Antiangiogenic Effect of Docetaxel and Everolimus as Individual and Dual-Drug-Loaded Micellar Nanocarriers

Purpose

The in vitro inhibitory effect of Docetaxel (DTX) and Everolimus (EVR) alone and together in poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) nanocarriers on angiogenic processes and acute toxicity in mice was evaluated.

Methods

PEG-b-PLA DTX and/or EVR nanocarriers were characterized for size, drug loading, stability, and drug release. Cell proliferation, tubule formation, and migration studies were performed in Human Umbilical Vein Endothelial Cells (HUVEC) and Maximum Tolerated Doses (MTD) studies were in mice.

Results

DTX and EVR loading was 1.93 and 2.00 mg/mL respectively with similar solubilities for dual-drug micelles. All micelles were below 30 nm with diffusion controlled drug release. The IC₅₀ for DTX, EVR micelles were, 6.80?±?0.67, 18.57?±?2.86 and 0.65?±?0.11 nM respectively with a synergistic inhibitory effect for dual-drug nanocarriers. Significant inhibition of tube formation occurred upon treatment with dual-drug nanocarriers as compared to individual micelles. EVR presence in dual-drug nanocarriers was able to significantly increase the inhibition of the migration of HUVEC by DTX. The MTDs for EVR, DTX and dual-drug micelles were 50, 30 and 20 mg/kg for each respectively.

Conclusions

DTX-EVR dual-drug nanocarriers have antiangiogenic effects in vitro mediated through cellular angiogenic process and possess clinically relevant MTD.     

An Eight-year Retrospective Study in “Flipped” Pharmacokinetics Courses

Objective. To assess the impact on student performance of increased active learning strategies in a foundational pharmacokinetics course and a clinical pharmacokinetics course over an 8-year period.Design. A foundational pharmacokinetics course with a lecture-with-active-learning (LAL) format was redesigned to a recitation-format (REC) using smaller groups of students (ie, the class divided into thirds) and eventually to a team-based learning (TBL) format. The lecture-based clinical pharmacokinetics course was redesigned to a case-based learning (CBL) format to encourage preclass preparation with class time used for application; this course format underwent minor redesigns over an 8-year period. An analysis of covariance (ANCOVA) was performed on examination scores in the clinical course based on foundational course format changes. End-of-semester student evaluations of the course were used as a secondary measure of impact.Assessment. The highest grades in the clinical course were associated with the TBL format within the foundational course compared to LAL format (effect size 0.78). The REC format in the foundational course compared to LAL was associated with higher performance in the clinical course (effect size 0.50). Examination performance in the clinical course had a small increase when the foundational course was transitioned from the REC format to the TBL format (effect size 0.27). There was a trend within the foundational course that overall student ratings of the course decreased with enhanced self-directed learning; there was no change in overall ratings of the clinical course.Conclusion. Increasing the amount of active learning within the foundational pharmacokinetics course increases performance in the clinical course but this increase in performance may be associated with decreases in student evaluations of the foundational course.     

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [¹¹C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [¹¹C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [¹¹C]PHNO binding between the groups at baseline. However, baseline [¹¹C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V_T: 16.5±4 vs 13.7±2.9, p=0.040), a region in which the [¹¹C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V_T) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V_T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [¹¹C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.     

Effect of Thermal Aging on the Mechanical Properties of High Tenacity Polyester Yarn

Textile materials produced from a high tenacity industrial polyester fiber are most widely used in the mechanical rubber goods industry to reinforce conveyor belts, tire cords, and hoses. Reinforcement of textile rubber undergoes a vulcanization process to adhere the textile materials with the rubber and to enhance the physio-mechanical properties of the product. The vulcanization process has an influence on the textile material being used as a reinforcement. In this work, the effects of aging temperature and time on the high tenacity polyester yarn’s mechanical and surface structural properties were investigated. An experiment was carried out on a pre-activated high tenacity polyester yarn of different linear densities, by aging the yarn specimens under various aging temperatures of 140, 160, 200, and 220 °C for six, twelve, and thirty-five minutes of aging time. The tensile properties and surface structural change in the yarns pre- and post-aging were studied. The investigation illustrates that aging time and temperature influence the surface structure of the fiber, tenacity, and elongation properties of the yarn. Compared to unaged yarn, an almost five times higher percentage of elongation was obtained for the samples aged at 220 °C for 6 min, while the lowest tenacity was obtained for the sample subjected to aging under 220 °C for 35 min.     

Fabrication of a Novel Protein Sponge with Dual-Scale Porosity and Mixed Wettability Using a Clean and Versatile Microwave-Based Process

An open-porous protein sponge with mixed wettability is presented made entirely from whey proteins and with promising applications in biomedicine, pharmaceutical, and food industry. The fabrication relies on an additive-free, clean and scalable process consisting of foaming followed by controlled microwave-convection drying. Volumetric heating throughout the matrix induced by microwaves causes fast expansion and elongation of the foam bubbles, retards crust formation and promotes early protein denaturation. These effects counteract collapse and shrinkage typically encountered in convection drying of foams. The interplay of high protein content, tailored gas incorporation and controlled drying result in a dried structure with dual-scale porosity composed of open macroscopic elongated foam bubbles and microscopic pores in the surrounding solid lamellae induced by water evaporation. Due to the insolubility and mixed wettability of the denatured protein network, polar and non-polar liquids are rapidly absorbed into the interconnected capillary system of the sponge without disintegrating. While non-watery liquids penetrate the pores by capillary suction, water diffuses also into the stiff protein matrix, inducing swelling and softening. Consequently, the water-filled soft sponge can be emptied by compression and re-absorbs any wetting liquid into the free capillary space.     

Foundation Piles—A New Feature for Concrete 3D Printers

Foundation piles that are made by concrete 3D printers constitute a new alternative way of founding buildings constructed using incremental technology. We are currently observing very rapid development of incremental technology for the construction industry. The systems that are used for 3D printing with the application of construction materials make it possible to form permanent formwork for strip foundations, construct load-bearing walls and partition walls, and prefabricate elements, such as stairs, lintels, and ceilings. 3D printing systems do not offer soil reinforcement by making piles. The paper presents the possibility of making concrete foundation piles in laboratory conditions using a concrete 3D printer. The paper shows the tools and procedure for pile pumping. An experiment for measuring pile bearing capacity is described and an example of a pile deployment model under a foundation is described. The results of the tests and analytical calculations have shown that the displacement piles demonstrate less settlement when compared to the analysed shallow foundation. The authors indicate that it is possible to replace the shallow foundation with a series of piles combined with a printed wall without locally widening it. This type of foundation can be used for the foundation of low-rise buildings, such as detached houses. Estimated calculations have shown that the possibility of making foundation piles by a 3D printer will reduce the cost of making foundations by shortening the time of execution of works and reducing the consumption of construction materials.     

The Formation of Cr-Al Spinel under a Reductive Atmosphere

In the present work, for the first time, the possibility of formation of CrAl₂O₄ was shown from the equimolar mixture of co-precipitated Al₂O₃ and Cr₂O₃ oxides under a reductive environment. The crystallographic properties of the formed compound were calculated using the DICVOL procedure. It was determined that it has a cubic crystal structure with space group Fd-3m and a unit cell parameter equal to 8.22(3) Å. The formed CrAl₂O₄ is not stable under ambient conditions and easily undergoes oxidation to α-Al₂O₃ and α-Cr₂O₃. The overall sequence of the phase transformations of co-precipitated oxides leading to the formation of spinel structure is proposed.     

FIB-SEM as a Volume Electron Microscopy Approach to Study Cellular Architectures in SARS-CoV-2 and Other Viral Infections: A Practical Primer for a Virologist

The visualization of cellular ultrastructure over a wide range of volumes is becoming possible by increasingly powerful techniques grouped under the rubric “volume electron microscopy” or volume EM (vEM). Focused ion beam scanning electron microscopy (FIB-SEM) occupies a “Goldilocks zone” in vEM: iterative and automated cycles of milling and imaging allow the interrogation of microns-thick specimens in 3-D at resolutions of tens of nanometers or less. This bestows on FIB-SEM the unique ability to aid the accurate and precise study of architectures of virus-cell interactions. Here we give the virologist or cell biologist a primer on FIB-SEM imaging in the context of vEM and discuss practical aspects of a room temperature FIB-SEM experiment. In an in vitro study of SARS-CoV-2 infection, we show that accurate quantitation of viral densities and surface curvatures enabled by FIB-SEM imaging reveals SARS-CoV-2 viruses preferentially located at areas of plasma membrane that have positive mean curvatures.     

Social Restrictions versus Testing Campaigns in the COVID-19 Crisis: A Predictive Model Based on the Spanish Case

The global COVID-19 spread has forced countries to implement non-pharmacological interventions (NPI) (i.e., mobility restrictions and testing campaigns) to preserve health systems. Spain is one of the most severely impacted countries, both clinically and economically. In an effort to support policy decision-making, we aimed to assess the impacts of different NPI on COVID-19 epidemiology, healthcare costs and Gross Domestic Product (GDP). A modified Susceptible-Exposed-Infectious-Removed epidemiological model was created to simulate the pandemic evolution. Its output was used to populate an economic model to quantify healthcare costs and GDP variation through a regression model which correlates NPI and GDP change from 42 countries. Thirteen scenarios combining different NPI were consecutively simulated in the epidemiological and economic models. Both increased testing and stringency could reduce cases, hospitalizations and deaths. While policies based on increased testing rates lead to higher healthcare costs, increased stringency is correlated with greater GDP declines, with differences of up to 4.4% points. Increased test sensitivity may lead to a reduction of cases, hospitalizations and deaths and to the implementation of pooling techniques that can increase throughput testing capacity. Alternative strategies to control COVID-19 spread entail differing economic outcomes. Decision-makers may utilize this tool to identify the most suitable strategy considering epidemiological and economic outcomes.     

Molecular Characterization of Closely Related H6N2 Avian Influenza Viruses Isolated from Turkey,Egypt, and Uganda

Genetic analysis of circulating avian influenza viruses (AIVs) in wild birds at different geographical regions during the same period could improve our knowledge about virus transmission dynamics in natural hosts, virus evolution as well as zoonotic potential. Here, we report the genetic and molecular characterization of H6N2 influenza viruses isolated from migratory birds in Turkey, Egypt, and Uganda during 2017–2018. The Egyptian and Turkish isolates were genetically closer to each other than they were to the virus isolated from Uganda. Our results also suggest that multiple reassortment events were involved in the genesis of the isolated viruses. All viruses contained molecular markers previously associated with increased replication and/or pathogenicity in mammals. The results of this study indicate that H6N2 viruses carried by migratory birds on the West Asian/East African and Mediterranean/Black Sea flyways have the potential to transmit to mammals including humans. Additionally, adaptation markers in these viruses indicate the potential risk for poultry, which also increases the possibility of human exposure to these viruses.