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ABSTRACT IMPACT: Improved radiation treatment will yield higher doses at the tumor site, while reducing damage to healthy tissue, which will improve clinical outcomes. OBJECTIVES/GOALS: Development of gold nanoparticles covalently linked to a photosensitizer for use to enhance radiation therapy. The particles will be thoroughly characterized and the mechanism uncovered. The efficacy of these particles will be tested in a murine system. METHODS/STUDY POPULATION: Gold nanoparticles were synthesized and coated with amine-terminated poly(ethylene) glycol then covalently conjugated to chlorin e6, a known, FDA approved photosensitizer. The system was characterized using UV-Vis spectroscopy, transmission electron microscopy, and nanoparticle tracking analysis. The generation of reactive oxygen species following X-irradiation was measured. Enhanced cell killing was measured clonogenically and in vivo efficacy and tumor pathology was assessed in a murine system. Further studies will determine the optimum combination of particle shape, photosensitizer structure, and ratio of components, as well as the optimal dosing schedule. RESULTS/ANTICIPATED RESULTS: Conjugation of the particle to the photosensitizer was successfully achieved, and the molecule was detectable by UV-Vis spectroscopy. TEM and NTA showed no aggregation of the particles, and an increase in reactive oxygen species generation was observed. The conjugates significantly increased cell killing during radiation treatment, while neither the particle alone or the photosensitizer significantly affected clonogenic survival at the same concentrations. Pathology of breast tumors grown in immunocompetent mice showed a significant increase in necrotic tissue following a single 20 gy treatment when the conjugate was present. DISCUSSION/SIGNIFICANCE OF FINDINGS: Radiation therapy is widely used clinically and it is a highly localized form of treatment. However, the total dose of radiation is limited largely to prevent injury to adjacent normal tissue. This conjugate has the potential to increase the effective dose in the tumor thereby reducing damage to healthy tissue and providing a more effective therapy.
The studied seep carbonates from Tsushima, Japan, are embedded within marine siliciclastics of the lower Miocene Taishu Group and represent the earliest evidence of hydrocarbon seepage in the Sea of Japan. In contrast to Miocene and Pliocene examples from Honshu, which are often found above anticlines, the seeps from Tsushima formed within a pull-apart basin before major anticlines had formed. The three carbonates from Fukuzaki, Kanoura and Tanohama are composed chiefly of calcite, with significant admixture of ankerite only at Kanoura. The stable carbon isotope composition of calcites (δ13C as low as −40.2 ‰ VPDB for Fukuzaki, −41.8 ‰ VPDB for Kanoura, and −52.8 ‰ VPDB for Tanohama) indicate methanogenic origin of the carbonates. Textures of these deposits, including radiaxial and yellow cements, are indicative of formation at a methane seep. The stable oxygen isotope composition of calcites (δ18O values as low as −14.4 ‰ VPDB for Fukuzaki, −14.5 ‰ VPDB for Kanoura and −13.9 ‰ VPDB for Tanohama) indicate that they were influenced by burial fluids. Burial diagenesis is also indicated by the stable isotopic compositions of ankerite (δ13C ranging from −19.1 ‰ to −7.1 ‰ VPDB, δ18O from −11.1 ‰ to −9.7 ‰ VPDB). Molecular fossils from Tanohama comprise n-alkanes with short-chain predominance, interpreted to have formed due to thermal cracking of organic matter. The carbonates yield a chemosynthesis-based community comprising vesicomyids Pleurophopsis chitanii, P. cf. hamuroi, the bathymodiolin ‘Bathymodiolus’ akanudaensis, the lucinid Lucinoma sp. and the provannid Provanna? sp., which have never been hitherto identified. ‘Bathymodiolus’ akanudaensis, Lucinoma sp. and Provanna? sp. are the oldest records of these taxa in the Sea of Japan.
Development of gold nanoparticles covalently linked to a photosensitizer for use to enhance radiation therapy. The particles will be thoroughly characterized structurally and mechanistically. The gold particles should enhance radiation activity by closer proximity to the photosensitizer and by increasing particle accumulation in the tumor.
Gold nanoparticles were synthesized and coated with amine-terminated poly(ethylene) glycol, then covalently conjugated to chlorin e6, a known FDA-approved photosensitizer. The system was characterized using UV-Vis spectroscopy, transmission electron microscopy, and nanoparticle tracking analysis. The generation of reactive oxygen species was measured after X-irradiation. Enhanced cell killing was evaluated clonogenically in addition to assessment of in vivo efficacy and tumor pathology.
Conjugation of the particle to the photosensitizer was achieved, and the molecule was detected by UV-Vis spectroscopy. TEM and NTA showed no aggregation of the particles, and an increase in reactive oxygen species generation was observed. The conjugates increased cell killing during radiation treatment, whereas neither the particle alone nor the photosensitizer significantly affected clonogenic survival at the same concentrations. Breast tumors grown in immunocompetent mice showed increased necrotic tissue after a single 20 gy treatment in the presence of the conjugate.
DISCUSSION/SIGNIFICANCE OF IMPACT: Radiation therapy is widely used clinically, but dosage is limited largely to prevent injury to adjacent normal tissue. By increasing the local effect of radiation therapy, our gold conjugate has the potential to augment the effective radiation dose in the tumor, thereby reducing damage to healthy tissue and providing a more effective therapy.
Little is known about the neural substrates of suicide risk in mood disorders. Improving the identification of biomarkers of suicide risk, as indicated by a history of suicide-related behavior (SB), could lead to more targeted treatments to reduce risk.
Participants were 18 young adults with a mood disorder with a history of SB (as indicated by endorsing a past suicide attempt), 60 with a mood disorder with a history of suicidal ideation (SI) but not SB, 52 with a mood disorder with no history of SI or SB (MD), and 82 healthy comparison participants (HC). Resting-state functional connectivity within and between intrinsic neural networks, including cognitive control network (CCN), salience and emotion network (SEN), and default mode network (DMN), was compared between groups.
Several fronto-parietal regions (k > 57, p < 0.005) were identified in which individuals with SB demonstrated distinct patterns of connectivity within (in the CCN) and across networks (CCN-SEN and CCN-DMN). Connectivity with some of these same regions also distinguished the SB group when participants were re-scanned after 1–4 months. Extracted data defined SB group membership with good accuracy, sensitivity, and specificity (79–88%).
These results suggest that individuals with a history of SB in the context of mood disorders may show reliably distinct patterns of intrinsic network connectivity, even when compared to those with mood disorders without SB. Resting-state fMRI is a promising tool for identifying subtypes of patients with mood disorders who may be at risk for suicidal behavior.
Replicate radiocarbon (14C) measurements of organic and inorganic control samples, with known Fraction Modern values in the range Fm = 0–1.5 and mass range 6 μg–2 mg carbon, are used to determine both the mass and radiocarbon content of the blank carbon introduced during sample processing and measurement in our laboratory. These data are used to model, separately for organic and inorganic samples, the blank contribution and subsequently “blank correct” measured unknowns in the mass range 25–100 μg. Data, formulas, and an assessment of the precision and accuracy of the blank correction are presented.
Recent commercialization of auxin herbicide–based weed control systems has led to increased off-target exposure of susceptible cotton cultivars to auxin herbicides. Off-target deposition of dilute concentrations of auxin herbicides can occur on cotton at any stage of growth. Field experiments were conducted at two locations in Mississippi from 2014 to 2016 to assess the response of cotton at various growth stages after exposure to a sublethal 2,4-D concentration of 8.3 g ae ha−1. Herbicide applications occurred weekly from 0 to 14 weeks after emergence (WAE). Cotton exposure to 2,4-D at 2 to 9 WAE resulted in up to 64% visible injury, whereas 2,4-D exposure 5 to 6 WAE resulted in machine-harvested yield reductions of 18% to 21%. Cotton maturity was delayed after exposure 2 to 10 WAE, and height was increased from exposure 6 to 9 WAE due to decreased fruit set after exposure. Total hand-harvested yield was reduced from 2,4-D exposure 3, 5 to 8, and 13 WAE. Growth stage at time of exposure influenced the distribution of yield by node and position. Yield on lower and inner fruiting sites generally decreased from exposure, and yield partitioned to vegetative or aborted positions and upper fruiting sites increased. Reductions in gin turnout, micronaire, fiber length, fiber-length uniformity, and fiber elongation were observed after exposure at certain growth stages, but the overall effects on fiber properties were small. These results indicate that cotton is most sensitive to low concentrations of 2,4-D during late vegetative and squaring growth stages.
Methods for identifying relevant policy impacts for valuation in benefit-cost analyses (BCAs) have received relatively little attention in academic research, applied policy analyses, and guidance documents. In this paper, we develop a systematic, transparent, and replicable process that draws upon information contained in records of Congressional hearings to identify relevant policy impacts for valuation in a BCA. Our approach involves classifying – and subsequently analyzing – statements from witnesses testifying in Congressional hearings on the topic of the BCA. By using Congressional hearings as the basis for our approach, we are identifying potential policy impacts from information provided during the very process the BCA is intended to inform. However, because this approach is quite resource-intensive and would be somewhat burdensome for agencies to implement, it may be best applied in the academic realm, with identified impacts resulting from such applications then made available to agency personnel for potential inclusion in BCAs. Using the case of the Glen Canyon Dam, we demonstrate the approach and its resulting improvements in the quality and transparency of the BCA it was intended to inform.
The introduction of auxin herbicide weed control systems has led to increased occurrence of crop injury in susceptible soybeans and cotton. Off-target exposure to sublethal concentrations of dicamba can occur at varying growth stages, which may affect crop response. Field experiments were conducted in Mississippi in 2014, 2015, and 2016 to characterize cotton response to a sublethal concentration of dicamba equivalent to 1/16X the labeled rate. Weekly applications of dicamba at 35 g ae ha−1 were made to separate sets of replicated plots immediately following planting until 14 wk after emergence (WAE). Exposure to dicamba from 1 to 9 WAE resulted in up to 32% visible injury, and exposure from 7 to 10 WAE delayed crop maturity. Exposure from 8 to 10 and 13 WAE led to increased cotton height, while an 18% reduction in machine-harvested yield resulted from exposure at 6 WAE. Cotton exposure at 3 to 9 WAE reduced the seed cotton weight partitioned to position 1 fruiting sites, while exposure at 3 to 6 WAE also reduced yield in position 2 fruiting sites. Exposure at 2, 3, and 5 to 7 WAE increased the percent of yield partitioned to vegetative branches. An increase in percent of yield partitioned to plants with aborted terminals occurred following exposure from 3 to 7 WAE and corresponded with reciprocal decreases in yield partitioned to positional fruiting sites. Minimal effects were observed on fiber quality, except for decreases in fiber length uniformity resulting from exposure at 9 and 10 WAE.
Five species of bivalves and two species of gastropods are described from late Selandian to earliest Thanetian wood-fall communities from the Katsuhira Formation in Urahoro Town, eastern Hokkaido, northern Japan. Three bivalves and two gastropods are new to science: Thyasira (Thyasira) oliveri Amano and Jenkins, new species, Astarte (Astarte) paleocenica Amano and Jenkins, new species, Poromya katsuhiraensis Amano and Jenkins, new species, Neverita majimai Amano and Jenkins, new species, and Biplica paleocenica Amano and Jenkins, new species. Poromya katsuhiraensis n. sp. and Neverita majimai n. sp. are the earliest records of their genus. Astarte paleocenica n. sp. is the last species before the genus disappeared from the northern Pacific region during the Eocene, only to reappear with the opening of the Bering Strait during the latest Miocene. Moreover, two bivalve species and one gastropod genus are Cretaceous relict forms: Propeamussium yubarense (Yabe and Nagao, 1928), Myrtea ezoensis (Nagao, 1938), and Biplica Popenoe, 1957. These species and other relict protobranch bivalves had wide geographical ranges in the deep sea during the Cretaceous, which helped them to survive the end-Cretaceous mass extinction. The chemosynthesis-based species Bathyacmaea? sp., Myrtea ezoensis, and Thyasira oliveri n. sp. were recovered, but small bathymodioline mussels have not been found. This confirms that the small deep-sea mussels did not appear in the wood-fall communities at least by the earliest Thanetian.
Four new species of the methane seep-inhabiting kalenterid bivalve genus Caspiconcha Kelly in Kelly et al., 2000 are described: Caspiconcha basquensis from the late Albian of northern Spain, C. yubariensis from the late Albian of northern Japan, C. raukumaraensis from the late Albian to mid-Cenomanian of New Zealand, and C. lastsamurai from the Campanian of northern Japan. The earliest confirmed record of the genus is known from the latest Jurassic. It reached its maximum diversity in the Albian and declined in diversity and abundance through the Late Cretaceous. The youngest species, C. lastsamurai, is currently known from a single specimen only.
Quasi-stationary distributions (QSDs) arise from stochastic processes that exhibit transient equilibrium behaviour on the way to absorption. QSDs are often mathematically intractable and even drawing samples from them is not straightforward. In this paper the framework of sequential Monte Carlo samplers is utilised to simulate QSDs and several novel resampling techniques are proposed to accommodate models with reducible state spaces, with particular focus on preserving particle diversity on discrete spaces. Finally, an approach is considered to estimate eigenvalues associated with QSDs, such as the decay parameter.
Survey-based contingent valuation (CV) techniques are commonly used to value the potential effects of a policy change when market-based valuation of those effects is not possible. The results of these analyses are often intended to inform policy decisions, which are made within the context of formal policymaking institutions. These institutions are typically designed to reduce the large number of potential options for addressing any given policy problem to a binary choice between the continuation of current policy and a single, specified alternative. In this research we develop an approach for conducting CV exercises in a manner consistent with the decision structure typically faced by policymakers. The data generated from this approach allow for an estimate of willingness to pay (WTP) for a defined policy alternative, relative to leaving policy unchanged, which we argue is of direct interest to policymakers. We illustrate our approach within the context of policy governing the storage of used nuclear fuel in the United States. We value the policy option of constructing an interim storage facility relative to continuation of current policy, wherein used nuclear fuel is stored on-site at or near commercial nuclear generating plants. We close the paper with a discussion of the implications for future research and the role of CV in the policymaking process.
The objective of this study was to report procedural characteristics and adverse events on the data collected in the IMproving Paediatric and Adult Congenital Treatment registry.
The IMproving Paediatric and Adult Congenital Treatment– registry is a catheterisation registry focussed on paediatric and adult patients with congenital heart disease who are undergoing diagnostic catheterisations and catheter-based interventions. This study reports procedural characteristics and adverse events of patients who have undergone selected catheterisation procedures from January, 2011 to June, 2013.
Demographic, clinical, procedural, and institutional data elements were collected at participating centres and entered via either a web-based platform or software provided by the American College of Cardiology-certified vendors, and were collected in a secure, centralised database. For the purpose of this study, procedures that were not classified as one of the ‘core’ IMproving Paediatric and Adult Congenital Treatment procedures originally chosen for additional data collection were identified and selected for further data analysis.
During the time frame of data collection, a total of 8021 cases were classified as other procedures and/or multiple procedures. The most commonly performed case types – isolated or in combination with other procedures – were right ventricular biopsy in 3433 (42.8%), conduit/MPA interventions in 979 (12.3%), and systemic pulmonary artery collateral occlusion in 601 (7.5%). For the whole cohort, adverse events of any severity occurred in 957 (12.0%) cases, whereas major adverse events occurred in 113 (1.4%) cases; six patients (0.1%) died in the catheterisation laboratory.
The IMproving Paediatric and Adult Congenital Treatment registry has provided important data on the frequency and spectrum of cardiac catheterisation procedures performed in the present era. For many procedures, more data and work are needed to identify more subtle differences between case categories, especially as it relates to the incidence of major adverse events, and to further develop a risk-adjustment methodology to allow equitable comparisons among institutions.
To report procedural characteristics and adverse events on data collected in the registry.
The IMPACT – IMproving Paediatric and Adult Congenital Treatment – Registry is a catheterisation registry of paediatric and adult patients with CHD undergoing diagnostic and interventional cardiac catheterisation. We are reporting the procedural characteristics and adverse events of patients undergoing diagnostic and interventional catheterisation procedures from January, 2011 to March, 2013.
Demographic, clinical, procedural, and institutional data elements were collected at the participating centres and entered via either a web-based platform or software provided by American College of Cardiology-certified vendors, and were collected in a secure, centralised database. Centre participation was voluntary.
During the time frame of data collection, 19,797 procedures were entered into the IMPACT Registry. Procedures were classified as diagnostic only (35.4%); one of six specific interventions (23.8%); other or multiple interventions (40.7%); and were further broken down into four age groups. Anaesthesia was used in 84.1% of diagnostic procedures and 87.8% of interventional ones. Adverse events occurred in 10.0% of diagnostic and 11.1% of interventional procedures.
The IMPACT Registry is gathering data to set national benchmarks for diagnostic and certain specific interventional procedures. We are seeing little differences in procedural characteristics or adverse events in diagnostic procedures compared with interventional procedures overall, but there is significant variation in adverse events amongst age categories. Risk stratification and patient acuity scores will be required for further analysis of these differences.