A Quantitative Pharmacology Model of Exosome-Mediated Drug Efflux and Perturbation-Induced Synergy

Exosomes, naturally occurring vesicles secreted by cells, are undergoing development as drug carriers. We used experimental and computational studies to investigate the kinetics of intracellular exosome processing and exosome-mediated drug efflux and the effects of exosome inhibition. The experiments used four human-breast or ovarian cancer cells, a cytotoxic drug paclitaxel (PTX), two exosome inhibitors (omeprazole (OME), which inhibits exosome release, and GW4869 (GW), which inhibits synthesis of sphingolipid ceramide required for exosome formation), LC-MS/MS analysis of PTX levels in exosomes, and confocal microscopic study of endocytic transport (monitored using fluorescent nanoparticles and endocytic organelle markers). In all four cells, exosome production was enhanced by PTX but diminished by OME or GW (p < 0.05); the PTX enhancement was completely reversed by OME or GW. Co-treatment with OME or GW simultaneously reduced PTX amount in exosomes and increased PTX amount and cytotoxicity in exosome-donor cells (corresponding to >2-fold synergy as indicated by curve shift and uncertainty envelope analyses). This synergy is consistent with the previous reports that OME co-administration significantly enhances the taxane activity in tumor-bearing mice and in patients with triple negative metastatic breast cancer. The experimental results were used to develop a quantitative pharmacology model; model simulations revealed the different effects of the two exosome inhibitors on intracellular PTX processing and subcellular distribution.

Relativistic Optimization Force Concept for gEUD Biological Optimization and Novel a-value Selection Viewpoint

Generalized equivalent uniform dose (gEUD) optimization is a biological optimization method used for intensity modulated radiation therapy (IMRT). Although parametric analyses have been widely reported, the use of parameter a-value in the optimization method remains elusive. This study aims to clarify the mathematical characteristics of the gEUD and to provide effective a-value selection. The gEUD is typically obtained using a differential dose volume histogram (DVH). This can be rewritten using a cumulative DVH (cDVH) and applied to variational analysis. The equivalence between the gEUD and the dose is then obtained; a low or high a-value corresponds to a wide or narrow dose range of optimization, respectively. Next, we focused on the gEUD curve behavior against a-value shifts and it retained its curve characteristics despite optimization. Using differential geometry, this curve shift can be considered as a geodesic deviation between pre- and post-optimization by a relativistic optimization force. The total action enacted by the force includes the curvature of the gEUD curve. This idea provides a novel viewpoint that the curvature of the gEUD curve is influenced by the optimization effect. The curvature stationary point of the gEUD curve (the vertex point, a = a_k) is expected to be a special point that leads to effective a-value selection. Eleven head and neck patient cases were used to verify the curvature effect. We used the Photon Optimizer (PO) of Eclipse for optimization and focused the upper gEUD to simplify the dose constraint for the organ at risk (OAR) that requires balancing of the overlapped planning target volume(PTV). Static seven-field IMRT was used for optimization, changing the a-value of the affected side of the parotid and retaining PTV D95% = 70Gy at the different a-value optimization. Finally, cDVH shift (ΔDVH), gEUD shift (ΔgEUD), their average values, and a_k were evaluated. The a = a_k optimization showed an intermediate effect of lower and higher a-values on ΔDVH, ΔgEUD, and their averages. “Lower” (a=0.5/1.0/2.0/3.0), “middle” (a=4.0/5.0/6.0/8.0/10/a_k), and “higher” (a=12/15/20/40) were defined using a=a_k as a base point. Lower a-value optimization was effective for the low-dose region and weakly affected the whole range of cDVH weight. In contrast, higher a-value optimization addressed the high-dose region and strongly affected the high-dose range of the cDVH weight as theoretically predicted. In addition, the middle range of the a-value optimization induced a decrease in the clinically important middle-to-high dose range, which retained the high dose of the PTV. Interestingly, the average ΔDVH and ΔgEUD corresponded exponentially to the curvature and the gradient of the gEUD curve. Using our relativistic optimization force concept, gEUD optimization is represented as a gEUD curve shift, highlighting that the curvature of the gEUD curve is the essence of gEUD optimization. The curvature stationary point (a = a_k), namely the vertex point of the gEUD curve, played an intermediate role in the low-to-high a-value condition. We can effectively select a lower/middle/higher a-value from a base point of a = a_k under clinically complex optimization situation.

Defect Analysis and Reliability Characteristics of (HfZrO4)1−x(SiO2)x High-κ Dielectrics

Hafnium zirconium silicon oxide ((HfZrO4)1−x(SiO2)x) materials were investigated through the defect analysis and reliability characterization for next generation high-κ dielectric. Silicate doped hafnium zirconium oxide (HfZrO4) films showed a reduction of negative flat-band voltage (Vfb) shift compared to pure HfZrO4. This result was caused by a decrease in donor-like interface traps (Dit) and positive border traps (Nbt). As the silicon oxide (SiO2) content increased, the Vfb was shifted in the positive direction from −1.23 to −1.10 to −0.91 V and the slope of the capacitance–voltage (C–V) curve increased. The nonparallel shift of the C–V characteristics was affected by the Dit, while the Nbt was responsible for the parallel C–V curve shift. The values of Dit reduced from 4.3 × 1011, 3.5 × 1011, and 3.0 × 1011 cm−2eV−1, as well as the values of Nbt were decreased from 5.24, 3.90 to 2.26 × 1012 cm−2. Finally, reduction of defects in the HfZrO4-base film with an addition of SiO2 affected the gate oxide reliability characteristics, such as gate leakage current (JG), bias temperature stress instability (BTSI), and time dependent gate dielectric breakdown (TDDB).

Quantitative assessment of the airway response to bronchial tests based on a spirometric curve shift

<i>Objective:</i> Although spirometry is the most common pulmonary function test, there is no method to quantitatively infer about airway resistance or other properties from the flow-volume curves. Recently, an identifiable inverse model for forced expiration was proposed, as well as the idea to deduce changes in airway resistances and compliances from spirometric curve evolution. The aim of this work was to combine the above advances in a method for assessing the airway response to bronchial tests from a spirometric curve shift. <i>Methods:</i> The approach is based on the differential measurement of the degree, site of maximal effect and width of changes, further recalculated into relative changes in the distribution of airway resistances (<i>δR_g</i>) and compliances (<i>δC_g</i>) along the bronchial tree. To this end, appropriate models were identified using the pre- and post-test spirometry data. The accuracy was validated using sets of data simulated by the anatomy and physiology based models. Finally, the method was used to analyze the bronchodilation tests of three asthmatic subjects. <i>Results:</i> The expected errors in assessing the degree, site and width of changes in the zone of conducting airways were 6.3%, 2.4 generations and 22%, respectively, and for <i>δR_g</i> and <i>δC_g</i> were 5-10% and 13-16%, respectively. The analyses of clinical data indicated a significant reduction in resistances and an increase in compliances of airway generations 8-12, consistent with clinical knowledge. <i>Conclusion:</i> An unprecedented method to plausibly transforming the spirometry data into the site and degree of changes in airway properties has been proposed. <i>Significance:</i> The method can be used to deduce about the effects of bronchial tests, as well as to monitor changes in the airways between visits or to investigate how inhaled pharmaceuticals affect the bronchi.

Quantitative assessment of the airway response to bronchial tests based on a spirometric curve shift

<i>Objective:</i> Although spirometry is the most common pulmonary function test, there is no method to quantitatively infer about airway resistance or other properties from the flow-volume curves. Recently, an identifiable inverse model for forced expiration was proposed, as well as the idea to deduce changes in airway resistances and compliances from spirometric curve evolution. The aim of this work was to combine the above advances in a method for assessing the airway response to bronchial tests from a spirometric curve shift. <i>Methods:</i> The approach is based on the differential measurement of the degree, site of maximal effect and width of changes, further recalculated into relative changes in the distribution of airway resistances (<i>δR_g</i>) and compliances (<i>δC_g</i>) along the bronchial tree. To this end, appropriate models were identified using the pre- and post-test spirometry data. The accuracy was validated using sets of data simulated by the anatomy and physiology based models. Finally, the method was used to analyze the bronchodilation tests of three asthmatic subjects. <i>Results:</i> The expected errors in assessing the degree, site and width of changes in the zone of conducting airways were 6.3%, 2.4 generations and 22%, respectively, and for <i>δR_g</i> and <i>δC_g</i> were 5-10% and 13-16%, respectively. The analyses of clinical data indicated a significant reduction in resistances and an increase in compliances of airway generations 8-12, consistent with clinical knowledge. <i>Conclusion:</i> An unprecedented method to plausibly transforming the spirometry data into the site and degree of changes in airway properties has been proposed. <i>Significance:</i> The method can be used to deduce about the effects of bronchial tests, as well as to monitor changes in the airways between visits or to investigate how inhaled pharmaceuticals affect the bronchi.