1,798 research outputs found
Role of Membrane Transporters in Drug Delivery, Drug Disposition And Drug-Drug Interactions
Title from PDF of title page, viewed on (February 12, 2015)Dissertation advisor: Ashim K. MitraVitaIncludes bibliographic references (pages 241-274)Thesis (Ph. D.) -- School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2014Tissues such as liver, kidney, brain and intestine expresses membrane transporters which play a vital role in drug absorption, distribution, metabolism and excretion. Understanding of functionality and molecular expression of drug transporters can prove to be of utmost importance in drug delivery or drug design by targeting specific transporter proteins. It’s a well-known fact that drug transporters play an important role in governing drug disposition which act as potential piece of information during the drug discovery and development process. By exploring the transporter functionality chances of delivering a therapeutic agent to the target organ enhances. Transporter targeted drug delivery helps in improving the bioavailability, controlling the elimination process and also avoid distribution to non-specific organs, hence diminishes the odds of toxic adverse effects. It is always suitable to choose a potential molecule which may or may not interact with the membrane transporters, depending on whether such an interaction is of any use or not. Activity of individual transport process can be examined by exploring the expression system of transporters. Therapeutic efficacy many important drugs, directly or indirectly, get affected due to genetic polymorphisms and drug-drug interactions involving membrane transporters which ultimately effects the pharmacokinetics of a drug molecule. During the drug discovery and development process, knowledge about the contribution of these transporters towards interindividual differences by regulating drug absorption, distribution, metabolism and excretion will act as an important tool. The objective of this dissertation project was to understand the role of hepatic uptake transporters (OATP-1B1 and -1B3) in governing the disposition of tyrosine kinase inhibitors (TKIs). Since selected TKIs are the substrates and/or inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter mediated drug-drug interactions (DDIs). Any alteration in the function of these hepatic OATPs might account for the pharmacokinetic variability of TKIs. These finding also provide the basis of further pre-clinical and clinical studies investigating the transporter based DDI potential of TKIs.
As a secondary aim of this investigation we developed novel pentablock (PB) copolymer nanoparticles of pazopanib for treatment of ocular neovascularization. Our results indicated that PB copolymer based drug delivery systems can serve as a platform technology for the development of sustained release therapy along with evasion of drug efflux for the treatment of ocular neovascularization. This drug delivery system can also be utilized for other chronic diseases as well.
We also investigated the presence of ascorbic acid-specific transport system and delineate the functional and molecular aspects of vitamin C transporter (SVCT2) in ocular and breast cancer cells. SVCT2 system can be targeted for the design of ascorbic acid prodrugs or for NPs surface modified with ascorbic acid to achieve enhanced permeability for highly potent but poorly bioavailable drugs by evading drug efflux in the treatment of cancer and ocular diseases.
Interaction of TKIs with hepatic OATP-1B1 and -1B3 delineates the role of hepatic uptake transporters in drug disposition and drug-drug interactions. These OATP transporters in conjunction with the efflux proteins (P-gp, MRP and BCRP) may eventually decide on the overall flux/loss of the therapeutic agents within the hepatic tissue. Similary, functionality of membrane tranporters have been exploited and examined in terms of drug delivery. Pazopanib encapsulated nanoparticles of novel pentablock polymers were successful in bypass drug efflux mediated via efflux proteins. Also, influx transporters (vitamin C transporter, SVCT2) on ocular cell lines can be further utilized as a potential target for enhancing absorption and permeability of AA-conjugated drugs or drug delivery systems by evading drug effluxThe convolutions involved in hepatic drug transport: focus on membrane transporters -- Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors -- Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors -- The role of transporters and efflux system in drug delivery -- Novel pentablock copolymer based nanoparticles containing pazopanib: a potential therapy for ocular neovascularization -- Functional characterization and molecular identification of vitamin C transporter (SVCT2) in human corneal epithelial (HCEC) and retinal pigment epithelial (D407) cells -- Molecular expression and functional activity of vitamin C specific transport system (SVCT2) in human breast cancer cells -- Summary and recommendations -- Appendi
Lattice Approximations in Wasserstein Space
We consider structured approximation of measures in Wasserstein space
for by discrete and piecewise constant
measures based on a scaled Voronoi partition of . We show that if
a full rank lattice is scaled by a factor of , then
approximation of a measure based on the Voronoi partition of is
regardless of or . We then use a covering argument to show that
-term approximations of compactly supported measures is
which matches known rates for optimal quantizers and empirical measure
approximation in most instances. Finally, we extend these results to
noncompactly supported measures with sufficient decay
Linearized Wasserstein dimensionality reduction with approximation guarantees
We introduce LOT Wassmap, a computationally feasible algorithm to uncover
low-dimensional structures in the Wasserstein space. The algorithm is motivated
by the observation that many datasets are naturally interpreted as probability
measures rather than points in , and that finding low-dimensional
descriptions of such datasets requires manifold learning algorithms in the
Wasserstein space. Most available algorithms are based on computing the
pairwise Wasserstein distance matrix, which can be computationally challenging
for large datasets in high dimensions. Our algorithm leverages approximation
schemes such as Sinkhorn distances and linearized optimal transport to speed-up
computations, and in particular, avoids computing a pairwise distance matrix.
We provide guarantees on the embedding quality under such approximations,
including when explicit descriptions of the probability measures are not
available and one must deal with finite samples instead. Experiments
demonstrate that LOT Wassmap attains correct embeddings and that the quality
improves with increased sample size. We also show how LOT Wassmap significantly
reduces the computational cost when compared to algorithms that depend on
pairwise distance computations.Comment: 38 pages, 10 figures. Submitte
Laryngeal Neuroendocrine Tumor - An Atypical Presentation
Neuroendocrine tumors of the larynx are the most common non-epidermoid tumors of the larynx and comprise less than 1% of the laryngeal tumors. Most of the symptoms and presentation mimic any usual laryngeal malignancy making the diagnosis difficult. Here, we report a case of laryngeal neuroendocrine carcinoma that was managed with total laryngectomy
Behavior Optimized Image Generation
The last few years have witnessed great success on image generation, which
has crossed the acceptance thresholds of aesthetics, making it directly
applicable to personal and commercial applications. However, images, especially
in marketing and advertising applications, are often created as a means to an
end as opposed to just aesthetic concerns. The goal can be increasing sales,
getting more clicks, likes, or image sales (in the case of stock businesses).
Therefore, the generated images need to perform well on these key performance
indicators (KPIs), in addition to being aesthetically good. In this paper, we
make the first endeavor to answer the question of "How can one infuse the
knowledge of the end-goal within the image generation process itself to create
not just better-looking images but also "better-performing'' images?''. We
propose BoigLLM, an LLM that understands both image content and user behavior.
BoigLLM knows how an image should look to get a certain required KPI. We show
that BoigLLM outperforms 13x larger models such as GPT-3.5 and GPT-4 in this
task, demonstrating that while these state-of-the-art models can understand
images, they lack information on how these images perform in the real world. To
generate actual pixels of behavior-conditioned images, we train a
diffusion-based model (BoigSD) to align with a proposed BoigLLM-defined reward.
We show the performance of the overall pipeline on two datasets covering two
different behaviors: a stock dataset with the number of forward actions as the
KPI and a dataset containing tweets with the total likes as the KPI, denoted as
BoigBench. To advance research in the direction of utility-driven image
generation and understanding, we release BoigBench, a benchmark dataset
containing 168 million enterprise tweets with their media, brand account names,
time of post, and total likes
Effects of nutrient addition and soil drainage on germination of N-fixing and non-N-fixing tropical dry forest tree species
To develop generalised predictions regarding the effects of atmospheric nitrogen (N) and phosphorus (P) deposition on vegetation communities, it is necessary to account for the impacts of increased nutrient availability on the early life history stages of plants. Additionally, it is important to determine if these responses (a) differ between plant functional groups and (b) are modulated by soil drainage, which may affect the persistence of added nutrients. We experimentally assessed seed germination responses (germination proportion and germination energy, i.e. time to germination) of commonly occurring N-fixing and non-N-fixing tropical dry forest tree species found in India to simulated N and P deposition in well-drained soils, as well as soils with impeded drainage. When soils were not allowed to drain, germination proportion declined with nutrient addition, while germination energy remained unchanged. Stronger declines in germination proportion were observed for N-fixing species. In free-draining soils, nutrient addition did not affect germination proportion in either functional group. However, we detected a trend of delayed germination with nutrient addition, especially in N-fixers. Our results suggest that nutrient deposition can lead to potential shifts in functional dominance and tree community composition of tropical dry forests in the long term through its effects on early life stages of trees, although the mechanisms underlying the observed germination responses remain unclear. Further, such effects are likely to be spatially variable across the geographic range in which tropical dry forests occur depending on soil drainage properties
Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an
Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis
Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV
Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio
Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation
One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced.
Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI
- …