Composites of multi-walled carbon nanotubes (MWCNT) of varied functionality (unfunctionalised and carboxyl and amine functionalised) with polymethyl methacrylate (PMMA) were prepared for use as a ...bone cement. The MWCNT loadings ranged from 0.1 to 1.0wt.%. The fatigue properties of these MWCNT–PMMA bone cements were characterised at MWCNT loading levels of 0.1 and 0.25wt.% with the type and wt.% loading of MWCNT used having a strong influence on the number of cycles to failure. The morphology and degree of dispersion of the MWCNT in the PMMA matrix at different length scales were examined using field emission scanning electron microscopy. Improvements in the fatigue properties were attributed to the MWCNT arresting/retarding crack propagation through the cement through a bridging effect and hindering crack propagation. MWCNT agglomerates were evident within the cement microstructure and the degree of agglomeration was dependent on the level of loading and functionality of the MWCNT. The biocompatibility of the MWCNT–PMMA cements at MWCNT loading levels upto 1.0wt.% was determined by means of established biological cell culture assays using MG-63 cells. Cell attachment after 4h was determined using the crystal violet staining assay. Cell viability was determined over 7days in vitro using the standard colorimetric MTT assay. Confocal scanning laser microscopy and SEM analysis was also used to assess cell morphology on the various substrates.
In recent years, various stakeholders and political decision-makers have recognized the significance of high-quality urban sound environments, stressing the need for user-centered trajectories. ...Despite the rising interest in this field, the soundscape approach has not yet fully permeated urban planning and design, possibly due to a lack of comprehensible guidelines on how to implement and curate successful soundscape designs, attributed to on-going developments on this subject. In the course of the Catalogue of Soundscape Interventions (CSI) Project, a taxonomy of eight dimensions was developed to serve as an orientation aid for practitioners, describing important aspects of soundscape-related measures that can be used as a brief to facilitate communication between authorities, consultants, and researchers. This study describes the theoretical framework and, in particular, the sequential coding process involved in deriving these dimensions, which is based on grounded theory. It lists observations and limitations of the resulting taxonomy and builds upon these findings to critically review and revisit existing nomenclature and concepts. Finally, a qualitative distinction in the form of a design pyramid according to ascending levels of epistemic rigor is proposed, to differentiate between documented practices, which may serve as a reference point for future harmonization and standardization.
Early detection of CO2 leakage through monitoring is important to ensure long-term safety for geologic carbon storage (GCS). A geochemically informed leak detection (GILD) model has been developed ...for groundwater chemistry monitoring at CO2 injection sites. The GILD model integrates a geochemical model that simulates fluid chemistry changes in CO2 leakage events and a Bayesian belief network (BBN) model that evaluates monitoring observations to identify leakages. The geochemical model is implemented using Geochemists’ Workbench to assess fluid chemistry changes as a result of small CO2 leakage in an above-zone monitoring interval (AZMI) formation with varying mineral assemblages and background fluids. Response functions are fitted to the output of the geochemical model and are translated to conditional probabilities in the BBN model. The BBN model gives operational prediction of the leak probability given a set of groundwater monitoring measurements and the probability of detecting a leak at a given magnitude. The detection capabilities of multiple monitoring parameters are compared. For aquifers that contain calcite, it is valuable to incorporate other monitoring parameters with pH to increase the sensitivity of detection. For aquifers with no calcite, pH alone is a sensitive parameter. This research illustrates a method of identifying CO2 leakage into aquifers with both geochemical and statistical tools.
Display omitted
•A model is developed for early small-leakage detection at CO injection sites using groundwater chemistry monitoring.•Fluid chemistry changes are simulated as a result of small CO2 leakage in an above-zone monitoring interval.•Bayesian belief networks are constructed for optimizing sensitive monitoring parameters using response functions.•Detection probabilities of monitoring systems are assessed by considering individual or combined monitoring parameters.
Abstract
BACKGROUND
Mutated neoantigens have shown promise as targets for cancer immunotherapy but embryonal pediatric brain tumors with notoriously low mutational burden have more limited ...opportunities for neoantigen directed therapies. Evidence suggests that embryonal brain tumors such as medulloblastoma (MB) and brain stem gliomas (BSG) arise from the aberrant reactivation of fetal developmental programming. We explored the hypothesis that neonatal mouse cerebellum and brainstem express developmentally regulated proteins that could serve as potent tumor rejection antigens for a preclinical model of Group 3 MB (NSC) and H3.3K27M positive BSG (K2), respectively. We thus generated tumor-reactive T cells by using P5 cerebellum and P4 brain stem RNA as sources of antigens. P5-cerebellum-specific T cells (cDevAg-T cells) and P4-brain stem-specific T cells (bsDevAg-T cells) demonstrated effector function against respective MB and BSG tumor cells with exquisite specificity.
METHODS
RNA was isolated from P5 cerebellum and P4 brain stem and pulsed into bone marrow-derived dendritic cells. These were then used to in vitro activate splenocytes from previously immunized mice, generating either cDevAg-T cells or bsDevAg-T cells. In vitro functionality assays against tumor targets were conducted to determine reactivity and specificity. DevAg-T cells were used in adoptive cellular therapy in orthotopic models to determine therapeutic efficacy of DevAg-specific T cells in vivo. Results and
CONCLUSIONS
DevAg-T cells produce high levels of Th1-type cytokines that recognize distinct subtypes of MB and BSG, show no cross-reactivity with normal brain. Adoptive cellular therapy employing DevAg-specific T cells demonstrate a significant survival benefit in orthotopic models of established Group 3 NSC MB and H3.3K27M mutation positive BSG. Our studies demonstrate that RNA encoding non-mutated and organ-specific developmental antigens can serve as novel tumor rejection antigens for pediatric brain cancers.
Abstract
Melanoma brain metastases (MBM) remain a primary driver of melanoma morbidity and mortality. It is estimated that as many as 60% of all metastatic melanoma patients will develop MBM during ...the course of their disease. Once found, dual checkpoint inhibitor therapy or BRAF/MEK inhibition in BRAF mutated cancers, are the best options currently available. Even with these treatments, the response to therapy is less than what is seen with disease outside the. In BRAF mutated cancers, which constitute 50% of all patients, initial response to targeted therapy is rapid but resistance to therapy develops 3 months sooner than resistance outside of the brain. Novel strategies to prevent onset of resistance or to work in concert with BRAF/MEK inhibition are needed for this treatment population. The exact mechanism of resistance to targeted therapy in MBM is not known, but mutations in EphA2, PI3K, pAKT, and re-activation of MAPK signaling through secondary mechanisms have all been identified as drivers of resistance. One pathway of MAPK reactivation is through activation of phospho-ERK (eIF2alpha kinase) which also activates the JNK pathway. Our group has previously shown that MBM express high levels of the inflammatory transcription factor IRAK-4, the terminal chaperone of the inflammatory myddosome downstream of TLR and IL1R signally. This increase in IRAK-4 results in constitutive activation of NF-KB, JNK, and MAPK. We have additionally shown the novel oral IRAK-4 inhibitor CA-4948 can reach therapeutically relevant concentrations past the blood brain barrier in both tumor-bearing and naïve mice. We additionally show CA-4948 inhibits MAPK expression in melanoma and suppresses the escape pathways pERK and JNK signaling which can contribute to the prevention of resistance to targeted therapy. This study supports further investigation into the combination potential of CA-4948 with BRAF/MEK inhibitors as triplet therapy to delay intracranial resistance.
A module on child functioning developed by UNICEF and the Washington Group on Disability Statistics (WG) for use in censuses and surveys reflects current thinking around disability measurement and is ...intended to produce internationally comparable data. The Child Functioning Module (CFM) was developed in response to limitations of the Ten Question Screening Instrument (TQSI) for use in surveys and builds on the WG Short Set (WG-SS) of questions that was designed to capture disability in censuses, particularly among the adult population.
This paper documents the testing of the module and summarizes its results, including a description of prevalence levels across countries using different cut-offs, and comparisons with prevalence levels obtained using the TQSI and the WG-SS.
Field tests were conducted in Samoa as part of the 2014 Demographic and Health Survey and in Mexico as part of the 2015 National Survey of Boys, Girls and Women. The module was also implemented in Serbia as part of a dedicated survey conducted in the province of Vojvodina, in February 2016.
Using the recommended cut-offcut-off, the percentage of children reported as having functional difficulty ranges from 1.1% in Serbia to 2% in Mexico among children aged 2-4 years, and from 3.2% in Samoa to 11.2% in Mexico among children aged 5-17 years. Across all three countries, the prevalence of functional difficulty was highest in the socio-emotional domains. A comparison of the prevalence levels obtained using the WG-SS and the CFM shows that, except for the question on cognition/learning, the WG-SS and the CFM are relatively close for children aged 5-17 years for the domains that are included in both question sets, but the WG-SS excludes many children identified by the CFM in other domains. The comparison between the TQSI and the CFM shows that, while the prevalence estimates are similar for seeing and hearing, significant differences affect other domains, particularly cognition/learning and communication.
The CFM addresses a full range of functional domains that are important for child development. The module represents an improvement on the TQSI in that it allows for scaled responses to determine the degree of difficulty, and so can separate out many potential false positives. The module is also preferred over the WG-SS for collecting data on children, first, because most of the questions in the WG-SS are not suitable for children under the age of 5 years, and second, because the WG-SS leaves out important functional domains for children aged 5-17 years, namely those related to developmental disabilities and behavioural issues.
Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and ...clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
Significance A significant proportion of head and neck cancer is driven by human papillomavirus (HPV) infection, and the expression of viral oncogenes is involved in the development of these tumors. However, the role of HPV integration in primary tumors beyond increasing the expression of viral oncoproteins is not understood. Here, we describe how HPV integration impacts the host genome by amplification of oncogenes and disruption of tumor suppressors as well as driving inter- and intrachromosomal rearrangements. Tumors that do and do not have HPV integrants display distinct gene expression profiles and DNA methylation patterns, which further support the view that the mechanisms by which tumors with integrated and nonintegrated HPV arise are distinct.
Objective:
The microscopic analysis of biopsied lung nodules represents the gold-standard for definitive diagnosis of lung cancer. Deep learning has achieved pathologist-level classification of ...non-small cell lung cancer histopathology images at high resolutions (0.5–2 µm/px), and recent studies have revealed tomography–histology relationships at lower spatial resolutions. Thus, we tested whether patterns for histological classification of lung cancer could be detected at spatial resolutions such as those offered by ultra-high-resolution CT.
Methods:
We investigated the performance of a deep convolutional neural network (inception-v3) to classify lung histopathology images at lower spatial resolutions than that of typical pathology. Models were trained on 2167 histopathology slides from The Cancer Genome Atlas to differentiate between lung cancer tissues (adenocarcinoma (LUAD) and squamous-cell carcinoma (LUSC)), and normal dense tissue. Slides were accessed at 2.5 × magnification (4 µm/px) and reduced resolutions of 8, 16, 32, 64, and 128 µm/px were simulated by applying digital low-pass filters.
Results:
The classifier achieved area under the curve ≥0.95 for all classes at spatial resolutions of 4–16 µm/px, and area under the curve ≥0.95 for differentiating normal tissue from the two cancer types at 128 µm/px.
Conclusions:
Features for tissue classification by deep learning exist at spatial resolutions below what is typically viewed by pathologists.
Advances in knowledge:
We demonstrated that a deep convolutional network could differentiate normal and cancerous lung tissue at spatial resolutions as low as 128 µm/px and LUAD, LUSC, and normal tissue as low as 16 µm/px. Our data, and results of tomography–histology studies, indicate that these patterns should also be detectable within tomographic data at these resolutions.
The structure and function of longleaf pine savanna ecosystems is regulated by cyclic fire, yet there is a lack of understanding about how the frequency of fire influences longleaf pine ecosystem ...energy dynamics. There are further uncertainties in how predicted changes in temperature and precipitation may affect the interaction between fire and energy exchange in these ecosystems. We investigated energy dynamics in three frequently burned longleaf pine ecosystems along a gradient of soil moisture availability using eddy covariance techniques. We analyzed sensible energy (
H
), latent energy (LE) and soil heat flux (
G
) over time since fire, using micrometeorological variables as covariates. Based on statistical tests of autocorrelation, data were analyzed as 30-day averages with general linear models. Over three years of measurement, we found that sensible energy, latent energy and soil heat flux recovered to pre-fire rates within one month following prescribed fire. Changes in water availability associated with drought over the study period had a stronger influence on energy dynamics than did fire. When precipitation was near long-term averages, annual evapotranspiration (ET) was 743, 816 and 666 mm y
−1
at the mesic, intermediate and xeric sites, respectively. During extreme drought, annual ET decreased 4 and 7% at the xeric and intermediate sites, to 754 and 642 mm y
−1
, respectively, and decreased 20% at the mesic site, to 594 mm y
−1
. Similarly, Bowen ratios were up to two times higher during drought years versus those with average precipitation. These frequently burned longleaf pine ecosystems are known to be well adapted to fire. The more xeric the site, the more resilient they were to drought, suggesting adaptations of this ecosystem maintained higher levels of physiological activity. This three-year study begins to illuminate longleaf pine ecosystem energy dynamics, however long-term observations over a greater range of environmental conditions are necessary to increase our knowledge of the complex interactions between fire, climate and energy dynamics in these ecosystems.
The mechanical function of the left atrium (LA) plays a pivotal role in modulation of left ventricular filling. Assessment of LA function might be a clinically useful prognostic tool for horses with ...mitral regurgitation or atrial fibrillation. However, the most accurate, reliable, and clinically useful methods to assess LA myocardial function are yet to be determined. The objective of this study was to describe the methods for quantification of LA wall motion using two-dimensional speckle tracking (2DST) echocardiography in healthy Warmblood horses to quantify measurement variability, to calculate reference intervals for 2DST variables, and to investigate their relationship to sex, age, body weight, and heart rate.
Twenty-six healthy Warmblood horses were included. 2DST analyses of LA wall motion were performed on digitally stored cine-loop recordings of a standardized right-parasternal four-chamber view focusing on the LA. Longitudinal strain, longitudinal strain rate, and time to peak LA contraction were measured to characterize LA contractile, reservoir, and conduit function. Intraobserver and interobserver measurement variability was quantified, and reference intervals were calculated.
The coefficient of variation for intraobserver and interobserver measurement variability ranged between 2.0–11.1% and 5.1–15.4%, respectively, for global strain, strain rate, and time to peak LA contraction. Reference intervals for healthy Warmblood horses were reported.
This study shows that 2DST is a feasible and reliable method to quantify LA wall motion throughout the cardiac cycle in healthy Warmblood horses. Further studies are required to establish the clinical value of 2DST for assessment of LA function.
PDF
