well as highlights challenges related to integration with heterogeneous BAS products.

Granderson, Jessica↗
DOE OSTI2018

The burden of overall and cause-specific respiratory morbidity due to ambient air pollution in Sichuan Basin, China: A multi-city time-series analysis

Highlights: • We assess the burden of respiratory HAs due to air pollution in Southwest China. • Risks of respiratory HAs were elevated following increased PM{sub 10}, PM{sub 2.5}, NO{sub 2} and SO{sub 2}. • The effect estimates might be modified by age, season and region. • 1.84% of respiratory HAs were attributed to PM{sub 10}, 1.73% to PM{sub 2.5} and 0.34% to SO{sub 2}. Few studies have investigated the respiratory morbidity burden due to ambient air pollution in China, especially in a multi-city setting. This study aimed to estimate the short-term effects of ambient air pollutants (PM{sub 10}, PM{sub 2.5}, NO{sub 2} and SO{sub 2}) on hospital admissions (HAs) for overall and cause-specific respiratory diseases, as well as the associated burden in 17 cities of Sichuan Basin, China during 2015–2016. Firstly, city-specific effect estimates for each pollutant on respiratory HAs were obtained using generalized additive model with quasi-Poisson link, and then random- or fixed-effects meta-analysis was applied to pool the effect estimates at the regional level. Subgroup analyses by sex, age, season and region were also performed. A total of 757,712 respiratory HAs were collected from all the tertiary and secondary hospitals located in the 17 cities. Risks of HAs for overall and cause-specific respiratory diseases were elevated following increased PM{sub 10}, PM{sub 2.5}, NO{sub 2} and SO{sub 2} exposure. An increase of 10 μg/m{sup 3} in PM{sub 10} at lag01, PM{sub 2.5} at lag01, NO{sub 2} at lag0 and SO{sub 2} at lag02 was associated with a 0.43% (95% CI: 0.33%, 0.53%), 0.53% (95% CI: 0.39%, 0.68%), 2.36% (95% CI: 1.75%, 2.98%) and 2.54% (95% CI: 1.51%, 3.59%) increases in total respiratory HAs, respectively. Children (≤ 14 years) and elderly (≥ 65 years) appeared to be more vulnerable to the effects of ambient air pollutants. Comparing to the WHO's air quality guidelines, we estimated that 1.84% (95%CI: 1.42%, 2.25%), 1.73% (95%CI: 1.27%, 2.19%) and 0.34% (95%CI: 0.21%, 0.48%) of respiratory HAs were due to PM{sub 10}, PM{sub 2.5} and SO{sub 2} exposure, respectively. This study suggests that air pollution might be an important trigger of respiratory admissions, and result in substantial burden of HAs for respiratory diseases in Sichuan Basin.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2016

Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the Risk of Prostate Cancer–Specific Mortality Stratified by the Extent of Competing Mortality

Purpose: The addition of androgen deprivation therapy (ADT) to radiation therapy (RT) is the standard of care for men with intermediate- and high-risk prostate cancer (PC). However, whether competing mortality (CM) affects the ability of ADT to improve, survival remains unanswered. Methods and Materials: We calculated a CM risk score using a Fine-Gray semiparametric model that included age and cardiometabolic comorbidities from a cohort of 17,669 men treated with high-dose RT with or without supplemental ADT for nonmetastatic PC. Fine and Gray competing risk regression analysis was used to assess whether ADT reduced the risk of PC-specific mortality for men with a low versus a high risk of CM among the 4550 patients within the intermediate- and high-risk cohort after adjustment for established PC prognostic factors, year of treatment, site, and ADT propensity score. Results: After a median follow-up of 8.4 years, 1065 men had died, 89 (8.36%) of PC. Among the men with a low CM score, ADT use was associated with a significant reduction in the risk of PC-specific mortality (adjusted hazard ratio 0.35, 95% confidence interval 0.14-0.87, P=.02) but was not for men with high CM (adjusted hazard ratio 1.33, 95% confidence interval 0.77-2.30, P=.30). Conclusions: Adding ADT to high-dose RT appears to be associated with decreased PC-specific mortality risk in men with a low but not a high CM score. These data should serve to heighten awareness about the importance of considering competing risks when determining whether to add ADT to RT for older men with intermediate- or high-risk PC.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2017

Predicting Patient-specific Dosimetric Benefits of Proton Therapy for Skull-base Tumors Using a Geometric Knowledge-based Method

Purpose: To predict the organ at risk (OAR) dose levels achievable with proton beam therapy (PBT), solely based on the geometric arrangement of the target volume in relation to the OARs. A comparison with an alternative therapy yields a prediction of the patient-specific benefits offered by PBT. This could enable physicians at hospitals without proton capabilities to make a better-informed referral decision or aid patient selection in model-based clinical trials. Methods and Materials: Skull-base tumors were chosen to test the method, owing to their geometric complexity and multitude of nearby OARs. By exploiting the correlations between the dose and distance-to-target in existing PBT plans, the models were independently trained for 6 types of OARs: brainstem, cochlea, optic chiasm, optic nerve, parotid gland, and spinal cord. Once trained, the models could estimate the feasible dose–volume histogram and generalized equivalent uniform dose (gEUD) for OAR structures of new patients. The models were trained using 20 patients and validated using an additional 21 patients. Validation was achieved by comparing the predicted gEUD to that of the actual PBT plan. Results: The predicted and planned gEUD were in good agreement. Considering all OARs, the prediction error was +1.4 ± 5.1 Gy (mean ± standard deviation), and Pearson's correlation coefficient was 93%. By comparing with an intensity modulated photon treatment plan, the model could classify whether an OAR structure would experience a gain, with a sensitivity of 93% (95% confidence interval: 87%-97%) and specificity of 63% (95% confidence interval: 38%-84%). Conclusions: We trained and validated models that could quickly and accurately predict the patient-specific benefits of PBT for skull-base tumors. Similar models could be developed for other tumor sites. Such models will be useful when an estimation of the feasible benefits of PBT is desired but the experience and/or resources required for treatment planning are unavailable.

62 RADIOLOGY AND NUCLEAR MEDICINE↗