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Promises and pitfalls of targeted agents in chronic lymphocytic leukemia

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Cancer Drug Resistance 2020年第3期3卷 415-444页

作者： thomas e.Lew Mary Ann Anderson John F.Seymour Department of Clinical Haematology The Royal Melbourne Hospital and Peter MacCallum Cancer CentreParkville 3050Australia. Blood Cells and Blood Cancer Division Walter and Eliza Hall Institute of Medical ResearchParkville 3050Australia. Faculty of Medicine Dentistry and Health SciencesThe University of MelbourneParkville 3050Australia.

Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited *** classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline ***,maturing clinical data have revealed promises and pitfalls for both *** drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy ***,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and *** patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease *** these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of *** drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.

关键词： Chronic lymphocytic leukemia drug resistance venetoclax B-cell lymphoma 2 ibrutinib bruton tyrosine kinase idelalisib phosphatidylinositol 3-kinase

Curcumin-loaded polymeric nanoparticles for neuro-protection in neonatal rats with hypoxic-ischemic encephalopathy

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Nano Research 2018年第10期11卷 5670-5688页

作者： Andrea Joseph thomas Wood Chih-Chung Chen Kylie Corry Jessica M. Snyder Sandra e. Juul Pratik Parikh elizabeth Nance Department of Chemical engineering University of Washington Seattle WA 98195 USA Division of Neonatology Department of Pediatrics University of Washington Seattle WA 98195 USA Department of Comparative Medicine University of Washington Seattle WA 98195 USA Department of Radiology University of Washington Seattle WA 98195 USA

Hypoxic-ischemic encephalopathy is the leading cause of permanent brain injury in term newborns and currently has no cure. Inflammatory processes play a key role in the progression of this disease and may be amenable to a targeted pharmaceutical intervention. Curcumin is a dietary compound with potent anti-inflammatory, antioxidant, and antiapoptotic properties but is limited in therapeutic applications due to its low aqueous solubility, low bioavailability, and rapid first-pass hepatic metabolism. To address these limitations, loading curcumin into poly（lactic-co-glycolic acid）-poly（ethylene glycol）（PLGA-PeG） nanoparticles may increase relevant pharmacokinetic parameters and allow for effective drug delivery to the brain. Using the Vannucci model of unilateral hypoxic-ischemic brain injury in neonatal rats, we studied the in vivo effect of curcumin-loaded PLGA-PeG nanoparticles on brain uptake and diffusion of curcumin and on neuroprotection. The curcumin-loaded nanoparticles were able to overcome the impaired blood-brain barrier, diffuse effectively through the brain parenchyma, localize in regions of injury, and deliver a protective effect in the injured neonatal brain. The application of curcumin and PLGA-PeG nanoparticle-mediated delivery to a clinically relevant model of neonatal brain injury provides greater opportunities for clinical translation of targeted therapies for hypoxic-ischemic encephalopathy.

关键词： drug delivery neuroprotection brain penetrating neonatal hypoxia-ischemia curcumin nanotherapeutics

Cyclosporine A, FK-506, 40-0-[2-hydroxyethyl]rapamycin and mycophenolate mofetil inhibit proliferation of human intrahepatic biliary epithelial cells in vitro

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World Journal of Gastroenterology 2005年第48期11卷 7602-7606页

作者： Chao Liu thomas Schreiter Andrea Frilling Uta Dahmen Christoph e Broelsch Guido Gerken Ulrich Treichel Department of Gastroenterology and Hepatology University Hospital Essen Germany Department of General Surgery and Transplantation University Hospital Essen Germany

AIM： To investigate the effect of cyclosporine A （CsA）, FK-506, and mycophenolate mofetil （MMF） and 40-0-[2- hydroxyethyl]rapamycin （RAD） on proliferation of human intrahepatic biliary epithelial cells （BeCs） in ***： BeCs were isolated from six human liver tissuespecimens with the immunomagnetic separation method and treated with different concentrations of CsA, FK-S06, RAD, and MMF in vitro. Proliferation of the cells was measured by MTT assay at 24 and 48 h after treatment, respectively. One-way analysis of variance was used to analyze the results. expression of CK 19 in BeCs was monitored by flow cytometry and Western ***： Six lines of BeCs were established. They survived for 4-18 wk in vitro. Flow cytometry analysis showed that these cells always expressed CK19. CsA, FK-506, RAD, and MMF inhibited proliferation of BeCs in a dose-dependent manner. The lowest concentration of CsA, FK-506, RAD, and MMF to inhibit proliferation of BeCs （P〈0.05） was 500, 100, 0.25, and 100 pg/L, respectively. However, the expression of CK19 by BeCs was not ***： CsA, FK-506, RAD, and MMF have an antiproliferative effect on human intrahepatic BeCs in vitro, while RAD has the strongest growth-inhibitory effect. Their possible effects on liver regeneration and bile duct injury in transplant patients should be further investigated.

关键词： Cyclosporine A FK-506, Rapamycin Mycophenolate mofetil Biliary epithelial cells

Dietary supplementation of sulfur amino acids improves intestinal immunity to eimeria in broilers treated with anti-interleukin-10 antibody

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Animal Nutrition 2022年第3期10卷 382-389页

作者： Zhouzheng Ren Jiakun Yan Rose Whelan Xujie Liao Daniel e.Bütz Maria K.Arendt Mark e.Cook Xiaojun Yang thomas D.Crenshaw College of Animal Science and Technology Northwest A&F UniversityYanglingShaanxiChina Department of Animal Sciences University of WisconsinMadisonWIUSA evonik Operations GmbH Hanau-WolfgangGermany

Oral antibody to interleukin-10(anti-IL-10)enhances the intestinal immune defense against *** sulfur amino acids methionine and cysteine(MtC)play essential roles in inducing and maintaining protective immune responses during intestinal ***,increased dietary MtC may support the anti-IL-10-induced intestinal immunity to ***(n=640)were arranged in a 2×2×2 factorial design with 2 levels of each of the 3 main factors:dietary standardized ileal digestible(SID)MtC levels(0.6%or 0.8%),dietary anti-IL-10 supplementation(with or without),and coccidiosis challenge(control or challenge).Briefly,the broilers were supplied with either 0.6%or 0.8%SID MtC,each with or without anti-IL-10(300 mg/kg),from d 10 to *** d 14,broilers from each diet were gavaged with either PBS or *** resulting eimeria infection induced fecal oocyst shedding and intestinal *** fed 0.8%SID MtC(main effects,P≤0.05)had decreased feed-to-gain ratio,increased duodenum and cecum luminal anti-eimeria IgA titers,and decreased fecal oocyst counts,when compared to 0.6%SID *** supplementation of anti-IL-10(main effects,P≤0.05)increased cecum luminal total IgA concentration and decreased cecum ***(P≤0.05)were detected for growth performance and cecum luminal IFN-γ.Briefly,the highest body weight gain and feed intake were reached in PBS-gavaged broilers fed 0.8%SID MtC with no anti-IL-10 and in eimeria-challenged broilers fed 0.8%SID MtC with *** eimeria-infected broilers,anti-IL-10 increased intestinal luminal IFN-γ and body weight gain only at 0.8%SID ***,anti-IL-10 increased intestinal luminal IFN-γ levels,decreased cecum lesions and restored growth only when fed with adequate amounts of sulfur amino *** findings underscore the importance of providing sufficient essential nutrients to support the anti-IL-10 induced immunity against coccidiosis.

关键词： Chicken Coccidiosis egg yolk antibody Interleukin-10 Sulfur amino acid

A different view： sensory drive in the polarized-light realm

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Current Zoology 2018年第4期64卷 513-523页

作者： thomas W. CRONIN Department of Biological Sciences University of Maryland Baltimore MD 21250 USA

Sensory drive, the concept that sensory systems primarily evolve under the influence of environmen tal features and that animal signals are evolutionarily shaped and tuned by these previously existing sensory systems, has been thoroughly studied regarding visual signals across many animals. Much of this work has focused on spectral aspects of vision and signals. Here, I review work on polarized light signals of animals and relate these to what is known of polarization visual systems, polarized light aspects of visual scenes, and polarizationrelated behavior （e.g., orientation, habitatfinding, contrast enhancement）. Other than the broad patterns of scattered polarized light in the sky, most po larization in both terrestrial and aquatic environments results from either reflection or scattering in the horizontal plane. With overhead illumination, horizontal features such as the surfaces of many leaves or of air： water interfaces reflect horizontal polarization, and water scatters horizontally polar ized light under most conditions. Several animal species have been demonstrated to use horizontally polarized light fields or features in critical aspects of their biology. Significantly, most biological sig nals are also horizontally polarized. Here, I present relevant polarizationrelated behavior and discuss the hypothesis that sensory drive has evolutionarily influenced the structure of polarization signals. The paper also considers the evolutionary origin of circular polarization vision and circularly polar ized signals. It appears that this class of signals did not evolve under the influence of sensory drive. The study of signals based on polarized light is becoming a mature field of research.

关键词： animal communication polarized light sensory drive vision visual signal

Intelligent Prediction Approach for Diabetic Retinopathy Using Deep Learning Based Convolutional Neural Networks Algorithm by Means of Retina Photographs

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Computers, Materials & Continua 2021年第2期66卷 1613-1629页

作者： G.Arun Sampaul thomas Y.Harold Robinson e.Golden Julie Vimal Shanmuganathan Seungmin Rho Yunyoung Nam CSe Department J.B.Institute of Engineering and TechnologyHyderabad500075India School of Information Technology and engineering Vellore Institute of TechnologyVellore632014India Department of Computer Science and engineering Anna University Regional CampusTirunelveli627007India Department of Information Technology National Engineering CollegeKovilpatti628503India Department of Software Sejong University209 Neungdong-roGwangjin-guSeoul05006Korea Department of Computer Science and engineering Soonchunhyang UniversityAsan31538Korea

Retinopathy is a human eye disease that causes changes in retinal blood vessels that leads to bleed,leak fluid and vision *** of retinopathy are blurred vision,changes in color perception,red spots,and eye pain and it cannot be detected with a naked *** this paper,a new methodology based on Convolutional Neural Networks(CNN)is developed and proposed to intelligent retinopathy prediction and give a decision about the presence of retinopathy with automatic diabetic retinopathy screening with accurate *** CNN model is trained by different images of eyes that have retinopathy and those which do not have *** fully connected layers perform the classification process of the images from the dataset with the pooling layers minimize the coherence among the adjacent *** feature loss factor increases the label value to identify the patterns with the kernel-based *** performance of the proposed model is compared with the related methods of DReAM,KNN,GD-CNN and *** results show that the proposed CNN performs better.

关键词： Convolutional neural networks dental diagnosis image recognition diabetic retinopathy detection

A review of direct numerical simulations of astrophysical detonations and their implications

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Frontiers of physics 2013年第2期8卷 189-198页

作者： Suzanne T. Parete-Koon Christopher R. Smith thomas L. Papatheodore O. e. Bronson Messer National Center for Computational Sciences Oak Ridge National Laboratory Oak Ridge USA TN 37831-6354 Department of Physics and Astronomy University of Tennessee KnoxvilleUSA TN 37996-1200

Multi-dimensional direct numerical simulations （DNS） of astrophysical detonations in degenerate matter have revealed that the nuclear burning is typically characterized by cellular structure caused by transverse instabilities in the detonation front. Type Ia supernova modelers often use one- dimensional DNS of detonations as inputs or constraints for their whole star simulations. While these one-dimensional studies are useful tools, the true nature of the detonation is multi-dimensional. The multi-dimensional structure of the burning influences the speed, stability, and the composition of the detonation and its burning products, and therefore, could have an impact on the spectra of Type Ia supernovae. Considerable effort has been expended modeling Type Ia supernovae at densities above 1 ~ 107 ***-3 where the complexities of turbulent burning dominate the flame propagation. How- ever, most full star models turn the nuclear burning schemes off when the density falls below 1 ~ 107 ***-3 and distributed burning begins. The deflagration to detonation transition （DDT） is believed to occur at just these densities and consequently they are the densities important for studying the properties of the subsequent detonation. This work will review the status of DNS studies of detona- tions and their possible implications for Type Ia supernova models. It will cover the development of Detonation theory from the first simple Chapman-Jouguet （C J） detonation models to the current models based on the time-dependent, compressible, reactive flow euler equations of fluid dynamics.

关键词： supernova detonations direct numerical simulations

Non-leaving-face property for marked surfaces

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Frontiers of Mathematics in China 2019年第3期14卷 521-534页

作者： thomas BRUSTLe Jie ZHANG Departement de Mathematiques Universite de Sherbrooke Sherbrooke J1K 2R1 Canada School of Mathematics and Statistics Beijing Institute of Technology Beijing 100081 China

Abstract We consider the polytope arising from a marked surface by flips of triangulations. D. D. Sleator, R. e. Tarjan, and W. P. Thurston [J. Amer. Math. Soc., 1988, 1(3): 647 681] studied the diameter of the associahedron, which is the polytope arising from a marked disc by flips of triangulations. They showed that every shortest path between two vertices in a face does not leave that face. We give a new method, which is different from the one used by V. Disarlo and H. Parlier [arXiv: 1411.4285] to establish the same non-leaving-face property for all unpunctured marked surfaces.

关键词： Marked surface non-leaving-face property exchange graph

MIXeD INTeRIOR PeNALTY DISCONTINUOUS GALeRKIN MeTHODS FOR ONe-DIMeNSIONAL FULLY NONLINeAR SeCOND ORDeR eLLIPTIC AND PARABOLIC eQUATIONS

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Journal of Computational Mathematics 2014年第2期32卷 107-135页

作者： Xiaobing Feng thomas Lewis Department of Mathematics The University of Tennessee Knoxville TN 37996 U.S.A. Department of Mathematics and Statistics The University of North Carolina at Greensboro NC 27402 U.S.A.

This paper is concerned with developing accurate and efficient numerical methods for one-dimensional fully nonlinear second order elliptic and parabolic partial differential equations （PDes）. In the paper we present a general framework for constructing high order interior penalty discontinuous Galerkin （IP-DG） methods for approximating viscosity solutions of these fully nonlinear PDes. In order to capture discontinuities of the second order derivative uxx of the solution u, three independent functions p1,p2 and p3 are introduced to represent numerical derivatives using various one-sided limits. The proposed DG frame- work, which is based on a nonstandard mixed formulation of the underlying PDe, embeds a nonlinear problem into a mostly linear system of equations where the nonlinearity has been modified to include multiple values of the second order derivative uxz. The proposed framework extends a companion finite difference framework developed by the authors in [9] and allows for the approximation of fully nonlinear PDes using high order polynomials and non-uniform meshes. In addition to the nonstandard mixed formulation setting, another main idea is to replace the fully nonlinear differential operator by a numerical operator which is consistent with the differential operator and satisfies certain monotonicity （called g-monotonicity） properties. To ensure such a g-monotonicity, the crux of the construction is to introduce the numerical moment, which plays a critical role in the proposed DG frame- work. The g-monotonicity gives the DG methods the ability to select the mathematically ＂correct＂ solution （i.e., the viscosity solution） among all possible solutions. Moreover, the g-monotonicity allows for the possible development of more efficient nonlinear solvers as the special nonlinearity of the algebraic systems can be explored to decouple the equations. This paper also presents and analyzes numerical results for several numerical test problems which are used to guage

关键词： Fully nonlinear PDes Viscosity solutions Discontinuous Galerkin methods.