Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment

Preparation of polycaprolactone nanoparticles via supercritical carbon dioxide extraction of emulsions

Polycaprolactone (PCL) nanoparticles were produced via supercritical fluid extraction of emulsions (SFEE) using supercritical carbon dioxide (scCO2). The efficiency of the scCO2 extraction was investigated and compared to that of solvent extraction at atmospheric pressure. The effects of process parameters including polymer concentration (0.6–10% w/w in acetone), surfactant concentration (0.07 and 0.14% w/w) and polymer-to-surfactant weight ratio (1:1–16:1 w/w) on the particle size and surface morphology were also investigated. Spherical PCL nanoparticles with mean particle sizes between 190 and 350 nm were obtained depending on the polymer concentration, which was the most important factor where increase in the particle size was directly related to total polymer content in the formulation. Nanoparticles produced were analysed using dynamic light scattering and scanning electron microscopy. The results indicated that SFEE can be applied for the preparation of PCL nanoparticles without agglomeration and in a comparatively short duration of only 1 h

After DART: Using the First Full-scale Test of a Kinetic Impactor to Inform a Future Planetary Defense Mission

NASA’s Double Asteroid Redirection Test (DART) is the first full-scale test of an asteroid deflection technology. Results from the hypervelocity kinetic impact and Earth-based observations, coupled with LICIACube and the later Hera mission, will result in measurement of the momentum transfer efficiency accurate to ∼10% and characterization of the Didymos binary system. But DART is a single experiment; how could these results be used in a future planetary defense necessity involving a different asteroid? We examine what aspects of Dimorphos’s response to kinetic impact will be constrained by DART results; how these constraints will help refine knowledge of the physical properties of asteroidal materials and predictive power of impact simulations; what information about a potential Earth impactor could be acquired before a deflection effort; and how design of a deflection mission should be informed by this understanding. We generalize the momentum enhancement factor β, showing that a particular direction-specific β will be directly determined by the DART results, and that a related direction-specific β is a figure of merit for a kinetic impact mission. The DART β determination constrains the ejecta momentum vector, which, with hydrodynamic simulations, constrains the physical properties of Dimorphos’s near-surface. In a hypothetical planetary defense exigency, extrapolating these constraints to a newly discovered asteroid will require Earth-based observations and benefit from in situ reconnaissance. We show representative predictions for momentum transfer based on different levels of reconnaissance and discuss strategic targeting to optimize the deflection and reduce the risk of a counterproductive deflection in the wrong direction

Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models

Whole-cell models that explicitly represent all cellular components at the molecular level have the potential to predict phenotype from genotype. However, even for simple bacteria, whole-cell models will contain thousands of parameters, many of which are poorly characterized or unknown. New algorithms are needed to estimate these parameters and enable researchers to build increasingly comprehensive models. We organized the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 8 Whole-Cell Parameter Estimation Challenge to develop new parameter estimation algorithms for whole-cell models. We asked participants to identify a subset of parameters of a whole-cell model given the model’s structure and in silico “experimental” data. Here we describe the challenge, the best performing methods, and new insights into the identifiability of whole-cell models. We also describe several valuable lessons we learned toward improving future challenges. Going forward, we believe that collaborative efforts supported by inexpensive cloud computing have the potential to solve whole-cell model parameter estimation

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study

BACKGROUND: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. METHODS: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. FINDINGS: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. INTERPRETATION: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. FUNDING: None

Achievement of the planetary defense investigations of the Double Asteroid Redirection Test (DART) mission

NASA's Double Asteroid Redirection Test (DART) mission was the first to demonstrate asteroid deflection, and the mission's Level 1 requirements guided its planetary defense investigations. Here, we summarize DART's achievement of those requirements. On 2022 September 26, the DART spacecraft impacted Dimorphos, the secondary member of the Didymos near-Earth asteroid binary system, demonstrating an autonomously navigated kinetic impact into an asteroid with limited prior knowledge for planetary defense. Months of subsequent Earth-based observations showed that the binary orbital period was changed by –33.24 minutes, with two independent analysis methods each reporting a 1σ uncertainty of 1.4 s. Dynamical models determined that the momentum enhancement factor, β, resulting from DART's kinetic impact test is between 2.4 and 4.9, depending on the mass of Dimorphos, which remains the largest source of uncertainty. Over five dozen telescopes across the globe and in space, along with the Light Italian CubeSat for Imaging of Asteroids, have contributed to DART's investigations. These combined investigations have addressed topics related to the ejecta, dynamics, impact event, and properties of both asteroids in the binary system. A year following DART's successful impact into Dimorphos, the mission has achieved its planetary defense requirements, although work to further understand DART's kinetic impact test and the Didymos system will continue. In particular, ESA's Hera mission is planned to perform extensive measurements in 2027 during its rendezvous with the Didymos–Dimorphos system, building on DART to advance our knowledge and continue the ongoing international collaboration for planetary defense