Dendrimer Conjugation Enhances Tumor Penetration and Cell Kill of Doxorubicin in 3D Coculture Lung Cancer Models

Background: Doxorubicin (DOX) is a potent chemotherapeutic widely used for solid tumors (1). Despite high efficacy in 2D cell culture, DOX efficacy does not translate to in vivo lung cancer models (2). Major side effects such as cardiotoxicity may be alleviated with nano-based drug delivery systems (nanoDDS). However, tumor penetration of DOX and DOX-nanoDDS is largely unknown and is an additional barrier to effective clinical therapy (3). Here we describe a nanoDDS capable of enhancing the penetration of DOX. Methods: DOX was conjugated to generation 4 poly(amido-amine) dendrimers through (GFLG) tumor- liable bond. G4SA-GFLG-DOX was synthesized/characterized. spheroids were formed of (A549) lung adenocarcinoma cells and (3T3) fibroblasts. Spheroids were characterized for ECM components with immunohistochemistry. Confocal microscopy was used to evaluate the penetration, internalization, and colocalization of DOX and G4SA-GFLG-DOX. MTT assay and Caspase 3/7 to assess 2D and 3D cytotoxicity. Flow cytometry to determine cells uptake. Results: DOX conjugation to dendrimer resulted in G4SA-GFLG-DOX with ~5.5 DOX, 10±1 nm hydrodynamic diameter, and a -17±3 mV zeta-potential. Spheroids of (A549:3T3) were ECM- rich, developed ECM containing collagen-I, hyaluronan, laminin, and fibronectin. While DOX and G4SA-GFLG-DOX had similar toxicities in 2D model, G4SA-GFLG-DOX demonstrated a 3.1-fold greater penetration into spheroids compared to DOX and correlated to a greater efficacy as measured by caspase 3/7 activity. Also, flow cytometry showed higher uptake of G4SA- GFLG-DOX in cancer cells compared to fibroblasts. Conclusion: The work demonstrates enhanced penetration of DOX, via dendrimer conjugation, into an ECM- rich 3D lung cancer model. The enhanced penetration of G4SA-GFLG-DOX correlated with greater antitumor efficacy. Acknowledgements: We acknowledge partial financial support from the Center for Pharmaceutical Engineering and Sciences - School of Pharmacy at VCU. This study was supported by VCU Quest for Distinction and NSF (DRM #1508363). Microscopy was performed at the VCU Microscopy Facility, supported, in part, by funding from NIH-NCI Cancer Center Support Grant P30 CA016059. RA would like to acknowledge King Faisal University (KFU) and Saudi Arabian Cultural Mission (SACM) for a scholarship.https://scholarscompass.vcu.edu/gradposters/1091/thumbnail.jp

Overcoming an “irreversible” threshold: A 15-year fire experiment

A key pursuit in contemporary ecology is to differentiate regime shifts that are truly irreversible from those that are hysteretic. Many ecological regime shifts have been labeled as irreversible without exploring the full range of variability in stabilizing feedbacks that have the potential to drive an ecological regime shift back towards a desirable ecological regime. Removing fire from grasslands can drive a regime shift to juniper woodlands that cannot be reversed using typical fire frequency and intensity thresholds, and has thus been considered irreversible. This study uses a unique, long-term experimental fire landscape co-dominated by grassland and closed-canopy juniper woodland to determine whether extreme fire can shift a juniper woodland regime back to grassland dominance using aboveground herbaceous biomass as an indicator of regime identity. We use a space-for-time substitute to quantify herbaceous biomass following extreme fire in juniper woodland up to 15 years post-fire and compare these with (i) 15 years of adjacent grassland recovery post-fire, (ii) unburned closed-canopy juniper woodland reference sites and (iii) unburned grassland reference sites. Our results show grassland dominance rapidly emerges following fires that operate above typical fire intensity thresholds, indicating that grassland-juniper woodlands regimes are hysteretic rather than irreversible. One year following fire, total herbaceous biomass in burned juniper stands was comparable to grasslands sites, having increased from 5 ± 3 g m–2to 142 ± 42 g m–2(+2785 ± 812 percent). Herbaceous dominance in juniper stands continued to persist 15- years after initial treatment, reaching a maximum of 337 ± 42 g m–2eight years post-fire. In juniper encroached grasslands, fires that operate above typical fire intensity thresholds can provide an effective method to reverse juniper woodland regime shifts. This has major implications for regions where juniper encroachment threatens rancher-based economies and grassland biodiversity and provides an example of how to operationalize resilience theory to disentangle irreversible thresholds from hysteretic system behavior

Towards a situated, multimodal interface for multiple UAV control

Multiple autonomous Unmanned Aerial Vehicles (UAVs) can be used to complement human teams. This paper presents the results of an exploratory study to investigate gesture/ speech interfaces for interaction with robots in a situated manner and the development of three iterations of a prototype command set. A command set was compiled from observing users interacting with a simulated interface in a virtual reality environment. We discovered that users find this type of interface intuitive and their commands tend to naturally group into both 'High-Level' and 'Low-Level' instructions. However, as the robots moved further away, the loss of depth perception and direct feedback was inimical to the interaction. In a second experiment we found that using simple heads up display elements could mitigate these issues. ©2010 IEEE

Impact of Eastern Redcedar Proliferation on Water Resources in the Great Plains USA—Current State of Knowledge

In the Great Plains of the central United States, water resources for human and aquatic life rely primarily on surface runoff and local recharge from rangelands that are under rapid transformation to woodland by the encroachment of Eastern redcedar (redcedar; Juniperus virginiana) trees. In this synthesis, the current understanding and impact of redcedar encroachment on the water budget and water resources available for non-ecosystem use are reviewed. Existing studies concluded that the conversion from herbaceous-dominated rangeland to redcedar woodland increases precipitation loss to canopy interception and vegetation transpiration. The decrease of soil moisture, particularly for the subsurface soil layer, is widely documented. The depletion of soil moisture is directly related to the observed decrease in surface runoff, and the potential of deep recharge for redcedar encroached watersheds. Model simulations suggest that complete conversion of the rangelands to redcedar woodland at the watershed and basin scale in the South-central Great Plains would lead to reduced streamflow throughout the year, with the reductions of streamflow between 20 to 40% depending on the aridity of the climate of the watershed. Recommended topics for future studies include: (i) The spatial dynamics of redcedar proliferation and its impact on water budget across a regional hydrologic network; (ii) the temporal dynamics of precipitation interception by the herbaceous canopy; (iii) the impact of redcedar infilling into deciduous forests such as the Cross Timbers and its impact on water budget and water availability for non-ecosystem use; (iv) land surface and climate interaction and cross-scale hydrological modeling and forecasting; (v) impact of redcedar encroachment on sediment production and water quality; and (vi) assessment and efficacy of different redcedar control measures in restoring hydrological functions of watershed

Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis

Rheumatoid arthritis (RA) is a prevalent systemic autoimmune disease, caused by a combination of genetic and environmental factors. Animal models suggest a role for intestinal bacteria in supporting the systemic immune response required for joint inflammation. Here we performed 16S sequencing on 114 stool samples from rheumatoid arthritis patients and controls, and shotgun sequencing on a subset of 44 such samples. We identified the presence of Prevotella copri as strongly correlated with disease in new-onset untreated rheumatoid arthritis (NORA) patients. Increases in Prevotella abundance correlated with a reduction in Bacteroides and a loss of reportedly beneficial microbes in NORA subjects. We also identified unique Prevotella genes that correlated with disease. Further, colonization of mice revealed the ability of P. copri to dominate the intestinal microbiota and resulted in an increased sensitivity to chemically induced colitis. This work identifies a potential role for P. copri in the pathogenesis of RA. DOI: http://dx.doi.org/10.7554/eLife.01202.00

High intensity neutrino oscillation facilities in Europe

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ+ and μ− beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He6 and Ne18, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive

Coupling early warning services, crowdsourcing, and modelling for improved decision support and wildfire emergency management

The threat of a forest fire disaster increases around the globe as the human footprint continues to encroach on natural areas and climate change effects increase the potential of extreme weather. It is essential that the tools to educate, prepare, monitor, react, and fight natural fire disasters are available to emergency managers and responders and reduce the overall disaster effects. In the context of the I-REACT project, such a big crisis data system is being developed and is based on the integration of information from different sources, automated data processing chains and decision support systems. This paper presents the wildfire monitoring for emergency management system for those involved and affected by wildfire disasters developed for European forest fire disasters

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13