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

dReDBox: Materializing a full-stack rack-scale system prototype of a next-generation disaggregated datacenter

Current datacenters are based on server machines, whose mainboard and hardware components form the baseline, monolithic building block that the rest of the system software, middleware and application stack are built upon. This leads to the following limitations: (a) resource proportionality of a multi-tray system is bounded by the basic building block (mainboard), (b) resource allocation to processes or virtual machines (VMs) is bounded by the available resources within the boundary of the mainboard, leading to spare resource fragmentation and inefficiencies, and (c) upgrades must be applied to each and every server even when only a specific component needs to be upgraded. The dRedBox project (Disaggregated Recursive Datacentre-in-a-Box) addresses the above limitations, and proposes the next generation, low-power, across form-factor datacenters, departing from the paradigm of the mainboard-as-a-unit and enabling the creation of function-block-as-a-unit. Hardware-level disaggregation and software-defined wiring of resources is supported by a full-fledged Type-1 hypervisor that can execute commodity virtual machines, which communicate over a low-latency and high-throughput software-defined optical network. To evaluate its novel approach, dRedBox will demonstrate application execution in the domains of network functions virtualization, infrastructure analytics, and real-time video surveillance.This work has been supported in part by EU H2020 ICTproject dRedBox, contract #687632.Peer ReviewedPostprint (author's final draft

Sm-Nd and Rb-Sr Systematics in Volcanics and Ultramafic Xenoliths From Malaita, Solomon Islands, and the Nature of the Ontong Java Plateau

A Rb-Sr and Sm-Nd study was carried out on five ultrabasic inclusions, three alnoite host rocks, and one sample of basalt from Malaita in an effort to determine the isotopic stratigraphy of the mantle in this area. The results of this study show the presence of relatively undepleted mantle segments underlying relatively older depleted upper mantle. The alnoite samples, three megacrysts and one Iherzolite inclusion, and the basalt are relatively uniform isotopically and yielded ε_(Nd) (T) ≈ +3.5 and ε_(Sr) (T) ≈ −6 to +17 (T = 100 m.y. for the basalt and Iherzolite and 34 m.y. for the rest of the samples). It is suggested that a mantle segment of that isotopic composition exists at a depth of more than 100 km. This mantle segment is relatively undepleted. A Iherzolite inclusion with ε_(Nd) (T) = 6.6 is included in the alnoite and indicates the location of a light rare earth element depleted layer overlying a less depleted mantle at a depth of approximately 100 km. The mantle source for the alnoite and basalt cannot be old, depleted oceanic mantle or subducted old continental crust but may come from a relatively young, slightly depleted mantle segment. The isotopic results are compatible with a mixture of about 99% depleted oceanic mantle homogenized with 1% continental crust possibly by metasomatic processes. Such a mixture is only slightly fractionated and has ƒ^(Sm/Nd) ≈ 0.13 and ƒ^(Rb/Sr) ≈ 0. Assuming that the basalt is characteristic of the Ontong Java Plateau, a volume greater than 108 km3 of mantle source with ε_(Nd) ∼ 3.5, ε_(Sr) ∼ 0 was involved. This corresponds to a block of continental crust of ∼ 10^6 km^3 which had to reach a depth greater than 100 km to produce the proposed nearly homogeneous isotopic mixture. Alternatively, the source of the Ontong Java Plateau may be a segment of a type of young continental crust with the appropriate isotopic signature which was subducted below 100 km. This would not require homogenization with a large volume of depleted mantle

The Digital Elevation Model Intercomparison eXperiment DEMIX, a community-based approach at global DEM benchmarking

This paper presents an initiative recently launched under the auspices of the Committee on Earth Observation Satellites (CEOS) aiming at providing harmonised terminology and methods, as well as practical guidelines and results allowing the intercomparison of continental or global Digital Elevation Models (DEM). As the work is still ongoing the main purpose of this article is not the dissemination of the outcome but rather to inform the wider community about the initiative, communicate the chosen approach to raise awareness, and attract possible further participants. Nevertheless, some preliminary results are included and an outlook on planned next steps is provided

The effect of chest compression frequency on the quality of resuscitation by lifeguards. A prospective randomized crossover multicenter simulation trial

BACKGROUND: The ability to perform high-quality cardiopulmonary resuscitation is one of the basic skills for lifeguards. The aim of the study was to assess the influence of chest compression frequency on the quality of the parameters of chest compressions performed by lifeguards. METHODS: This prospective observational, randomized, crossover simulation study was performed with 40 lifeguards working in Warsaw, Wroclaw, and Poznan, Poland. The subjects then participated in a target study, in which they were asked to perform 2-min cycles of metronome-guided chest compressions at different rates: 80, 90, 100, 110, 120, 130, 140, and 150 compressions per minute (CPM). RESULTS: The study involved 40 lifeguards. Optimal chest compression score calculated by manikin software was achieved for 110-120 CPM. Chest compression depth achieved 53 (interquartile range [IQR] 52-54) mm, 56 (IQR 54-57) mm, 52.5 (IQR 50-54) mm, 53 (IQR 52-53) mm, 50 (IQR 49-51) mm, 47 (IQR 44-51) mm, 41 (IQR 40-42) mm, 38 (IQR 38-43) mm for 80, 90, 100, 110, 120, 130, 140 and 150 CPM, respectively. The percentage of chest compressions with the correct depth was lower for rates exceeding 120 CPM. CONCLUSIONS: The rate of 100-120 CPM, as recommended by international guidelines, is the optimal chest compression rate for cardiopulmonary resuscitation performed by lifeguards. A rate above 120 CPM was associated with a dramatic decrease in chest compression depth and overall chest compression quality. The role of full chest recoil should be emphasized in basic life support training

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

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