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"Hackett, Michael"
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Tumor-targeted Delivery of siRNA by Self-assembled Nanoparticles
We have developed a self-assembled nanoparticle (NP) that efficiently delivers small interfering RNA (siRNA) to the tumor by intravenous (IV) administration. The NP was obtained by mixing carrier DNA, siRNA, protamine, and lipids, followed by post-modification with polyethylene glycol and a ligand, anisamide. Four hours after IV injection of the formulation into a xenograft model, 70–80% of injected siRNA/g accumulated in the tumor, ∼10% was detected in the liver and ∼20% recovered in the lung. Confocal microscopy showed that fluorescent-labeled siRNA was efficiently delivered into the cytoplasm of the sigma receptor expressing NCI-H460 xenograft tumor by the targeted NPs, whereas free siRNA and non-targeted NPs showed little uptake. Three daily injections (1.2 mg/kg) of siRNA formulated in the targeted NPs silenced the epidermal growth factor receptor (EGFR) in the tumor and induced ∼15% tumor cell apoptosis. Forty percent tumor growth inhibition was achieved by treatment with targeted NPs, while complete inhibition lasted for 1 week when combined with cisplatin. The serum level of liver enzymes and body weight monitoring during the treatment indicated a low level of toxicity of the formulation. The carrier itself also showed little immunotoxicity (IMT).
Journal Article
Cancer imaging: Lighting up tumours
Detection of a wide range of tumours remains a challenge in cancer diagnostics. By exploiting changes in the tumour microenvironment, a pH-responsive polymeric nanomaterial enables ultrasensitive tumour-specic imaging in many types of cancer. Ling et al comment on a study by Gao et al in which they report an imaging strategy that is ultrasensitiveto the tumour microenvironment: they have developed a polymeric, micelle-based nanoprobe that is highly responsive to both the angiogenic tumour vasculature and the extracellular pH.
Journal Article
Iron oxide nanoclusters for T1 magnetic resonance imaging of non-human primates
Iron-oxide-based contrast agents for magnetic resonance imaging (MRI) had been clinically approved in the United States and Europe, yet most of these nanoparticle products were discontinued owing to failures to meet rigorous clinical requirements. Significant advances have been made in the synthesis of magnetic nanoparticles and their biomedical applications, but several major challenges remain for their clinical translation, in particular large-scale and reproducible synthesis, systematic toxicity assessment, and their preclinical evaluation in MRI of large animals. Here, we report the results of a toxicity study of iron oxide nanoclusters of uniform size in large animal models, including beagle dogs and the more clinically relevant macaques. We also show that iron oxide nanoclusters can be used as
T
1
MRI contrast agents for high-resolution magnetic resonance angiography in beagle dogs and macaques, and that dynamic MRI enables the detection of cerebral ischaemia in these large animals. Iron oxide nanoclusters show clinical potential as next-generation MRI contrast agents.
Uniform iron oxide nanoparticle clusters are highly biocompatible and can be used as contrast agents for high-resolution magnetic resonance angiography of large animals.
Journal Article
Anomaly Detection in a Smart Microgrid System Using Cyber-Analytics: A Case Study
Smart microgrids are being increasingly deployed within the Department of Defense. The microgrid at Marine Corps Air Station (MCAS) Miramar is one such deployment that has fostered the integration of different technologies, including 5G and Advanced Metering Infrastructure (AMI). The objective of this paper is to develop an anomaly detection framework for the smart microgrid system at MCAS Miramar to enhance its cyber-resilience. We implement predictive analytics using machine learning to deal with cyber-uncertainties and threats within the microgrid environment. An autoencoder neural network is implemented to classify and identify specific cyber-attacks against this infrastructure. Both network traffic in the form of packet captures (PCAP) and time series data (from the AMI sensors) are considered. We train the autoencoder model on three traffic data sets: (1) Modbus TCP/IP PCAP data from the hardwired network apparatus of the smart microgrid, (2) experimentally generated 5G PCAP data that mimic traffic on the smart microgrid and (3) AMI smart meter sensor data provided by the Naval Facilities (NAVFAC) Engineering Systems Command. Distributed denial-of-service (DDoS) and false data injection attacks (FDIA) are synthetically generated. We show the effectiveness of the autoencoder on detecting and classifying these types of attacks in terms of accuracy, precision, recall, and F-scores.
Journal Article
A Long, Hard Year: Russia-Ukraine War Lessons Learned 2023
This special commentary summarizes the major findings and lessons taken from the Russia-Ukraine War integrated research project conducted by members of the US Army War College class of 2024—all subject matter experts on their topics. It outlines seven lessons covering doctrinal, operational, technological, strategic, and political issues related to the second year of the war, including Russia’s use of mercenaries, the need to create a culture of mission command, ways to deal with a transparent battlefield because of persistent, ubiquitous surveillance, air superiority as a prerequisite for successful combined arms ground offensives, and changes to the intelligence and information domains.
Journal Article
Efficacy of ceftazidime in a murine model following a lethal aerosol exposure to Burkholderia pseudomallei
Melioidosis is an endemic disease in numerous tropical regions. Additionally, the bacterium that causes melioidosis,
Burkholderia pseudomallei
, has potential to be used as a biological weapon. Therefore, development of effective and affordable medical countermeasures to serve regions affected by the disease and to have medical countermeasures available in the event of a bioterrorism attack remains critical. The current study evaluated the efficacy of eight distinct acute phase ceftazidime treatment regimens administered therapeutically in the murine model. At the conclusion of the treatment period, survival rates were significantly greater in several of the treated groups when compared to the control group. Pharmacokinetics of a single dose of ceftazidime were examined at 150 mg/kg, 300 mg/kg, and 600 mg/kg and were compared to an intravenous clinical dose administered at 2000 mg every eight hours. The clinical dose has an estimated 100%
f
T > 4*MIC which exceeded the highest murine dose of 300 mg/kg every six hours at 87.2%
f
T > 4*MIC. Based upon survival at the end of the treatment regimen and supplemented by pharmacokinetic modeling, a daily dose of 1200 mg/kg of ceftazidime, administered every 6 h at 300 mg/kg, provides protection in the acute phase of inhalation melioidosis in the murine model.
Journal Article
Neutralizing Concentrations of Anti-Botulinum Toxin Antibodies Positively Correlate with Mouse Neutralization Assay Results in a Guinea Pig Model
Botulinum neurotoxins (BoNT) are some of the most toxic proteins known and can induce respiratory failure requiring long-term intensive care. Treatment of botulism includes the administration of antitoxins. Monoclonal antibodies (mAbs) hold considerable promise as BoNT therapeutics and prophylactics, due to their potency and safety. A three-mAb combination has been developed that specifically neutralizes BoNT serotype A (BoNT/A), and a separate three mAb combination has been developed that specifically neutralizes BoNT serotype B (BoNT/B). A six mAb cocktail, designated G03-52-01, has been developed that combines the anti-BoNT/A and anti-BoNT/B mAbs. The pharmacokinetics and neutralizing antibody concentration (NAC) of G03-52-01 has been determined in guinea pigs, and these parameters were correlated with protection against an inhalation challenge of BoNT/A1 or BoNT/B1. Previously, it was shown that each antibody demonstrated a dose-dependent mAb serum concentration and reached maximum circulating concentrations within 48 h after intramuscular (IM) or intraperitoneal (IP) injection and that a single IM injection of G03-52-01 administered 48 h pre-exposure protected guinea pigs against an inhalation challenge of up to 93 LD50s of BoNT/A1 and 116 LD50s of BoNT/B1. The data presented here advance our understanding of the relationship of the neutralizing NAC to the measured circulating antibody concentration and provide additional support that a single IM or intravenous (IV) administration of G03-52-01 will provide pre-exposure prophylaxis against botulism from an aerosol exposure of BoNT/A and BoNT/B.
Journal Article
Vision System for the Mars Sample Return Capture Containment and Return System (CCRS)
The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.
Journal Article