Constant Release Research Articles

HTERT-molecular targeted therapy of ovarian cancer cells via folate-functionalized PLGA nanoparticles co-loaded with MNPs/siRNA/wortmannin

Effective telomerase-molecular targeted cancer therapy might be a promising approach for the efficient treatment of ovarian cancer. Therefore, folate-functionalized PLGA nanoparticles (NPs) were co-loaded with hTERT siRNA, Wortmannin (Wtmn), as a potent PI3K inhibitor, and magnetic nanoparticle (MNPs) as a theranostic agent to gain a multifunctional NPs for targeted drug delivery as well as molecular targeted therapy. 1HNMR, FTIR, DLS, FE-SEM and TEM were applied to characterize the synthesized NPs. In vitro discharge pattern for siRNA and Wtmn from the dual drug-loaded NPs showed an early fast release followed by a constant release up to 200 h. According to the MRI analysis, by increasing the concentration of Fe3O4 in NPs, the weaker T2 signal intensity was enhanced, and a considerable contrast was detected in the MRI images. MTT assay and median-effect analysis showed that the Wtmn/siRNA-loaded MNPs-PLGA-F2 NPs display the most synergistic cytotoxicity on the SKOV-3 ovarian cancer cells. Moreover, the Wtmn/siRNA-loaded MNPs-PLGA-FA NPs could significantly reduce the expression of hTERT, AKT, and p-AKT than the single drug-encapsulated NPs (P < 0.05). Taken together, the findings showed that the multifunctional NPs relying on combinatorial therapy might have considerable potential for effective telomerase-molecular targeted therapy of ovarian cancer.

The Effect of CTAB on Bentonite for Slow Release Fertilizer

Effect of CTAB (Cetyltrimethylammonium Bromide) surfactant concentration on synthesized CTAB modified bentonite and release of NPK has been studied. Besides, the release kinetic model was also determined. Characterizations of the modified bentonite were done using FTIR (Fourier Transform Infra-Red), XRD (X-Ray Diffraction), and SEM (Scanning Electron Microscope). The amount of released NPK was analyzed using Spectrophotometer UV-Visible and AAS (Atomic Absorption Spectrometer). The release kinetics of NPK were determined using zeroth, first, second, pseudo-first, pseudo-second order, and Korsmeyer-Peppas kinetics models. The result of the study showed that CTAB modified bentonite has been successfully synthesized for NPK slow-release fertilizer. The CTAB concentration in CTAB modified bentonite affects the amount of NPK released out of bentonite and also could reduce the release of NPK. Among modified bentonite synthesized, CMB-3 (bentonite modified by CTAB 2 times CEC of bentonite) could reduce NPK release rate in water very well. The release kinetic of NPK followed the pseudo-second order kinetics model, with the release rate constant (k) of N, P, and K were 0.0027, 0.0540, and 0.0169 g mg−1 day−1, respectively.

Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin.

Mutations in the cardiac myosin regulatory light chain (RLC, MYL2 gene) are known to cause inherited cardiomyopathies with variable phenotypes. In this study, we investigated the impact of a mutation in the RLC (K104E) that is associated with hypertrophic cardiomyopathy (HCM). Previously in a mouse model of K104E, older animals were found to develop cardiac hypertrophy, fibrosis, and diastolic dysfunction, suggesting a slow development of HCM. However, variable penetrance of the mutation in human populations suggests that the impact of K104E may be subtle. Therefore, we generated human cardiac myosin subfragment-1 (M2β-S1) and exchanged on either the wild type (WT) or K104E human ventricular RLC in order to assess the impact of the mutation on the mechanochemical properties of cardiac myosin. The maximum actin-activated ATPase activity and actin sliding velocities in the in vitro motility assay were similar in M2β-S1 WT and K104E, as were the detachment kinetic parameters, including the rate of ATP-induced dissociation and the ADP release rate constant. We also examined the mechanical performance of α-cardiac myosin extracted from transgenic (Tg) mice expressing human wild type RLC (Tg WT) or mutant RLC (Tg K104E). We found that α-cardiac myosin from Tg K104E animals demonstrated enhanced actin sliding velocities in the motility assay compared with its Tg WT counterpart. Furthermore, the degree of incorporation of the mutant RLC into α-cardiac myosin in the transgenic animals was significantly reduced compared with wild type. Therefore, we conclude that the impact of the K104E mutation depends on either the length or the isoform of the myosin heavy chain backbone and that the mutation may disrupt RLC interactions with the myosin lever arm domain.

Mapping the routes of the Internet for geopolitics: The case of Eastern Ukraine

In this paper, we argue that data routing is of geopolitical significance. We propose new methodologies to understand and represent the new forms of power rivalries and imbalances that occur within the lower layers of cyberspace, through the analysis of Eastern Ukraine. The Internet is a network of networks where each network is an Autonomous System (ASes). ASes are independent administrative entities controlled by a variety of actors such as governments, companies, and universities. Their administrators have to agree and communicate on paths followed by packets travelling across the Internet, which is made possible by the Border Gateway Protocol (BGP). Agreements between ASes are often confidential but BGP requires neighbouring ASes to interact with each other in order to coordinate routing through the constant release of connectivity update messages. These messages announce the availability (or withdrawal) of a sequence of ASes that can be followed to reach an IP address prefix. We select Eastern Ukraine as a case study as in 2020, six years after the beginning of the war in Donbass, data is available to analyze and map changes to data routing. In our study, we conducted a longitudinal analysis of Ukraine’s connectivity through the capture and analysis of these BGP announcements. Our results show how Donbass ASes progressively migrated from Ukraine’s cyberspace towards Russia, while still sharing connections with Ukrainian ASes. Donbass cyberspace therefore sits at the interface of Ukraine and Russia but has been relegated to the periphery of both networks; it is marginalized from the Ukrainian network but not fully integrated into the Russian network. These evolutions both reflect and affect ongoing geopolitical power rivalries in the physical world and demonstrate their strategic significance. Our methodology can be used to conduct studies in other regions subject to geopolitical open conflicts and to infer the strategies developed by states in anticipation of potential threats.

Curcumin-Loaded Hydrophobic Surface-Modified Hydroxyapatite as an Antioxidant for Sarcopenia Prevention.

Oxidative stress and later-induced chronic inflammation have been reported to play an important role on the progression of sarcopenia. Current treatments for sarcopenia are mainly administered to patients whom sarcopenia already developed. However, there has been no promising results shown in therapy. Therefore, the development of therapeutic and preventive strategies against sarcopenia would be necessary. Curcumin is a traditional medicine that possesses anti-inflammatory and antioxidative properties. In the present study, hydroxyapatite was subjected to hydrophobic surface modifications for curcumin loading (Cur-SHAP). It was, subsequently, utilized for delivery to the patient’s body via intramuscular injection in order to achieve constant release for more than 2 weeks, preventing the progression of the sarcopenia or even leading to recovery from the early stage of the illness. According to the results of WST-1, LIVE/DEAD, DCFDA, and gene expression assays, Cur-SHAP exhibited good biocompatibility and showed great antioxidant/anti-inflammatory effects through the endocytic pathway. The results of the animal studies showed that the muscle endurance, grip strength, and fat/lean mass ratio were all improved in Cur-SHAP-treated rats from LPS-induced sarcopenia. In summary, we successfully synthesized hydrophobic surface modification hydroxyapatite for curcumin loading (Cur-SHAP) and drug delivery via the IM route. The LPS-induced sarcopenia rats were able to recover from disease after the Cur-SHAP treatment.

Nanophytosome as a promising carrier for improving cumin essential oil properties

The health benefits of nanoparticles in preservation of sensitive compounds such as essential oil (EO) to overcome its application difficulties, e.g., instability, low water solubility, and oral bioavailability. In this study, CEO-loaded nanophytosomes (NP) were prepared using a thin layer hydration technique in different ratios of CEO to phosphatidylcholine (PC). Colloidal properties of NP such as particle size, ζ-potential, polydispersity index (PDI), encapsulation efficiency (EE), CEO-PC ionic interactions, antioxidant activity, turbidity, stability and release behavior were investigated. CEO-NP showed good characteristics, i.e., d<100 nm particle sizes, low size distribution (PDI<0.3), EE>90% and relatively uniform size (unchanged size and turbidity during one month of storage). The ζ-potential changed from +9 mV in the blank (B) NP to -19 mV in encapsulated EO. EO-encapsulated in NP showed a relative constant release pattern. About 88% of free CEO remained stable in simulated gastric fluid at pH 2 while 95% was eliminated during 2.5 h in simulated intestinal fluid at pH 7. However, NP improved the stability of CEO 6.7 times in SIF. This study indicated that the release of bioactive compounds from NP can be efficiently reduced using encapsulation into NP, and offered CEO-loaded NP as an efficient candidate for food and beverage fortification to produce functional foods.

LES analysis of fire source aspect ratio effects on fire-wind enhancement

Enhancement of wind by bushfire, referred to as bushfire-wind enhancement phenomenon, causes damages to buildings located in bushfire-prone areas by increasing pressure load around the structures. This study focuses on the effects of point source aspect ratio (AR) on the wind enhanced by fire. FireFOAM solver of OpenFOAM platform is used to perform Large Eddy Simulation analysis for different fire source aspect ratios under two different fire source conditions: (i) identical fire intensity (fire heat release rate per unit area) and (ii) identical fire heat release rate conditions. Simulations were performed for three different fire source aspect ratios under these fire source boundary conditions. An appropriate normalization group based on fire source hydraulic diameter was introduced for fire-induced pressure gradient to explain the variation of wind enhancement with fire source aspect ratio. The results reveal that under a constant fire intensity condition, increasing the fire source aspect ratio causes a higher normalized fire-induced pressure gradient which leads to more intensified wind enhancement. In contrast, the increase of fire source aspect ratio while fire heat release rate is kept constant culminates in a reduction in the normalized fire-induced pressure gradient, reducing wind enhancement. Moreover, with the increase of the fire source aspect ratio, the area of counter-rotating vortices (CRV) where maximum wind enhancement occurs is expanded. The results also show that with the increase of fire source aspect ratio, the length of flame attachment to the ground immediately downstream of fire increases. In addition to the longitudinal wind enhancement, the effects of fire source aspect ratio on vertical velocity were also analyzed based on the Richardson number defined by hydraulic diameter and flow reference velocity. The effects of the aspect ratio on flame length were also studied. It was shown as a result of the increase of aspect ratio for one unit, flame length increases by approximately 14% and reduces by 7% under constant fire intensity and constant fire heat release rate condition, respectively.

Calibration of silicone for passive sampling of semivolatile organic contaminants in indoor air

Semivolatile organic compounds (SVOCs) are mostly man-made chemicals that distribute between the gas and solid phase in the environment. Many of them could pose harm to people and therefore it is important to know their concentrations in the indoor environment to evaluate the related risks. Inhalation exposure can be assessed using passive sampling. In this study, we employed silicone elastomer as a passive sampler for monitoring gaseous polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs) in indoor air. We performed a sampler calibration study in which samplers consisting of 0.5 mm thick silicone sheets with a total surface area of 300 cm2 were exposed to indoor air in a university lecture theatre for up to 56 days. Uptake kinetics of SVOCs was studied by collecting 2 samplers every week. The results were used to develop a model based on mass transfer theory that can be used to estimate the air sampling rate RS as a function of compound’s molecular volume. We examined release kinetics of performance reference compounds that covered a broad range of silicone-air partition coefficient (log KSA 5.95–9.49) and investigated a hypothesis of isotropic exchange kinetics, i.e. equality of rate constants for uptake and release, of SVOCs. PCBs and OCPs concentration in air calculated from contaminant amounts accumulated in passive samplers were in good agreement with those determined by active sampling running simultaneously during the entire study. The use of performance reference compounds is suitable for in situ passive sampler calibration.

Photo-degradation of P-Nitro Toluene Using Modified Risk Assessment of Gasoline Storage Unit of National Iranian Oil Product Distribution Company using PHAST Software

The present study evaluates the risk of the gasoline tank of the National Iranian Oil Product Distribution Company (NIOPDC) in Sari region using process hazard analysis software tool (PHAST) and according to the environmental and process data of the unit. The consequences of different scenarios such as small and medium leakage, constant release rate and complete rupture were modeled and then the range of each one was obtained according to the intensity of radiation or pressure wave and the safe distances of each was determined. Due to the consequences of the explosion, the worst results were related to the weather conditions of 2/3 F for 4700, 2400, and 2300 meters, respectively. Also, based on eruptive and sudden fire data, the intensity of radiation which corresponds to the immediate death or destruction of equipment was seen in climatic conditions of (2/3 F and 4/1 D), at intervals of 180 and 160 meters distances, respectively. In these two weather conditions flammability intervals were 10520 and 450 meters. Then, by combining the severity of these accidents with the distribution of the population and the probability of their occurrence, the level of risk for these storages was determined.

A New Approach to the Dissolution Tests Management to Obtain Kinetic and Thermodynamic Data: Release of a Model Drug from Glyceryl Behenate Matrix Tablets

AbstractThis study is focused on the use of glyceryl behenate as a lipophilic excipient of matrix tablets providing controlled drug release. The aim of this study is to evaluate activation energy (EA) and changes of the thermodynamic parameters (ΔH, ΔS, ΔG) of a dissolution process. These values, which have not yet been published, can lead to better understanding of a drug release mechanism and can extend the use options of glyceryl behenate in the pharmaceutical industry. Values of ΔH, ΔS, ΔG and EA, providing an overall thermodynamic view on the studied matrix tablets, are evaluated based on the temperature‐dependences of the release rate constant of a model drug (temperature range 25 ‐ 45 °C). The studied lipophilic matrix tablets contain 10% to 50% of glyceryl behenate. Dissolution testing is carried out in an aqueous solution of HCl with addition of NaCl (pH1.2). Positive values of ΔH in the range of 3.83 to 56.13 kJ mol‐1 and positive values of ΔG indicate that the dissolution of the studied glyceryl behenate matrix tablets is an endothermic process which does not proceed spontaneously (in a temperature range of 25 ‐ 45 °C). The negative slope of the linear curves of enthalpy‐entropy compensation confirms the entropy‐driven dissolution.Practical Applications: A better understanding of the dissolution process is an important aspect, e.g., in the field of drug formulation strategy. In this study, it is confirmed that the influence of temperature on the model drug release rate is negligible for tablets containing more than 40% of glyceryl behenate. It is an important result for drug design due to the reduction of risk of a possible dose dumping effect induced by temperature and the prevention of in vivo therapeutic failure.

Evaluation of in-vitro drug release of polyvinylcyclohexane carbonate as a CO2-derived degradable polymer blended with PLA and PCL as drug carriers

Drug delivery via polymers provides advantages such as controlled release over time and constant release rate. Polyvinylcyclohexane carbonate (PVCHC) is a new CO2-derived biodegradable polymer with potential biomedical applications. In this study, biodegradable polymers polycaprolactone (PCL), polylactic acid (PLA), and for the first time, PVCHC, as well as the mixed polymeric matrix of PCL-PVCHC and PLA-PVCHC, were tested as carriers for hydrophilic drugs acetaminophen and clindamycin. The polymeric carriers were prepared as matrix systems by dispersing the polymer powder in acetone solvent and finally by evaporating the matrix's solvent. Thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and FT-IR spectroscopy techniques were employed to characterize the properties of the polymeric drug-carrier matrices. In vitro drug release profiles of acetaminophen and clindamycin in saline phosphate buffer (PBS) and at a temperature of 37 °C were analyzed by UV–Vis spectroscopic technique. The release percentage was calculated at specific time intervals over 24 h. The highest release efficiency for PCL-acetaminophen, PCL-PVCHC-acetaminophen, PLA-acetaminophen, PCL-clindamycin, PLA-clindamycin, and PLA-PVCHC-clindamycin was calculated as 38%, 29%, 39%, 96%, 95%, and 40%, respectively. The kinetic behavior of the drug release was investigated by fitting the release data to the Zero-order model, First-order model, Higuchi model, and Korsmeyer-Peppas model, among which the Korsmeyer-Peppas model had the best agreement with the drug release results.

Plant exposure to herbivore-induced plant volatiles: a sustainable approach through eliciting plant defenses

Modern agricultural policies across the globe are committed to a significant reduction in chemical pesticide dependency; however, pest management strategies are still based on the use of synthetic pesticides. There is an urgent need to find new, sustainable and biorational tools for pest management programs. Plants communicate with each other and activate defense mechanisms against pests using herbivore-induced plant volatiles (HIPVs). The use of such HIPVs could be an ecologically sustainable alternative. However, as of now, there have been no comprehensive studies on HIPVs, from selection to practical use in industry production. Here, we describe the first case of an HIPV successfully implemented for pest control under commercial greenhouse conditions. In this research, tomato plants induced with (Z)-3-hexenyl propanoate [(Z)-3-HP] were less susceptible to the attack of economically important tomato pests. We designed and calibrated polymeric dispensers for the constant release of (Z)-3-HP. These dispensers maintained commercial tomato plant defenses activated for more than two months reducing herbivore pest damage without reducing plant productivity. Transcriptomic and metabolomic analyses of plants induced with (Z)-3-HP confirmed that genes involved in specialized anti-herbivore defense were up-regulated, resulting in an increased production of fatty acid-derived compounds, activation of the lipoxygenase pathway and accumulation of specific defense compounds. Our work demonstrates under commercial greenhouse conditions how the release of HIPVs as elicitors of plant defenses via designed polymeric dispensers can be successfully integrated as a new biorational and sustainable tool for pest control.

TEMPO-Oxidized Cellulose Beads as Potential pH-Responsive Carriers for Site-Specific Drug Delivery in the Gastrointestinal Tract.

The development of controlled drug delivery systems based on bio-renewable materials is an emerging strategy. In this work, a controlled drug delivery system based on mesoporous oxidized cellulose beads (OCBs) was successfully developed by a facile and green method. The introduction of the carboxyl groups mediated by the TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyradical)/NaClO/NaClO2 system presents the pH-responsive ability to cellulose beads, which can retain the drug in beads at pH = 1.2 and release at pH = 7.0. The release rate can be controlled by simply adjusting the degree of oxidation to achieve drug release at different locations and periods. A higher degree of oxidation corresponds to a faster release rate, which is attributed to a higher degree of re-swelling and higher hydrophilicity of OCBs. The zero-order release kinetics of the model drugs from the OCBs suggested a constant drug release rate, which is conducive to maintaining blood drug concentration, reducing side effects and administration frequency. At the same time, the effects of different model drugs and different drug-loading solvents on the release behavior and the physical state of the drugs loaded in the beads were studied. In summary, the pH-responsive oxidized cellulose beads with good biocompatibility, low cost, and adjustable release rate have shown great potential in the field of controlled drug release.

Immunological Endotyping of Chronic Critical Illness After Severe Sepsis

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early “cytokine or genomic storm,” but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed.

Customizable drug tablets with constant release profiles via 3D printing technology

Medicine should ideally be personalized as each individual has his/her own unique biological, physical, and medical dispositions. Medicine can be personalized by customizing drug tablets with the specific drug dosages, release durations, and combinations of multiple drugs. This study presents a method for fabricating drug tablets with customizable dosages, durations, and combinations of multiple drugs by using the 3D printing technology. The method focuses on fabricating customizable drug tablets with a very simple structure for delivering the constant release profile due to its importance in treatment (i.e., the drug may produce side effects if too much is released andmay not have therapeutic value is too little is released). The method is simple: it involves first printing a template using the 3D printer and fabricating the drug tablet via the template. The tablets are customized by varying the amount of excipient used, the height of the tablet, and the numberand amount of drugs used. Three different common drugs (i.e., paracetamol, phenylephrine HCl and diphenhydramine HCl) and FDA-approved excipients are studied. The simplicity of the structure of the tablet and method via templating allows the fabrication of these fully customizable drug tablets to be easily performed, low-cost, efficient, and safe for consumption. These features enable the customizable tablets to be made widely accessible to the public; hence, the concept of personalized medicine can be realized.

Electrospun composite fibers of PLA/PLGA blends and mesoporous silica nanoparticles for the controlled release of gentamicin sulfate

With the objective of developing a localized gentamicin sulfate (GS) delivery system with a controlled release kinetics for the prevention/management of osteomyelitis, composite electrospun fibers composed of poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) blends and GS loaded mesoporous silica nanoparticles (npSiGS) were prepared (PLA/PLGA: 1:3, 1:1, 3:1 w/w). GS was loaded into silica nanoparticles by adsorption, using a concentrated GS solution, and npSiGS were dispersed in the polymer solutions and immobilized in the polymeric matrix by occlusion, during fibers formations. For comparison, non-composite fibers with the same blend compositions containing GS simply dispersed in the polymeric phase were also produced. GS loaded nanoparticles were characterized by nitrogen adsorption/desorption isotherms and GS loading was quantified by thermogravimetric analysis. The morphology of the electrospun fibers, assessed by SEM, revealed that npSiGS were embedded along the composite fibers, some in the form of small aggregates. In vitro release studies showed that composite fibers exhibited lower initial burst releases and slower release kinetics, dependent on blend composition. Composite fibers with PLGA as the major component (25PLA-npSiGS) had the fastest release kinetics, while fibers with equal amounts of both polymers (50PLA-npSiGS) or with PLGA as the minor component (75PLA-npSiGS) had slower release kinetics, with constant GS release rates after the first day. These results suggest that PLA/PLGA blend composition can be manipulated to obtain composite fibers with a controlled and tailored GS release for at least three weeks. Finally, the antibacterial effect against Staphylococcus aureus of all produced fibers containing GS was confirmed by a disk diffusion method.

Inclusion complex of clausenidin with hydroxypropyl-β-cyclodextrin: Improved physicochemical properties and anti-colon cancer activity

The long-term objective of the present study was to prepare, physicochemically characterize and determine the anticancer of clausenidin/hydroxypropyl-β-cyclodextrin (Clu/HPβCD) inclusion complex. We used differential scanning calorimetry, X-ray diffractometer, fourier transform infrared spectroscopy, ultraviolet–visible spectrophotometer and 13C and 1H nuclear magnetic resonance followed by in vitro anticancer assays. The orientation and intermolecular interactions of Clausenidin within cyclodextrin cavity were also ascertained by molecular docking simulation accomplished by AutoDock Vina. The guest molecule was welcomed by the hydrophobic cavity of the host molecule and sustained by hydrogen bond between host/guest molecules. The constant drug release with time, and increased solubility were found after successful complexation with HPβCD as confirmed by physicochemical characterizations. Clausenidin had greater cytotoxic effect on colon cancer HT29 cells when incorporated into HPβCD cavity than dissolved in DMSO. Also, from a comparison of cell viability between normal and cancer cells, a reduced side effect was observed. The Clu/HPβCD inclusion complex triggered reactive oxygen species-mediated cytotoxicity in HT29 cells. The inclusion complex-treated HT29 cells showed cell cycle arrest and death by apoptosis associated with caspases activation. The presence of HPβCD seems to aid the anticancer activity of clausenidin.

In vitro to Clinical Translation of Combinatorial Effects of Doxorubicin and Abemaciclib in Rb-Positive Triple Negative Breast Cancer: A Systems-Based Pharmacokinetic/Pharmacodynamic Modeling Approach.

BackgroundDoxorubicin (DOX) and its pegylated liposomal formulation (L_DOX) are the standard of care for triple-negative breast cancer (TNBC). However, resistance to DOX often occurs, motivating the search for alternative treatment approaches. The retinoblastoma protein (Rb) is a potential pharmacological target for TNBC treatment since its expression has been associated with resistance to DOX-based therapy.MethodsDOX (0.01–20 μM) combination with abemaciclib (ABE, 1–6 μM) was evaluated over 72 hours on Rb-positive (MDA-MB-231) and Rb-negative (MDA-MB-468) TNBC cells. Combination indices (CI) for DOX+ABE were calculated using Compusyn software. The TNBC cell viability time-course and fold-change from the control of phosphorylated-Rb (pRb) protein expression were measured with CCK8-kit and enzyme-linked immunosorbent assay. A cell-based pharmacodynamic (PD) model was developed, where pRb protein dynamics drove cell viability response. Clinical pharmacokinetic (PK) models for DOX, L_DOX, and ABE were developed using data extracted from the literature. After scaling cancer cell growth to clinical TNBC tumor growth, the time-to-tumor progression (TTP) was predicted for human dosing regimens of DOX, ABE, and DOX+ABE.ResultsDOX and ABE combinations were synergistic (CI<1) in MDA-MB-231 and antagonistic (CI>1) in MDA-MB-468. The maximum inhibitory effects (Imax) for both drugs were set to one. The drug concentrations producing 50% of Imax for DOX and ABE were 0.565 and 2.31 μM (MDA-MB-231) and 0.121 and 1.61 μM (MDA-MB-468). The first-orders rate constants of abemaciclib absorption (ka) and doxorubicin release from L_DOX (kRel) were estimated at 0.31 and 0.013 h−1. Their linear clearances were 21.7 (ABE) and 32.1 L/h (DOX). The estimated TTP for intravenous DOX (75 mg/m2 every 21 days), intravenous L_DOX (50 mg/m2 every 28 days), and oral ABE (200 mg twice a day) were 125, 31.2, and 8.6 days shorter than drug-free control. The TTP for DOX+ABE and L_DOX+ABE were 312 days and 47.5 days shorter than control, both larger than single-agent DOX, suggesting improved activity with the DOX+ABE combination.ConclusionThe developed translational systems-based PK/PD model provides an in vitro-to-clinic modeling platform for DOX+ABE in TNBC. Although model-based simulations suggest improved outcomes with combination over monotherapy, tumor relapse was not prevented with the combination. Hence, DOX+ABE may not be an effective treatment combination for TNBC.

Effects of span-depth ratios on the energy release rate for three-point bending beams

The effects of span-depth ratios on the energy release rate for three-point bending beams were examined. Expressions for the energy release rate for three-point bending specimens with various span-depth ratios were developed using linear interpolation method. The double-G fracture parameters were calculated through tests of three-point bending beams with the same span (800 mm) but various depths (100 mm, 150 mm, 200 mm, 250 mm and 300 mm) and the findings in literature. Results indicate that (1) with increasing the span-depth ratio, an almost constant initial fracture energy release rate was obtained, and slight decrease tendency of the unstable energy release rate was observed; (2) The empirical relationship between the initial fracture energy and total fracture energy suggested in size effect model was conformed using the unstable fracture energy release rate which was the same as the initial fracture energy; (3) Equivalence between double-G and double-K fracture model was verified; (4) Moreover, the analytical results of unstable fracture energy release rate exhibited a good consistency with the experimental ones, which were insensitive to the softening function.

Controlled Odor Mimic Permeation Systems for Olfactory Training and Field Testing.

The Controlled Odor Mimic Permeation System (COMPS) was developed to provide a convenient field testing method of odor delivery at controlled and reproducible rates. COMPS are composed of an odorant of interest on an absorbent material sealed inside of a permeable polymer bag. The permeable layer allows for a constant release of the odorant over a given amount of time. The permeable bag is further stored in a secondary, impermeable bag. The double-containment procedure allows for equilibration of the odorant from the permeable bag but within the impermeable outer layer, resulting in an instant and reproducible source of odorant vapor upon removal from the outer packaging. COMPS are used in both olfactory testing for experimental scenarios and for olfactory detection training, such as with detection canines. COMPS can be used to contain a wide range of odorants (e.g., narcotics powders) and provide a controlled release of the associated odorants. Odor availability from COMPS is expressed in terms of permeation rate (i.e., the rate of the odorant vapor released from a COMPS per unit time) and is typically measured by gravimetric means. The permeation rate for a given mass or volume of odorant can be adjusted as needed by varying the bag thickness, surface area, and/or polymer type. The available odor concentration from a COMPS can also be measured by headspace analysis techniques such as solid phase microextraction with gas chromatography/mass spectrometry (SPME-GC/MS).