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Sample records for enhance antiglaucoma efficacy

  1. Dual-drug delivery system based on in situ gel-forming nanosuspension of forskolin to enhance antiglaucoma efficacy.

    PubMed

    Gupta, Saurabh; Samanta, Malay K; Raichur, Ashok M

    2010-03-01

    The present study was designed to improve the bioavailability of forskolin by the influence of precorneal residence time and dissolution characteristics. Nanosizing is an advanced approach to overcome the issue of poor aqueous solubility of active pharmaceutical ingredients. Forskolin nanocrystals have been successfully manufactured and stabilized by poloxamer 407. These nanocrystals have been characterized in terms of particle size by scanning electron microscopy and dynamic light scattering. By formulating Noveon AA-1 polycarbophil/poloxamer 407 platforms, at specific concentrations, it was possible to obtain a pH and thermoreversible gel with a pH(gel)/T (gel) close to eye pH/temperature. The addition of forskolin nanocrystals did not alter the gelation properties of Noveon AA-1 polycarbophil/poloxamer 407 and nanocrystal properties of forskolin. The formulation was stable over a period of 6 months at room temperature. In vitro release experiments indicated that the optimized platform was able to prolong and control forskolin release for more than 5 h. The in vivo studies on dexamethasone-induced glaucomatous rabbits indicated that the intraocular pressure lowering efficacy for nanosuspension/hydrogel systems was 31% and lasted for 12 h, which is significantly better than the effect of traditional eye suspension (18%, 4-6 h). Hence, our investigations successfully prove that the pH and thermoreversible polymeric in situ gel-forming nanosuspension with ability of controlled drug release exhibits a greater potential for glaucoma therapy.

  2. Forskolin: upcoming antiglaucoma molecule.

    PubMed

    Wagh, V D; Patil, P N; Surana, S J; Wagh, K V

    2012-01-01

    Forskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in 2006. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is a diterpenoid isolated from plant Coleus forskohlii (Lamiaceae). It is a lipid-soluble compound that can penetrate cell membranes and stimulates the enzyme adenylate cyclase which, in turn, stimulates ciliary epithelium to activate cyclic adenosine monophosphate, which decreases intraocular pressure (IOP) by reducing aqueous humor inflow. The topical application of forskolin is capable of reducing IOP in rabbits, monkeys, and humans. In its drug interactions, forskolin may act synergistically with epinephrine, ephedrine and pseudoephedrine. Whereas the effects of anti-clotting medications like warfarin, clopidogre, aspirin, anoxaparin, etc., may be enhanced by forskolin. Forskolin is contraindicated in the medications for people with ulcers as forskolin may increase acid level. Forskolin has a very good shelf-life of five years. Recently, its Ophthalmic inserts and in situ gels for sustained and delayed-release drug delivery systems were tested in New Zealand Albino Rabbits for its antiglaucoma efficacy. This drug review explains Forskolin as a drug, its antiglaucoma potential and recent findings of forskolin as an antiglaucoma agent. The literature search method used for this review was different databases and search engines like PubMed, International Pharmaceutical Abstracts, Google, Medicinal and Aromatic Plants (MAPA).

  3. Gallic acid grafting effect on delivery performance and antiglaucoma efficacy of antioxidant-functionalized intracameral pilocarpine carriers.

    PubMed

    Chou, Shih-Feng; Luo, Li-Jyuan; Lai, Jui-Yang

    2016-07-01

    Functionalization of therapeutic carrier biomaterials can potentially provide additional benefits in drug delivery for disease treatment. Given that this modification determines final therapeutic efficacy of drug carriers, here, we investigate systematically the role of grafting amount of antioxidant gallic acid (GA) onto GN in situ gelling copolymers made of biodegradable gelatin and thermo-responsive poly(N-isopropylacrylamide) for intracameral delivery of pilocarpine in antiglaucoma treatment. As expected, increasing redox reaction time increased total antioxidant activities and free radical scavenging abilities of synthesized carrier biomaterials. The hydrophilic nature of antioxidant molecules strongly affected physicochemical properties of carrier materials with varying GA grafting amounts, thereby dictating in vitro release behaviors and mechanisms of pilocarpine. In vitro oxidative stress challenges revealed that biocompatible carriers with high GA content alleviated lens epithelial cell damage and reduced reactive oxygen species. Intraocular pressure and pupil diameter in glaucomatous rabbits showed correlations with GA-mediated release of pilocarpine. Additionally, enhanced pharmacological treatment effects prevented corneal endothelial cell loss during disease progression. Increasing GA content increased total antioxidant level and decreased nitrite level in the aqueous humor, suggesting a much improved antioxidant status in glaucomatous eyes. This work significantly highlights the dependence of physicochemical properties, drug release behaviors, and bioactivities on intrinsic antioxidant capacities of therapeutic carrier biomaterials for glaucoma treatment. Development of injectable biodegradable polymer depots and functionalization of carrier biomaterials with antioxidant can potentially provide benefits such as improved bioavailability, controlled release pattern, and increased therapeutic effect in intracameral pilocarpine administration for glaucoma

  4. Betaxolol hydrochloride loaded chitosan nanoparticles for ocular delivery and their anti-glaucoma efficacy.

    PubMed

    Jain, Kunal; Kumar, R Suresh; Sood, Sumeet; Dhyanandhan, G

    2013-10-01

    Many effective anti-glaucoma drugs available for the treatment of ocular hypertension and open angle glaucoma are associated with rapid and extensive precorneal loss caused by the drainage and high tear fluid turnover. The present study involved design of mucoadhesive nanoparticulate carrier system containing betaxolol hydrochloride for ocular delivery to improve its corneal permeability and precorneal residence time. Nanoparticles were prepared by spontaneous emulsification method and had a particle size of 168-260 nm with zeta potential of 25.2-26.4 mV. The in vitro release studies in simulated tear fluid exhibited biphasic release pattern with an initial burst followed by sustained release upto 12 h. The sterility tests confirmed that formulation was free from viable microorganisms and suitable for ocular delivery. The ocular tolerance of nanoparticles was evaluated using Hen Egg-Chorion Allantoic Membrane (HE-CAM) method and was found to be non-irritant. Stability studies of nanoparticles revealed that there was no significant change in particle size and drug content after storage at 25 ± 2°C/60 ± 5% RH over a period of 3 months. In vivo pharmacodynamic studies were carried out in dexamethasone induced glaucoma model in rabbits. The developed nanoparticles showed significant decrease in intraocular pressure (IOP) compared to marketed formulation. Optimized formulation of BN3 showed gradual reduction of IOP reaching peak value of 9.9 ± 0.5mm Hg, equivalent to 36.39 ± 1.84% reduction in IOP compared to control at the end of 5 h which was significant (p < 0.05) compared to marketed formulation. Thus, our studies demonstrate that developed nanoparticles offer a promising delivery system for the management of glaucoma.

  5. Sustained Release of an Anti-Glaucoma Drug: Demonstration of Efficacy of a Liposomal Formulation in the Rabbit Eye

    PubMed Central

    Ang, Marcus; Darwitan, Anastasia; Foo, Selin; Zhen, Ma; Koo, Magdalene; Wong, Tina T.; Venkatraman, Subbu S.

    2011-01-01

    Topical medication remains the first line treatment of glaucoma; however, sustained ocular drug delivery via topical administration is difficult to achieve. Most drugs have poor penetration due to the multiple physiological barriers of the eye and are rapidly cleared if applied topically. Currently, daily topical administration for lowering the intra-ocular pressure (IOP), has many limitations, such as poor patient compliance and ocular allergy from repeated drug administration. Poor compliance leads to suboptimal control of IOP and disease progression with eventual blindness. The delivery of drugs in a sustained manner could provide the patient with a more attractive alternative by providing optimal therapeutic dosing, with minimal local toxicity and inconvenience. To investigate this, we incorporated latanoprost into LUVs (large unilamellar vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by the film hydration technique. Relatively high amounts of drug could be incorporated into this vesicle, and the drug resides predominantly in the bilayer. Vesicle stability monitored by size measurement and DSC (differential scanning calorimetry) analysis showed that formulations with a drug/lipid mole ratio of about 10% have good physical stability during storage and release. This formulation demonstrated sustained release of latanoprost in vitro, and then tested for efficacy in 23 rabbits. Subconjunctival injection and topical eye drop administration of the latanoprost/liposomal formulation were compared with conventional daily administration of latanoprost eye drops. The IOP lowering effect with a single subconjunctival injection was shown to be sustained for up to 50 days, and the extent of IOP lowering was comparable to daily eye drop administration. Toxicity and localized inflammation were not observed in any treatment groups. We believe that this is the first demonstration, in vivo, of sustained delivery to the anterior segment of the eye

  6. [Long-term efficacy and safety of combined topical antiglaucoma therapy--timolol & unoprostone vs. betaxolol & unoprostone].

    PubMed

    Ohtake, Yuichiro; Tanino, Tomihiko; Kimura, Itaru; Mashima, Yukihiko; Oguchi, Yoshihisa

    2004-01-01

    To evaluate long-term efficacy and safety of treatment combining topical beta-blockers and isopropyl unoprostone in primary open-angle glaucoma and normal-tension glaucoma patients. A prospective, open-label, parallel-group clinical comparison trial was performed to evaluate efficacy and safety of treatment combining 0.5% betaxolol and 0.12% isopropyl unoprostone (B&U) or 0.5% timolol and 0.12% isopropyl unoprostone (T&U). Forty eyes of 40 patients, which were matched in the aging and the stage of glaucomatous visual field defect, were studied. Twenty patients were treated with B&U and the other twenty patients with T&U twice daily for 24 months. Goldmann intraocular pressure(IOP), Humphrey automated perimetry, blood pressure, heart rate, and peak flow were done every six months in each group. In the B&U treatment group, mean IOP was 21.2 mmHg at baseline and 18.3 mmHg(p < 0.005) after 2 years, and in the T&U treatment group it was 21.1 mmHg at baseline and 17.9 mmHg (p < 0.001) after 2 years. The cases in which MD value decreased over 2 dB were one in the B&U treatment group and three in the T&U treatment group. The average MD value was significantly improved from -7.40 dB to -5.90 dB after 2 years with B&U treatment(p < 0.05), but there was no difference with the T&U treatment. None of the patients stopped combined therapy because of side effects, though heart rate was significantly reduced only in T&U treatment group. Both combined treatments were effective for IOP reduction in glaucoma patients, and the data from the B&U treatment group suggested that B&U was more effective in maintaining visual field than T&U.

  7. Betaxolol and levobunolol: new beta-blocking antiglaucoma agents.

    PubMed

    Tierney, D W

    1987-09-01

    The Food and Drug Administration has recently approved the use of two new ophthalmic beta-adrenergic antagonistic agents: betaxolol hydrochloride (Betoptic) and levobunolol hydrochloride (Betagan). This paper reviews the history, pharmacologic properties, clinical efficacy and potential side effects of this expanding class of antiglaucoma medication.

  8. Antiglaucoma drugs: The role of preservative-free formulations

    PubMed Central

    Bagnis, Alessandro; Papadia, Marina; Scotto, Riccardo; Traverso, Carlo E.

    2011-01-01

    Hypersensitive reactions to eyedrops are a common finding in clinical practice and represent a frequent cause of discontinuation of the therapy. Moreover, experimental and clinical studies show that long term use of topical drugs may induce ocular surface changes causing discomfort and potentially negatively affecting the compliance to the treatment as well as the success rate of filtering procedures. The exact mechanism involved and the roles of the active compound and the preservatives in inducing such detrimental effects of ophthalmic solutions are unclear. During the last years several antiglaucoma agents have been marketed as either preservative-free or benzalkonium chloride-free formulations in an attempt to reduce the adverse effects related to preservatives. This paper summarizes the body of evidence from existing studies about preservatives in antiglaucoma eyedrops, focusing on the latest compounds commercially available. A systematic review of the literature was performed. Current research is focusing not only on the efficacy of the drugs but also on their tolerability. Based on the existing data, there is a rationale to support the use of benzalkonium-free solutions whenever possible, especially in patients suffering from concomitant ocular surface diseases, experiencing local side effects and in those expected to need multiple and prolonged topical treatments. PMID:23960953

  9. Controversy: Is Benzalkonium Chloride Necessary in Antiglaucoma Drops?

    PubMed Central

    Louati, Y

    2012-01-01

    ABSTRACT Medical therapy is the first-line option in glaucoma management, with benzalkonium chloride (BAC) being the most frequently used preservative in antiglaucoma medications. Its use is however, known to be associated with deleterious effects on the ocular surface. This review is an attempt to critically evaluate whether BAC really is indispensable for better bioavailability of antiglaucoma drugs and consequently, better IOP control. How to cite this article: Louati Y, Shaarawy T. Controversy: Is Benzalkonium Chloride Necessary in Antiglaucoma Drops? J Current Glau Prac 2012;6(3):104-107. PMID:26997764

  10. A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost.

    PubMed

    Krupa, Małgorzata; Chodyński, Michał; Ostaszewska, Anna; Cmoch, Piotr; Dams, Iwona

    2017-01-31

    Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to β-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

  11. Antioxidant Gallic Acid-Functionalized Biodegradable in Situ Gelling Copolymers for Cytoprotective Antiglaucoma Drug Delivery Systems.

    PubMed

    Lai, Jui-Yang; Luo, Li-Jyuan

    2015-09-14

    In clinical ophthalmology, oxidative stress has been proposed as the initiating cause of ocular hypertension, which is one of the risk factors for glaucomatous damage and disease progression. In an attempt to improve the therapeutic efficacy of intracamerally administered pilocarpine, herein, a cytoprotective antiglaucoma drug delivery system composed of antioxidant gallic acid (GA)-functionalized gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling copolymer was developed for the first time. Analyses by UV-vis and Fourier transform infrared spectroscopies showed the formation of biopolymer-antioxidant covalent linkages in GNGA structures through a radical reaction in the presence of water-soluble redox initiators. The synthesized GNGA polymers with strong free radical scavenging effectiveness exhibited appropriate phase transition temperature and degradation rate as injectable bioerodible depots for minimally invasive pilocarpine delivery to the ocular anterior chamber. During the 2-week in vitro study, the sustained releases of sufficient amounts of pilocarpine for a therapeutic action in alleviating ocular hypertension could be achieved under physiological conditions. Results of cell viability, intracellular reactive oxygen species level, and intracellular calcium concentration indicated that the incorporation of antioxidant GA into GN structure can enhance cytoprotective effects of carrier materials against hydrogen peroxide-induced oxidative stress in lens epithelial cultures. Effective pharmacological responses (i.e., reduction of intraocular pressure and preservation of corneal endothelial cell morphology and density) in rabbits receiving intracameral GNGA injections containing pilocarpine were evidenced by clinical observations. The findings of in vivo studies also support the hypothesis that the GNGA carriers are more advantageous over their GN counterparts for the improvement of total antioxidant status in glaucomatous eyes with

  12. Efficacy Enhancing Communication within the Online Courseroom

    ERIC Educational Resources Information Center

    Kasitz, Christine M.

    2013-01-01

    Online learning is becoming more prevalent in high schools especially with at-risk students who may need to recover credits to meet graduation requirements. The purpose of this study was to examine the effects of an online courseroom design that delivers performance-based efficacy enhancing feedback at regular intervals, rather than relying on the…

  13. Efficacy Enhancing Communication within the Online Courseroom

    ERIC Educational Resources Information Center

    Kasitz, Christine M.

    2013-01-01

    Online learning is becoming more prevalent in high schools especially with at-risk students who may need to recover credits to meet graduation requirements. The purpose of this study was to examine the effects of an online courseroom design that delivers performance-based efficacy enhancing feedback at regular intervals, rather than relying on the…

  14. Effects of antiglaucoma drugs on blood supply to eye tissues

    SciTech Connect

    Chiou, G.C.Y.; Yan, H.Y.

    1986-03-01

    Although it is essential that intraocular pressure (IOP) be reduced in glaucoma treatment, it is also vitally important to provide sufficient blood flow to eye tissues so that healthy visual field is maintained. It is possible for an agent to reduce IOP and blood supply to the eye. In that case, glaucoma appears to be under control since IOP has been reduced to within normal range yet the disease is actually progressing, causing damage to the retina, optic nerve, and other tissues. /sup 85/Sr-Microsphere technique was used to study the effects of several antiglaucoma drugs on blood supply to various eye tissues. Clearly, L-timolol, D-timolol and pilocarpine are good drugs to use in treating glaucoma because they do not reduce blood flow. On the other hand, although moperone reduced IOP effectively, it also decreased blood supply markedly. Therefore, it should not be used for the treatment of glaucoma.

  15. Longitudinal effect of topical antiglaucoma medications on central corneal thickness.

    PubMed

    Viswanathan, Deepa; Goldberg, Ivan; Graham, Stuart L

    2013-01-01

    To determine the change in central corneal thickness over time and whether the use of long-term topical antiglaucoma medications influences central corneal thickness. Case control study with retrospective and prospective data collection. One hundred eighty-seven eyes of 187 glaucoma patients (mean follow up 6.92 ± 1.67 years) being treated with topical antiglaucoma medications (at least 3 years) with no history of surgery or laser were included and compared with 100 eyes of 100 age-matched, untreated control subjects (mean follow up 6.58 ± 1.93 years) who were glaucoma suspects with normal intraocular pressure not on any treatment. Demographic data, central corneal thickness and intraocular pressure were collected at initial glaucoma diagnosis and at most recent visit, and findings were compared between two groups. Mean change in central corneal thickness in microns (μm). Central corneal thickness fell significantly (P < 0.0001) in treated eyes but not in control eyes (P = 0.18); mean central corneal thickness reduction was 12.29 ± 13.65 μm in treated eyes and 1.17 ± 8.75 μm in controls. Among treated eyes, central corneal thickness reduction was significant (P < 0.0001) in those treated with either prostaglandins or a combination of prostaglandin and beta-blockers, while no significant reduction occurred in eyes treated with only beta-blockers (P = 0.15) when compared with control eyes. Prostaglandins appear to be associated with a small but significant central corneal thickness reduction over time. Serial central corneal thickness measurements might be helpful in glaucoma patients, particularly those on prostaglandins. © 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.

  16. Novel 'soft' beta-blockers as potential safe antiglaucoma agents.

    PubMed

    Bodor, N; elKoussi, A

    1988-04-01

    A series of novel "soft" beta-blockers was designed and synthesized based on the "inactive metabolite approach". Accordingly, the acidic metabolite of metoprolol was converted into various lipophilic esters. The new compounds were tested for their effect on the intraocular pressure (IOP) of rabbits using the ultra-short acting beta-adrenergic antagonist "Esmolol" as a reference compound. Most of the tested compounds displayed a higher and a more prolonged ocular hypotensive activity than the reference methyl ester. The adamantaneethyl ester 2 emerged as the best potential candidate for ophthalmic use as an antiglaucoma agent. This compound exhibited an effective and long lasting ocular hypotensive activity without local irritation to the eye. At the same time, it showed a very fast rate of hydrolysis in human blood (t1/2 = 7.0 minutes) to the inactive acid metabolite. This makes possible effective separation of the desired ocular activity from unwanted systemic beta-blocking action. Unilateral treatment with 2 produced reduction in the IOP only in the treated eye, consistent with the mechanism proposed.

  17. Drug Attitude and Adherence to Anti-Glaucoma Medication

    PubMed Central

    Hong, Samin; Kang, Sung Yong; Yoon, Jong Uk; Kang, Uicheon; Seong, Gong Je

    2010-01-01

    Purpose The purpose of this study is to assess patient attitudes towards anti-glaucoma medication and their association with adherence, visual quality of life, and personality traits. Materials and Methods One hundred and forty-seven glaucoma patients were enrolled this study. The participants were divided into 'pharmacophobic' and 'pharmacophilic' groups according to their scores on the Modified Glaucoma Drug Attitude Inventory (MG-DAI). To establish a correlation with patient drug attitude, each group had their subjective drug adherence, visual quality of life, and personality traits examined. For personality traits, the Myers-Briggs Type Indicator (MBTI) was used to sub-classify each group. Results Among the patients analyzed, 91 (72.80%) patients showed a 'pharmacophobic' attitude and 34 (27.20%) patients showed a 'pharmacophilic' attitude. The pharmacophobic group tended to have worse adherence than the pharmacophilic group. Personality dichotomies from the MBTI also showed different patterns for each group. Conclusion In glaucoma patients, pharmacological adherence was influenced by their attitude towards drugs; an association might exist between drug attitude and underlying personality traits. PMID:20191020

  18. Does the use of preoperative antiglaucoma medications influence trabeculectomy success?

    PubMed

    Öztürker, Zeynep Kayaarasi; Öztürker, Can; Bayraktar, Sukru; Altan, Cigdem; Yilmaz, Omer Faruk

    2014-09-01

    To investigate the influence of preoperative antiglaucoma medications on trabeculectomy outcome. Two hundred fifteen eyes, which underwent primary trabeculectomy, were retrospectively analyzed. The average follow-up was 39.8±30.3 months. The only cases of primary open-angle glaucoma, with or without pseudoexfoliation (PXF), were included. "Complete success" was defined as intraocular pressure (IOP) <18 mmHg without glaucoma medications, whereas relative success was defined as the same IOP target with medications. The influence of the preoperatively used glaucoma medications on surgical success was analyzed by univariate Pearson correlation and multivariate (ordinal) regression analysis. There were 118 male (54.9%) and 97 female (45.1%) patients with a mean age of 66.9±9.3 years. PXF glaucoma (PXFG) was present in 93 eyes (43.3%). In 33 patients (15.3%), diabetes mellitus (DM) was present. Complete success was achieved in 116 eyes (54%), relative success in 81 eyes (37.6%), and failure in 18 eyes (8.4%). Neither the total number nor the duration of glaucoma medications used before trabeculectomy was found to have any statistically significant influence on surgical success. In statistical analysis, a combination of topical beta-blocker and carbonic anhydrase inhibitor (BB+CAI) used before surgery was found to be associated with statistically better outcome, whereas the preoperative use of topical beta-blockers alone could have a negative influence on success. PXF was shown to be independently associated with trabeculectomy outcome on multivariate regression analysis. The glaucoma medications used preoperatively were not found to have any statistically significant negative influence on the trabeculectomy outcome and use of the combined BB+CAI preparation could have a positive influence, whereas the use of topical beta-blockers alone could have a negative influence on success, although not statistically significant. The presence of PXF was independently associated

  19. Conjunctival and corneal sensitivity in patients under topical antiglaucoma treatment.

    PubMed

    Romero-Díaz de León, Lorena; Morales-León, Jorge-Emmanuel; Ledesma-Gil, Jasbeth; Navas, Alejandro

    2016-06-01

    The purpose of the study is to measure corneal and conjunctival sensitivity in patients under glaucoma topical treatment as compared to a control group. It is a case-control study. Corneal and conjunctival esthesiometry were carried out through a Cochet-Bonnet esthesiometer. We took healthy individuals as controls, who did not use any type of ophthalmic topical medications and without history of ocular surface pathology or irritation. The study group was subdivided per number of applications (1, 2, and 3 or more applications). From a total 182 eyes from 91 patients, of which 26 (28.57 %) were controls and 65 (71.43 %) were in the study group, a mean corneal sensitivity of 58.98 ± 2.25 mm was found in the control group and 52.97 ± 6.41 mm in patients using topical medication. Mean conjunctival sensitivity was 18.80 ± 5.40 mm in the control group and 11.76 ± 5.45 mm in the study group. There was no statistically significant difference among groups when separated by 1, 2, and 3 or more applications. Eyes under use of timolol-containing medications showed lower sensitivity values as compared to other topical antiglaucoma medications. Corneal and conjunctival sensitivities are diminished in patients with chronic use of topical hypotensive medications and these results can explain the lack of correlation between signs and symptoms that is typically found in patients treated for glaucoma or ocular hypertension.

  20. Bt Toxin Modification for Enhanced Efficacy

    PubMed Central

    Deist, Benjamin R.; Rausch, Michael A.; Fernandez-Luna, Maria Teresa; Adang, Michael J.; Bonning, Bryony C.

    2014-01-01

    Insect-specific toxins derived from Bacillus thuringiensis (Bt) provide a valuable resource for pest suppression. Here we review the different strategies that have been employed to enhance toxicity against specific target species including those that have evolved resistance to Bt, or to modify the host range of Bt crystal (Cry) and cytolytic (Cyt) toxins. These strategies include toxin truncation, modification of protease cleavage sites, domain swapping, site-directed mutagenesis, peptide addition, and phage display screens for mutated toxins with enhanced activity. Toxin optimization provides a useful approach to extend the utility of these proteins for suppression of pests that exhibit low susceptibility to native Bt toxins, and to overcome field resistance. PMID:25340556

  1. Current status of epibulbar anti-glaucoma drainage devices in glaucoma surgery.

    PubMed

    Thieme, Hagen

    2012-10-01

    The term "glaucoma" covers a heterogeneous group of progressive optic neuropathies that are accompanied by characteristic visual-field defects. Primary open-angle glaucoma, the most common type, progresses insidiously and causes blindness if untreated. All current forms of treatment aim at lowering the intraocular pressure (IOP) in patients whose IOP is elevated. The implantation of anti-glaucoma drainage systems is one of the available options for surgical treatment. This review is based on pertinent literature retrieved by a selective search, including glaucoma treatment guidelines from Germany and abroad. A paradigm shift is currently underway regarding the indications for the implantation of anti-glaucoma drainage systems. Trabeculectomy (a "fistulating" operation in which the aqueous humor is led out of the eye under the conjunctiva) is still considered the surgical gold standard, but drainage systems have been implanted with increasing frequency in recent years. Studies have shown that these systems are more likely to be beneficial the earlier they are implanted in the course of the patient's disease. Five-year follow-up data from the randomized, multicenter Tube Versus Trabeculectomy (TVT) study have now revealed that anti-glaucoma drainage systems are equivalent to trabeculectomy with respect to long-term IOP reduction, complication rates, and absolute and relative clinical success rates. Glaucoma is a major clinical and socio-economic problem whose surgical treatment increasingly involves the implantation of anti-glaucoma drainage systems.

  2. In vitro effects of preserved or preservative-free antiglaucoma medications on human complement system.

    PubMed

    Blondin, Catherine; Hamard, Pascale; Cholley, Béatrice; Haeffner-Cavaillon, Nicole; Baudouin, Christophe

    2003-10-01

    Antiglaucoma drugs have been associated with conjunctival and trabecular inflammatory cell infiltrates. However, the underlying mechanisms are still poorly understood. The aim of this study was to assess the effects of antiglaucoma medications on the complement system, an early mediator of the inflammatory response. Human serum was first treated with a classical or alternative pathway activator (aggregated human IgG or zymosan, respectively) in the presence or the absence of preservative-free or benzalkonium (BAK)-preserved antiglaucoma drugs. CH50 assay was then performed to assess the functional activity of residual complement in treated serum. In the absence of complement activator, the antiglaucoma drugs tested in this study were all devoid of intrinsic complement-activating potency. Preserved and preservative-free carteolol as well as preserved latanoprost did not worsen or prevent complement activation induced by zymosan or aggregated IgG. Unexpectedly, both preserved and unpreserved timolol and betaxolol significantly counteracted the effects of complement activators. Timolol prevented activation triggered by both IgG and zymosan to the same extent (24% to 29%), despite the presence of BAK in the preserved formulation. Betaxolol was twice as effective at preventing the effect of IgG (34% to 37%) than that of zymosan (14%), regardless of the presence of BAK. However, BAK itself strongly aggravated complement activation by both activators. Carteolol, timolol, betaxolol and latanoprost did not activate complement system. On the contrary, the beta-blockers timolol and betaxolol exerted an anti-inflammatory effect by preventing complement activation. The deleterious effect of benzalkonium seems to have been neutralized within the preserved eyedrops through a mechanism that remains to be elucidated. Our study suggests that inflammatory signs in glaucoma patients should not be attributed to complement activation by antiglaucoma drugs.

  3. [Effect of various anti-glaucoma eyedrops on human corneal epithelial cells].

    PubMed

    Aoyama, Yumiko; Motoki, Masamitsu; Hashimoto, Mariko

    2004-02-01

    To investigate the effects of antiglaucoma eyedrops and vehicles on the proliferation of human corneal epithelial cells. Seven eyedrops[prostaglandin F2 alpha analogs(2), beta blockers(40), topical carbonic anhydrase inhibitor(1)], and six of the eyedrop vehicles, excluding that of Xalatan, were used. Anti-glaucoma eyedrops and vehicles were serially diluted 2-fold with culture medium(10-2,560 fold). The mixture was added to human corneal epithelial cells and incubated for 48 hrs. Cell proliferation was measured by commercial assay kit. Dye-reagents were added to the wells and incubated for 1 h at 37 degrees C. Optical density were measured at 490 nm. The dilution rate for 50% inhibition was calculated as the dilution rate of drugs or vehicles necessary to produce 50% inhibition of cell proliferation. All drugs completely inhibited cell proliferation when the dilution rate was low. At 40-fold dilution, Trusopt and Timoptol showed a significant decrease in cell growth inhibition. On the other hand, Rescula showed almost 100% inhibition at 160-fold dilution. Above 640-fold dilution, the inhibition rate of all drugs became 50% or less and there was no significant difference between drugs. Vehicles also inhibited cell growth. The dilution rates for growth inhibition by vehicles were different from those of drugs. The dilution rate at 50% inhibition of anti-glaucoma eyedrops decreased in the following order: Rescula > Xalatan > Betoptic > Hypadil > Mikelan > Timoptol > Trusopt. The dilution rate for 50% inhibition of vehicles decreased in the following order: Rescula vehicle > Hypadil vehicle > Betoptic vehicle > Mikelan vehicle > Timoptol vehicle > Trusopt vehicle. All anti-glaucoma eyedrops inhibited cell proliferation. These effects were stronger in prostaglandin F2 alpha analogs and weakest in Trusopt. Furthermore, the inhibition of cell proliferation was caused also by the vehicle of eyedrops, and the influence of the vehicle varied in each type of eyedrops.

  4. Toxicity of antiglaucoma drugs with and without benzalkonium chloride to cultured human corneal endothelial cells

    PubMed Central

    Ayaki, Masahiko; Iwasawa, Atsuo; Inoue, Yoichi

    2010-01-01

    Purpose The toxicity of antiglaucoma medications to ocular surface cells has been evaluated extensively; however, the toxicity to corneal endothelial cells (CECs) remains elusive. Our aim is to evaluate the toxicity of antiglaucoma medications to CECs using an in vitro toxicity assay. Methods Primary cultures of human (H) CECs derived from eye bank specimens were established. Following exposure of HCECs to test solutions for 10, 30, or 60 minutes, or 48 hours, we measured cell viability using a WST-1 assay. Test solutions were diluted in culture media and included 0.5% Timoptol®, preservative-free 0.5% timolol maleate, 1% Trusopt®, preservative-free 1% dorzolamide, Travatan®, Travatan Z®, Xalatan®, and benzalkonium chloride (BAK). To assess cell viability, the value of the test culture well after treatment was expressed as a percentage of that of the control well. Toxicity of each solution was compared using the cell viability score (CVS). Results After exposure to 10-fold dilutions of test solutions for 48 hours, HCEC viabilities were 48.5% for 0.5% Timoptol, 80.9% for preservative-free 0.5% timolol maleate, 47.0% for 1% Trusopt, 71.7% for preservative-free 1% dorzolamide, 55.5% for Travatan, 88.5% for Travatan Z, and 52.5% for Xalatan. Exposure to test solutions diluted 100-fold or more resulted in HCEC viabilities >80%, with the exception of preservative-free 1% dorzolamide, which resulted in a viability of 72.0% at a dilution of 100-fold. Based on CVS, the order of cell viability was Travatan Z ≥ preservative-free timolol maleate = preservative-free dorzolamide > 0.5% Timoptol = 1% Trusopt > Travatan ≥ Xalatan. Assessment of the combined effect of drug and BAK revealed that latanoprost reduced the toxicity of BAK. Conclusion Antiglaucoma eye drops produced HCEC toxicity that appeared to depend on the presence of BAK. Because dilution of the antiglaucoma solutions resulted in markedly lower HCEC toxicity, HCEC damage due to antiglaucoma medication may

  5. Enhancement of optical skin clearing efficacy using a microneedle roller

    PubMed Central

    Yoon, Jinhee; Son, Taeyoon; Choi, Eung-ho; Choi, Bernard; Nelson, J. Stuart; Jung, Byungjo

    2009-01-01

    Light scattering in biological tissues can be reduced by using optical clearing agents. Various physical methods in conjunction with agents have been studied to enhance the optical clearing efficacy of skin for diagnostic and therapeutic applications. In this study, we propose a new physical method to enhance the optical clearing potential of topically applied glycerol. A microneedle roller is used to easily create numerous transdermal microchannels prior to glycerol application. The optical clearing efficacy of skin is quantitatively evaluated with the use of a modulation transfer function target placed underneath ex vivo porcine skin samples. From cross-polarized images acquired at various time points after glycerol application, we find that samples treated with the microneedle roller resulted in an approximately two-fold increase in contrast compared to control samples 30 min after glycerol application. In conclusion, our data suggest that the microneedle roller can be a good physical method to enhance transdermal delivery of optical clearing agents, and hence their optical clearing potential over large regions of skin. PMID:18465952

  6. Enhancement of optical skin clearing efficacy using a microneedle roller.

    PubMed

    Yoon, Jinhee; Son, Taeyoon; Choi, Eung-Ho; Choi, Bernard; Nelson, J Stuart; Jung, Byungjo

    2008-01-01

    Light scattering in biological tissues can be reduced by using optical clearing agents. Various physical methods in conjunction with agents have been studied to enhance the optical clearing efficacy of skin for diagnostic and therapeutic applications. In this study, we propose a new physical method to enhance the optical clearing potential of topically applied glycerol. A microneedle roller is used to easily create numerous transdermal microchannels prior to glycerol application. The optical clearing efficacy of skin is quantitatively evaluated with the use of a modulation transfer function target placed underneath ex vivo porcine skin samples. From cross-polarized images acquired at various time points after glycerol application, we find that samples treated with the microneedle roller resulted in an approximately two-fold increase in contrast compared to control samples 30 min after glycerol application. In conclusion, our data suggest that the microneedle roller can be a good physical method to enhance transdermal delivery of optical clearing agents, and hence their optical clearing potential over large regions of skin.

  7. Effects of Long-Term Antiglaucoma Eye Drops on Conjunctival Structures: An In Vivo Confocal Microscopy Study

    PubMed Central

    Zhu, Wenqing; Kong, Xiangmei; Xu, Jianjiang; Sun, Xinghuai

    2015-01-01

    Purpose. The study was aimed at comparing the long-term effects of different antiglaucoma eye drops on conjunctival structures using laser scanning confocal microscopy. Methods. Eighty patients diagnosed with primary open-angle glaucoma and twenty healthy volunteers were included in this study. The participants were divided into 5 groups according to the different medications. The lachrymal film break-up time, Schirmer's I test, and Ocular Surface Disease Index Questionnaire were performed in all subjects. The confocal microscopy was used to observe the basal epithelial cell density (ECD), goblet cell density (GCD), dendritic cell density (DCD), and subepithelial collagen fiber diameter (SFD). Results. Statistically significant differences were found among the control group and the antiglaucoma therapy groups in the values of three clinical data (P < 0.05). The GCD, DCD, and SFD showed significant differences in all glaucoma groups when compared to the control (P < 0.001). Moreover, the prostaglandin group differed from the other antiglaucoma therapy groups in the GCD and SFD (P < 0.05). Conclusions. Our study confirmed the significant differences in the conjunctival structures based on the effects of antiglaucoma medications. Less pronounced changes were found in the patients treated with prostaglandin analogue than in the other kinds of antiglaucoma therapies. PMID:26171239

  8. Effects of Long-Term Antiglaucoma Eye Drops on Conjunctival Structures: An In Vivo Confocal Microscopy Study.

    PubMed

    Zhu, Wenqing; Kong, Xiangmei; Xu, Jianjiang; Sun, Xinghuai

    2015-01-01

    Purpose. The study was aimed at comparing the long-term effects of different antiglaucoma eye drops on conjunctival structures using laser scanning confocal microscopy. Methods. Eighty patients diagnosed with primary open-angle glaucoma and twenty healthy volunteers were included in this study. The participants were divided into 5 groups according to the different medications. The lachrymal film break-up time, Schirmer's I test, and Ocular Surface Disease Index Questionnaire were performed in all subjects. The confocal microscopy was used to observe the basal epithelial cell density (ECD), goblet cell density (GCD), dendritic cell density (DCD), and subepithelial collagen fiber diameter (SFD). Results. Statistically significant differences were found among the control group and the antiglaucoma therapy groups in the values of three clinical data (P < 0.05). The GCD, DCD, and SFD showed significant differences in all glaucoma groups when compared to the control (P < 0.001). Moreover, the prostaglandin group differed from the other antiglaucoma therapy groups in the GCD and SFD (P < 0.05). Conclusions. Our study confirmed the significant differences in the conjunctival structures based on the effects of antiglaucoma medications. Less pronounced changes were found in the patients treated with prostaglandin analogue than in the other kinds of antiglaucoma therapies.

  9. Novel antiglaucoma prodrugs and codrugs of ethacrynic acid.

    PubMed

    Cynkowska, Grazyna; Cynkowski, Tadeusz; Al-Ghananeem, Abeer M; Al-Ghananeem, Abeer A; Guo, Hong; Ashton, Paul; Crooks, Peter A

    2005-08-01

    The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.

  10. Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy

    SciTech Connect

    Choi, Seo-Hyun; Nam, Jae-Kyung; Jang, Junho; Lee, Hae-June Lee, Yoon-Jin

    2015-06-26

    Radiotherapy is a widely used treatment for many tumors. Combination therapy using anti-angiogenic agents and radiation has shown promise; however, these combined therapies are reported to have many limitations in clinical trials. Here, we show that radiation transformed tumor endothelial cells (ECs) to fibroblasts, resulting in reduced vascular endothelial growth factor (VEGF) response and increased Snail1, Twist1, Type I collagen, and transforming growth factor (TGF)-β release. Irradiation of radioresistant Lewis lung carcinoma (LLC) tumors greater than 250 mm{sup 3} increased collagen levels, particularly in large tumor vessels. Furthermore, concomitant sunitinib therapy did not show a significant difference in tumor inhibition versus radiation alone. Thus, we evaluated multimodal therapy that combined pirfenidone, an inhibitor of TGF-induced collagen production, with radiation and sunitinib treatment. This trimodal therapy significantly reduced tumor growth, as compared to radiation alone. Immunohistochemical analysis revealed that radiation-induced collagen deposition and tumor microvessel density were significantly reduced with trimodal therapy, as compared to radiation alone. These data suggest that combined therapy using pirfenidone may modulate the radiation-altered tumor microenvironment, thereby enhancing the efficacy of radiation therapy and concurrent chemotherapy. - Highlights: • Radiation changes tumor endothelial cells to fibroblasts. • Radio-resistant tumors contain collagen deposits, especially in tumor vessels. • Pirfenidone enhances the efficacy of combined radiation and sunitinib therapy. • Pirfenidone reduces radiation-induced collagen deposits in tumors.

  11. Enhancement of skin optical clearing efficacy using photo-irradiation.

    PubMed

    Liu, Caihua; Zhi, Zhongwei; Tuchin, Valery V; Luo, Qingming; Zhu, Dan

    2010-02-01

    Tissue optical clearing technique based on immersion of tissues into optical clearing agents (OCAs) can reduce the scattering and enhance the penetration of light in tissue. However, the barrier function of epidermis limits the penetration of OCAs, and hence is responsible for the poor optical clearing efficacy of skin by topical action. In this study, a variety of light irradiation was applied to increase permeability of agents in skin and improve the optical clearing efficacy. Different light sources with different dose, i.e, CO(2) laser, Nd:YAG laser (532 and 1,064 nm) with different pulse modes and Intense Pulsed Light (IPL) (400-700 and 560-950 nm) were used to irradiate rat skin in vivo, and then glycerol was applied onto the irradiated zone. VIS-NIR spectrometer was utilized to monitor the changes of reflectance. In vitro skin samples were also irradiated by Q-switched Nd:YAG laser (1,064 nm) and then treated by glycerol for 10-60 minutes. Based on the measurement of the reflectance and transmittance of the samples, the optical properties of skin and penetration depth of light were calculated. Results show that photo-irradiation with appropriate dose combining with the following glycerol treatment is able to reduce in vivo skin reflectance. Compared with the control group, the maximal changes in reflectance are ninefold at 575 nm and eightfold at 615 nm, respectively, which were caused by Q-switched 1,064-nm Nd:YAG laser irradiation and following glycerol treatment. The results for in vitro skin demonstrate that the joint action can significantly increase the optical penetration depth in samples. The combination of Q-switched Nd:YAG (1,064 nm) laser and glycerol could enhance optical skin clearing efficacy significantly. This study provides a non-invasive way to improve the optical clearing of skin, which will benefit the skin optical therapy.

  12. Unintentional ingestion of brimonidine antiglaucoma drops: a case report and review of the literature.

    PubMed

    Soto-Pérez-de-Celis, Enrique; Skvirsky, David Oldak; Cisneros, Beatriz Guzmán

    2007-09-01

    A previously healthy, 1-year 7-month-old boy was brought to the emergency department after having unintentionally ingested topical brimonidine antiglaucoma drops. He was pale and lethargic and had brief periods of apnea and bradycardia. Activated charcoal was administered, and supportive measures were initiated, achieving complete resolution of the symptoms 4 hours after admission. Brimonidine poisoning is very rare, and a high index of suspicion is necessary to identify its signs and symptoms in the pediatric emergency department. To our knowledge, only 1 case of brimonidine poisoning after oral ingestion of this topical drug has been previously reported in the literature.

  13. Ocular surface evaluation in eyes with chronic glaucoma on long term topical antiglaucoma therapy

    PubMed Central

    Saini, Manu; Vanathi, Murugesan; Dada, Tanuj; Agarwal, Tushar; Dhiman, Rebika; Khokhar, Sudarshan

    2017-01-01

    AIM To evaluate ocular surface changes and its correlation with the central corneal subbasal nerve fibre layer in chronic glaucoma patients. METHODS A prospective comparative study of ocular surface evaluation was performed in 50 eyes of 25 patients using two or more antiglaucoma medications for at least 6mo and 50 eyes of 25 normal subjects without any ocular problems as controls. The study parameters evaluated included visual acuity, intraocular pressure, ocular surface evaluation parameters [fluorescein break-up time (FTBUT), Schirmer's I test, ocular surface staining scores and ocular surface disease index score (OSDI)], central corneal sensation (Cochet Bonnett aesthesiometer), central subbasal nerve fiber layer density (SBNFLD) by confocal microscopy. RESULTS The mean values in the glaucoma cases and control groups respectively were as follows: OSDI score (35.89±16.07/6.02±3.84; P=0.001), Schirmer's I test score (7.63±2.64 mm/12.86±1.93 mm; P=0.001), FTBUT (9.44±2.76s/11.8±1.88s; P=0.001), corneal (5.7±2.33/ 1.1±0.58; P=0.001) and conjunctival staining score (5.06±1.94/0.84±0.46; P=0.001), corneal sensitivity (4.68±0.44/5.07±0.37; P=0.076), mean subbasal nerve fiber number (3.58±0.99/5.40±1.70; P=0.001), SBNFL length (1101.44±287.56 µm/1963.70±562.56 µm; P=0.001) and density (6883.94±1798.03 µm/mm2/12 273.15±3516.04 µm/mm2; P=0.001). Dry eye severity of level 2 and 3 was seen in 66% of glaucoma group. Corneal (R2=0.86) and conjunctival staining (R2=0.71) and OSDI score (R2=0.67) showed statistically significant negative correlation with central corneal SBNFLD while FTBUT (R2=0.84), corneal sensitivity (R2=0.52) showed positive correlation to central corneal SBNFLD in the long term topical antiglaucoma medication group. CONCLUSION Ocular surface changes and antiglaucoma therapy induced dry eye is found to be associated with decreased SBNFLD in eyes on long term topical antiglaucoma medications. PMID:28730085

  14. Ocular surface evaluation in eyes with chronic glaucoma on long term topical antiglaucoma therapy.

    PubMed

    Saini, Manu; Vanathi, Murugesan; Dada, Tanuj; Agarwal, Tushar; Dhiman, Rebika; Khokhar, Sudarshan

    2017-01-01

    To evaluate ocular surface changes and its correlation with the central corneal subbasal nerve fibre layer in chronic glaucoma patients. A prospective comparative study of ocular surface evaluation was performed in 50 eyes of 25 patients using two or more antiglaucoma medications for at least 6mo and 50 eyes of 25 normal subjects without any ocular problems as controls. The study parameters evaluated included visual acuity, intraocular pressure, ocular surface evaluation parameters [fluorescein break-up time (FTBUT), Schirmer's I test, ocular surface staining scores and ocular surface disease index score (OSDI)], central corneal sensation (Cochet Bonnett aesthesiometer), central subbasal nerve fiber layer density (SBNFLD) by confocal microscopy. The mean values in the glaucoma cases and control groups respectively were as follows: OSDI score (35.89±16.07/6.02±3.84; P=0.001), Schirmer's I test score (7.63±2.64 mm/12.86±1.93 mm; P=0.001), FTBUT (9.44±2.76s/11.8±1.88s; P=0.001), corneal (5.7±2.33/ 1.1±0.58; P=0.001) and conjunctival staining score (5.06±1.94/0.84±0.46; P=0.001), corneal sensitivity (4.68±0.44/5.07±0.37; P=0.076), mean subbasal nerve fiber number (3.58±0.99/5.40±1.70; P=0.001), SBNFL length (1101.44±287.56 µm/1963.70±562.56 µm; P=0.001) and density (6883.94±1798.03 µm/mm(2)/12 273.15±3516.04 µm/mm(2); P=0.001). Dry eye severity of level 2 and 3 was seen in 66% of glaucoma group. Corneal (R(2)=0.86) and conjunctival staining (R(2)=0.71) and OSDI score (R(2)=0.67) showed statistically significant negative correlation with central corneal SBNFLD while FTBUT (R(2)=0.84), corneal sensitivity (R(2)=0.52) showed positive correlation to central corneal SBNFLD in the long term topical antiglaucoma medication group. Ocular surface changes and antiglaucoma therapy induced dry eye is found to be associated with decreased SBNFLD in eyes on long term topical antiglaucoma medications.

  15. Implementation of efficacy enhancement nursing interventions with cardiac elders.

    PubMed

    Hiltunen, Elizabeth F; Winder, Patricia A; Rait, Michelle A; Buselli, Elizabeth F; Carroll, Diane L; Rankin, Sally H

    2005-01-01

    Intervention strategies based on social cognitive theory and encompassing the bio-psycho-behavioral domains are proposed to enhance self-efficacy in men and women 65 years and older recovering from myocardial infarction and coronary artery bypass grafting. This paper describes a study in which the theory-based development of efficacy enhancement (EE) nursing interventions and their implementation and utilization with interventions from the Nursing Interventions Classification (NIC) were used with cardiac elders in the treatment group of the community-based randomized clinical, trial, "Improving Health Outcomes in Unpartnered Cardiac Elders." Advanced practice nurses (APNs) provided the nursing intervention to 110 participants (mean age = 76.2, SD = 6.0) for the first 12 weeks after discharge to home. After an initial introductory meeting in the acute-care setting, participant contacts by the APNs were made at a home visit and telephone calls at 2, 6, and 10 weeks. Results describe the number of participants receiving interventions at all contacts over 12 weeks, at specified contact points, and the intensity (nurse time) of the interventions. Verbal encouragement and mastery were EE interventions used with the greatest number of participants. Exercise promotion, energy management and active listening were NIC interventions used with the most participants. Variations in the use of interventions over 12 weeks and their intensities, suggest patterns of recovery in the elders. During rehabilitation EE interventions can be successfully implemented with men and women 65 years and older and individualized to the recovery trajectory. Nurses can integrate specific EE interventions with more general interventions from the bio-psycho-behavioral domains to enhance the recovery process for cardiac elders.

  16. Osmotic Compounds Enhance Antibiotic Efficacy against Acinetobacter baumannii Biofilm Communities.

    PubMed

    Falghoush, Azeza; Beyenal, Haluk; Besser, Thomas E; Omsland, Anders; Call, Douglas R

    2017-10-01

    Biofilm-associated infections are a clinical challenge, in part because a hydrated matrix protects the bacterial community from antibiotics. Herein, we evaluated how different osmotic compounds (maltodextrin, sucrose, and polyethylene glycol [PEG]) enhance antibiotic efficacy against Acinetobacter baumannii biofilm communities. Established (24-h) test tube biofilms (strain ATCC 17978) were treated with osmotic compounds in the presence or absence of 10× the MIC of different antibiotics (50 μg/ml tobramycin, 20 μg/ml ciprofloxacin, 300 μg/ml chloramphenicol, 30 μg/ml nalidixic acid, or 100 μg/ml erythromycin). Combining antibiotics with hypertonic concentrations of the osmotic compounds for 24 h reduced the number of biofilm bacteria by 5 to 7 log (P < 0.05). Increasing concentrations of osmotic compounds improved the effect, but there was a trade-off with increasing solution viscosity, whereby low-molecular-mass compounds (sucrose, 400-Da PEG) worked better than higher-mass compounds (maltodextrin, 3,350-Da PEG). Ten other A. baumannii strains were similarly treated with 400-Da PEG and tobramycin, resulting in a mean 2.7-log reduction in recoverable bacteria compared with tobramycin treatment alone. Multivariate regression models with data from different osmotic compounds and nine antibiotics demonstrated that the benefit from combining hypertonic treatments with antibiotics is a function of antibiotic mass and lipophilicity (r(2) > 0.82; P < 0.002), and the relationship was generalizable for biofilms formed by A. baumannii and Escherichia coli K-12. Augmenting topical antibiotic therapies with a low-mass hypertonic treatment may enhance the efficacy of antibiotics against wound biofilms, particularly when using low-mass hydrophilic antibiotics.IMPORTANCE Biofilms form a barrier that protects bacteria from environmental insults, including exposure to antibiotics. We demonstrated that multiple osmotic compounds can enhance antibiotic efficacy against

  17. The Effects of Topical Antiglaucoma Drugs as Monotherapy on the Ocular Surface: A Prospective Study

    PubMed Central

    Aydin Kurna, Sevda; Acikgoz, Semih; Ozbay, Nurver; Sengor, Tomris; Olcaysu, Osman Okan

    2014-01-01

    Purpose. The aim was to compare the effects of antiglaucoma eye drops on the tear functions and ocular surface. Method. Eighty-five eyes of 43 patients with glaucoma were included into this randomized prospective study. Timolol without preservative (1), timolol with benzododecinium bromide (2), latanoprost (3), bimatoprost (4), travoprost with benzalkonium chloride (5), and brimonidine with purite (6) were given to 6 groups. Schirmer I, tear film breakup time (TBUT), staining scores, and impression cytology samples were evaluated before and during 12-month-follow-up period. Results. At the end of 12 months, there was no detected change in Schirmer I and TBUT tests indicating dry eye. Corneal staining scores were higher in groups 1 and 2, while conjunctival staining scores were higher in group 6. Goblet cell count decreased in groups 1 and 5 in superior and inferior, group 2 in superior, and groups 3 and 6 in inferior conjunctiva. Squamous metaplasia grades showed a significant increase in groups 1 and 2 at 3rd, 6th, and 12th month controls (P < 0.05). Conclusion. We observed nonserious impact on tear functions and ocular surface with antiglaucoma monotherapy. Beta blockers induced more damage on the ocular surface suggesting the role of the dosing and active substances beside preservatives. PMID:25009742

  18. The effect of additional topical cyclosporine or vitamin A on the ocular surface during antiglaucoma medication administration.

    PubMed

    Cho, Hyun Kyung; Park, Myoung Hee; Moon, Jung Il

    2012-01-01

    To investigate the effects of topical application of cyclosporine or vitamin A on the ocular surface during the concurrent administration of antiglaucoma drugs. Thirty rabbits were randomized into 5 groups. Group 1 was administered timolol, group 2 received travoprost, group 3 received a travoprost/timolol fixed combination solution, group 4 received timolol and travoprost, and group 5 received timolol, travoprost, and dorzolamide. Each group was divided into a subgroup that received only the antiglaucoma medication (subgroup A), a subgroup that received topical cyclosporine in addition to the antiglaucoma medication (subgroup B), and a subgroup that received topical vitamin A in addition to the antiglaucoma medication (subgroup C). Conjunctival impression cytology specimens were collected at baseline and at weeks 1, 3, and 6. Conjunctival biopsy specimens were collected at week 6. The impression cytologic study results are as follows: statistically significant differences were found between groups 4A and 4B and between groups 4A and 4C at week 6 (p = 0.004, p = 0.006, respectively) and between groups 5A and 5B and between groups 5A and 5C at weeks 3 and 6 (p = 0.006, p = 0.008 at week 3, p = 0.003, p = 0.004 at week 6, respectively). No statistically significant differences were found between subgroup B and subgroup C in any of the groups at any of the times evaluated (p > 0.05). The conjunctival biopsy specimens from groups 1, 2, and 3 showed no distortion, but groups 4A and 5A showed distortion of the conjunctival epithelial structures. Groups 4B, 4C, 5B, and 5C showed less distortion of the conjunctival epithelial structures. Administration of cyclosporine or vitamin A may reduce the adverse ocular surface changes caused by long-term administration of antiglaucoma drugs. Copyright © 2012 S. Karger AG, Basel.

  19. Enhanced brain targeting efficacy of Olanzapine through solid lipid nanoparticles.

    PubMed

    Natarajan, Jawahar; Baskaran, Mahendran; Humtsoe, Lireni C; Vadivelan, R; Justin, A

    2017-03-01

    Olanzapine (OLZ) is a typical anti-psychotic drug, which is highly lipophilic in nature, belongs to Biopharmaceutical Classification System (BCS) class II category. Though OLZ is an effective agent in the treatment of Schizophrenia, but it exhibits poor bioavailability (57%) due to extensive first-pass metabolism resulted in high dose is required to achieve therapeutic concentration in brain. Emerging evidences are indicating that high dose administration of OLZ may cause Extrapyramidal symptoms (EPS) in the psychotic patients. Hence, the present study is designed to develop Olanzapine solid lipid (OLZ-SLNs) using minimal dose of OLZ thereby enhancing the brain efficacy as well as to reduce the side effects associated with OLZ. OLZ-SLNs have been prepared by "solvent diffusion method" using lipids, such as glyceryl monostearate (GMS), tripalmitin (TP), Tween 80, and Stearyl amine as positive charge inducer. The prepared OLZ-SLNs were subjected to particle size analysis, zeta potential, and poly dispersity index measurement by using Malvern Zetasizer. Pharmacokinetics assessments of OLZ-SLNs were carried in conscious male Wistar rats through intravenous administration. Results have shown that average particle size and zeta potential of SLNs of GMS and TP were ranged from 165.1 ± 2.2 to 110.5 ± 0.5 and 35.29 ± 1.2 and 66.50 ± 0.7 mV, respectively. Relative bioavailability of OLZ in the brain was increased up to 23-fold and clearance was decreased when OLZ-SLNs while administrated intravenously. The area under the curve (AUC) and mean residence time (MRT) of OLZ-SLNs in brain were higher than OLZ suspension. These results indicate that SLNs are a promising drug delivery for OLZ. It may be an effective tool to enhance the bioavailability of OLZ in the brain with less dose administration, which could reduce the EPS associated with OLZ.

  20. Carbonic Anhydrase Inhibitors. Part 541: Metal Complexes of Heterocyclic Sulfonamides: A New Class of Antiglaucoma Agents

    PubMed Central

    Scozzafava, Andrea; Jitianu, Andrei

    1997-01-01

    Metal complexes of heterocyclic sulfonamides possessing carbonic anhydrase (CA) inhibitory properties were recently shown to be useful as intraocular pressure (IOP) lowering agents in experimental animals, and might be developed as a novel class of antiglaucoma drugs. Here we report the synthesis of a heterocyclic sulfonamide CA inhibitor and of the metal complexes containing main group metal ions, such as Be(II), Mg(II), Al(III), Zn(II), Cd(II) and Hg(II) and the new sulfonamide as well as 5-amino-1,3,4-thiadiazole-2-sulfonamide as ligands. The new complexes were characterized by standard physico-chemical procedures, and assayed as inhibitors of three CA isozymes, CA I, II and IV. Some of them (but not the parent sulfonamides) strongly lowered IOP in rabbits when administered as a 2% solution into the eye. PMID:18475811

  1. Changing antiglaucoma therapy from timolol to betaxolol: effect on ocular blood flow.

    PubMed

    Rainer, Georg; Dorner, Guido T; Garhöfer, Gerhard; Vass, Clemens; Pfleger, Thomas; Schmetterer, Leopold

    2003-01-01

    The aim of the present study was to investigate the effect of a therapy change from timolol to betaxolol on ocular blood flow in patients with open-angle glaucoma. This randomized double-blind study comprised 34 consecutive patients with open-angle glaucoma, already treated with either timolol alone or in combination with other antiglaucoma agents. The patients were randomly allocated to receive either betaxolol (n = 17) or timolol (n = 17) instead of the present timolol drops. Additional antiglaucoma therapy remained unchanged. The retinal blood flow was assessed by scanning laser Doppler flowmetry and the pulsatile choroidal blood flow was assessed by laser interferometric measurement of fundus pulsation amplitude. Ocular blood flow measurement as well as systemic hemodynamic and intraocular pressure (IOP) measurements were performed at baseline and 1 week and 1 and 3 months after the therapy change. Visual field testing was performed at baseline and at 3 months. After 3 months of treatment with either timolol or betaxolol, neither the retinal nor the pulsatile choroidal blood flow were significantly altered. The power to detect a 9% change in pulsatile choroidal blood flow and a 20% change in retinal blood flow in the present study was 90%. The IOP was not significantly altered in either group. In contrast, visual fields slightly improved after betaxolol treatment compared to baseline (p = 0.047), but this effect was not significant versus timolol. Changing therapy from timolol to betaxolol has no effect on ocular blood flow in patients with open-angle glaucoma. Copyright 2003 S. Karger AG, Basel

  2. Omeprazole enhances efficacy of triple therapy in eradicating Helicobacter pylori.

    PubMed Central

    Borody, T J; Andrews, P; Fracchia, G; Brandl, S; Shortis, N P; Bae, H

    1995-01-01

    Triple therapy has been recommended as the most effective treatment for Helicobacter pylori eradication. Despite achieving a comparatively high eradication result, however, around 10% of patients still fail to be cured. Omeprazole can enhance efficacy of single and double antibiotic protocols and is particularly effective when combined with clarithromycin and a nitroimidazole. This study examined the effect of combining triple therapy with omeprazole. A prospective, randomised, unblinded, single centre trial was carried out on consecutive patients with symptoms of dyspepsia and H pylori infection confirmed by rapid urease test, microbiological culture, and histological assessment. Patients were given a five times/day, 12 day course of colloidal bismuth subcitrate chewable tablets (108 mg), tetracycline HCl (250 mg), and metronidazole (200 mg) with either 20 mg omeprazole twice daily (triple therapy+omeprazole) or 40 mg famotidine (triple therapy+famotidine) at night. Compliance and side effects were determined using a standard questionnaire form. One hundred and twenty five of 165 triple therapy+omeprazole patients and 124 of 171 triple therapy+famotidine patients returned for rebiopsy four weeks after completion of treatment. Significantly more triple therapy+omeprazole patients achieved eradication 122 of 125 (97.6%) as assessed by negative urease test, culture, and histological assessment, when compared with 110 of 124 (89%) triple therapy+famotidine patients (p = 0.006; chi 2). There were 30 triple therapy+omeprazole (24%) and 26 triple therapy+famotidine (21%) patients with de novo metronidazole resistant H pylori included in the study. Side effects were mild and infrequent and were comparable in both groups, although pain in duodenal ulcer, gastric ulcer, and oesophagitis patients seemed to subside earlier in those taking omeprazole. Compliance (>95% of drugs taken) was achieved by 98% of patients of both groups. A 12 days regimen of triple therapy with

  3. Enhancing the Career Decision-Making Self-Efficacy of Upward Bound Students.

    ERIC Educational Resources Information Center

    O'Brien, Karen M.; Bikos, Lynette Heim; Epstein, Kimberly L.; Flores, Lisa Y.; Dukstein, Rebecca D.; Kamatuka, Ngondi A.

    2000-01-01

    In study 1, 34 Upward Bound students slightly enhanced career decision-making self-efficacy after 10 hours of career exploration. In study 2, 22 Upward Bound summer institute participants who received 5 weeks of career exploration had higher self-efficacy than 26 participants who did not. No differences in the number of occupations considered were…

  4. Enhancement of Luminous Efficacy by Random Patterning of Phosphor Matrix

    NASA Astrophysics Data System (ADS)

    Fellows, Natalie; Masul, Hisashi; Diana, Frederic; Denbaars, Steven P.; Nakamura, Shuji

    We have demonstrated the ability to increase the luminous flux and luminous efficacy of white light-emitting diodes (LEDs) by randomly patterning the surface of the yellow phosphor matrix. The phosphor was moved away from the LED die by placing it on top of a silicone optic and then roughening the surface of the phosphor/resin mixture. It was found that the roughening increases the luminous flux and efficacy by 10% over the smooth, non-patterned phosphor mixture. The roughened sample’s operating voltage, luminous flux, luminous efficacy, CCT, color coordinates, and CRI were 3.2 V, 7.4 lm, 115.6 lm/W, 4244 K, (0.388, 0.448), and 61 at 20 mA, CW, and room temperature operation. A brief presentation on phosphor scattering is introduced to help explain the effect of the roughening.

  5. Biofilm disruption with rotating microrods enhances antimicrobial efficacy

    NASA Astrophysics Data System (ADS)

    Mair, Lamar O.; Nacev, Aleksandar; Hilaman, Ryan; Stepanov, Pavel Y.; Chowdhury, Sagar; Jafari, Sahar; Hausfeld, Jeffrey; Karlsson, Amy J.; Shirtliff, Mark E.; Shapiro, Benjamin; Weinberg, Irving N.

    2017-04-01

    Biofilms are a common and persistent cause of numerous illnesses. Compared to planktonic microbes, biofilm residing cells often demonstrate significant resistance to antimicrobial agents. Thus, methods for dislodging cells from the biofilm may increase the antimicrobial susceptibility of such cells, and serve as a mechanical means of increasing antimicrobial efficacy. Using Aspergillus fumigatus as a model microbe, we magnetically rotate microrods in and around biofilm. We show that such rods can improve the efficacy of antimicrobial Amphotericin B treatments in vitro. This work represents a first step in using kinetic magnetic particle therapy for disrupting fungal biofilms.

  6. Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer

    DTIC Science & Technology

    2015-10-01

    Award Number: W81XWH-11-1-0548 TITLE: Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer 5b. GRANT NUMBER W81XWH-11-1-0548...antigen discovery. 15. SUBJECT TERMS Breast cancer , immunotherapy, vaccine, antigens 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18

  7. Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer

    DTIC Science & Technology

    2012-10-01

    Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Jill E. Slansky...24 September 2012 4. TITLE AND SUBTITLE Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer 5a. CONTRACT NUMBER 5b...ENHANCING  THE  BREADTH  AND  EFFICACY  OF  THERAPEUTIC   VACCINES  FOR  BREAST   CANCER ,  we  have  made  clear

  8. Therapeutic Effects of Sodium Hyaluronate on Ocular Surface Damage Induced by Benzalkonium Chloride Preserved Anti-glaucoma Medications

    PubMed Central

    Liu, Xing; Yu, Fen-Fen; Zhong, Yi-Min; Guo, Xin-Xing; Mao, Zhen

    2015-01-01

    Background: Long-term use of benzalkonium chloride (BAC)-preserved drugs is often associated with ocular surface toxicity. Ocular surface symptoms had a substantial impact on the glaucoma patients’ quality of life and compliance. This study aimed to investigate the effects of sodium hyaluronate (SH) on ocular surface toxicity induced by BAC-preserved anti-glaucoma medications treatment. Methods: Fifty-eight patients (101 eyes), who received topical BAC-preserved anti-glaucoma medications treatment and met the severe dry eye criteria, were included in the analysis. All patients were maintained the original topical anti-glaucoma treatment. In the SH-treated group (56 eyes), unpreserved 0.3% SH eye drops were administered with 3 times daily for 90 days. In the control group (55 eyes), phosphate-buffered saline were administered with 3 times daily for 90 days. Ocular Surface Disease Index (OSDI) questionnaire, break-up time (BUT) test, corneal fluorescein staining, corneal and conjunctival rose Bengal staining, Schirmer test, and conjunctiva impression cytology were performed sequentially on days 0 and 91. Results: Compared with the control group, SH-treated group showed decrease in OSDI scores (Kruskal-Wallis test: H = 38.668, P < 0.001), fluorescein and rose Bengal scores (Wilcoxon signed-ranks test: z = −3.843, P < 0.001, and z = −3.508, P < 0.001, respectively), increase in tear film BUT (t-test: t = −10.994, P < 0.001) and aqueous tear production (t-test: t = −10.328, P < 0.001) on day 91. The goblet cell density was increased (t-test: t = −9.981, P < 0.001), and the morphology of the conjunctival epithelium were also improved after SH treatment. Conclusions: SH significantly improved both symptoms and signs of ocular surface damage in patients with BAC-preserved anti-glaucoma medications treatment. SH could be proposed as a new attempt to reduce ocular surface toxicity, and alleviate symptoms of ocular surface damage in BAC-preserved anti-glaucoma

  9. Enhancing Science Teaching Self-Efficacy in Preservice Elementary Teachers.

    ERIC Educational Resources Information Center

    Ramey-Gassert, Linda; Shroyer, M. Gail

    1992-01-01

    Using the construct of personal self-efficacy as a foundation, methods for building science teaching confidence in preservice teachers are described. Methods include microteaching, cooperative learning, role models, experiential learning, computer use, and others. The interrelatedness of science anxiety, attitude toward science, and low science…

  10. Enhancing Students' Self-Efficacy in Making Positive Career Decisions

    ERIC Educational Resources Information Center

    Reddan, Gregory

    2015-01-01

    Field Project A is an elective course in the Bachelor of Exercise Science program at Griffith University and includes elements of both career development learning and work-integrated learning. This paper aims to determine the effects of the learning activities and assessment items developed for the course on students' self-efficacy in making…

  11. Enhancing Entrepreneurial Self-Efficacy through Vocational Entrepreneurship Education Programmes

    ERIC Educational Resources Information Center

    Maritz, Alex; Brown, Chris

    2013-01-01

    The purpose of this study is to report the results of a longitudinal evaluation of a vocational entrepreneurship education programme (EEP) using entrepreneurial self-efficacy (ESE) measures. An empirical, mixed methods longitudinal and effectuation scale was used to measure ESE scores. Results indicate that participation in the programme had a…

  12. Cysteamine Enhances Biofilm Eradication Efficacy of Calcium Hydroxide.

    PubMed

    Guo, Weidi; Quah, Samantha Yiling; Lim, Kian Chong; Yu, Victoria Soo Hoon; Tan, Kai Soo

    2016-05-01

    Calcium hydroxide (Ca[OH]2) is a widely used interappointment dressing, but its antibacterial property is compromised by dentin. Hence, the addition of chlorhexidine (CHX) with Ca(OH)2 has been proposed. However, the antimicrobial efficacy of this mixture compared with Ca(OH)2 alone is currently still debatable. Cysteamine is a mucolytic agent used to reduce the viscosity of mucus through the disruption of proteins, which are also important components of the extracellular matrix of biofilms. The aims of this study were to determine the efficacy of cysteamine alone and in combination with Ca(OH)2 to eradicate Enterococcus faecalis biofilm compared with CHX with Ca(OH)2, and to determine if this effect is affected by dentin. The biofilm eradication efficacies of Ca(OH)2 alone and with cysteamine were determined using 7-day E. faecalis biofilm cultured on dentin discs and compared with Ca(OH)2 with 2% CHX. The effects of dentin on the efficacies of Ca(OH)2 alone and with either cysteamine or CHX were examined. Cysteamine alone completely abolished E. faecalis biofilm at 200 mg/mL. The combination of Ca(OH)2 with either cysteamine at 10 mg/mL or 2% CHX completely obliterated E. faecalis biofilm. Cysteamine with Ca(OH)2 completely eradicated E. faecalis biofilm despite preincubation with dentin, whereas CHX with Ca(OH)2 was less effective. Cysteamine effectively eliminated E. faecalis biofilm and showed synergistic effects in combination with Ca(OH)2, which were unaffected by dentin. Hence, our findings support the use of cysteamine as a potential adjunct to Ca(OH)2 as an interappointment dressing. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  13. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy

    PubMed Central

    Schadler, Keri L.; Thomas, Nicholas J.; Galie, Peter A.; Bhang, Dong Ha; Roby, Kerry C.; Addai, Prince; Till, Jacob E.; Sturgeon, Kathleen; Zaslavsky, Alexander; Chen, Christopher S.; Ryeom, Sandra

    2016-01-01

    Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant. PMID:27589843

  14. The effect of preservatives and antiglaucoma treatments on the ocular surface of mice with dry eye.

    PubMed

    Barabino, Stefano; Antonelli, Sophie; Cimbolini, Nicolas; Mauro, Virginie; Bouzin, Marielle

    2014-09-09

    To test the hypothesis that benzalkonium chloride (BAK) alters the ocular surface in normal and dry eye mice and that a BAK-free commercially available antiglaucoma treatment does not induce the same effects. Eight- to 12-week-old female C57BL/6 mice were used under normal environmental conditions and in a controlled environment chamber (CEC) which induces dry eye. Study and control groups included treatment with BAK, bimatoprost, BAK-free travoprost, and 0.9% NaCl and nontreated mice exposed and nonexposed to the CEC, respectively. Treatments were instilled 4 times a day in the right eye for 7 days. Aqueous tear production was measured by cotton thread test, corneal fluorescein staining (score 0-15), corneal thickness, goblet cell density, and CD45(+) cell expression in superior, inferior, and fornix conjunctiva by a masked observer. After 7 days of treatment with BAK, mice showed significant increase of corneal staining, reduction of goblet cells, and increase of inflammation under normal and CEC conditions. The commercial preparations of bimatoprost containing BAK and travopost did not show the same effects. Travoprost showed a significant corneal thickening under CEC conditions compared to that in all other groups. This study indicated that use of BAK has negative effects on the ocular surface under normal and dry eye conditions, even if the association with bimatoprost does not confirm the same results. A BAK-free travoprost preparation showed positive effects on tear secretion and corneal protection. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  15. Enhancing antibiofilm efficacy in antimicrobial photodynamic therapy: effect of microbubbles

    NASA Astrophysics Data System (ADS)

    Kishen, Anil; George, Saji

    2013-02-01

    In this study, we tested the hypothesis that a microbubble containing photosensitizer when activated with light would enable comprehensive disinfection of bacterial biofilms in infected root dentin by antimicrobial photodynamic therapy (APDT). Experiments were conducted in two stages. In the stage-1, microbubble containing photosensitizing formulation was tested for its photochemical properties. In the stage-2, the efficacy of microbubble containing photosensitizing formulation was tested on in vitro infected root canal model, developed with monospecies biofilm models of Enterococcus faecalis on root dentin substrate. The findings from this study showed that the microbubble containing photosensitizing formulation was overall the most effective formulation for photooxidation, generation of singlet oxygen, and in disinfecting the biofilm bacteria in the infected root canal model. This modified photosensitizing formulation will have potential advantages in eliminating bacterial biofilms from infected root dentin.

  16. Liposome encapsulated albumin-paclitaxel nanoparticle for enhanced antitumor efficacy.

    PubMed

    Ruttala, Hima Bindu; Ko, Young Tag

    2015-03-01

    Albumin nanoparticles have been explored as a promising delivery system for various therapeutic agents. One limitation of such formulations is their poor colloidal stability in vivo. Present study aimed at enhancing the chemotherapeutic potential of paclitaxel by improving the colloidal stability and pharmacokinetic properties of albumin-paclitaxel nanoparticles (APNs) such as Abraxane®. This was accomplished by encapsulating the preformed APNs into PEGylated liposomal bilayer by thin-film hydration/extrusion technique. The resulting liposome-encapsulated albumin-paclitaxel hybrid nanoparticles (L-APNs) were nanosized (~200 nm) with uniform spherical dimensions. The successful incorporation of albumin-paclitaxel nanoparticle (NP) in liposome was confirmed by size exclusion chromatography analysis. Such hybrid NP showed an excellent colloidal stability even at 100-fold dilutions, overcoming the critical drawback associated with simple albumin-paclitaxel NP system. L-APNs further showed higher cytotoxic activity towards B16F10 and MCF-7 cells than APN; this effect was characterized by arrest at the G2/M phase and a higher prevalence of apoptotic subG1 cells. Finally, pharmacokinetic and biodistribution studies in tumor mice demonstrated that L-APNs showed a significantly enhanced plasma half-life, and preferential accumulation in the tumor. Taken together, the data indicate that L-APNs can be promising therapeutic vehicles for enhanced delivery of PTX to tumor sites.

  17. Enhancing elementary-school mathematics teachers' efficacy beliefs: a qualitative action research

    NASA Astrophysics Data System (ADS)

    Katz, Sara; Stupel, Moshe

    2016-04-01

    Individuals and societies that can use mathematics effectively in this period of rapid changes will have a voice on increasing the opportunities and potentials which can shape their future. This has brought affective characteristics, such as self-efficacy, that affect mathematics achievement into focus of the research. Teacher efficacy refers to the extent to which a teacher feels capable to help students learn, influence students' performance and commitment, and thus plays a crucial role in developing the student in all aspects. In this study, we used two sources of efficacy beliefs, mastery experiences and physiological and emotional states, in an interesting and challenging seven month workshop, as tools to foster teacher efficacy for six elementary-school teachers who were frustrated and wanted to leave their job. Our aim was to study the nature of these teachers' efficacy in order to change it. In this qualitative action research, we used open interviews, non-participant observations and field notes. Results show that these teachers became efficacious, their students' achievements and motivation were enhanced, and the school climate was changed. Qualitative inquiry of this construct sheds light on efficacy beliefs of mathematics teachers. Nurturing teacher efficacy has borne much fruit in the field of mathematics in school.

  18. Electrical enhancement of biocide efficacy against Pseudomonas aeruginosa biofilms.

    PubMed Central

    Blenkinsopp, S A; Khoury, A E; Costerton, J W

    1992-01-01

    When applied within a low-strength electric field (+/- 12 V/cm) with a low current density (+/- 2.1 mA/cm2), several industrial biocides exhibited enhanced killing action against Pseudomonas aeruginosa biofilms grown on stainless steel studs. Biocide concentrations lower than those necessary to kill planktonic cells of P. aeruginosa (1, 5, and 10 ppm of the active ingredients of kathon, glutaraldehyde, and quaternary ammonium compound, respectively) were bactericidal within 24 h when applied within our electrified device. PMID:1482196

  19. Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy

    NASA Astrophysics Data System (ADS)

    Paraskar, Abhimanyu; Soni, Shivani; Roy, Bhaskar; Papa, Anne-Laure; Sengupta, Shiladitya

    2012-02-01

    Nanoscale drug delivery vehicles have been extensively studied as carriers for cancer chemotherapeutics. However, the formulation of platinum chemotherapeutics in nanoparticles has been a challenge arising from their physicochemical properties. There are only a few reports describing oxaliplatin nanoparticles. In this study, we derivatized the monomeric units of a polyisobutylene maleic acid copolymer with glucosamine, which chelates trans-1,2-diaminocyclohexane (DACH) platinum (II) through a novel monocarboxylato and O → Pt coordination linkage. At a specific polymer to platinum ratio, the complex self-assembled into a nanoparticle, where the polymeric units act as the leaving group, releasing DACH-platinum in a sustained pH-dependent manner. Sizing was done using dynamic light scatter and electron microscopy. The nanoparticles were evaluated for efficacy in vitro and in vivo. Biodistribution was quantified using inductively coupled plasma atomic absorption spectroscopy (ICP-AAS). The PIMA-GA-DACH-platinum nanoparticle was found to be more active than free oxaliplatin in vitro. In vivo, the nanoparticles resulted in greater tumor inhibition than oxaliplatin (equivalent to 5 mg kg-1 platinum dose) with minimal nephrotoxicity or body weight loss. ICP-AAS revealed significant preferential tumor accumulation of platinum with reduced biodistribution to the kidney or liver following PIMA-GA-DACH-platinum nanoparticle administration as compared with free oxaliplatin. These results indicate that the rational engineering of a novel polymeric nanoparticle inspired by the bioactivation of oxaliplatin results in increased antitumor potency with reduced systemic toxicity compared with the parent cytotoxic. Rational design can emerge as an exciting strategy in the synthesis of nanomedicines for cancer chemotherapy.

  20. Quaternization enhances the transgene expression efficacy of aminoglycoside-derived polymers.

    PubMed

    Miryala, Bhavani; Feng, Yunpeng; Omer, Ala; Potta, Thrimoorthy; Rege, Kaushal

    2015-07-15

    The objective of the present study was to synthesize and investigate the transgene expression efficacy of quaternized derivatives of aminoglycoside polymers in different cancer cell lines. A series of glycidyltrimethylammonium chloride (GTMAC) derivatives of aminoglycoside polymers (GTMAC-AM polymers), containing varying degrees of quaternization (13-45%), were synthesized. The structures and properties of GTMAC-AM polymers were investigated using FT-IR and (1)H NMR spectroscopy. Physicochemical factors that influence transgene expression efficacy including DNA binding, hydrodynamic size, zeta potential and cytotoxicity, were determined. Formation of polymer-plasmid DNA complexes was also visualized using atomic force microscopy. GTMAC-AM polymers demonstrated higher transgene expression efficacies compared to their parent polymers, 25 kDa poly(ethyleneimine), as well as Lipofectamine-3000. Our results indicate that quaternization enhances the transgene expression efficacy and reduces the cytotoxicity of aminoglycoside-derived polymers, making it an attractive strategy for nucleic acid delivery with these new materials.

  1. Using an Attribution Support Tool to Enhance the Teacher Efficacy of Student Science Teachers

    NASA Astrophysics Data System (ADS)

    de Boer, Eveline; Janssen, Fred J. J. M.; van Driel, Jan H.

    2016-04-01

    To increase the teacher efficacy of student teachers, they need positive classroom experiences: mastery experiences. These mastery experiences have to be created by the student teachers themselves. Therefore, student teachers need a tool to better understand problematic teaching experiences and help them create positive classroom experiences. Nine student biology teachers used this attribution support tool when reflecting on multiple lessons taught in classes they considered difficult. They scored their lessons and filled in a teacher efficacy questionnaire after each lesson. The results show that teacher efficacy increased and the number of failures during the lessons decreased; on average, the self-awarded marks per teacher per lesson increased, indicating an increase in mastery experiences. Therefore, the attribution tool seems to be a promising tool for student teachers to enhance their teacher efficacy and to support reflection on problematic teaching experiences.

  2. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment.

    PubMed

    Yeku, Oladapo O; Purdon, Terence J; Koneru, Mythili; Spriggs, David; Brentjens, Renier J

    2017-09-05

    Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.

  3. EFFICACY OF COMMERCIAL PRODUCTS IN ENHANCING OIL BIODEGRADATION IN CLOSED LABORATORY REACTORS

    EPA Science Inventory

    A laboratory screening protocol was designed and conducted to test the efficacy of eight commercial bacterial cultures and two non-bacterial products in enhancing the biodegradation of weathered Alaska North Slope crude oil in closed flasks. Three lines of evidence were used to ...

  4. Enhancing Self-Efficacy and Performance: An Experimental Comparison of Psychological Techniques

    ERIC Educational Resources Information Center

    Wright, Bradley James; O'Halloran, Paul Daniel; Stukas, Arthur Anthony

    2016-01-01

    Purpose: We assessed how 6 psychological performance enhancement techniques (PETs) differentially improved self-efficacy (SE) and skill performance. We also assessed whether vicarious experiences and verbal persuasion as posited sources of SE (Bandura, 1982) were supported and, further, if the effects of the 6 PETs remained after controlling for…

  5. Enhancing HIV Communication between Parents and Children: Efficacy of the Parents Matter! Program

    ERIC Educational Resources Information Center

    Miller, Kim S.; Lin, Carol Y.; Poulsen, Melissa N.; Fasula, Amy; Wyckoff, Sarah C.; Forehand, Rex; Long, Nicholas; Armistead, Lisa

    2011-01-01

    We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV-prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages…

  6. Enhancing Self-Efficacy and Performance: An Experimental Comparison of Psychological Techniques

    ERIC Educational Resources Information Center

    Wright, Bradley James; O'Halloran, Paul Daniel; Stukas, Arthur Anthony

    2016-01-01

    Purpose: We assessed how 6 psychological performance enhancement techniques (PETs) differentially improved self-efficacy (SE) and skill performance. We also assessed whether vicarious experiences and verbal persuasion as posited sources of SE (Bandura, 1982) were supported and, further, if the effects of the 6 PETs remained after controlling for…

  7. "I Think I Can": Mentoring as a Means of Enhancing Teacher Efficacy.

    ERIC Educational Resources Information Center

    Yost, Rosanne

    2002-01-01

    Examines the effectiveness of a graduate-level mentor program at a small midwestern university. Finds that the four veteran mentor teachers experienced enhanced teacher efficacy and stated they became more aware of their teaching and of the responsibilities they had to their elementary school students. (RS)

  8. Enhancing Professional Self-Efficacy: Factors Contributing to Successful Implementation of Articulated Workplace Intentions

    ERIC Educational Resources Information Center

    Kile, Kimberly S.

    2012-01-01

    Competency-based education programs foster participants' abilities to perform or implement a skill taught within the curriculum. A competency-based course enhances a participant's professional self-efficacy by imparting in them the confidence to successfully implement one or more of the skills taught within the course. The Career…

  9. Enhancing HIV Communication between Parents and Children: Efficacy of the Parents Matter! Program

    ERIC Educational Resources Information Center

    Miller, Kim S.; Lin, Carol Y.; Poulsen, Melissa N.; Fasula, Amy; Wyckoff, Sarah C.; Forehand, Rex; Long, Nicholas; Armistead, Lisa

    2011-01-01

    We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV-prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages…

  10. Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer

    DTIC Science & Technology

    2014-10-01

    Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR: Jill E. Slansky CONTRACTING ORGANIZATION: University of Colorado School of Medicine Auro...COVERED 2 2013 – 24 2014 4. TITLE AND SUBTITLE Enhancing the Breadth of Efficacy of Therapeutic Vaccines for Breast Cancer 5a...15. SUBJECT TERMS Breast cancer, tumor antigens, T cell receptor, cancer vaccine 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT

  11. Gemcitabine enhances antitumor efficacy of recombinant lipoimmunogen-based immunotherapy

    PubMed Central

    Chang, Li-Sheng; Yan, Wan-Lun; Chang, Yu-Wen; Yeh, Yi-Chen; Chen, Hsin-Wei; Leng, Chih-Hsiang; Liu, Shih-Jen

    2016-01-01

    ABSTRACT Although immunotherapy is an attractive approach for cancer treatment, increasing evidence has shown that the combination of immunotherapy with other treatment modalities may improve the outcome of advanced malignancy. We combined the anticancer drug gemcitabine (Gem) with recombinant lipoprotein-based immunotherapy (rlipo-E7m/CpG) to treat advanced cancer. Mice bearing huge solid tumors (≧ 12 mm in diameter) or orthotopic cervical cancer were treated with a therapeutic regimen consisting of rlipo-E7m/CpG and Gem. In addition, tumor-infiltrating immune cells were quantified by flow cytometry following the chemotherapy and/or immunotherapy. We observed the eradication of huge tumors following the administration of Gem on days 21, 24, and 27 or following rlipo-E7m/CpG therapy on day 30 post-tumor implantation. The combination therapy substantially reduced the number of immunosuppressive cells (CD11b+Gr-1+, CD11b+F4/80+, and CD4+CD25+FOXP3+) and increased the number of tumor-infiltrating antigen-specific CD8+ T cells compared to Gem or rlipo-E7m/CpG monotherapy. Interestingly, the administration of Gem and rlipo-E7m/CpG reduced the quantity of programmed cell death protein 1 (PD-1)-expressing antigen-specific cytotoxic T lymphocytes (CTLs) in the regressing tumors. These findings demonstrated that Gem enhances the eradication of huge tumors by inhibiting a broad range of immunosuppressive cells when combined with immunotherapy. Based on the promising results from this animal study, Gem chemotherapy combined with recombinant lipoimmunogen-based immunotherapy represents a feasible approach for cancer therapy. PMID:27141356

  12. Health game interventions to enhance physical activity self-efficacy of children: a quantitative systematic review.

    PubMed

    Pakarinen, Anni; Parisod, Heidi; Smed, Jouni; Salanterä, Sanna

    2017-04-01

    To describe and explore health game interventions that enhance the physical activity self-efficacy of children and to evaluate the effectiveness of these interventions. Physical inactivity among children has increased globally. Self-efficacy is one of the key determinants of physical activity engagement in children. There is a need to explore new and innovative interventions to enhance physical activity self-efficacy that are also acceptable for today's children. Quantitative systematic review. MEDLINE (Ovid), CINAHL, PsychInfo, EMBASE and the Cochrane Library between 1996-2016. A review was conducted in accordance with the Cochrane Collaboration guidelines. A systematic search was done in June 2016 by two independent reviewers according to the eligibility criteria as follows: controlled trial, comparison of digital game intervention with no game intervention control condition, participants younger than 18 years of age and reported statistical analyses of a physical activity self-efficacy outcome measure. Altogether, five studies met the eligibility criteria. Four game interventions, employing three active games and one educational game, had positive effects on children's physical activity self-efficacy. An intervention, employing a game-themed mobile application, showed no intervention effects. The variation between intervention characteristics was significant and the quality of the studies was found to be at a medium level. Although health game interventions seemingly enhance the physical activity self-efficacy of children and have potential as a means of increasing physical activity, more rigorous research is needed to clarify how effective such interventions are in the longer run to contribute to the development of game-based interventions. © 2016 John Wiley & Sons Ltd.

  13. Blockade of TGF-beta enhances tumor vaccine efficacy mediated by CD8(+) T cells.

    PubMed

    Takaku, Shun; Terabe, Masaki; Ambrosino, Elena; Peng, Judy; Lonning, Scott; McPherson, John M; Berzofsky, Jay A

    2010-04-01

    Though TGF-beta inhibition enhances antitumor immunity mediated by CD8(+) T cells in several tumor models, it is not always sufficient for rejection of tumors. In this study, to maximize the antitumor effect of TGF-beta blockade, we tested the effect of anti-TGF-beta combined with an irradiated tumor vaccine in a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine alone in prophylactic setting significantly delayed tumor growth, whereas anti-TGF-beta antibodies alone did not show any antitumor effect. However, tumor growth was inhibited significantly more in vaccinated mice treated with anti-TGF-beta antibodies compared to vaccinated mice without anti-TGF-beta, suggesting that anti-TGF-beta synergistically enhanced irradiated tumor vaccine efficacy. CD8(+) T-cell depletion completely abrogated the vaccine efficacy, and so protection required CD8(+) T cells. Depletion of CD25(+) T regulatory cells led to the almost complete rejection of tumors without the vaccine, whereas anti-TGF-beta did not change the number of CD25(+) T regulatory cells in unvaccinated and vaccinated mice. Though the abrogation of CD1d-restricted NKT cells, which have been reported to induce TGF-beta production by MDSC through an IL-13-IL-4R-STAT6 pathway, partially enhanced antitumor immunity regardless of vaccination, abrogation of the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway did not enhance vaccine efficacy. Taken together, these data indicated that anti-TGF-beta enhances efficacy of a prophylactic vaccine in normal individuals despite their not having the elevated TGF-beta levels found in patients with cancer and that the effect is not dependent on TGF-beta solely from CD4(+)CD25(+) T regulatory cells or the NKT cell-IL-13-IL-4R-STAT-6 immunoregulatory pathway.

  14. Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer

    NASA Astrophysics Data System (ADS)

    Salaam, Amanee D.; Hwang, Patrick T. J.; Poonawalla, Aliza; Green, Hadiyah N.; Jun, Ho-wook; Dean, Derrick

    2014-10-01

    Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 μg mL-1 DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 μg mL-1 DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 μg mL-1 of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX.

  15. Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV.

    PubMed

    Yoo, Ji Young; Pradarelli, Jason; Haseley, Amy; Wojton, Jeffrey; Kaka, Azeem; Bratasz, Anna; Alvarez-Breckenridge, Christopher A; Yu, Jun-Ge; Powell, Kimerly; Mazar, Andrew P; Teknos, Theodoros N; Chiocca, E Antonio; Glorioso, Joseph C; Old, Matthew; Kaur, Balveen

    2012-09-15

    Copper in serum supports angiogenesis and inhibits replication of wild-type HSV-1. Copper chelation is currently being investigated as an antiangiogenic and antineoplastic agent in patients diagnosed with cancer. Herpes simplex virus-derived oncolytic viruses (oHSV) are being evaluated for safety and efficacy in patients, but several host barriers limit their efficacy. Here, we tested whether copper inhibits oHSV infection and replication and whether copper chelation would augment therapeutic efficacy of oHSV. Subcutaneous and intracranial tumor-bearing mice were treated with oHSV ± ATN-224 to evaluate tumor burden and survival. Virus replication and cell killing was measured in the presence or absence of the copper chelating agent ATN-224 and in the presence or absence of copper in vitro. Microvessel density and changes in perfusion were evaluated by immunohistochemistry and dynamic contrast enhanced MRI (DCE-MRI). Serum stability of oHSV was measured in mice fed with ATN-224. Tumor-bearing mice were injected intravenously with oHSV; tumor burden and amount of virus in tumor tissue were evaluated. Combination of systemic ATN-224 and oHSV significantly reduced tumor growth and prolonged animal survival. Immunohistochemistry and DCE-MRI imaging confirmed that ATN-224 reduced oHSV-induced blood vessel density and vascular leakage. Copper at physiologically relevant concentrations inhibited oHSV replication and glioma cell killing, and this effect was rescued by ATN-224. ATN-224 increased serum stability of oHSV and enhanced the efficacy of systemic delivery. This study shows that combining ATN-224 with oHSV significantly increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy. ©2012 AACR.

  16. Tamoxifen nanostructured lipid carriers: enhanced in vivo antitumor efficacy with reduced adverse drug effects.

    PubMed

    Shete, Harshad K; Selkar, Nilakash; Vanage, Geeta R; Patravale, Vandana B

    2014-07-01

    A novel approach of enhancing the Tamoxifen uptake via Intestinal Lymphatic System is executed by developing long chain lipid and oil based nanostructured lipid carrier system (Tmx-NLC). The aim was to achieve improved systemic bioavailability of Tamoxifen, prevent systemic and hepatotoxicity and enhance antitumor efficacy. Following the proof of concept achieved in cell culture experiments and in vivo pharmacokinetic and biodistribution study, the current work focuses on investigation of antitumor efficacy and treatment associated toxicity in murine mammary tumor mice model. The efficacy study demonstrated greater tumor suppression and 100% survival with 1.5 and 3 mg/kg Tmx-NLC compared to 3 mg/kg Tamoxifen suspension and Mamofen(®) (Khandelwal Pharmaceuticals, Mumbai, India). Tmx-NLC treatment for a month demonstrated improved systemic toxicity profile and no evidences of hepatotoxicity. Thus, developed Tmx-NLC could prove to be a promising delivery strategy to confer superior therapeutic efficacy and ability to address the biopharmaceutical and toxicity associated issues of drug. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Polymeric Nanoparticles Containing Taxanes Enhance Chemoradiotherapeutic Efficacy in Non-small Cell Lung Cancer

    SciTech Connect

    Jung, Joohee; Park, Sung-Jin; Chung, Hye Kyung; Kang, Hye-Won; Lee, Sa-Won; Seo, Min Hyo; Park, Heon Joo; Song, Si Yeol; Jeong, Seong-Yun; Choi, Eun Kyung

    2012-09-01

    Purpose: To reduce the side effects and improve the efficacy of chemoradiation therapy, taxanes were incorporated into polymeric nanoparticles (PNP), and their synergic effect on radiation therapy in non-small cell lung cancer was evaluated. Methods and Materials: The properties of PNP-taxanes were characterized by transmission electron microscopy and dynamic light scattering. The chemoradiotherapeutic efficacy of PNP-taxanes was determined by clonogenic assay, cellular morphology, and flow cytometry in A549 cells. In mice bearing A549-derived tumors, the tumor growth delay was examined after the treatment of PNP-taxanes and/or ionizing radiation (IR). Results: The PNP-taxanes were found to be approximately 45 nm in average diameter and to have high solubility in water. They showed the properties of active internalization into cells and preserved the anticancer effect of free taxanes. The survival fraction of A549 cells by clonogenic assay was significantly reduced in the group receiving combined treatment of PNP-taxanes and IR. In addition, in vivo radiotherapeutic efficacy was markedly enhanced by the intravenous injection of PNP-taxanes into the xenograft mice. Conclusions: We have demonstrated the feasibility of PNP-taxanes to enhance the efficacy of chemoradiation therapy. These results suggest PNP-taxanes can hold an invaluable and promising position in treating human cancers as a novel and effective chemoradiation therapy agent.

  18. Enhancement of the antimalarial efficacy of amodiaquine by chlorpheniramine in vivo.

    PubMed

    Sowunmi, Akintunde; Gbotosho, Grace O; Happi, Christian T; Adedeji, Ahmed A; Bolaji, Olayinka M; Fehintola, Fatai A; Fateye, Babasola A; Oduola, Ayoade M J

    2007-06-01

    Resistance in Plasmodium falciparum to amodiaquine (AQ) can be reversed in vitro with with antihistaminic and tricyclic antidepressant compounds, but its significance in vivo is unclear. The present report presents the enhancement of the antimalarial efficacy of AQ by chlorpheniramine, an H1 receptor antagonist that reverses chloroquine (CQ) resistance in vitro and enhances its efficacy in vivo, in five children who failed CQ and/or AQ treatment, and who were subsequently retreated and cured with a combination of AQ plus CP, despite the fact that parasites infecting the children harboured mutant pfcrtT76 and pfmdr1Y86 alleles associated with AQ resistance. This suggests a potential clinical application of the reversal phenomenon.

  19. An interactive course to enhance self-efficacy of family practitioners to treat obesity

    PubMed Central

    Katz, Sara; Feigenbaum, Amiel; Pasternak, Shmuel; Vinker, Shlomo

    2005-01-01

    Background Physicians' awareness of their important role in defusing the obesity epidemic has increased. However, the number of family practitioners who treat obesity problems continues to be low. Self-efficacy refers to the belief in one's ability to organize and execute the courses of action required to produce given attainments. Thus, practitioners who judge themselves incapable of managing obesity do not even try. We hypothesized that practitioners' self-efficacy and motivation would be enhanced as a result of participating in an interactive course designed to enrich their knowledge of obesity management. Methods Twenty-nine family practitioners participated in the course, which was accompanied by qualitative interviews. The difference between the physicians' pre-course and post-course appraisals was tested by paired t-test. The interviews were analyzed by qualitative methods. Results Post-course efficacy appraisals were significantly higher than pre-course appraisals (p < 0.0005). A deeper insight on the practitioners' self-efficacy processes was gained through reflection of the practitioners on their self-efficacy during the interviews. Conclusions Up-to-date information and workshops where skills, attitudes and social support were addressed were important in making the program effective. PMID:15679894

  20. Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Nonanticoagulant Heparins

    DTIC Science & Technology

    2009-05-14

    Iqbal O, Kaiser B. Tissue factor pathway inhibitor in thrombosis and beyond. In Methods in Molecular Medicine, vol 93: Anticoagulants , Antiplatelets ...TITLE: “Enhancing the Efficacy of Chemotherapeutic Breast Cancer Treatment with Non- anticoagulant Heparins” PRINCIPAL INVESTIGATOR: Shaker... anticoagulant Heparins" 5b. GRANT NUMBER W81XWH-07-1-0344 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 5e. TASK NUMBER 6. AUTHOR(S

  1. Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus Infection

    DTIC Science & Technology

    2009-05-01

    2001. Pathogenesis of experimental Ebola Zaire virus infec- tion in BALB/c mice. J. Comp. Pathol. 125:233–242. 13. Han, Z., H. Boshra, J. O. Sunyer, S...Property Organization , Geneva, Switzerland. 38. World Health Organization . 2008. Outbreak news. Ebola haemorrhagic fe- ver, Uganda—end of the outbreak...American Society for Microbiology. All Rights Reserved. Chemical Modifications of Antisense Morpholino Oligomers Enhance Their Efficacy against Ebola Virus

  2. The efficacy of topical prophylactic antiglaucoma therapy in primary closed angle glaucoma in dogs: a multicenter clinical trial.

    PubMed

    Miller, P E; Schmidt, G M; Vainisi, S J; Swanson, J F; Herrmann, M K

    2000-01-01

    The ability of either 0.5% betaxolol (1 drop topically, bid; n=31) or a combination of 0.25% demecarium bromide and a topical corticosteroid (gentamicin/betamethasone) (DB/GB; 1 drop of each topically, sid; n=55) to prevent glaucoma in the fellow eye of dogs with unilateral, primary closed angle glaucoma (PCAG) was investigated in a multicenter, open-label, clinical trial. Untreated control dogs (n=20) developed glaucoma significantly sooner (median, eight mos; p less than 0.001) than dogs treated either with DB/GB (median, 31 mos) or betaxolol (median, 30.7 mos). Although DB/GB and betaxolol equally delayed or prevented the onset of glaucoma in the second eye, a less frequent dosing schedule for DB/GB suggests demecarium bromide in combination with a topical corticosteroid may be preferable to betaxolol in preventing PCAG in dogs.

  3. Amorphous Silica Based Nanomedicine with Safe Carrier Excretion and Enhanced Drug Efficacy

    NASA Astrophysics Data System (ADS)

    Zhang, Silu

    With recent development of nanoscience and nanotechnology, a great amount of efforts have been devoted to nanomedicine development. Among various nanomaterials, silica nanoparticle (NP) is generally accepted as non-toxic, and can provide a versatile platform for drug loading. In addition, the surface of the silica NP is hydrophilic, being favorable for cellular uptake. Therefore, it is considered as one of the most promising candidates to serve as carriers for drugs. The present thesis mainly focuses on the design of silica based nanocarrier-drug systems, aiming at achieving safe nanocarrier excretion from the biological system and enhanced drug efficacy, which two are considered as most important issues in nanomedicine development. To address the safe carrier excretion issue, we have developed a special type of selfdecomposable SiO2-drug composite NPs. By creating a radial concentration gradient of drug in the NP, the drug release occurred simultaneously with the silica carrier decomposition. Such unique characteristic was different from the conventional dense SiO2-drug NP, in which drug was uniformly distributed and can hardly escape the carrier. We found that the controllable release of the drug was primarily determined by diffusion, which was caused by the radial drug concentration gradient in the NP. Escape of the drug molecules then triggered the silica carrier decomposition, which started from the center of the NP and eventually led to its complete fragmentation. The small size of the final carrier fragments enabled their easy excretion via renal systems. Apart from the feature of safe carrier excretion, we also found the controlled release of drugs contribute significantly to the drug efficacy enhancement. By loading an anticancer drug doxorubicin (Dox) to the decomposable SiO 2-methylene blue (MB) NPs, we achieved a self-decomposable SiO 2(MB)-Dox nanomedicine. The gradual escape of drug molecules from NPs and their enabled cytosolic release by optical

  4. HemoHIM enhances the therapeutic efficacy of ionizing radiation treatment in tumor-bearing mice.

    PubMed

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho

    2010-02-01

    Although radiotherapy is commonly used for a variety of cancers, radiotherapy alone does not achieve a satisfactory therapeutic outcome. In this study, we examined the possibility that HemoHIM can enhance the anticancer effects of ionizing radiation (IR) in melanoma-bearing mice. The HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs-Angelica Radix, Cnidium Rhizoma, and Paeonia Radix. Anticancer effects of HemoHIM were evaluated in melanoma-bearing mice exposed to IR. IR treatment (5 Gy at 7 days after melanoma cell injection) reduced the weight of the solid tumors, and HemoHIM supplementation with IR enhanced the decreases in tumor weight (P < .03). In the melanoma-bearing mice treated with IR, HemoHIM administration also increased the activity of natural killer cells and cytotoxic T cells, although the proportions of these cells in spleen were not different. In addition, HemoHIM administration increased the interleukin-2 and tumor necrosis factor-alpha secretion from lymphocytes stimulated with concanavalin A, which seemed to contribute to the enhanced efficacy of HemoHIM in tumor-bearing mice treated with IR. In conclusion, HemoHIM may be a beneficial supplement during radiotherapy for enhancing the antitumor efficacy.

  5. Preparation and characterization of oxybenzone-loaded gelatin microspheres for enhancement of sunscreening efficacy.

    PubMed

    Patel, M; Jain, Sunil K; Yadav, Awesh K; Gogna, D; Agrawal, G P

    2006-01-01

    The objective of our present study was to prepare and evaluate gelatin microspheres of oxybenzone to enhance its sunscreening efficacy. The gelatin microspheres of oxybenzone were prepared by emulsion method. Process parameters were analyzed to optimize the formulation. The in vitro drug release study was performed in pH 7.4 using cellulose acetate membrane. Microspheres prepared using oxybenzone:gelatin ratio of 1:6 showed slowest drug release and those prepared with oxybenzone:gelatin ratio of 1:2 showed fastest drug release. The gelatin microspheres of oxybenzone were incorporated in aloe vera gel. Sun exposure method using sodium nitroprusside solution was used for in vitro sunscreen efficacy testing. The formulation C5 containing oxybenzone-bearing gelatin microspheres in aloe vera gel showed best sunscreen efficacy. The formulations were evaluated for skin irritation test in human volunteers, sun protection factor, and minimum erythema dose in albino rats. These studies revealed that the incorporation of sunscreening agent-loaded microspheres into aloe vera gel greatly increased the efficacy of sunscreen formulation more than four times.

  6. The mechanism of methylated seed oil on enhancing biological efficacy of topramezone on weeds.

    PubMed

    Zhang, Jinwei; Jaeck, Ortrud; Menegat, Alexander; Zhang, Zongjian; Gerhards, Roland; Ni, Hanwen

    2013-01-01

    Methylated seed oil (MSO) is a recommended adjuvant for the newly registered herbicide topramezone in China and also in other countries of the world, but the mechanism of MSO enhancing topramezone efficacy is still not clear. Greenhouse and laboratory experiments were conducted to determine the effects of MSO on efficacy, solution property, droplet spread and evaporation, active ingredient deposition, foliar absorption and translocation of topramezone applied to giant foxtail (Setaria faberi Herrm.) and velvetleaf (Abutilon theophrasti Medic.). Experimental results showed that 0.3% MSO enhanced the efficacy of topramezone by 1.5-fold on giant foxtail and by 1.0-fold on velvetleaf. When this herbicide was mixed with MSO, its solution surface tension and leaf contact angle decreased significantly, its spread areas on weed leaf surfaces increased significantly, its wetting time was shortened on giant foxtail but not changed on velvetleaf, and less of its active ingredient crystal was observed on the treated weed leaf surfaces. MSO increased the absorption of topramezone by 68.9% for giant foxtail and by 45.9% for velvetleaf 24 hours after treatment. It also apparently promoted the translocation of this herbicide in these two weeds.

  7. The Mechanism of Methylated Seed Oil on Enhancing Biological Efficacy of Topramezone on Weeds

    PubMed Central

    Zhang, Jinwei; Jaeck, Ortrud; Menegat, Alexander; Zhang, Zongjian; Gerhards, Roland; Ni, Hanwen

    2013-01-01

    Methylated seed oil (MSO) is a recommended adjuvant for the newly registered herbicide topramezone in China and also in other countries of the world, but the mechanism of MSO enhancing topramezone efficacy is still not clear. Greenhouse and laboratory experiments were conducted to determine the effects of MSO on efficacy, solution property, droplet spread and evaporation, active ingredient deposition, foliar absorption and translocation of topramezone applied to giant foxtail (Setaria faberi Herrm.) and velvetleaf (Abutilon theophrasti Medic.). Experimental results showed that 0.3% MSO enhanced the efficacy of topramezone by 1.5-fold on giant foxtail and by 1.0-fold on velvetleaf. When this herbicide was mixed with MSO, its solution surface tension and leaf contact angle decreased significantly, its spread areas on weed leaf surfaces increased significantly, its wetting time was shortened on giant foxtail but not changed on velvetleaf, and less of its active ingredient crystal was observed on the treated weed leaf surfaces. MSO increased the absorption of topramezone by 68.9% for giant foxtail and by 45.9% for velvetleaf 24 hours after treatment. It also apparently promoted the translocation of this herbicide in these two weeds. PMID:24086329

  8. Immunosuppression Enhances Oncolytic Adenovirus Replication and Antitumor Efficacy in the Syrian Hamster Model

    PubMed Central

    Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William SM

    2012-01-01

    We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth. PMID:18665155

  9. Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model.

    PubMed

    Thomas, Maria A; Spencer, Jacqueline F; Toth, Karoly; Sagartz, John E; Phillips, Nancy J; Wold, William S M

    2008-10-01

    We recently described an immunocompetent Syrian hamster model for oncolytic adenoviruses (Ads) that permits virus replication in tumor cells as well as some normal tissues. This model allows exploration of interactions between the virus, tumor, normal organs, and host immune system that could not be examined in the immunodeficient or nonpermissive animal models previously used in the oncolytic Ad field. Here we asked whether the immune response to oncolytic Ad enhances or limits antitumor efficacy. We first determined that cyclophosphamide (CP) is a potent immunosuppressive agent in the Syrian hamster and that CP alone had no effect on tumor growth. Importantly, we found that the antitumor efficacy of oncolytic Ads was significantly enhanced in immunosuppressed animals. In animals that received virus therapy plus immunosuppression, significant differences were observed in tumor histology, and in many cases little viable tumor remained. Notably, we also determined that immunosuppression allowed intratumoral virus levels to remain elevated for prolonged periods. Although favorable tumor responses can be achieved in immunocompetent animals, the rate of virus clearance from the tumor may lead to varied antitumor efficacy. Immunosuppression, therefore, allows sustained Ad replication and oncolysis, which leads to substantially improved suppression of tumor growth.

  10. Gold nanoparticles enhance 5-fluorouracil anticancer efficacy against colorectal cancer cells.

    PubMed

    Safwat, Mohamed A; Soliman, Ghareb M; Sayed, Douaa; Attia, Mohamed A

    2016-11-20

    5-Fluorouracil (5-FU), an antimetabolite drug, is extensively used in the treatment solid tumors. However, its severe side effects limit its clinical benefits. To enhance 5-FU anticancer efficacy and reduce its side effects it was loaded onto gold nanoparticles (GNPs) using two thiol containing ligands, thioglycolic acid (TGA) and glutathione (GSH). The GNPs were prepared at different 5-FU/ligand molar ratios and evaluated using different techniques. Anticancer efficacy of 5-FU/GSH-GNPs was studied using flow cytometry in cancerous tissue obtained from patients having colorectal cancer. The GNPs were spherical in shape and had a size of ∼9-17nm. Stability of the GNPs and drug release were studied as a function of salt concentration and solution pH. Maximum 5-FU loading was achieved at 5-FU/ligand molar ratio of 1:1 and 2:1 for TGA-GNPs and GSH-GNPs, respectively. GNPs coating with pluronic F127 improved their stability against salinity. 5-FU release from GNPs was slow and pH-dependent. 5-FU/GSH-GNPs induced apoptosis and stopped the cell cycle progression in colorectal cancer cells. They also had a 2-fold higher anticancer effect compared with free 5-FU. These results confirm the potential of GNPs to enhance 5-FU anticancer efficacy.

  11. Liposomal carfilzomib nanoparticles effectively target multiple myeloma cells and demonstrate enhanced efficacy in vivo.

    PubMed

    Ashley, Jonathan D; Stefanick, Jared F; Schroeder, Valerie A; Suckow, Mark A; Alves, Nathan J; Suzuki, Rikio; Kikuchi, Shohei; Hideshima, Teru; Anderson, Kenneth C; Kiziltepe, Tanyel; Bilgicer, Basar

    2014-12-28

    Carfilzomib, a recently FDA-approved proteasome inhibitor, has remarkable anti-myeloma (MM) activity. However, its effectiveness is limited by associated severe side-effects, short circulation half-life, and limited solubility. Here, we report the engineering of liposomal carfilzomib nanoparticles to overcome these problems and enhance the therapeutic efficacy of carfilzomib by increasing tumoral drug accumulation while decreasing systemic toxicity. In our design, carfilzomib was loaded into the bilayer of liposomes to yield stable and reproducible liposomal nanoparticles. Liposomal carfilzomib nanoparticles were efficiently taken up by MM cells, demonstrated proteasome inhibition, induced apoptosis, and exhibited enhanced cytotoxicity against MM cells. In vivo, liposomal carfilzomib demonstrated significant tumor growth inhibition and dramatically reduced overall systemic toxicity compared to free carfilzomib. Finally, liposomal carfilzomib demonstrated enhanced synergy in combination with doxorubicin. Taken together, this study establishes the successful synthesis of liposomal carfilzomib nanoparticles that demonstrates improved therapeutic index and the potential to improve patient outcome in MM.

  12. CHO glycosylation mutants as potential host cells to produce therapeutic proteins with enhanced efficacy.

    PubMed

    Zhang, Peiqing; Chan, Kah Fai; Haryadi, Ryan; Bardor, Muriel; Song, Zhiwei

    2013-01-01

    CHO glycosylation mutants, pioneered by Stanley and co-workers, have proven to be valuable tools in glycobiology and biopharmaceutical research. Here we aim to provide a summary of our efforts to isolate industrially applicable CHO glycosylation mutants, termed CHO-gmt cells, using cytotoxic lectins and zinc-finger nuclease technology. The genetic defects in the glycosylation machinery in these cells lead to the production of recombinant glycoproteins with consistent and unique glycan structures. In addition, these mutant cells can be easily adapted to serum-free medium in suspension cultures, the condition used by the biotech industry for large-scale production of recombinant therapeutics. In light of the critical impact of glycosylation on biopharmaceutical performances, namely, safety and efficacy, the CHO-gmt lines have enormous potential in producing glycoprotein therapeutics with optimal glycosylation profiles, thus, representing a panel of ideal host cell lines for producing recombinant biopharmaceuticals with improved safety profiles and enhanced efficacy.

  13. Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells

    PubMed Central

    Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G; Koo, Jin Mo; Lin, Ran; Masood, Asad; Schiapparelli, Paula; Quiñones-Hinojosa, Alfredo; Cui, Honggang

    2016-01-01

    Chemical modification of small molecule hydrophobic drugs is a clinically proven strategy to devise prodrugs with enhanced treatment efficacy. While this prodrug strategy improves the parent drug's water solubility and pharmacokinetic profile, it typically compromises the drug's potency against cancer cells due to the retarded drug release rate and reduced cellular uptake efficiency. Here we report on the supramolecular design of self-assembling prodrugs (SAPD) with much improved water solubility while maintaining high potency against cancer cells. We found that camptothecin (CPT) prodrugs created by conjugating two CPT molecules onto a hydrophilic segment can associate into filamentous nanostructures in water. Our results suggest that these SAPD exhibit much greater efficacy against primary brain cancer cells relative to that of irinotecan, a clinically used CPT prodrug. We believe these findings open a new avenue for rational design of supramolecular prodrugs for cancer treatment. PMID:27217839

  14. Co-administration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs

    PubMed Central

    Sugahara, Kazuki N.; Teesalu, Tambet; Karmali, Priya Prakash; Kotamraju, Venkata Ramana; Agemy, Lilach; Greenwald, Daniel R.; Ruoslahti, Erkki

    2010-01-01

    Poor penetration of anti-cancer drugs into tumors can be an important factor limiting their efficacy. Studying mouse tumor models, we show that a previously characterized tumor-penetrating peptide, iRGD (CRGDK/RGPD/EC), increased vascular and tissue permeability in a tumor-specific and neuropilin-1-dependent manner, allowing co-administered drugs to penetrate into extravascular tumor tissue. Importantly, this effect did not require the drugs to be chemically conjugated to the peptide. Systemic injection with iRGD improved the therapeutic index of drugs of various compositions including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab). Thus, co-administration of iRGD may be a valuable way to enhance the efficacy of anti-cancer drugs while reducing their side effects, a primary goal of cancer therapy research. PMID:20378772

  15. Enhancing self-efficacy for self-management in people with cystic fibrosis.

    PubMed

    Cummings, Elizabeth; Hauser, Jenny; Cameron-Tucker, Helen; Fitzpatrick, Petya; Jessup, Melanie; Walters, E Haydn; Reid, David; Turner, Paul

    2011-01-01

    This paper reports on a research trial designed to evaluate the benefits of a health mentoring programme supported with a web and mobile phone based self-monitoring application for enhancing self-efficacy for self-management skills and quality of life for people with CF. This randomised, single-blind controlled trial evaluated two strategies designed to improve self-management behaviour and quality of life. Task-specific self-efficacy was fostered through mentorship and self-monitoring via a mobile phone application. Trial participants were randomised into one of three groups: Control, Mentor-only and Mentor plus mobile phone. Analysis and discussion focus on the experiences of participants through a methodology utilising descriptive statistics and semi-structured interviews. The results highlight the challenges of stimulating self-management behaviours particularly in adolescents and in the evaluation of the role of mobile applications in supporting them.

  16. Chloroquine enhances the efficacy of cisplatin by suppressing autophagy in human adrenocortical carcinoma treatment

    PubMed Central

    Qin, Liang; Xu, Tianyuan; Xia, Leilei; Wang, Xianjin; Zhang, Xiang; Zhang, Xiaohua; Zhu, Zhaowei; Zhong, Shan; Wang, Chuandong; Shen, Zhoujun

    2016-01-01

    Background It has been demonstrated that chloroquine (CQ) enhances the efficacy of chemotherapy. However, little is known about whether CQ could enhance the efficacy of cisplatin (DDP) in the treatment of adrenocortical carcinoma (ACC). In this study, we explore the efficacy and mechanism by which CQ affects DDP sensitivity in human ACC in vitro and in vivo. Methods The autophagic gene Beclin-1 expression was detected by immunohistochemistry, and the protein levels were analyzed using immunoblotting assays of ACC tissues and normal adrenal cortex tissues. The ACC SW13 cells were treated with DDP and/or CQ. The cell viability assay was performed using the MTT method. Qualitative autophagy detection was performed by monodansylcadaverine staining of autophagic vacuoles. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to count cell apoptosis by flow cytometry. The autophagy-related protein (Beclin-1, LC3, and p62) and apoptosis relative protein (Bax and Bcl-2) levels were evaluated with Western blot analysis. Furthermore, a murine model of nude BALB/c mice bearing SW13 cell xenografts was established to evaluate the efficacy of concomitant therapy. Results The expression of the autophagic gene Beclin-1 was significantly downregulated in ACC tissues compared to normal adrenal cortex tissues. The Beclin-1 protein level in ACC tissues was lower than that in normal adrenal cortex tissues (P<0.05). In vitro concomitant therapy (DDP and CQ) was more effective in restraining SW13 cell proliferation. DDP could promote cell apoptosis and induce autophagy in SW13 cells. Concomitant therapy further promoted cell apoptosis by inhibiting autophagy. In vivo, we found that concomitant therapy was more potent than DDP monotherapy in inhibiting the growth of xenografted tumors and prolonging the survival of tumor-bearing mice. Conclusion The antitumor ability of DDP was related to autophagy activity, and the concomitant therapy (DDP and CQ) could be an

  17. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics

    PubMed Central

    CHENG, KA-WING; WONG, CHI C.; MATTHEOLABAKIS, GEORGE; XIE, GANG; HUANG, LIQUN; RIGAS, BASIL

    2013-01-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination. PMID:23807084

  18. Curcumin enhances the lung cancer chemopreventive efficacy of phospho-sulindac by improving its pharmacokinetics.

    PubMed

    Cheng, Ka-Wing; Wong, Chi C; Mattheolabakis, George; Xie, Gang; Huang, Liqun; Rigas, Basil

    2013-09-01

    Phospho-sulindac (PS) is a safe sulindac derivative with promising anticancer efficacy in colon cancer. We evaluated whether its combination with curcumin could enhance the efficacy in the treatment of lung cancer. Curcumin, the principal bioactive component in turmeric, has demonstrated versatile capabilities to modify the therapeutic efficacy of a wide range of anticancer agents. Here, we evaluated the effect of co-administration of curcumin on the anticancer activity of PS in a mouse xenograft model of human lung cancer. Curcumin enhanced the cellular uptake of PS in human lung and colon cancer cell lines. To assess the potential synergism between curcumin and PS in vivo, curcumin was suspended in 10% Tween-80 or formulated in micellar nanoparticles and given to mice by oral gavage prior to the administration of PS. Both formulations of curcumin significantly improved the pharmacokinetic profiles of PS, with the 10% Tween-80 suspension being much more effective than the nanoparticle formation. However, curcumin did not exhibit any significant modification of the metabolite profile of PS. Furthermore, in a mouse subcutaneous xenograft model of human lung cancer, PS (200 mg/kg) in combination with curcumin (500 mg/kg) suspended in 10% Tween-80 (51% inhibition, p<0.05) was significantly more efficacious than PS plus micelle curcumin (30%) or PS (25%) or curcumin alone (no effect). Consistent with the improved pharmacokinetics, the combination treatment group had higher levels of PS and its metabolites in the xenografts compared to PS alone. Our results show that curcumin substantially improves the pharmacokinetics of PS leading to synergistic inhibition of the growth of human lung cancer xenografts, representing a promising drug combination.

  19. Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy.

    PubMed

    Shrimali, Rajeev; Ahmad, Shamim; Berrong, Zuzana; Okoev, Grigori; Matevosyan, Adelaida; Razavi, Ghazaleh Shoja E; Petit, Robert; Gupta, Seema; Mkrtichyan, Mikayel; Khleif, Samir N

    2017-01-01

    We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4(+) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4(+) and CD8(+) T cells along with a decrease of inhibitory cells. To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall

  20. Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy.

    PubMed

    Shrimali, Rajeev; Ahmad, Shamim; Berrong, Zuzana; Okoev, Grigori; Matevosyan, Adelaida; Razavi, Ghazaleh Shoja E; Petit, Robert; Gupta, Seema; Mkrtichyan, Mikayel; Khleif, Samir N

    2017-08-15

    We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4(+) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4(+) and CD8(+) T cells along with a decrease of inhibitory cells. To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall

  1. Anticipation, anti-glaucoma drug treatment response and phenotype of a Chinese family with glaucoma caused by the Pro370Leu myocilin mutation.

    PubMed

    Li, Chun-Mei; Zhang, Yue-Hong; Ye, Rong-Hua; Yi, Chang-Xian; Zhong, Yi-Min; Cao, Dan; Liu, Xing

    2014-01-01

    To describe the anticipation and anti-glaucoma drugs response of a Chinese family with juvenile-onset open angle glaucoma (JOAG) caused by the Pro370Leu myocilin (MYOC) mutation. Fifteen members of a three-generation Chinese family with JOAG were recruited to this study. They all underwent ophthalmic common examinations. Patients suspected to have JOAG got an assessment of visual field and optical coherence tomography. Intraocular pressures (IOPs) of four patients were measured at 8, 10, 12, 14, 17 o'clock respectively after using anti-glaucoma drugs. Mutation screening of all MYOC gene coding exons of the participants was performed by using direct sequencing of PCR products. Clinical examinations and pedigree analysis revealed eight family members were suffered from JOAG. Apparent genetics anticipation phenomenon was observed in this family. Their clinical features included elevated IOP of 35-55mmHg, loss of visual field, thinning of retinal nerve fiber layer, and glaucomatous optic disc damage. Noticeably, their intraocular pressure levels could be controlled within normal range at 8 and 10 o'clock by anti-glaucoma drugs, but their IOPs would elevate >21mmHg after 12 o'clock. Seven patients received trabeculectomy produced thin-walled, pale, and saccate filtering blebs maintaining lower intraocular pressure efficiently. Mutation screening indentified a heterozygous C→T missense mutation in the MYOC gene at position 1 109 in exon 3, corresponding to a substitution of a highly conserved proline to leucine at codon 370 in the olfactomedin domain of MYOC. The clinical characteristics of JOAG in this family were 1) genetics anticipation; 2) high IOP; 3) temporay response to anti-glaucoma drugs; 4) filtering surgery produced thin-walled and saccate filtering blebs, helping maintain lower IOP.

  2. Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display.

    PubMed

    Nair, Pradeep M; Flores, Heather; Gogineni, Alvin; Marsters, Scot; Lawrence, David A; Kelley, Robert F; Ngu, Hai; Sagolla, Meredith; Komuves, Laszlo; Bourgon, Richard; Settleman, Jeffrey; Ashkenazi, Avi

    2015-05-05

    TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes--synthetic lipid-bilayer nanospheres--similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.

  3. β2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

    PubMed Central

    Koeberl, Dwight D.; Li, Songtao; Dai, Jian; Thurberg, Beth L.; Bali, Deeksha; Kishnani, Priya S.

    2011-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  4. β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.

    PubMed

    Koeberl, Dwight D; Li, Songtao; Dai, Jian; Thurberg, Beth L; Bali, Deeksha; Kishnani, Priya S

    2012-02-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes.

  5. Three-Dimensional Cell Grafting Enhances the Angiogenic Efficacy of Human Umbilical Vein Endothelial Cells

    PubMed Central

    Bhang, Suk Ho; Lee, Seahyoung; Lee, Tae-Jin; La, Wan-Geun; Yang, Hee-Seok; Cho, Seung-Woo

    2012-01-01

    Despite the great potential of cell therapy for ischemic disease, poor cell survival after engraftment in ischemic tissue limits its efficacy. Here we tested a hypothesis that three-dimensionally grafted human umbilical vein endothelial cell (HUVEC) spheroids would exhibit improved angiogenic efficacy following transplantation into mouse ischemic limbs compared with HUVECs prepared by conventional two-dimensional monolayer culture. One day after surgical induction of hindlimb ischemia in athymic mice, HUVECs cultured in monolayer or HUVEC spheroids were transplanted intramuscularly into ischemic limbs. Four weeks after the treatment, in the spheroid HUVEC transplantation group, we observed increased hypoxia-inducible factor-1α expression, decreased apoptosis, and increased HUVEC survival in the ischemic tissue compared with the monolayer HUVEC transplantation group. Transplantation of HUVEC spheroids also resulted in enhanced and prolonged secretion of paracrine factors as well as enhanced expression of factors involved in the recruitment of circulating angiogenic progenitor cells. In summary, transplantation of HUVECs as spheroids enhanced cell survival, increased paracrine factor secretion, and showed a potential as a therapeutic method to treat ischemic tissue damages by promoting angiogenesis. PMID:21902465

  6. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice

    PubMed Central

    2009-01-01

    Background Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. Methods HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. Results In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-γ secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. Conclusion HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin. PMID:19292900

  7. Enhanced antitumor efficacy of cisplatin in combination with HemoHIM in tumor-bearing mice.

    PubMed

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho; Yee, Sung-Tae

    2009-03-17

    Although cisplatin is one of the most effective chemotherapeutic agents, cisplatin alone does not achieve a satisfactory therapeutic outcome. Also cisplatin accumulation shows toxicity to normal tissues. In this study, we examined the possibility of HemoHIM both to enhance anticancer effect with cisplatin and to reduce the side effects of cisplatin in melanoma-bearing mice. HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of 3 edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Anticancer effects of HemoHIM with cisplatin were evaluated in melanoma-bearing mice. We used a Cr51-release assay to measure the activity of NK/Tc cell and ELISA to evaluate the production of cytokines. In melanoma-bearing mice, cisplatin (4 mg/kg B.W.) reduced the size and weight of the solid tumors, and HemoHIM supplementation with cisplatin enhanced the decrease of both the tumor size (p < 0.1) and weight (p < 0.1). HemoHIM itself did not inhibit melanoma cell growth in vitro, and did not disturb the effects of cisplatin in vitro. However HemoHIM administration enhanced both NK cell and Tc cell activity in mice. Interestingly, HemoHIM increased the proportion of NK cells in the spleen. In melanoma-bearing mice treated with cisplatin, HemoHIM administration also increased the activity of NK cells and Tc cells and the IL-2 and IFN-gamma secretion from splenocytes, which seemed to contribute to the enhanced efficacy of cisplatin by HemoHIM. Also, HemoHIM reduced nephrotoxicity as seen by tubular cell of kidney destruction. HemoHIM may be a beneficial supplement during cisplatin chemotherapy for enhancing the anti-tumor efficacy and reducing the toxicity of cisplatin.

  8. An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine

    PubMed Central

    Schmauss, C.

    2015-01-01

    Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy. PMID:25639887

  9. Recent Approaches to Platinum(IV) Prodrugs: A Variety of Strategies for Enhanced Delivery and Efficacy.

    PubMed

    Najjar, Anas; Rajabi, Naeema; Karaman, Rafik

    2017-01-01

    Intensive efforts have been implemented to improve the efficacy of platinum complexes especially with emerging cisplatin resistance and elevated cancer deaths. Platinum(IV) agents show better pharmacokinetics and decreased side effects compared to Platinum(II) agents. This review aims to summarize and categorize the strategies being employed to improve the efficacy of Platinum-based anticancer agents in recent years. Nanoparticles and nanoplatforms offer a vast variety of strategies in targeting specific tumor types and delivering one or two lethal drugs simultaneously. Theranostic agents are being developed to achieve enhanced imaging and provide further insight into the activity of platinum containing chemotherapy. Moreover, photoactivation of Pt(IV) prodrugs specifically at the tumor site is gaining attention due to a controlled activity. A platinum agent formulated as large multi-activity complex is the most common strategy being employed. Platinum(IV) agents offer great potential in targeting, increasing efficacy, and decreasing toxicity of Platinum-based anticancer agents. The strategies being employed are aiming to increase specificity and targeting as well as provide more potent agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Effectiveness of cultural immersion and culture classes for enhancing nursing students' transcultural self-efficacy.

    PubMed

    Larsen, Rachelle; Reif, LuAnn

    2011-06-01

    With diversity increasing in the United States, educators are struggling to find the most effective methods to prepare nursing students to care for diverse populations. This study's purpose was to determine the impact of immersion experiences and cultural classes on nursing students' transcultural competence. A pretest-posttest, quasi-experimental design was used. Nursing students completing a 2-week to 3-week immersion experience (n = 14) completed the Transcultural Self-Efficacy Tool online 1 week prior to and immediately following an immersion experience. The control group (n = 25), who were students not participating in an immersion experience, completed the instrument during the same time frame. Students who participated in an immersion experience had significantly higher posttest transcultural self-efficacy scores (p < 0.001). Compared with the control group, the students in the immersion group had significantly higher change scores (p < 0.001). In addition, the number of culture classes completed was not correlated with transcultural self-efficacy scores. Recommendations included encouraging student participation in immersion experiences to enhance transcultural competence. Copyright 2011, SLACK Incorporated.

  11. Treatment Strategies that Enhance the Efficacy and Selectivity of Mitochondria-Targeted Anticancer Agents

    PubMed Central

    Modica-Napolitano, Josephine S.; Weissig, Volkmar

    2015-01-01

    Nearly a century has passed since Otto Warburg first observed high rates of aerobic glycolysis in a variety of tumor cell types and suggested that this phenomenon might be due to an impaired mitochondrial respiratory capacity in these cells. Subsequently, much has been written about the role of mitochondria in the initiation and/or progression of various forms of cancer, and the possibility of exploiting differences in mitochondrial structure and function between normal and malignant cells as targets for cancer chemotherapy. A number of mitochondria-targeted compounds have shown efficacy in selective cancer cell killing in pre-clinical and early clinical testing, including those that induce mitochondria permeability transition and apoptosis, metabolic inhibitors, and ROS regulators. To date, however, none has exhibited the standards for high selectivity and efficacy and low toxicity necessary to progress beyond phase III clinical trials and be used as a viable, single modality treatment option for human cancers. This review explores alternative treatment strategies that have been shown to enhance the efficacy and selectivity of mitochondria-targeted anticancer agents in vitro and in vivo, and may yet fulfill the clinical promise of exploiting the mitochondrion as a target for cancer chemotherapy. PMID:26230693

  12. Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy.

    PubMed

    Gorityala, Bala Kishan; Guchhait, Goutam; Fernando, Dinesh M; Deo, Soumya; McKenna, Sean A; Zhanel, George G; Kumar, Ayush; Schweizer, Frank

    2016-01-11

    The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits.

    PubMed

    Briggs, Farran; Mangun, George R; Usrey, W Martin

    2013-07-25

    Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behaviour are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by increasing the efficacy of presynaptic input in driving postsynaptic responses, by increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and by decreasing redundant signals between postsynaptic neurons receiving common input. The results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory environment.

  14. Enhancement of the anti-damping spin torque efficacy of platinum by interface modification

    SciTech Connect

    Nguyen, Minh-Hai; Pai, Chi-Feng; Nguyen, Kayla X.; Buhrman, R. A.; Muller, David A.; Ralph, D. C.

    2015-06-01

    We report a strong enhancement of the efficacy of the spin Hall effect (SHE) of Pt for exerting anti-damping spin torque on an adjacent ferromagnetic layer by the insertion of ≈0.5 nm layer of Hf between a Pt film and a thin, ≤2 nm, Fe{sub 60}Co{sub 20}B{sub 20} ferromagnetic layer. This enhancement is quantified by measurement of the switching current density when the ferromagnetic layer is the free electrode in a magnetic tunnel junction. The results are explained as the suppression of spin pumping through a substantial decrease in the effective spin-mixing conductance of the interface, but without a concomitant reduction of the ferromagnet's absorption of the SHE generated spin current.

  15. Solid lipid nanoparticle suspension enhanced the therapeutic efficacy of praziquantel against tapeworm.

    PubMed

    Xie, Shuyu; Pan, Baoliang; Shi, Baoxin; Zhang, Zhuangzhi; Zhang, Xu; Wang, Ming; Zhou, Wenzhong

    2011-01-01

    Hydatid disease caused by tapeworm is an increasing public health and socioeconomic concern. In order to enhance the therapeutic efficacy of praziquantel (PZQ) against tapeworm, PZQ-loaded hydrogenated castor oil solid lipid nanoparticle (PZQ-HCO-SLN) suspension was prepared by a hot homogenization and ultrasonication method. The stability of the suspension at 4°C and room temperature was evaluated by the physicochemical characteristics of the nanoparticles and in-vitro release pattern of the suspension. Pharmacokinetics was studied after subcutaneous administration of the suspension in dogs. The therapeutic effect of the novel formulation was evaluated in dogs naturally infected with Echinococcus granulosus. The results showed that the drug recovery of the suspension was 97.59% ± 7.56%. Nanoparticle diameter, polydispersivity index, and zeta potential were 263.00 ± 11.15 nm, 0.34 ± 0.06, and -11.57 ± 1.12 mV, respectively and showed no significant changes after 4 months of storage at both 4°C and room temperature. The stored suspensions displayed similar in-vitro release patterns as that of the newly prepared one. SLNs increased the bioavailability of PZQ 5.67-fold and extended the mean residence time of the drug from 56.71 to 280.38 hours. Single subcutaneous administration of PZQ-HCO-SLN suspension obtained enhanced therapeutic efficacy against tapeworm in infected dogs. At the dose of 5 mg/kg, the stool-ova reduction and negative conversion rates and tapeworm removal rate of the suspension were 100%, while the native PZQ were 91.55%, 87.5%, and 66.7%. When the dose reduced to 0.5 mg/kg, the native drug showed no effect, but the suspension still got the same therapeutic efficacy as that of the 5 mg/kg native PZQ. These results demonstrate that the PZQ-HCO-SLN suspension is a promising formulation to enhance the therapeutic efficacy of PZQ.

  16. Enhanced photodynamic therapy efficacy of methylene blue-loaded calcium phosphate nanoparticles.

    PubMed

    Seong, Da-Young; Kim, Young-Jin

    2015-05-01

    Although methylene blue (MB) is the most inexpensive photosensitizer with promising applications in the photodynamic therapy (PDT) for its high quantum yield of singlet oxygen generation, the clinical use of MB has been limited by its rapid enzymatic reduction in the biological environment. To enhance PDT efficacy of MB by preventing the enzymatic reduction, we have developed a new mineralization method to produce highly biocompatible MB-loaded calcium phosphate (CaP-MB) nanoparticles in the presence of polymer templates. The resulting CaP-MB nanoparticles exhibited spherical shape with a size of under 50 nm. Fourier transform infrared (FT-IR) and zeta-potential analyses confirmed the insertion of MB into the CaP-MB nanoparticles. The encapsulation of MB in CaP nanoparticles could effectively protect MB from the enzymatic reduction. In addition, the CaP-MB nanoparticles exhibited a good biocompatibility in the dark condition and significantly enhanced PDT efficacy due to apoptotic cell death against human breast cancer cells as compared with free MB, implying that CaP-MB nanoparticle system might be potentially applicable in PDT. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Atorvastatin calcium encapsulated eudragit nanoparticles with enhanced oral bioavailability, safety and efficacy profile.

    PubMed

    Kumar, Nagendra; Chaurasia, Sundeep; Patel, Ravi R; Khan, Gayasuddin; Kumar, Vikas; Mishra, Brahmeshwar

    2017-03-01

    Atorvastatin calcium (ATR), a second generation statin drug, was encapsulated in eudragit RSPO-based polymeric nanoparticles. The effect of independent variables (polymer content, stabilizer concentration, volume of chloroform and homogenization speed) on response variables (mean diameter particle size and entrapment efficiency) were investigated by employing central composite experimental design. All the independent variables were found to be significant for determining the response variables. Solid-state characterization study indicated the absence of physicochemical interaction between drug and polymer in formulation. Morphological study exhibited homogenous spherical shape of formulated nanoparticles. In vitro release study in phosphate buffer (pH 7.4) demonstrated sustained release profile over 24 h. Pharmacokinetic study in Charles Foster rats showed significant enhancement in oral bioavailability as compared to pure drug suspension. Efficacy study (lipid profile and blood glucose level) significantly justified the effectiveness of formulation having 50% less dose of ATR as compared to pure drug suspension. The effectiveness of formulation was further justified with an improved plasma safety profile of treated rats. Hence, ATR encapsulated eudragit RSPO nanoparticles can serve as potential drug delivery approach to enhance drug bioavailability, efficacy and safety profiles to alter existing marketed drug products.

  18. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma.

    PubMed

    Dai, Wei; Gao, Quangen; Qiu, Jianping; Yuan, Jianmao; Wu, Guoliang; Shen, Genhai

    2016-05-01

    Quercetin (Q), a flavonoid compound, which is obtained in variety of fruits, seeds, and vegetables, has been reported to possess many pharmacological properties including cancer-preventive and anticancer effects. However, studies on the anticancer effects and underlying mechanisms of Q in human hepatocellular carcinoma (HCC) are still limited. The present study is conducted to investigate the anticancer efficacy and adjuvant chemotherapy action of Q in HCC. HCC cell lines HepG2 and SMCC-7721 were treated with different concentrations of Q. The antiproliferative effects of Q were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and the apoptosis and cell cycle dynamics were assessed by flow cytometry; the expression of apoptosis-associated proteins were evaluated by Western blot and immunohistochemistry staining; the tumor growth in vivo was evaluated in a xenograft mouse model. Our results showed that Q effectively inhibited human HCC cell proliferation and induced apoptosis by upregulating the expression of Bad and Bax and downregulating the expression of Bcl-2 and Survivin in vitro. Furthermore, Q obviously inhibited the tumor growth and enhanced the 5-fluorouracil (5-FU) therapeutic efficacy in vitro and in vivo. Taken together, our findings highlight that Q effectively inhibited the growth of tumor and enhanced the sensitivity to thermotherapy, indicating Q is a potential treatment option for HCC.

  19. Cross-evaluation of optimal glycerol concentration to enhance optical tissue clearing efficacy.

    PubMed

    Son, T; Jung, B

    2015-08-01

    The efficacy of light therapeutic and diagnostic applications can be enhanced by employing optical tissue clearing (OTC) agents to minimize light scattering in tissue. This study aimed to investigate the optimal concentration of glycerol, so that it can be efficiently used as an OTC agent in dermatology. Glycerol was topically applied to avoid the possibility of edema that could be caused by dermal injection. The efficacy of glycerol was quantitatively evaluated for various concentrations using optical coherence tomography (OCT) to evaluate light scattering and ultrasound imaging modality to evaluate collagen dissociation. The intensity in the OCT images in the deeper regions increased over time after glycerol application owing to enhanced light penetration caused by glycerol permeation into the sample. A comparable decrease over time in the collagen distribution was observed in the ultrasound images after glycerol application. The optimal concentration of glycerol to maximize OTC was found to be 70%. The finding of this study may provide a guideline regarding the use of glycerol for efficient light diagnosis and therapy in dermatology. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Enhancing Self-Efficacy for Optimized Patient Outcomes through the Theory of Symptom Self-Management

    PubMed Central

    Hoffman, Amy J.

    2012-01-01

    Background In today’s world, greater patient empowerment is imperative since 90 million Americans live with one or more chronic conditions such as cancer. Evidence reveals that healthy behaviors such as effective symptom self-management can prevent or reduce much of the suffering from cancer. Oncology nurses play a pivotal role in developing a symptom self-management plan that is critical to optimizing a patient’s symptom self-management behaviors. Objective This article uses exemplars to describe how oncology nurses can apply a tested middle-range theory, the Theory of Symptom Self-Management, to clinical practice by incorporating interventions to increase a patient’s perceived self-efficacy to optimize patient outcomes. Methods The Theory of Symptom Self-Management provides a means to understand the dynamic aspects of symptom self-management and provides a tested framework for the development of efficacy enhancing interventions for use by oncology nurses in clinical practice. Results Exemplars based on the Theory of Symptom Self-Management that depict how oncology nursing can use perceived self-efficacy enhancing symptom self-management interventions to improve the functional status and quality of life of their patients. Conclusion Guided by a theoretical approach, oncology nurses can have a significant positive impact on the lives of their patients by reducing the symptom burden associated with cancer and its treatment. Implications for Practice Oncology nurses can partner with their patients to design tailored approaches to symptom self-management. These tailored approaches provide the ability to implement patient specific behaviors that recognize, prevent, relieve, or decrease the timing, intensity, distress, concurrence, and unpleasant quality of symptoms. PMID:22495550

  1. A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension

    PubMed Central

    Toba, Michie; Alzoubi, Abdallah; O’Neill, Kealan; Abe, Kohtaro; Urakami, Takeo; Komatsu, Masanobu; Alvarez, Diego; Järvinen, Tero A.H.; Mann, David; Ruoslahti, Erkki; McMurtry, Ivan F.; Oka, Masahiko

    2015-01-01

    A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH. PMID:24401613

  2. Quantum dots as enhancers of the efficacy of bacterial lethal photosensitization

    NASA Astrophysics Data System (ADS)

    Narband, N.; Mubarak, M.; Ready, D.; Parkin, I. P.; Nair, S. P.; Green, M. A.; Beeby, A.; Wilson, M.

    2008-11-01

    Because of the increasing resistance of bacteria to antibiotics there is considerable interest in light-activated antimicrobial agents (LAAAs) as alternatives to antibiotics for treating localized infections. The purpose of this study was to determine whether CdSe/ZnS quantum dots (QD) could enhance the antibacterial activity of the LAAA, toluidine blue O (TBO). Suspensions of Staphylococcus aureus and Streptococcus pyogenes were exposed to white light (3600 lux) and TBO (absorbance maximum = 630 nm) in the presence and absence of 25 nm diameter QD (emission maximum = 627 nm). When the TBO:QD ratio was 2667:1, killing of Staph. aureus was enhanced by 1.72log10 units. In the case of Strep. pyogenes, an enhanced kill of 1.55log10 units was achieved using TBO and QD in the ratio 267:1. Singlet oxygen and fluorescence measurements showed that QD suppress the formation of singlet oxygen from TBO and that QD fluorescence is significantly quenched in the presence of TBO (70-90%). Enhanced killing appears to be attributable to a non-Förster resonance energy transfer mechanism, whereby the QD converts part of the incident light to the absorption maximum for TBO; hence more light energy is harvested, resulting in increased concentrations of bactericidal radicals. QD may, therefore, be useful in improving the efficacy of antimicrobial photodynamic therapy.

  3. Enhancing HIV communication between parents and children: efficacy of the Parents Matter! Program.

    PubMed

    Miller, Kim S; Lin, Carol Y; Poulsen, Melissa N; Fasula, Amy; Wyckoff, Sarah C; Forehand, Rex; Long, Nicholas; Armistead, Lisa

    2011-12-01

    We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV-prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages and 95% confidence intervals compare parents' perception of child readiness to learn about sexual issues, communication effectiveness, and dyad concordance from baseline to 12 months postintervention. Wilcoxon rank sum tests compare the changes in scores measuring communication content in HIV/AIDS, abstinence, and condom use. Compared to control, parents in the enhanced arm increased perception of child readiness to learn about sex (16% vs. 29%; p < .001), and a greater proportion of parent-child dyads reported concordant responses on communication topics: HIV/AIDS (15%, 95% CI = 8-21%; p < .001), abstinence (13%, 95% CI = 7-20%; p < .001), condoms (15%, 95% CI = 9-22%; p < .001). Increases in communication scores in HIV/AIDS, abstinence, and condom use were greater in the enhanced arm than control (p < 0.01). We conclude that the enhanced PMP can help parents educate children about HIV and prepare children to avoid sexual risk.

  4. The health-enhancing efficacy of Zumba® fitness: An 8-week randomised controlled study.

    PubMed

    Domene, Pablo A; Moir, Hannah J; Pummell, Elizabeth; Knox, Allan; Easton, Chris

    2016-08-01

    The purpose of this study was to gain a holistic understanding of the efficacy of Zumba® fitness in a community-recruited cohort of overweight and physically inactive women by evaluating (i) its physiological effects on cardiovascular risk factors and inflammatory biomarkers and (ii) its mental health-enhancing effects on factors of health-related quality of life (HRQoL). Participants were randomly assigned to either engagement in one to two 1 h classes of Zumba® fitness weekly (intervention group; n = 10) or maintenance of habitual activity (control group; n = 10). Laboratory assessments were conducted pre- (week 0) and post-intervention (week 8) with anthropometric, physiological, inflammatory and HRQoL data collected. In the intervention group, maximal oxygen uptake significantly increased (P < 0.05; partial η(2) = 0.56) by 3.1 mL · kg(-1) · min(-1), per cent body fat significantly decreased (P < 0.05; partial η(2) = 0.42) by -1.2%, and interleukin-6 and white blood cell (WBC) count both significantly decreased (P < 0.01) by -0.4 pg · mL(-1) (partial η(2) = 0.96) and -2.1 × 10(9) cells · L(-1) (partial η(2) = 0.87), respectively. Large magnitude enhancements were observed in the HRQoL factors of physical functioning, general health, energy/fatigue and emotional well-being. When interpreted in a community-based physical activity and psychosocial health promotion context, our data suggest that Zumba® fitness is indeed an efficacious health-enhancing activity for adults.

  5. Encapsulation of essential oils within a polymeric liposomal formulation for enhancement of antimicrobial efficacy.

    PubMed

    van Vuuren, Sandy F; du Toit, Lisa C; Parry, Ashleigh; Pillay, Viness; Choonara, Yahya E

    2010-09-01

    Essential oils and their constituents are known to possess antimicrobial activity; however, their inherent volatility is a limiting factor. In order to exploit the antimicrobial efficacy of essential oils, encapsulation within polymeric liposomal systems was undertaken. The liposomes were subsequently polymer-coated in order to further enhance the stability of the formulations. Essential oils distilled from Artemisia afra, Eucalyptus globulus and Melaleuca alternifolia were encapsulated into diastearoyl phosphatidylcholine and diastearoyl phosphatidylethanolamine liposomes employing a reverse phase evaporation methodology. A polyelectrolyte coating was then applied via the layer-by-layer self-deposition technique. A batch of the liposomes was polymer-coated with a 0.15%w/v chitosan solution. Using the minimum inhibitory concentration assay, the liposome-encapsulated, unencapsulated and polymer-coated liposome-encapsulated essential oils were compared in order to observe whether the antimicrobial efficacy was improved with encapsulation and polymer coating. Fractional inhibitory concentrations (FICs) were calculated in order to determine the antimicrobial interactions amongst the lipoid components, polymer coating and essential oils (synergistic, additive, indifferent and antagonistic interactions). With the exception of A. afra, microbial growth was inhibited at lower concentrations for the encapsulated formulations in comparison with the nonencapsulated oils. Synergistic to additive interactions were noted for encapsulated E. globulus (sigmaFIC values 0.25-0.45) and M alternifolia (sigmaFIC values 0.26-0.52) formulations. The addition of the polymer coating did not enhance antimicrobial activity, but owing to their positive effects on membrane stability, its presence is important as a means of extending the shelf life of these formulations. Additionally, the presence of the polymeric coating availed the essential oil at a slower rate. This investigation is a

  6. Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo

    PubMed Central

    Miller, Joanna L.; Lachica, Ruben; Sayce, Andrew C.; Williams, James P.; Bapat, Manisha; Dwek, Raymond; Beatty, P. Robert; Harris, Eva

    2012-01-01

    A key challenge faced by promising antiviral drugs, such as iminosugars, is in vivo delivery to achieve effective levels of drug without toxicity. Four iminosugars, all deoxynojirimycin (DNJ) derivatives—N-butyl DNJ (NB-DNJ), N-nonyl DNJ, N-(9-methoxynonyl) DNJ, and N-(6′-[4″-azido-2″-nitrophenylamino]hexyl)-1-DNJ (NAP-DNJ)—potently inhibited both the percentage of cells infected with dengue virus and release of infectious virus from primary human monocyte-derived macrophages, demonstrating their efficacy in primary cells. In a lethal antibody-dependent enhancement mouse model of dengue pathogenesis, free NB-DNJ significantly enhanced survival and lowered viral load in organs and serum. Liposome-mediated delivery of NB-DNJ, in comparison with free NB-DNJ, resulted in a 3-log10 reduction in the dose of drug sufficient to enhance animal survival. The optimizing of the effective dose in this way could liberate the therapeutic potential of many cytotoxic antivirals against both dengue virus and a wide array of other viruses. PMID:23070155

  7. Enhanced anti-melanoma efficacy of interferon alfa-2b via inhibition of Shp2.

    PubMed

    Win-Piazza, Hla; Schneeberger, Valentina E; Chen, Liwei; Pernazza, Daniele; Lawrence, Harshani R; Sebti, Said M; Lawrence, Nicholas J; Wu, Jie

    2012-07-01

    Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.

  8. Enhancement of cisplatin efficacy by thalidomide in a 9L rat gliosarcoma model.

    PubMed

    Murphy, Susan; Davey, Ross A; Gu, Xiao-Qing; Haywood, Miriam C; McCann, Lauren A; Mather, Laurence E; Boyle, Frances M

    2007-11-01

    With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.

  9. Enhanced antitumor efficacy with combined administration of astragalus and pterostilbene for melanoma.

    PubMed

    Huang, Xin-Yan; Zhang, Song-Zhao; Wang, Wen-Xi

    2014-01-01

    Astragalus, a commonly used traditional Chinese medicine, has exhibited antitumor actions in patients. In this study, in vitro and in vivo antitumor effects of astragalus and synergistic antitumor efficacy in combination with pterostilbene were investigated. Melanoma cells were treated with pterostilbene (Pt), graduated doses of astragalus injection (AI), or these in combination. Cell viability was measured using a MTT assay. Released nucleosomes and caspase activity were measured using enzyme-linked immunosorbent assay. Growth inhibition in vitro and in vivo was also assessed. Analysis of variance and t tests were used for statistical analysis. Significant reduction (p<0.05) in cellular proliferation were observed with AI and AI-Pt in a time- and concentration-dependent manner. Apoptosis and caspase-3/7 activity were significantly increased by AI and AI-Pt treatment (p<0.05). In vivo, AI inhibited melanoma tumor growth, with inhibition rates ranging from 36.5 to 62.3%, by inducing apoptosis via up-regulation Bax expression and the Bax/Bcl-2 ratio and down-regulating Bcl-2 expression. AI significantly inhibits the growth of melanoma in vitro and in vivo by inducing apoptosis. These data suggest that combined treatment of astragalus with pterostilbene enhances antitumor efficacy.

  10. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy

    PubMed Central

    Ahmad, Tanveer; Mukherjee, Shravani; Pattnaik, Bijay; Kumar, Manish; Singh, Suchita; Kumar, Manish; Rehman, Rakhshinda; Tiwari, Brijendra K; Jha, Kumar A; Barhanpurkar, Amruta P; Wani, Mohan R; Roy, Soumya S; Mabalirajan, Ulaganathan; Ghosh, Balaram; Agrawal, Anurag

    2014-01-01

    There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Earlier studies show that epithelial mitochondrial dysfunction is critical in asthma pathogenesis. Here we show for the first time that Miro1, a mitochondrial Rho-GTPase, regulates intercellular mitochondrial movement from mesenchymal stem cells (MSC) to epithelial cells (EC). We demonstrate that overexpression of Miro1 in MSC (MSCmiroHi) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown (MSCmiroLo) leads to loss of efficacy. Treatment with MSCmiroHi was associated with greater therapeutic efficacy, when compared to control MSC, in mouse models of rotenone (Rot) induced airway injury and allergic airway inflammation (AAI). Notably, airway hyperresponsiveness and remodeling were reversed by MSCmiroHi in three separate allergen-induced asthma models. In a human in vitro system, MSCmiroHi reversed mitochondrial dysfunction in bronchial epithelial cells treated with pro-inflammatory supernatant of IL-13-induced macrophages. Anti-inflammatory MSC products like NO, TGF-β, IL-10 and PGE2, were unchanged by Miro1 overexpression, excluding non-specific paracrine effects. In summary, Miro1 overexpression leads to increased stem cell repair. PMID:24431222

  11. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

    PubMed Central

    Beavis, Paul A.; Henderson, Melissa A.; Giuffrida, Lauren; Mills, Jane K.; Sek, Kevin; Cross, Ryan S.; Davenport, Alexander J.; John, Liza B.; Mardiana, Sherly; Slaney, Clare Y.; Johnstone, Ricky W.; Trapani, Joseph A.; Stagg, John; Loi, Sherene; Kats, Lev; Gyorki, David; Kershaw, Michael H.; Darcy, Phillip K.

    2017-01-01

    Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types. PMID:28165340

  12. Itraconazole IV nanosuspension enhances efficacy through altered pharmacokinetics in the rat.

    PubMed

    Rabinow, Barrett; Kipp, James; Papadopoulos, Pavlos; Wong, Joseph; Glosson, Jill; Gass, Jerome; Sun, Chong-Son; Wielgos, Todd; White, Randy; Cook, Chyung; Barker, Kerry; Wood, Kristy

    2007-07-18

    The goal of this research was to evaluate an intravenous itraconazole nanosuspension dosage form, relative to a solution formulation, in the rat. Itraconazole was formulated as a nanosuspension by a tandem process of microcrystallization followed by homogenization. Acute toxicity, pharmacokinetics, and distribution were studied in the rat, and compared with a solution formulation of itraconazole. Efficacy was studied in an immunocompromised rat model, challenged with a lethal dose of either itraconazole-sensitive or itraconazole-resistant C. albicans. Itraconazole nanosuspension was tolerated at significantly higher doses compared with a solution formulation. Pharmacokinetics of the nanosuspension were altered relative to the solution formulation. C(max) was reduced and t(1/2) was much prolonged. This occurred due to distribution of the nanosuspension to organs of the monocyte phagocytic system (MPS), followed by sustained release from this IV depot. The higher dosing of the drug, enabled in the case of the nanosuspension, led to higher kidney drug levels and reduced colony counts. Survival was also shown to be superior relative to the solution formulation. Thus, formulation of itraconazole as a nanosuspension enhances efficacy of this antifungal agent relative to a solution formulation, because of altered pharmacokinetics, leading to increased tolerability, permitting higher dosing and resultant tissue drug levels.

  13. Chronomodulation of topotecan or X-radiation treatment increases treatment efficacy without enhancing acute toxicity

    SciTech Connect

    Mullins, Dana; Proulx, Denise; Saoudi, A.; Ng, Cheng E. . E-mail: cng@ohri.ca

    2005-05-01

    Purpose: Topotecan (TPT), a camptothecin analog, is currently used to treat human ovarian and small-cell lung cancer and is in clinical trials for other tumor sites. However, it is unknown whether chronomodulation of TPT treatment is beneficial. We examined the effects of administering TPT or X-radiation (XR) alone at different times of the day or night. Methods: We treated mice bearing human colorectal tumor xenografts at four different times representing the early rest period (9 AM or 3 HALO [hours after light onset]), late rest period (3 PM or 9 HALO), early active period (9 PM or 15 HALO), and late active period (3 AM or 21 HALO) of the mice. We gave either TPT (12 mg/kg, injected i.p.) or XR (4 Gy, directed to the tumor) twice weekly on Days 0, 4, 7, 10 within 2 weeks. Results: Treatment with either TPT or XR at 3 AM demonstrated the greatest efficacy (measured by a tumor regrowth assay) without significantly increasing acute toxicity (assessed by a decrease in leukocyte counts or body weight). Conversely, treatment at 3 PM, in particular, showed increased toxicity without any enhanced efficacy. Conclusions: Our study provided the first evidence that chronomodulation of TPT treatments, consistent with the findings of other camptothecin analogs, is potentially clinically beneficial. Additionally, our findings suggest that chronomodulation of fractionated XR treatments is also potentially clinically beneficial.

  14. Efficacy of Contrast-enhanced Harmonic Endoscopic Ultrasonography in the Diagnosis of Pancreatic Ductal Carcinoma

    PubMed Central

    Uekitani, Toshiyuki; Kaino, Seiji; Harima, Hirofumi; Suenaga, Shigeyuki; Sen-yo, Manabu; Sakaida, Isao

    2016-01-01

    Background/Aims: Distinguishing pancreatic ductal carcinoma (DC) from other pancreatic masses remains challenging. This study aims at evaluating the efficacy of contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) in the diagnosis of DC. Patients and Methods: Forty-nine patients with solid pancreatic mass lesions underwent CEH-EUS. EUS (B-mode) was used to evaluate the inner echoes, distributions, and borders of the masses. The vascular patterns of the masses were evaluated with CEH-EUS at 30–50 s (early phase) and 70–90 s (late phase) after the administration of Sonazoid®. Results: The final diagnoses included DCs (37), mass-forming pancreatitis (6), endocrine neoplasms (3), a solid pseudopapillary neoplasm (1), a metastatic carcinoma (1), and an acinar cell carcinoma (1). The sensitivity, specificity, and accuracy of the diagnoses of DC in hypoechoic masses using EUS (B-mode) were 89.2%, 16.7%, and 71.4%, respectively. The sensitivity, specificity, and accuracy for the diagnosis of DC in hypovascular masses using CEH-EUS were 73.0%, 91.7%, and 77.6% in the early phase and 83.8%, 91.7%, and 85.7% in the late phase, respectively. Conclusions: CEH-EUS for the diagnosis of DC is superior to EUS. CEH-EUS in the late phase was particularly efficacious in the diagnosis of DC. PMID:27184637

  15. Structure-activity relationship among purpurinimides and bacteriopurpurinimides: trifluoromethyl substituent enhanced the photosensitizing efficacy.

    PubMed

    Gryshuk, Amy; Chen, Yihui; Goswami, Lalit N; Pandey, Suresh; Missert, Joseph R; Ohulchanskyy, Tymish; Potter, William; Prasad, Paras N; Oseroff, Allan; Pandey, Ravindra K

    2007-04-19

    At similar lipophilicity, compared to the nonfluorinated purpurinimide 11, the corresponding fluorinated analog 8 with a trifluoromethyl substituent at the lower half (position-132) of the molecule showed enhanced photosensitizing efficacy. The structural parameters established in purpurinimides (lambdamax: 700 nm) were successfully translated to the bacteriopurpurin imide system 19 (lambdamax: 792 nm) and within both series, a monotonic relationship between the lipophilicity and the in vivo PDT activity was observed. For preparing water-soluble compounds, the photosensitizers 8 and 19 were converted into the corresponding aminobenzyl-diethylenetriamine pentaacetate conjugates 23 and 26. Acid treatment of purpurinimide 23 produced the corresponding water-soluble analog 24. Bacteriochlorin 26 under acidic or basic conditions mainly gave the decomposition products. At similar in vivo treatment conditions (C3H mice with RIF tumors and BALB-C mice with colon-26 tumors) the water-soluble purpurinimide 24 was found to be more effective than the methyl ester analog 8. These results suggest that besides overall lipophilicity the inherent charge of the photosensitizer also influences the PDT efficacy.

  16. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.

    PubMed

    Munson, Jennifer M; Fried, Levi; Rowson, Sydney A; Bonner, Michael Y; Karumbaiah, Lohitash; Diaz, Begoña; Courtneidge, Sara A; Knaus, Ulla G; Brat, Daniel J; Arbiser, Jack L; Bellamkonda, Ravi V

    2012-03-28

    The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.

  17. Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.

    PubMed

    Pilat, Dominika; Piotrowska, Anna; Rojewska, Ewelina; Jurga, Agnieszka; Ślusarczyk, Joanna; Makuch, Wioletta; Basta-Kaim, Agnieszka; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.

  18. Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers

    PubMed Central

    Fuchs, Hendrik; Weng, Alexander; Gilabert-Oriol, Roger

    2016-01-01

    The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments. PMID:27376327

  19. Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO.

    PubMed

    Basu, Gargi D; Tinder, Teresa L; Bradley, Judy M; Tu, Tony; Hattrup, Christine L; Pockaj, Barbara A; Mukherjee, Pinku

    2006-08-15

    We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.

  20. EGCG/gelatin-doxorubicin gold nanoparticles enhance therapeutic efficacy of doxorubicin for prostate cancer treatment.

    PubMed

    Tsai, Li-Chu; Hsieh, Hao-Ying; Lu, Kun-Ying; Wang, Sin-Yu; Mi, Fwu-Long

    2016-01-01

    Development of epigallocatechin gallate (EGCG) and gelatin-doxorubicin conjugate (GLT-DOX)-coated gold nanoparticles (DOX-GLT/EGCG AuNPs) for fluorescence imaging and inhibition of prostate cancer cell growth. AuNPs alternatively coated with EGCG and DOX-GLT conjugates were prepared by a layer-by-layer assembly method. The physicochemical properties of the AuNPs and the effect of Laminin 67R receptor-mediated endocytosis on the anticancer efficacy of the AuNPs were examined. The AuNPs significantly inhibit the proliferation of PC-3 cancer cell and the enzyme-responsive intracellular release of DOX could be tracked by monitoring the recovery of the fluorescence signal of DOX. Laminin 67R receptor-mediated delivery of DOX using the AuNPs enhanced cellular uptake of DOX and improved apoptosis of PC-3 cells.

  1. Microorganisms from aphid honeydew attract and enhance the efficacy of natural enemies

    PubMed Central

    Leroy, Pascal D.; Sabri, Ahmed; Heuskin, Stéphanie; Thonart, Philippe; Lognay, Georges; Verheggen, François J.; Francis, Frédéric; Brostaux, Yves; Felton, Gary W.; Haubruge, Eric

    2011-01-01

    Aphids are one of the most serious pests of crops worldwide, causing major yield and economic losses. To control aphids, natural enemies could be an option but their efficacy is sometimes limited by their dispersal in natural environment. Here we report the first isolation of a bacterium from the pea aphid Acyrthosiphon pisum honeydew, Staphylococcus sciuri, which acts as a kairomone enhancing the efficiency of aphid natural enemies. Our findings represent the first case of a host-associated bacterium driving prey location and ovipositional preference for the natural enemy. We show that this bacterium has a key role in tritrophic interactions because it is the direct source of volatiles used to locate prey. Some specific semiochemicals produced by S. sciuri were also identified as significant attractants and ovipositional stimulants. The use of this host-associated bacterium could certainly provide a novel approach to control aphids in field and greenhouse systems. PMID:21673669

  2. Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer

    PubMed Central

    Schöttle, Jakob; Chatterjee, Sampurna; Volz, Caroline; Siobal, Maike; Florin, Alexandra; Rokitta, Dennis; Hinze, Yvonne; Dietlein, Felix; Plenker, Dennis; König, Katharina; Albus, Kerstin; Heuckmann, Johannes M.; Rauh, Daniel; Franz, Thomas; Neumaier, Bernd; Fuhr, Uwe; Heukamp, Lukas C.; Ullrich, Roland T.

    2015-01-01

    Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was tolerable and prolonged progression-free survival and reduced the frequency of acquired resistance. Intermittent EGFR-targeted high-dose schedules induce more profound as well as sustained target inhibition and may afford enhanced therapeutic efficacy. PMID:26540572

  3. Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer.

    PubMed

    Schöttle, Jakob; Chatterjee, Sampurna; Volz, Caroline; Siobal, Maike; Florin, Alexandra; Rokitta, Dennis; Hinze, Yvonne; Dietlein, Felix; Plenker, Dennis; König, Katharina; Albus, Kerstin; Heuckmann, Johannes M; Rauh, Daniel; Franz, Thomas; Neumaier, Bernd; Fuhr, Uwe; Heukamp, Lukas C; Ullrich, Roland T

    2015-11-17

    Treatment with EGFR kinase inhibitors improves progression-free survival of patients with EGFR-mutant lung cancer. However, all patients with initial response will eventually acquire resistance and die from tumor recurrence. We found that intermittent high-dose treatment with erlotinib induced apoptosis more potently and improved tumor shrinkage significantly than the established low doses. In mice carrying EGFR-mutant xenografts intermittent high-dose treatment (200 mg/kg every other day) was tolerable and prolonged progression-free survival and reduced the frequency of acquired resistance. Intermittent EGFR-targeted high-dose schedules induce more profound as well as sustained target inhibition and may afford enhanced therapeutic efficacy.

  4. Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies

    SciTech Connect

    Dutta, Kaushik; Varshney, Avanish K.; Franklin, Matthew C.; Goger, Michael; Wang, Xiaobo; Fries, Bettina C.

    2015-01-08

    Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Lastly structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.

  5. Mechanisms mediating enhanced neutralization efficacy of Staphylococcal enterotoxin B by combinations of monoclonal antibodies

    DOE PAGES

    Dutta, Kaushik; Varshney, Avanish K.; Franklin, Matthew C.; ...

    2015-01-08

    Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used tomore » validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Lastly structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.« less

  6. Lactobionic acid-conjugated TPGS nanoparticles for enhancing therapeutic efficacy of etoposide against hepatocellular carcinoma

    NASA Astrophysics Data System (ADS)

    Tsend-Ayush, Altansukh; Zhu, Xiumei; Ding, Yu; Yao, Jianxu; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2017-05-01

    Many effective anti-cancer drugs have limited use in hepatocellular carcinoma (HCC) therapy due to the drug resistance mechanisms in liver cells. In recent years, tumor-targeted drug delivery and the inhibition of drug-resistance-related mechanisms has become an integrated strategy for effectively combating chemo-resistant cancer. Herein, lactobionic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-LA conjugate) has been developed as a potential asialoglycoprotein receptor (ASGPR)-targeted nanocarrier and an efficient inhibitor of P-glycoprotein (P-gp) to enhance etoposide (ETO) efficacy against HCC. The main properties of ETO-loaded TPGS-LA nanoparticles (NPs) were tested through in vitro and in vivo studies after being prepared using the nanoprecipitation method and characterized by dynamic light scattering (DLS). According to the results, smaller (∼141.43 nm), positively charged ETO-loaded TPGS-LA NPs were more suitable for providing efficient delivery to hepatoma cells by avoiding the clearance mechanisms. It was found that ETO-loaded TPGS-LA NPs were noticeably able to enhance the cytotoxicity of ETO in HepG2 cells. Besides this, markedly higher internalization by the ASGPR-overexpressed HepG2 cells and efficient accumulation at the tumor site in vivo were revealed in the TPGS-LA NP group. More importantly, animal studies confirmed that ETO-loaded TPGS-LA NPs achieved the highest therapeutic efficacy against HCC. Interestingly, ETO-loaded TPGS-LA NPs also exhibited a great inhibitory effect on P-gp compared to the ETO-loaded TPGS NPs. These results suggest that TPGS-LA NPs could be used as a potential ETO delivery system against HCC.

  7. Local vibration enhanced the efficacy of passive exercise on mitigating bone loss in hindlimb unloading rats

    NASA Astrophysics Data System (ADS)

    Huang, Yunfei; Luan, Huiqin; Sun, Lianwen; Bi, Jingfang; Wang, Ying; Fan, Yubo

    2017-08-01

    Spaceflight induced bone loss is seriously affecting astronauts. Mechanical stimulation from exercise has been shown to restrain bone resorption as well as improve bone formation. Current exercise countermeasures in space cannot prevent it completely. Active exercise may convert to passive exercise in some ways because of the loss of gravity stimulus and inertia of exercise equipment. The aim of this study was to compare the efficacy of passive exercise or/and local vibration on counteracting the deterioration of the musculoskeletal system, including bone, muscle and tendons in tail-suspended rats. We hypothesized that local vibration could enhance the efficacy of passive exercise on countering bone loss. 40 Sprague Dawley rats were randomly distributed into five groups (n = 8, each): tail-suspension (TS), TS+35 Hz vibration (TSV), TS + passive exercise (TSP), TS + passive exercise coupled with 35 Hz vibration (TSPV) and control (CON). Passive exercise or/and local vibration was performed for 21 days. On day 0 and 21, bone mineral density (BMD) was observed by dual energy X-ray absorptiometry (DXA), and trabecular microstructure was evaluated by microcomputer tomography (μCT) analysis in vivo. Mechanical properties of tibia and tendon were determined by a mechanical testing system. Soleus and bone ash weight was tested by an electronic balance. Results showed that the passive exercise could not prevent the decrease of trabecular BMD, microstructure and bone ash weight induced by TS, whereas vibration and passive exercise coupled with local vibration (PV) could. Biomechanical properties of the tibia and tendon in TSPV group significantly increased compared with TS group. In summary, PV in this study was the best method in preventing weightlessness-induced bone loss. Consistent with our hypothesis, local vibration partly enhanced the effect of passive exercise. Furthermore, this study will be useful in improving countermeasure for astronauts, but also for the

  8. Enhanced efficacy of photodynamic therapy by inhibiting ABCG2 in colon cancers.

    PubMed

    Kim, Ju Hee; Park, Jae Myung; Roh, Yoon Jin; Kim, In-Wook; Hasan, Tayyaba; Choi, Myung-Gyu

    2015-07-07

    Photodynamic therapy (PDT) contains a photosensitizing process, which includes cellular uptake of photosensitizer and delivery of light to the target. ATP-binding cassette subfamily G2 (ABCG2) regulates endogenous protoporphyrin levels. In human colon cancers, it is not fully examined the role of ABCG2 in porphyrin-based photodynamic therapy. SW480 and HT29 cells were selected because they showed low and high ABCG2 expression levels, respectively. Pyropheophorbid-a (PPa) was used as a photosensitizer. Cells were exposed to a 670 nm diod laser. Cell viability and necrosi apoptosis was examined. Production level of singlet oxygen was detected with the photomultiplier-tube s/ -based singlet oxygen detection system. SW480 cells, which expressed lower level of ABCG2, showed the higher uptake of PPa than HT-29 cells. The uptake level of PPa was significantly correlated with the decreased cell viability after PDT. Pretreatment with a ABCG2 inhibitor, Ko-143, significantly enhanced the PDT efficacy in HT29 cells compared to vehicle-pretreated cells. To confirm the ABCG2 effect on PDT, we established ABCG2 over-expressing stable cells in SW480 cells (SW480/ABCG2). Furthermore, SW480/ABCG2 cells showed significantly decreased PDT effect compared to the control cells. The increased or decreased cell survival was significantly correlated with the production level of singlet oxygen after PDT. ABCG2 plays an important role in determining the PDT efficacy by controlling the photosensitizer efflux rate. This implies the control of ABCG2 expression may be a potential solution to enhance photosensitivity.

  9. Mechanisms mediating enhanced neutralization efficacy of staphylococcal enterotoxin B by combinations of monoclonal antibodies.

    PubMed

    Dutta, Kaushik; Varshney, Avanish K; Franklin, Matthew C; Goger, Michael; Wang, Xiaobo; Fries, Bettina C

    2015-03-13

    Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Finally structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.

  10. Lactobionic acid-conjugated TPGS nanoparticles for enhancing therapeutic efficacy of etoposide against hepatocellular carcinoma.

    PubMed

    Tsend-Ayush, Altansukh; Zhu, Xiumei; Ding, Yu; Yao, Jianxu; Yin, Lifang; Jianping, Zhou; Yao, Jing

    2017-03-14

    Many effective anticancer drugs are limited to use for hepatocellular carcinoma (HCC) therapy due to drug resistance mechanisms in liver cells. In recent years, tumor-targeted drug delivery and inhibition of drug resistance-related mechanisms become an integrated strategy to combat effectively chemo-resistant cancer. Herein, lactobionic acid-conjugated D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS-LA conjugate) was developed as a potential asialoglycoprotein receptor (ASGPR)-targeted nanocarrier and an efficient inhibitor of P-glycoprotein (P-gp) to enhance etoposide (ETO) efficacy against HCC. Main properties of ETO-loaded TPGS-LA nanoparticles (NPs) were tested through in vitro and in vivo studies after prepared using nanoprecipitation method and characterized by dynamic light scattering (DLS). According to the results, smaller sized (~141.43 nm) and positively charged ETO-loaded TPGS-LA NPs were more suitable to provide an efficient delivery to hepatoma cells by avoiding clearance mechanisms. It was found that ETO-loaded TPGS-LA NPs could enhance noticeably cytotoxicity of ETO in HepG2 cells. Besides, markedly higher internalization by ASGPR-overexpressed HepG2 cells and efficient accumulation at tumor site in vivo were revealed in TPGS-LA NPs group. More importantly, animal studies confirmed that ETO-loaded TPGS-LA NPs achieved the highest therapeutic efficacy against HCC. Interestingly, ETO-loaded TPGS-LA NPs also exhibited a great inhibitory effect on P-gp compared to ETO-loaded TPGS NPs. These results suggest that TPGS-LA NPs could be used as a potential delivery system of ETO against HCC.

  11. Enhancing Antitumor Efficacy of Chimeric Antigen Receptor T Cells Through Constitutive CD40L Expression

    PubMed Central

    Curran, Kevin J; Seinstra, Beatrijs A; Nikhamin, Yan; Yeh, Raymond; Usachenko, Yelena; van Leeuwen, Dayenne G; Purdon, Terence; Pegram, Hollie J; Brentjens, Renier J

    2015-01-01

    Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40+ tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40+ tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19+ systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy. PMID:25582824

  12. Superselective Particle Embolization Enhances Efficacy of Radiofrequency Ablation: Effects of Particle Size and Sequence of Action

    SciTech Connect

    Tanaka, Toshihiro; Isfort, Peter; Braunschweig, Till Westphal, Saskia; Woitok, Anna; Penzkofer, Tobias Bruners, Philipp; Kichikawa, Kimihiko; Schmitz-Rode, Thomas Mahnken, Andreas H.

    2013-06-15

    Purpose. To evaluate the effects of particle size and course of action of superselective bland transcatheter arterial embolization (TAE) on the efficacy of radiofrequency ablation (RFA). Methods. Twenty pigs were divided into five groups: group 1a, 40-{mu}m bland TAE before RFA; group 1b, 40-{mu}m bland TAE after RFA; group 2a, 250-{mu}m bland TAE before RFA; group 2b, 250-{mu}m bland TAE after RFA and group 3, RFA alone. A total of 40 treatments were performed with a combined CT and angiography system. The sizes of the treated zones were measured from contrast-enhanced CTs on days 1 and 28. Animals were humanely killed, and the treated zones were examined pathologically. Results. There were no complications during procedures and follow-up. The short-axis diameter of the ablation zone in group 1a (mean {+-} standard deviation, 3.19 {+-} 0.39 cm) was significantly larger than in group 1b (2.44 {+-} 0.52 cm; P = 0.021), group 2a (2.51 {+-} 0.32 cm; P = 0.048), group 2b (2.19 {+-} 0.44 cm; P = 0.02), and group 3 (1.91 {+-} 0.55 cm; P < 0.001). The greatest volume of ablation was achieved by performing embolization with 40-{mu}m particles before RFA (group 1a; 20.97 {+-} 9.65 cm{sup 3}). At histology, 40-{mu}m microspheres were observed to occlude smaller and more distal arteries than 250-{mu}m microspheres. Conclusion. Bland TAE is more effective before RFA than postablation embolization. The use of very small 40-{mu}m microspheres enhances the efficacy of RFA more than the use of larger particles.

  13. Doxorubicin conjugated functionalizable carbon dots for nucleus targeted delivery and enhanced therapeutic efficacy

    NASA Astrophysics Data System (ADS)

    Yang, Lei; Wang, Zheran; Wang, Ju; Jiang, Weihua; Jiang, Xuewei; Bai, Zhaoshi; He, Yunpeng; Jiang, Jianqi; Wang, Dongkai; Yang, Li

    2016-03-01

    Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy.Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared

  14. Systemic and ocular vascular roles of the antiglaucoma agents beta-adrenergic antagonists and Ca2+ entry blockers.

    PubMed

    Yu, D Y; Su, E N; Cringle, S J; Alder, V A; Yu, P K; DeSantis, L

    1999-06-01

    This review addresses whether the antiglaucoma agents beta-adrenergic antagonists and Ca2+ entry blockers cause vasoactive effects in the retinal and other ocular vasculatures, as they do in other tissues. The potent vasodilating effects of Ca2+ entry blockers on ocular vessels have recently been demonstrated in in vivo and in vitro studies, implying that the maintenance of ocular vascular tone relies almost exclusively on extracellular Ca2+. Ca2+ entry blockers may potentially play a role in relaxing the retinal, long posterior ciliary, and ophthalmociliary arteries to improve the ocular circulation in vascular diseases in which there is considerable vascular tone present. The beta-adrenergic antagonists are discussed with reference to their antihypertensive role, their effect on other vascular beds, and finally what is known of their effect in the ocular vasculature. The emerging evidence that particular selective beta-adrenergic antagonists, such as betaxolol, are also potent Ca2+ channel entry blockers in other vascular beds is presented. Betaxolol has been shown to induce vasodilatation in the retinal and other ocular vascular beds, although studies have shown that beta1-adrenergic receptors are sparse in these vascular beds. This implies that an alternative mechanism must be responsible for betaxolol-induced vasodilatation. Evidence is presented that betaxolol vasodilates via its potent Ca2+ channel entry blocking properties, and its potency and ability to vasodilate are compared with those of nimodipine and timolol, as well as with those of other Ca2+ channel entry blockers. Important areas for future research in this area are discussed.

  15. Enhancement of the antitumor efficacy of lomustine by the radiosensitizer RSU 1069.

    PubMed

    Siemann, D W; Alliet, K; Maddison, K; Wolf, K

    1985-12-01

    Previous investigations have shown that combining the radiation sensitizer misonidazole with conventional alkylating chemotherapeutic agents can lead to a therapeutic advantage. More recently, another sensitizer, RSU 1069, has been reported to give an enhancement of antitumor agent efficacy similar to that observed with misonidazole, but at an approximately tenfold lower sensitizer dose. One chemotherapeutic agent whose activity has been modified by sensitizers to a greater extent in tumors than in critical normal tissues is the nitrosourea lomustine (CCNU). The present studies evaluated the therapeutic benefit of combining RSU 1069 and CCNU in KHT sarcoma-bearing C3H/HeJ mice. The drugs were administered ip, and tumor response was assessed by measuring the survival of clonogenic KHT cells 22-24 hours after treatment. Normal tissue toxicity was determined using peripheral wbc counts 3 days after treatment and a 30-day lethality assay. Combining CCNU with a 0.38-mmol/kg dose of RSU 1069 increased tumor cell killing by a factor of approximately 1.9. Wbc toxicity and 30-day animal lethality increased with CCNU dose, but the addition of RSU 1069 enhanced either endpoint only slightly (factor of 1.0-1.2). The addition of RSU 1069 to CCNU treatment, therefore, led to a significant therapeutic benefit.

  16. Redirecting transport of nanoparticle albumin-bound paclitaxel to macrophages enhances therapeutic efficacy against liver metastases

    PubMed Central

    Tanei, Tomonori; Leonard, Fransisca; Liu, Xuewu; Alexander, Jenolyn F.; Saito, Yuki; Ferrari, Mauro; Godin, Biana; Yokoi, Kenji

    2015-01-01

    Current treatments for liver metastases arising from primary breast and lung cancers are minimally effective. One reason for this unfavorable outcome is that liver metastases are poorly vascularized, limiting the ability to deliver therapeutics from the systemic circulation to lesions. Seeking to enhance transport of agents into the tumor microenvironment, we designed a system in which nanoparticle albumin-bound paclitaxel (nAb-PTX) is loaded into a nanoporous solid multistage nanovector (MSV) to enable the passage of the drug through the tumor vessel wall and enhance its interaction with liver macrophages. MSV enablement increased nAb-PTX efficacy and survival in mouse models of breast and lung liver metastasis. MSV-nAb-PTX also augmented the accumulation of PTX and MSV in the liver, specifically in macrophages, whereas PTX levels in the blood were unchanged after administering MSV-nAb-PTX or nAb-PTX. In vitro studies demonstrated that macrophages treated with MSV-nAb-PTX remained viable and were able to internalize, retain, and release significantly higher quantities of PTX compared to treatment with nAb-PTX. The cytotoxic potency of the released PTX was also confirmed in tumor cells cultured with the supernatants of macrophage treated with MSV-nAB-PTX. Collectively, our findings showed how redirecting nAb-PTX to liver macrophages within the tumor microenvironment can elicit a greater therapeutic response in patients with metastatic liver cancer, without increasing systemic side-effects. PMID:26744528

  17. Targeting Thymic Epithelia AR Enhances T-Cell Reconstitution and Bone Marrow Transplant Grafting Efficacy

    PubMed Central

    Lai, Kuo-Pao; Lai, Jiann-Jyh; Chang, Philip; Altuwaijri, Saleh; Hsu, Jong-Wei; Chuang, Kuang-Hsiang; Shyr, Chih-Rong; Yeh, Shuyuan

    2013-01-01

    Although thymic involution has been linked to the increased testosterone in males after puberty, its detailed mechanism and clinical application related to T-cell reconstitution in bone marrow transplantation (BMT) remain unclear. By performing studies with reciprocal BMT and cell-specific androgen receptor (AR) knockout mice, we found that AR in thymic epithelial cells, but not thymocytes or fibroblasts, played a more critical role to determine thymic cellularity. Further dissecting the mechanism using cell-specific thymic epithelial cell-AR knockout mice bearing T-cell receptor transgene revealed that elevating thymocyte survival was due to the enhancement of positive selection resulting in increased positively selected T-cells in both male and female mice. Targeting AR, instead of androgens, either via genetic knockout of thymic epithelial AR or using an AR-degradation enhancer (ASC-J9®), led to increased BMT grafting efficacy, which may provide a new therapeutic approach to boost T-cell reconstitution in the future. PMID:23250486

  18. Sonodynamic therapy using 5-aminolevulinic acid enhances the efficacy of bleomycin.

    PubMed

    Osaki, Tomohiro; Ono, Misato; Uto, Yoshihiro; Ishizuka, Masahiro; Tanaka, Tohru; Yamanaka, Nobuyasu; Kurahashi, Tsukasa; Azuma, Kazuo; Murahata, Yusuke; Tsuka, Takeshi; Ito, Norihiko; Imagawa, Tomohiro; Okamoto, Yoshiharu

    2016-04-01

    Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound and a sonosensitizer agent. We examined whether 5-aminolevulinic acid (5-ALA)-based SDT at 1 or 3 MHz could enhance the cytotoxicity of bleomycin (BLM) toward mouse mammary tumor cells both in vitro and in vivo. At 1 MHz, cell viability in the 5-ALA-based SDT group at 1, 2, and 3 W/cm(2) was 34.30%, 50.90%, and 60.16%, respectively. Cell viability in the 5-ALA-based SDT+BLM group at 1, 2, and 3 W/cm(2) was 0.09%, 0.32%, and 0.17%, respectively. In contrast, at 3 MHz, 5-ALA-based SDT+BLM did not show pronounced cytotoxicity. In the in vivo study, 5-ALA-based SDT+BLM was significantly more cytotoxic than 5-ALA-based SDT at 1 MHz and 3 MHz. These findings suggest that the mechanism of tumor shrinkage induced by 5-ALA-based SDT+BLM might involve not only direct cell killing, but also vascular shutdown. Thus, we show here that 5-ALA-based SDT enhances the efficacy of BLM both in vitro and in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Fluorination of phthalocyanine substituents: Improved photoproperties and enhanced photodynamic efficacy after optimal micellar formulations.

    PubMed

    Pucelik, Barbara; Gürol, Ilke; Ahsen, Vefa; Dumoulin, Fabienne; Dąbrowski, Janusz M

    2016-11-29

    A fluorinated phthalocyanine and its non-fluorinated analogue were selected to evaluate the potential enhancement of fluorination on photophysical, photochemical and redox properties as well as on biological activity in cellular and animal models. Due to the pharmacological relevance, the affinity of these phthalocyanines towards biological membranes (logPow) as well as their primary interaction with human serum albumin (HSA) or low-density lipoprotein (LDL) were determined. Water-dispersible drug formulation of phthalocyanines via Pluronic(®)-based triblock copolymer micelles was prepared to avoid self-aggregation effects and to improve their delivery. The obtained results demonstrate that phthalocyanines incorporation into tunable-polymeric micelles significantly enhanced their cellular uptake and their photocytotoxicity. The improved biodistribution and photodynamic efficacy of the phthalocyanines-triblock copolymer conjugates was also confirmed in vivo in CT26 bearing BALB/c mice. PDT with both compounds led to tumor growth inhibition in all treated animals. Fluorinated phthalocyanine 2 turned out to be the most effective anticancer agent as the tumors of 20% of mice treated regressed completely and did not appear for over one year after treatment.

  20. Targeting myeloid cells in the tumor microenvironment enhances vaccine efficacy in murine epithelial ovarian cancer.

    PubMed

    Khan, Anm Nazmul H; Kolomeyevskaya, Nonna; Singel, Kelly L; Grimm, Melissa J; Moysich, Kirsten B; Daudi, Sayeema; Grzankowski, Kassondra S; Lele, Sashikant; Ylagan, Lourdes; Webster, Gill A; Abrams, Scott I; Odunsi, Kunle; Segal, Brahm H

    2015-05-10

    Epithelial ovarian cancer (EOC) is typically diagnosed at advanced stages, and is associated with a high relapse rate. Patients in remission are ideal candidates for immunotherapy aimed at cure or prolonging disease-free periods. However, immunosuppressive pathways in the tumor microenvironment are obstacles to durable anti-tumor immunity. In a metastatic syngeneic mouse model of EOC, immunosuppressive macrophages and myeloid-derived suppressor cells (MDSCs) accumulate in the local tumor environment. In addition, resident peritoneal macrophages from non-tumor-bearing mice were highly immunosuppressive, abrogating stimulated T cell proliferation in a cell contact-dependent manner. Immunization with microparticles containing TLR9 and NOD-2 ligands (MIS416) significantly prolonged survival in tumor-bearing mice. The strategy of MIS416 immunization followed by anti-CD11b administration further delayed tumor progression, thereby establishing the proof of principle that myeloid depletion can enhance vaccine efficacy. In patients with advanced EOC, ascites analysis showed substantial heterogeneity in the relative proportions of myeloid subsets and their immunosuppressive properties. Together, these findings point to immunosuppressive myeloid cells in the EOC microenvironment as targets to enhance vaccination. Further studies of myeloid cell accumulation and functional phenotypes in the EOC microenvironment may identify patients who are likely to benefit from vaccination combined with approaches that deplete tumor-associated myeloid cells.

  1. Tailoring shape and size of biogenic silver nanoparticles to enhance antimicrobial efficacy against MDR bacteria.

    PubMed

    Kumari, Madhuree; Pandey, Shipra; Giri, Ved Prakash; Bhattacharya, Arpita; Shukla, Richa; Mishra, Aradhana; Nautiyal, C S

    2017-04-01

    Spherical, rectangular, penta, and hexagonal silver nanoparticles of different dimensions were biosynthesized in an eco-friendly manner by biocontrol agent, Trichoderma viride by manipulating physical parameters, pH, temperature, and reaction time. The particles were characterized by UV-vis spectroscopy; Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and Fourier Transform Infra-red Spectroscopy (FTIR). Shape and size dependent antimicrobial activity of nanoparticles against human pathogens was observed. Maximum inhibition was found with spherical nanoparticles (2-5 nm) showing 40, 51, 43, 53.9 and 55.8% against Shigella sonnei, Escherichia coli, Serratia marcescens, Staphylococcus. aureus and Pseudomonas aeruginosa respectively, where as pentagonal and hexagonal nanoparticles (50-100 nm) demonstrated 32, 41, 31, 42.84 and 42.80% of inhibition as compared to control. Nanoparticles of different geometry and dimension established enhanced antagonistic activity against pathogens with all the tested antibiotics. Excellent antimicrobial efficacy was obtained with spherical nanoparticles of 2-5 nm with ampicillin and penicillin. Shape and size played major role in enhancing antimicrobial potential of silver nanoparticles, both singly and synergistically with antibiotics which can be exploited to combat the spread of multidrug resistant pathogens. Copyright © 2016. Published by Elsevier Ltd.

  2. Engineering of Hollow Mesoporous Silica Nanoparticles for Remarkably Enhanced Tumor Active Targeting Efficacy

    PubMed Central

    Chen, Feng; Hong, Hao; Shi, Sixiang; Goel, Shreya; Valdovinos, Hector F.; Hernandez, Reinier; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

    2014-01-01

    Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to date. Here, we report the in vivo tumor targeted positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modality imaging and enhanced drug delivery of HMSN using a generally applicable surface engineering technique. Systematic in vitro and in vivo studies have been performed to investigate the stability, tumor targeting efficacy and specificity, biodistribution and drug delivery capability of well-functionalized HMSN nano-conjugates. The highest uptake of TRC105 (which binds to CD105 on tumor neovasculature) conjugated HMSN in the 4T1 murine breast cancer model was ~10%ID/g, 3 times higher than that of the non-targeted group, making surface engineered HMSN a highly attractive drug delivery nano-platform for future cancer theranostics. PMID:24875656

  3. Enhanced antitumor efficacy of ultrasonic cavitation with up-sized microbubbles in pancreatic cancer

    PubMed Central

    Huang, Pintong; Zhang, Ying; Chen, Jian; Shentu, Weihui; Sun, Yu; Yang, Zhijian; Liang, Tingbo; Chen, Shuyuan; Pu, Zhaoxia

    2015-01-01

    Ultrasonic cavitation is a novel potential approach for cancer treatment. We optimized the techniques of ultrasonic cavitation to enhance antitumor efficacy in a mouse model with human pancreatic cancer. A polydisperse MB contrast agent formulation (TS-P) with a mean number diameter of 1.9 μm was depleted in small diameter particles by differential centrifugation, producing an “up-sized” size distribution (TS-PL) possessing a mean diameter of 2.9 μm. Mice bearing the XPA-1-RFP pancreatic tumor were treated daily for 3 consecutive days with either up-sized or standard MB. Both treatment cohorts exhibited a significant reduction in tumor volume relative to the untreated control cohort (P < 0.05), and TS-PL group has significantly reduction in tumor volume (1215.1± 324.7 mm3) compared with standard TS-P group (2131.2±753.4 mm3) (P < 0.05). The treatment with TS-PL resulted in more tumor cell necrosis and apoptosis than with TS-P. Decreased expression of CD31 and MVD was observed histologically in tumors treated with TS-PL relative to TS-P. This study demonstrates that tuning the size distribution of existing contrast agent products, specifically to reduce the concentration of small MB, is required for enhanced anti-tumor cavitation activity. PMID:26036312

  4. Surface decoration by Spirulina polysaccharide enhances the cellular uptake and anticancer efficacy of selenium nanoparticles

    PubMed Central

    Yang, Fang; Tang, Quanming; Zhong, Xueyun; Bai, Yan; Chen, Tianfeng; Zhang, Yibo; Li, Yinghua; Zheng, Wenjie

    2012-01-01

    A simple and solution-phase method for functionalization of selenium nanoparticles (SeNPs) with Spirulina polysaccharides (SPS) has been developed in the present study. The cellular uptake and anticancer activity of SPS-SeNPs were also evaluated. Monodisperse and homogeneous spherical SPS-SeNPs with diameters ranging from 20 nm to 50 nm were achieved under optimized conditions, which were stable in the solution phase for at least 3 months. SPS surface decoration significantly enhanced the cellular uptake and cytotoxicity of SeNPs toward several human cancer cell lines. A375 human melanoma cells were found extremely susceptible to SPS-SeNPs with half maximal (50%) inhibitory concentration value of 7.94 μM. Investigation of the underlying mechanisms revealed that SPS-SeNPs inhibited cancer cell growth through induction of apoptosis, as evidenced by an increase in sub-G1 cell population, deoxyribonucleic acid fragmentation, chromatin condensation, and phosphatidylserine translocation. Results suggest that the strategy to use SPS as a surface decorator could be an effective way to enhance the cellular uptake and anticancer efficacy of nanomaterials. SPS-SeNPs may be a potential candidate for further evaluation as a chemopreventive and chemotherapeutic agent against human cancers. PMID:22359460

  5. Using on-line video clips to enhance self-efficacy toward dealing with difficult situations among nursing students.

    PubMed

    McConville, Sally A; Lane, Andrew M

    2006-04-01

    The aim of the study was twofold. The first aim was to develop on-line video clip material that showed examples of nurses dealing with potentially difficult and delicate patient groups. The second aim was to evaluate the effectiveness of video clip materials for enhancing nursing student's self-efficacy to effectively communicate with the type of patients described above. The production of contextually relevant video clip material involved the identification of relevant material based on real experiences, writing appropriate scripts, recruiting actors, recording the performances and producing them in a form that could be accessed on-line. Self-report questionnaires were used to assess the effectiveness of video clip material. Level 1 (n = 145) nursing students completed a self-efficacy measure that assessed confidence to deal with situations such as breaking news of death, working with children, people with disability and aggressive behaviour at the start and the end of the module. Results indicated that student's self-efficacy increased noticeably over the course of the module. Differences between increases in self-efficacy attributed to watching videos or attending lectures were marginal. Findings suggest that using video clips that show students effectively coping with adverse situations provide an effective teaching approach for enhancing self-efficacy. Future research is needed to test the extent to which self-efficacy measures relate with nursing performance.

  6. "Killing Two Birds with One Stone": Alcohol Use Reduction Interventions with Potential Efficacy in Enhancing Self-Control.

    PubMed

    Leeman, Robert F; Bogart, Devorah; Fucito, Lisa M; Boettiger, Charlotte A

    2014-03-01

    We review interventions with empirical support for reducing alcohol use and enhancing self-control. While any intervention that decreases drinking could improve self-control, we focus here on interventions with evidence of direct benefit for both indications. Although no intervention yet shows strong evidence for dual efficacy, multiple interventions have strong evidence for one indication and solid or suggestive evidence for the other. Among pharmacotherapies, opioid antagonists currently have the best evidence for reducing alcohol use and enhancing self-control. Nicotinic partial agonist varenicline also appears to be efficacious for alcohol use and self-control. Many psychosocial and behavioral interventions (e.g., cognitive behavioral therapy, contingency management, mindfulness training) may have efficacy for both indications based on purported mechanisms of action and empirical evidence. Cognitive bias modification and neurophysiological interventions have promise for alcohol use and self-control as well and warrant further research. We offer several other suggestions for future research directions.

  7. Inspiring Instructional Change in Elementary School Science: The Relationship Between Enhanced Self-efficacy and Teacher Practices

    NASA Astrophysics Data System (ADS)

    Sandholtz, Judith Haymore; Ringstaff, Cathy

    2014-10-01

    This longitudinal study examined the extent to which teachers' participation in a 3-year professional development program enhanced their self-efficacy and prompted changes in science instruction in the early elementary grades. The study used a mixed-methods design, and included 39 teachers who taught in kindergarten, first grade, or second grade classrooms in rural school districts. Data sources, administered pre-program and at the end of each year, included a self-efficacy assessment and teacher survey. Interviews and classroom observations provided corroborating data about teachers' beliefs and science instruction. Results showed significant increases in teachers' overall self-efficacy in teaching science, personal efficacy, and outcome expectancy efficacy during the 3 years. Gains in self-efficacy were correlated with changes in reported instructional practices, particularly student participation activities. However, changes in self-efficacy tended not to be correlated with changes in instructional time. Contextual factors beyond teachers' direct control, such as curricular and testing requirements in mathematics and language arts influenced time allotted to science instruction.

  8. Enhancing self-efficacy improves episodic future thinking and social-decision making in combat veterans with posttraumatic stress disorder.

    PubMed

    Brown, Adam D; Kouri, Nicole A; Rahman, Nadia; Joscelyne, Amy; Bryant, Richard A; Marmar, Charles R

    2016-08-30

    Posttraumatic Stress Disorder (PTSD) is associated with maladaptive changes in self-identity, including impoverished perceived self-efficacy. This study examined if enhancing perceptions of self-efficacy in combat veterans with and without symptoms of PTSD promotes cognitive strategies associated with positive mental health outcomes. Prior to completing a future thinking and social problem-solving task, sixty-two OEF/OIF veterans with and without symptoms of PTSD were randomized to either a high self-efficacy (HSE) induction in which they were asked to recall three autobiographical memories demonstrating self-efficacy or a control condition in which they recalled any three autobiographical events. An interaction between HSE and PTSD revealed that individuals with symptoms of PTSD in the HSE condition generated future events with more self-efficacious statements than those with PTSD in the control condition, whereas those without PTSD did not differ in self-efficacy content across the conditions. In addition, individuals in the HSE condition exhibited better social problem solving than those in the control condition. Increasing perceptions of self-efficacy may promote future thinking and problem solving in ways that are relevant to overcoming trauma and adversity.

  9. Using Community Arts Events to Enhance Collective Efficacy and Community Engagement toAddress Depression in an African American Community

    PubMed Central

    Jones, Loretta; Jones, Andrea; Corbett, Charles E.; Booker, Theodore; Wells, Kenneth B.; Collins, Barry

    2009-01-01

    Objectives. We used community-partnered participatory research (CPPR) to measure collective efficacy and its role as a precursor of community engagement to improve depression care in the African American community of South Los Angeles. Methods. We collected survey data from participants at arts events sponsored by a CPPR workgroup. Both exploratory (photography exhibit; n = 747) and confirmatory (spoken word presentations; n = 104) structural equation models were developed to examine how knowledge and attitudes toward depression influenced community engagement. Results. In all models, collective efficacy to improve depression care independently predicted community engagement in terms of addressing depression (B = 0.64–0.97; P < .001). Social stigma was not significantly associated with collective efficacy or community engagement. In confirmatory analyses, exposure to spoken word presentations and previous exposure to CPPR initiatives increased perceived collective efficacy to improve depression care (B = 0.19–0.24; P < .05). Conclusions. Enhancing collective efficacy to improve depression care may be a key component of increasing community engagement to address depression. CPPR events may also increase collective efficacy. Both collective efficacy and community engagement are relevant constructs in the South Los Angeles African American community. PMID:19059844

  10. Using community arts events to enhance collective efficacy and community engagement to address depression in an African American community.

    PubMed

    Chung, Bowen; Jones, Loretta; Jones, Andrea; Corbett, Charles E; Booker, Theodore; Wells, Kenneth B; Collins, Barry

    2009-02-01

    We used community-partnered participatory research (CPPR) to measure collective efficacy and its role as a precursor of community engagement to improve depression care in the African American community of South Los Angeles. We collected survey data from participants at arts events sponsored by a CPPR workgroup. Both exploratory (photography exhibit; n = 747) and confirmatory (spoken word presentations; n = 104) structural equation models were developed to examine how knowledge and attitudes toward depression influenced community engagement. In all models, collective efficacy to improve depression care independently predicted community engagement in terms of addressing depression (B = 0.64-0.97; P < .001). Social stigma was not significantly associated with collective efficacy or community engagement. In confirmatory analyses, exposure to spoken word presentations and previous exposure to CPPR initiatives increased perceived collective efficacy to improve depression care (B = 0.19-0.24; P < .05). Enhancing collective efficacy to improve depression care may be a key component of increasing community engagement to address depression. CPPR events may also increase collective efficacy. Both collective efficacy and community engagement are relevant constructs in the South Los Angeles African American community.

  11. Convection-enhanced delivery of maghemite nanoparticles: Increased efficacy and MRI monitoring

    PubMed Central

    Perlstein, Benny; Ram, Zvi; Daniels, Dianne; Ocherashvilli, Aharon; Roth, Yiftach; Margel, Shlomo; Mardor, Yael

    2008-01-01

    Convection-enhanced drug delivery (CED) is a novel approach to delivering drugs into brain tissue. Drugs are delivered continuously via a catheter, enabling large volume distributions of high drug concentrations with minimum systemic toxicity. Previously we demonstrated that CED formation/extent of small molecules may be significantly improved by increasing infusate viscosities. In this study we show that the same methodology can be applied to monodispersed maghemite nanoparticles (MNPs). For this purpose we used a normal rat brain model and performed CED of MNPs over short infusion times. By adding 3% sucrose or 3%–6% polyethylene glycol (PEG; molecular weight 400) to saline containing pristine MNPs, we increased infusate viscosity and obtained increased CED efficacy. Further, we show that CED of dextran-coated MNPs (dextran-MNPs) resulted in increased efficacy over pristine MNPs (p < 0.007). To establish the use of MRI for reliable depiction of MNP distribution, CED of fluorescent dextran-MNPs was performed, demonstrating a significant correlation between the distributions as depicted by MRI and spectroscopic images (r2 = 0.74, p < 0.0002). MRI follow-up showed that approximately 80%–90% of the dextran-MNPs were cleared from the rat brain within 40 days of CED; the rest remained in the brain for more than 4 months. MNPs have been tested for applications such as targeted drug delivery and controlled drug release and are clinically used as a contrast agent for MRI. Thus, combining the CED method with the advantages of MNPs may provide a powerful tool to treat and monitor brain tumors. PMID:18316474

  12. Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells.

    PubMed

    Arora, Sanjeevani; Kothandapani, Anbarasi; Tillison, Kristin; Kalman-Maltese, Vivian; Patrick, Steve M

    2010-07-01

    Bulky cisplatin lesions are repaired primarily by nucleotide excision repair (NER), in which the structure specific endonuclease XPF-ERCC1 is a critical component. It is now known that the XPF-ERCC1 complex has repair functions beyond NER and plays a role in homologous recombination (HR). It has been suggested that expression of ERCC1 correlates with cisplatin drug resistance in non-small cell lung cancer (NSCLC). In our study, using NSCLC, ovarian, and breast cancer cells, we show that the XPF-ERCC1 complex is a valid target to increase cisplatin cytotoxicity and efficacy. We targeted XPF-ERCC1 complex by RNA interference and assessed the repair capacity of cisplatin intrastrand and interstrand crosslinks by ELISA and alkaline comet assay, respectively. We also assessed the repair of cisplatin-ICL-induced double-strand breaks (DSBs) by monitoring gamma-H2AX focus formation. Interestingly, XPF protein levels were significantly reduced following ERCC1 downregulation, but the converse was not observed. The transcript levels were unaffected suggesting that XPF protein stability is likely affected. The repair of both types of cisplatin-DNA lesions was decreased with downregulation of XPF, ERCC1 or both XPF-ERCC1. The ICL-induced DSBs persist in the absence of XPF-ERCC1. The suppression of the XPF-ERCC1 complex significantly decreases the cellular viability which correlates well with the decrease in DNA repair capacity. A double knockdown of XPF-ERCC1 displays the greatest level of cellular cytotoxicity when compared with XPF or ERCC1 alone. The difference in cytotoxicity observed is likely due to the level of total protein complex remaining. These data demonstrate that XPF-ERCC1 is a valid target to enhance cisplatin efficacy in cancer cells by affecting cisplatin-DNA repair pathways.

  13. Dynamic enhancement of drug product labels to support drug safety, efficacy, and effectiveness

    PubMed Central

    2013-01-01

    Out-of-date or incomplete drug product labeling information may increase the risk of otherwise preventable adverse drug events. In recognition of these concerns, the United States Federal Drug Administration (FDA) requires drug product labels to include specific information. Unfortunately, several studies have found that drug product labeling fails to keep current with the scientific literature. We present a novel approach to addressing this issue. The primary goal of this novel approach is to better meet the information needs of persons who consult the drug product label for information on a drug’s efficacy, effectiveness, and safety. Using FDA product label regulations as a guide, the approach links drug claims present in drug information sources available on the Semantic Web with specific product label sections. Here we report on pilot work that establishes the baseline performance characteristics of a proof-of-concept system implementing the novel approach. Claims from three drug information sources were linked to the Clinical Studies, Drug Interactions, and Clinical Pharmacology sections of the labels for drug products that contain one of 29 psychotropic drugs. The resulting Linked Data set maps 409 efficacy/effectiveness study results, 784 drug-drug interactions, and 112 metabolic pathway assertions derived from three clinically-oriented drug information sources (ClinicalTrials.gov, the National Drug File – Reference Terminology, and the Drug Interaction Knowledge Base) to the sections of 1,102 product labels. Proof-of-concept web pages were created for all 1,102 drug product labels that demonstrate one possible approach to presenting information that dynamically enhances drug product labeling. We found that approximately one in five efficacy/effectiveness claims were relevant to the Clinical Studies section of a psychotropic drug product, with most relevant claims providing new information. We also identified several cases where all of the drug

  14. Interleukin 12 Secretion Enhances Antitumor Efficacy of Oncolytic Herpes Simplex Viral Therapy for Colorectal Cancer

    PubMed Central

    Bennett, Joseph J.; Malhotra, Sandeep; Wong, Richard J.; Delman, Keith; Zager, Jonathan; St-Louis, Maryse; Johnson, Paul; Fong, Yuman

    2001-01-01

    Objective To assess the strategy of combining oncolytic herpes simplex virus (HSV) therapy with immunomodulatory therapy as treatment for experimental colon cancer. The oncolytic HSV recombinant NV1023 and the interleukin 12 (IL-12)-secreting oncolytic NV1042 virus were evaluated in vitro and in vivo with respect to antitumor efficacy. Summary Background Data Genetically engineered, replication-conditional, attenuated HSVs have shown oncolytic activity against a wide variety of solid malignancies. Other strategies for treating cancer have involved immunomodulation and cytokine gene transfer using viral vectors. This study has combined both of these strategies by inserting the murine IL-12 gene into a replication-competent HSV. This approach allows oncolytic therapy to replicate selectively within and lyse tumor cells while providing the host immune system with the cytokine stimulus necessary to recruit and activate inflammatory cells needed to enhance the antitumor effect. Methods NV1023 is a multimutant HSV based on the wild-type HSV-1 F strain. NV1042 was created by insertion of the mIL-12 gene into NV1023. Cytotoxicity and viral proliferation of both NV1023 and NV1042 within murine CT26 colorectal cancer cells were first shown. Cells infected with NV1042 were then shown to produce significant levels of IL-12. Using an experimental flank model of colon cancer, mice were treated with both high and low doses of NV1023 or NV1042 and were followed up for both cure and reduction in tumor burden. Results Both viruses could replicate within and kill CT26 cells in vitro, with 100% cytotoxicity achieved after infection by either virus. Only NV1042 could produce mIL-12. Therapy using high viral doses to treat animals in vivo showed equal efficacy between NV1023 and NV1042, with five of seven cures for each virus. When viral doses were lowered, only the cytokine-producing NV1042 virus could reduce tumor burden and cure animals of their disease. Conclusions Both NV1023 and

  15. Inspiring Instructional Change in Elementary School Science: The Relationship between Enhanced Self-Efficacy and Teacher Practices

    ERIC Educational Resources Information Center

    Sandholtz, Judith Haymore; Ringstaff, Cathy

    2014-01-01

    This longitudinal study examined the extent to which teachers' participation in a 3-year professional development program enhanced their self-efficacy and prompted changes in science instruction in the early elementary grades. The study used a mixed-methods design, and included 39 teachers who taught in kindergarten, first grade, or second…

  16. Efficacy of Information and Communication Technology in Enhancing Learning Outcomes of Students with Hearing Impairment in Ibadan

    ERIC Educational Resources Information Center

    Egaga, Patrick I.; Aderibigbe, S. Akinwumi

    2015-01-01

    The study aimed at examining the efficacy of Information and Communication Technology (ICT) in enhancing learning outcomes of students with hearing impairment in Ibadan. The study adopted a pretest, post-test, control group quasi-experimental research design. Purposive sampling techniques was used for the selection of thirty participants…

  17. Ultrasound enhanced sanitizer efficacy in reduction of Escherichia coli O157:H7 population on spinach leaves

    USDA-ARS?s Scientific Manuscript database

    The use of ultrasound to enhance the efficacy of selected sanitizers in reduction of Escherichia coli O157:H7 populations on spinach was investigated. Spot-inoculated spinach samples were treated with water, chlorine, acidified sodium chlorite (ASC), peroxyacetic acid (POAA), and acidic electrolyzed...

  18. A poly(ε-caprolactone) device for sustained release of an anti-glaucoma drug.

    PubMed

    Natu, Mădălina V; Gaspar, Manuel N; Ribeiro, Carlos A Fontes; Correia, Ilídio J; Silva, Daniela; de Sousa, Hermínio C; Gil, M H

    2011-04-01

    Implantable dorzolamide-loaded discs were prepared by blending poly(ε-caprolactone), PCL, with poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Lu. By blending, crystallinity, water uptake and mass loss were modified relative to the pure polymers. Burst was diminished by coating the discs with a PCL shell. All samples presented burst release except PCL-coated samples that showed controlled release during 18 days. For PCL-coated samples, barrier control of diffusion coupled with partition control from the core slowed down the release, while for 50/50 Lu/PCL-coated samples, the enhancement in the porosity of the core diminished partition control of drug release. Nonlinear regression analysis suggested that a degradation model fully describes the release curve considering a triphasic release mechanism: the instantaneous diffusion (burst), diffusion and polymer degradation stages. The MTT test indicated that the materials are not cytotoxic for corneal endothelial cells. A good in vitro-in vivo correlation was obtained, with similar amounts of drug released in vitro and in vivo. The discs decreased intraocular pressure (IOP) in normotensive rabbit eyes by 13.0% during 10 days for PCL-coated and by 13.0% during 4 days for 50/50 Lu/PCL-coated samples. The percentages of IOP decrease are similar to those obtained by dorzolamide eyedrop instillation (11.0%).

  19. Design of Novel Ophthalmic Formulation Containing Drug Nanoparticles and Its Usefulness as Anti-glaucoma Drugs.

    PubMed

    Nagai, Noriaki

    2016-01-01

     The ophthalmic application of drugs is the primary route of administration for the therapy of glaucoma; however, in traditional formulations, only small amounts of the administered drug penetrate the cornea to reach the desired intraocular tissue due to corneal barriers. Recently, nanoparticulate drug delivery is expected as a technology to overcome the difficulties in delivering drugs across biological barriers (improvement of bioavailability). In this study, we attempted to establish a new method for preparing solid drug nanoparticles by using a bead mill and various additives, and succeeded in preparing a high quality dispersion containing drug nanoparticles. For a more concrete example, a mean particle size of disulfiram (DSF) treated with bead mill is 183 nm. The corneal penetration and corneal residence time of DSF from the ophthalmic dispersion containing DSF nanoparticles were significantly higher than those from a 2-hydroxypropyl-β-cyclodextrin solution containing DSF (DSF solution). It is known that the administration of DSF has intraocular pressure (IOP)-reducing effects. The IOP-reducing effects of the ophthalmic dispersion containing DSF nanoparticles were significantly greater than those of the DSF solution in rabbits (the IOP was enhanced by placing the rabbits in a dark room for 5 h). In addition, the ophthalmic dispersion containing DSF nanoparticles is better tolerated by corneal epithelial cells than DSF solution. It is possible that dispersions containing DSF nanoparticles provide new possibilities for effectively treating glaucoma, and that ocular drug delivery systems using drug nanoparticles may expand their usage for therapy in the ophthalmologic field.

  20. The role of alkyl chain length of monothiol-terminated alkyl carboxylic acid in the synthesis, characterization, and application of gelatin-g-poly(N-isopropylacrylamide) carriers for antiglaucoma drug delivery.

    PubMed

    Luo, Li-Jyuan; Lai, Jui-Yang

    2017-02-01

    To improve ocular bioavailability and extend pharmacological response, this study aims to investigate the role of alkyl chain length of monothiol-terminated alkyl carboxylic acids in the synthesis, characterization, and application of gelatin-g-poly(N-isopropylacrylamide) (GN) biodegradable in situ gelling carriers for antiglaucoma drug delivery. In the presence of mercaptoacetic acid (MAA), mercaptopropionic acid (MPA), mercaptobutyric acid (MBA), or mercaptohexanoic acid (MHA) as a chain transfer agent, the carboxylic end-capped poly(N-isopropylacrylamide) samples were prepared by free radical polymerization technique. Our results showed that with increasing alkyl chain length, the hydrophobicity of thermo-responsive polymer segments significantly increased, mainly due to an increase in CH stretching frequencies. In addition, the greater hydrophobic association favored the decrease in both phase transition temperature and weight loss of GN copolymers, thereby accelerating their temperature-triggered gelation process and retarding the degradation progress under physiological conditions. The benefits from these features allowed the pilocarpine carriers to increase drug payload and extend drug release. Irrespective of carbon number of monothiol-terminated alkyl carboxylic acid, the synthesized GN materials exhibited high tolerance to corneal endothelial cells without any evidence of inhibited proliferation, viability loss, inflammatory stimulation, and functional abnormality, indicating good biocompatibility. Results of clinical observations and histological examinations demonstrated that the therapeutic efficacies in treating glaucomatous damage are in response to in vivo drug release profiles from various intracamerally injected GN carriers. The research findings suggest the influence of alkyl chain length of chain transfer agent-mediated polymer hydrophobicity and degradability on pharmacological bioavailability and action of pilocarpine in a glaucomatous rabbit

  1. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.

    PubMed

    Ren, Dongmei; Villeneuve, Nicole F; Jiang, Tao; Wu, Tongde; Lau, Alexandria; Toppin, Henry A; Zhang, Donna D

    2011-01-25

    The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

  2. Nanoparticulated docetaxel exerts enhanced anticancer efficacy and overcomes existing limitations of traditional drugs.

    PubMed

    Choi, Jinhyang; Ko, Eunjung; Chung, Hye-Kyung; Lee, Jae Hee; Ju, Eun Jin; Lim, Hyun Kyung; Park, Intae; Kim, Kab-Sig; Lee, Joo-Hwan; Son, Woo-Chan; Lee, Jung Shin; Jung, Joohee; Jeong, Seong-Yun; Song, Si Yeol; Choi, Eun Kyung

    2015-01-01

    Nanoparticulation of insoluble drugs improves dissolution rate, resulting in increased bioavailability that leads to increased stability, better efficacy, and reduced toxicity of drugs. Docetaxel (DTX), under the trade name Taxotere™, is one of the representative anticancer chemotherapeutic agents of this era. However, this highly lipophilic and insoluble drug has many adverse effects. Our novel and widely applicable nanoparticulation using fat and supercritical fluid (NUFS™) technology enabled successful nanoscale particulation of DTX (Nufs-DTX). Nufs-DTX showed enhanced dissolution rate and increased aqueous stability in water. After confirming the preserved mechanism of action of DTX, which targets microtubules, we showed that Nufs-DTX exhibited similar effects in proliferation and clonogenic assays using A549 cells. Interestingly, we observed that Nufs-DTX had a greater in vivo tumor growth delay effect on an A549 xenograft model than Taxotere™, which was in agreement with the improved drug accumulation in tumors according to the biodistribution result, and was caused by the enhanced permeability and retention (EPR) effect. Although both Nufs-DTX and Taxotere™ showed negative results for our administration dose in the hematologic toxicity test, Nufs-DTX showed much less toxicity than Taxotere™ in edema, paralysis, and paw-withdrawal latency on a hot plate analysis that are regarded as indicators of fluid retention, peripheral neuropathy, and thermal threshold, respectively, for toxicological tests. In summary, compared with Taxotere™, Nufs-DTX, which was generated by our new platform technology using lipid, supercritical fluid, and carbon dioxide (CO2), maintained its biochemical properties as a cytotoxic agent and had better tumor targeting ability, better in vivo therapeutic effect, and less toxicity, thereby overcoming the current hurdles of traditional drugs.

  3. Enhanced Protective Efficacy of a Chimeric Form of the Schistosomiasis Vaccine Antigen Sm-TSP-2

    PubMed Central

    Pearson, Mark S.; Pickering, Darren A.; McSorley, Henry J.; Bethony, Jeffrey M.; Tribolet, Leon; Dougall, Annette M.; Hotez, Peter J.; Loukas, Alex

    2012-01-01

    The large extracellular loop of the Schistosoma mansoni tetraspanin, Sm-TSP-2, when fused to a thioredoxin partner and formulated with Freund's adjuvants, has been shown to be an efficacious vaccine against murine schistosomiasis. Moreover, Sm-TSP-2 is uniquely recognised by IgG1 and IgG3 from putatively resistant individuals resident in S. mansoni endemic areas in Brazil. In the present study, we expressed Sm-TSP-2 at high yield and in soluble form in E. coli without the need for a solubility enhancing fusion partner. We also expressed in E. coli a chimera called Sm-TSP-2/5B, which consisted of Sm-TSP-2 fused to the immunogenic 5B region of the hookworm aspartic protease and vaccine antigen, Na-APR-1. Sm-TSP-2 formulated with alum/CpG showed significant reductions in adult worm and liver egg burdens in two separate murine schistosomiasis challenge studies. Sm-TSP-2/5B afforded significantly greater protection than Sm-TSP-2 alone when both antigens were formulated with alum/CpG. The enhanced protection obtained with the chimeric fusion protein was associated with increased production of anti-Sm-TSP-2 antibodies and IL-4, IL-10 and IFN-γ from spleen cells of vaccinated animals. Sera from 666 individuals from Brazil who were infected with S. mansoni were screened for potentially deleterious IgE responses to Sm-TSP-2. Anti-Sm-TSP-2 IgE to this protein was not detected (also shown previously for Na-APR-1), suggesting that the chimeric antigen Sm-TSP-2/5B could be used to safely and effectively vaccinate people in areas where schistosomes and hookworms are endemic. PMID:22428079

  4. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    NASA Astrophysics Data System (ADS)

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  5. Pluronic P85 enhances the efficacy of outer membrane vesicles as a subunit vaccine against Brucella melitensis challenge in mice.

    PubMed

    Jain-Gupta, Neeta; Contreras-Rodriguez, Araceli; Vemulapalli, Ramesh; Witonsky, Sharon G; Boyle, Stephen M; Sriranganathan, Nammalwar

    2012-12-01

    Brucellosis is the most common zoonotic disease worldwide, and there is no vaccine for human use. Brucella melitensis Rev1, a live attenuated strain, is the commercial vaccine for small ruminants to prevent B. melitensis infections but has been associated with abortions in animals. Moreover, strain Rev1 is known to cause disease in humans and cannot be used for human vaccination. Outer membrane vesicles (OMVs) obtained from B. melitensis have been shown to provide protection similar to strain Rev1 in mice against B. melitensis challenge. In the present work, we tested the efficacy of Pluronic P85 as an adjuvant to enhance the efficacy of Brucella OMVs as a vaccine. P85 enhanced the in vitro secretion of TNF-α by macrophages induced with OMVs and P85. Further, P85 enhanced the protection provided by OMVs against B. melitensis challenge. This enhanced protection was associated with higher total IgG antibody production but not increased IFN-γ or IL-4 cytokine levels. Moreover, P85 alone provided significantly better clearance of B. melitensis compared to saline-vaccinated mice. Further studies are warranted to find the mechanism of action of P85 that provides nonspecific protection and enhances the efficacy of OMVs as a vaccine against B. melitensis.

  6. Pluronic P85 enhances the efficacy of outer membrane vesicles as a subunit vaccine against Brucella melitensis challenge in mice

    PubMed Central

    Jain-Gupta, Neeta; Contreras-Rodriguez, Araceli; Vemulapalli, Ramesh; Witonsky, Sharon G.; Boyle, Stephen M.; Sriranganathan, Nammalwar

    2015-01-01

    Brucellosis is the most common zoonotic disease worldwide and there is no vaccine for human use. Brucella melitensis Rev1, a live attenuated strain, is the commercial vaccine for small ruminants to prevent B. melitensis infections but has been associated with abortions in animals. Moreover, strain Rev1 is known to cause disease in humans and cannot be used for human vaccination. Outer membrane vesicles (OMVs) obtained from B. melitensis have been shown to provide protection similar to strain Rev1 in mice against B. melitensis challenge. In the present work we tested the efficacy of Pluronic P85 as an adjuvant to enhance the efficacy of Brucella OMVs as a vaccine. P85 enhanced the in vitro secretion of TNF-α by macrophages induced with OMVs and P85. Further, P85 enhanced the protection provided by OMVs against B. melitensis challenge. This enhanced protection was associated with higher total IgG antibody production but not increased IFN-γ or IL-4 cytokine levels. Moreover, P85 alone provided significantly better clearance of B. melitensis compared to saline vaccinated mice. Further studies are warranted to find the mechanism of action of P85 that provides non-specific protection and enhances the efficacy of OMVs as a vaccine against B. melitensis. PMID:23163875

  7. PLK1 inhibition enhances temozolomide efficacy in IDH1 mutant gliomas.

    PubMed

    Koncar, Robert F; Chu, Zhengtao; Romick-Rosendale, Lindsey E; Wells, Susanne I; Chan, Timothy A; Qi, Xiaoyang; Bahassi, El Mustapha

    2017-02-28

    Despite multimodal therapy with radiation and the DNA alkylating agent temozolomide (TMZ), malignant gliomas remain incurable. Up to 90% of grades II-III gliomas contain a single mutant isocitrate dehydrogenase 1 (IDH1) allele. IDH1 mutant-mediated transformation is associated with TMZ resistance; however, there is no clinically available means of sensitizing IDH1 mutant tumors to TMZ. In this study we sought to identify a targetable mechanism of TMZ resistance in IDH1 mutant tumors to enhance TMZ efficacy. IDH1 mutant astrocytes rapidly bypassed the G2 checkpoint with unrepaired DNA damage following TMZ treatment. Checkpoint adaptation was accompanied by PLK1 activation and IDH1 mutant astrocytes were more sensitive to treatment with BI2536 and TMZ in combination (<20% clonogenic survival) than either TMZ (~60%) or BI2536 (~75%) as single agents. In vivo, TMZ or BI2536 alone had little effect on tumor size. Combination treatment caused marked tumor shrinkage in all mice and complete tumor regression in 5 of 8 mice. Mutant IDH1 promotes checkpoint adaptation which can be exploited therapeutically with the combination of TMZ and a PLK1 inhibitor, indicating PLK1 inhibitors may be clinically valuable in the treatment of IDH1 mutant gliomas.

  8. Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil

    NASA Astrophysics Data System (ADS)

    Le, Van Minh; Tran Nho, Trung Duc; Trieu Ly, Hai; Vo, Thanh Sang; Dung Nguyen, Hoang; Thu Huong Phung, Thi; Zou, Aihua; Liu, Jianwen

    2017-03-01

    Cancer targeted therapies have attracted considerable attention over the past year. Recently, 5-fluouracil (5-FU), which has high toxicity to normal cells and short half-life associated with rapid metabolism, is one of the most commonly used therapies in the treatment of cancer. In this study the folic acid-conjugated pegylated nanoliposomes were synthesized and then loaded into them with 5-FU to improve the anti-tumor efficacy. The average size of liposomes (LPs) was about 52.7 nm which was identified by TEM. In the liposome uptake studies, the level uptake of folate-conjugated liposomes has increased compared to non-conjugated LPs according to LPs concentration, incubation time and presence of concentration of free folic acid (FA). The MTT assay and apoptotic test were carried out in HCT116 and MCF-7 cells for 24 or 48 h. The results revealed that the folate-PEG modified 5-Fu loaded nanoliposomes had strong cytotoxicity to cancer cell compared to pure 5-FU or PEG modified 5-FU loaded liposomes in a concentration- and time-dependent manner, and mainly enhanced the cancer cell death through folate-mediated endocytosis. Hence, the folate-PEG modified nanoliposome is a potential targeted drug-delivery system for the treatment of FR-positive cancers.

  9. Modern adjuvants do not enhance the efficacy of an inactivated African swine fever virus vaccine preparation.

    PubMed

    Blome, Sandra; Gabriel, Claudia; Beer, Martin

    2014-06-30

    African swine fever (ASF) is among the most devastating viral diseases of pigs. In recent years, the disease has spread alarmingly. Despite intensive research activities, promising vaccine candidates are still lacking. For this reason, a study was undertaken to re-assess inactivated ASFV preparations with state-of-the-art adjuvants. Inactivated preparations of ASF virus (ASFV) "Armenia08" were adjuvanted with either Polygen™ or Emulsigen(®)-D, respectively, and used to immunize six weaner pigs two times with a three-week interval. Six weeks after the first immunization, animals were challenged with the homologues highly virulent ASFV. Although ASFV-specific antibodies were detectable in all but one vaccinated animal prior to challenge, no protective effect of immunization was observed. All animals developed acute-lethal ASF and had to be euthanized within eleven days post challenge. A slightly accelerated clinical course in vaccinees could even indicate an antibody dependent enhancement, which could also influence efficacy of other vaccine approaches.

  10. Transferrin-conjugated polymeric nanomedicine to enhance the anticancer efficacy of edelfosine in acute myeloid leukemia.

    PubMed

    Sun, Yu; Sun, Zhong-Liang

    2016-10-01

    In this study, transferrin (Tf)-conjugated polyethylene glycol (PEG)-poly-l-lysine (PLL)-poly(lactic-co-glycolic acid) (PLGA) (PEG-PLL-PLGA)-based micellar formulations were successfully prepared for the delivery of edelfosine (EDS) in leukemia treatment. The micelles were nanosized and presented spherical shaped particles. Our in vitro data suggest that the nanoformulations maintain the biological activity of drugs for longer periods and lead to a continuous release of active drug. The enhanced cellular uptake of EDS-TM resulted in significantly higher cytotoxic effect in K562 leukemia cells. Cell cycle analysis further demonstrated the significantly higher G2/M phase arrest of cancer cells. Immunoblot analysis clearly revealed the potential of EDS-TM in inducing apoptosis of cancer cells which could improve the anticancer efficacy in leukemia. Importantly, EDS-M and EDS-TM significantly prolonged the circulation profile of EDS throughout until 24h, indicating the potential of targeted nanoparticulate delivery system. The prolonged blood circulation potential of micellar formulations might improve the therapeutic potential of drug by increasing its bioavailability in the serum. It would be worthwhile evaluating the effects of the EDS-loaded micelles on cancer cells in vivo for clinical application.

  11. Enhanced photodynamic efficacy of PLGA-encapsulated 5-ALA nanoparticles in mice bearing Ehrlich ascites carcinoma

    NASA Astrophysics Data System (ADS)

    Shaker, Maryam N.; Ramadan, Heba S.; Mohamed, Moustafa M.; El khatib, Ahmed M.; Roston, Gamal D.

    2014-10-01

    Nanoparticles (NPs) fabricated from the biodegradable copolymer poly(lactic- co-glycolic acid) (PLGA) were investigated as a drug delivery system to enhance the photodynamic efficacy of 5-aminolevulinic acid (5-ALA) in mice bearing Ehrlich ascites carcinoma. The PLGA-encapsulated 5-ALA NPs were prepared using binary organic solvent diffusion method and characterized in terms of shape and particle size. The in vivo photodynamic efficiency in Ehrlich ascites-bearing mice was studied. The obtained particles were uniform in size with spherical shape of mean size of 249.5 nm as obtained by particle size analyzer and the in vitro release studies demonstrated a controlled release profile of 5-ALA. Tumor-bearing mice injected with PLGA-encapsulated 5-ALA NPs exhibited significantly smaller mean tumor volume, increased tumor growth delay compared with the control group and the group injected with free 5-ALA during the time course of the experiment. Histopathological examination of tumor from mice treated with PLGA-encapsulated 5-ALA NPs showed regression of tumor cells, in contrast to those obtained from mice treated with free 5-ALA. The results indicate that PLGA-encapsulated 5-ALA NPs are a successful delivery system for improving photodynamic activity in the target tissue.

  12. SAMHD1 enhances nucleoside-analogue efficacy against HIV-1 in myeloid cells

    PubMed Central

    Ordonez, Paula; Kunzelmann, Simone; Groom, Harriet C. T.; Yap, Melvyn W.; Weising, Simon; Meier, Chris; Bishop, Kate N.; Taylor, Ian A.; Stoye, Jonathan P.

    2017-01-01

    SAMHD1 is an intracellular enzyme that specifically degrades deoxynucleoside triphosphates into component nucleoside and inorganic triphosphate. In myeloid-derived dendritic cells and macrophages as well as resting T-cells, SAMHD1 blocks HIV-1 infection through this dNTP triphosphohydrolase activity by reducing the cellular dNTP pool to a level that cannot support productive reverse transcription. We now show that, in addition to this direct effect on virus replication, manipulating cellular SAMHD1 activity can significantly enhance or decrease the anti-HIV-1 efficacy of nucleotide analogue reverse transcription inhibitors presumably as a result of modulating dNTP pools that compete for recruitment by viral polymerases. Further, a variety of other nucleotide-based analogues, not normally considered antiretrovirals, such as the anti-herpes drugs Aciclovir and Ganciclovir and the anti-cancer drug Clofarabine are now revealed as potent anti-HIV-1 agents, under conditions of low dNTPs. This in turn suggests novel uses for nucleotide analogues to inhibit HIV-1 in differentiated cells low in dNTPs. PMID:28220857

  13. Sequential application of a cytotoxic nanoparticle and a PI3K inhibitor enhances antitumor efficacy

    PubMed Central

    Pandey, Ambarish; Goldman, Aaron; Sarangi, Sasmit; Sengupta, Poulomi; Phipps, Colin; Kopparam, Jawahar; Oh, Michael; Basu, Sudipta; Kohandel, Mohammad; Sengupta, Shiladitya

    2013-01-01

    Nanomedicines that preferentially deploy cytotoxic agents to tumors, and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited pro-survival signaling via an epidermal growth factor receptor-phosphatidylinositol 3 kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacological inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer. PMID:24121494

  14. Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy

    PubMed Central

    Maheswari, K. M.; Devineni, Pavan Kumar; Deekonda, Sravanthi; Shaik, Salma; Uppala, Naga Pravallika; Nalluri, Buchi N.

    2014-01-01

    The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of Amlodipine Besylate (AMLO) to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC) and methyl cellulose (MC) along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30), and sodium lauryl sulphate (SLS) as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w) of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism. PMID:26556197

  15. [Evolving 5-Fluorouracil Therapy to Achieve Enhanced Efficacy-Past and Current Efforts of Researchers].

    PubMed

    Maehara, Yoshihiko; Oki, Eiji; Saeki, Hiroshi; Tokunaga, Eriko; Kitao, Hiroyuki; Iimori, Makoto; Niimi, Shinichiro; Kataoka, Yuki; Emi, Yasunori; Kakeji, Yoshihiro; Baba, Hideo; Shirasaka, Tetsuhiko

    2016-07-01

    5-fluorouracil(5-FU)therapy has advanced greatly over the past 50 years, achieving enhanced therapeutic effects and reduced adverse effects. By taking advantage of the metabolism of 5-FU, researchers have made efforts to develop prodrugs, combination drug products, and combination therapy regimens via biochemical modulation(BCM)with alteration of the drug metabolism. Examples include the advent of the prodrug tegafur(FT), followed by tegafur-uracil(UFT)and tegafurgimeracil- potassium oxonate(S-1)as combined products based on BCM. In the current standard treatment for gastrointestinal cancers, anticancer 5-FU derivatives serve as a platform for combination regimens with other cytotoxic agents or molecular- targeted drugs. To provide further improvements in anticancer therapy outcomes, novel molecular-targeted agents, immune checkpoint inhibitors, and other drugs are being developed, but 5-FU remains an attractive target that shows further potential for increased efficacy. In the future, the evolution of anticancer therapy with 5-FU derivatives is expected to continue via a variety of approaches.

  16. Blockade of the Kv1.3 K+ Channel Enhances BCG Vaccine Efficacy by Expanding Central Memory T Lymphocytes.

    PubMed

    Singh, Dhiraj Kumar; Dwivedi, Ved Prakash; Ranganathan, Anand; Bishai, William R; Van Kaer, Luc; Das, Gobardhan

    2016-11-01

    Tuberculosis is the oldest known infectious disease, yet there is no effective vaccine against adult pulmonary tuberculosis. Emerging evidence indicates that T-helper 1 and T-helper 17 cells play important roles in host protection against tuberculosis. However, tuberculosis vaccine efficacy in mice is critically dependent on the balance between antigen-specific central memory T (Tcm) and effector memory T (Tem) cells. Specifically, a high Tcm/Tem cell ratio is essential for optimal vaccine efficacy. Here, we show that inhibition of Kv1.3, a potassium channel preferentially expressed by Tem cells, by Clofazimine selectively expands Tcm cells during BCG vaccination. Furthermore, mice that received clofazimine after BCG vaccination exhibited significantly enhanced resistance against tuberculosis. This superior activity against tuberculosis could be adoptively transferred to naive, syngeneic mice by CD4(+) T cells. Therefore, clofazimine enhances Tcm cell expansion, which in turn provides improved vaccine efficacy. Thus, Kv1.3 blockade is a promising approach for enhancing the efficacy of the BCG vaccine in humans. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  17. The impact of a culturally enhanced drug prevention program on drug and alcohol refusal efficacy among urban African American girls.

    PubMed

    Belgrave, Faye Z; Reed, Melba C; Plybon, Laura E; Corneille, Maya

    2004-01-01

    This study examined the utility of the Specific Event Drug and Alcohol Refusal Efficacy scale (SEDARE) as an outcome of a culturally enhanced drug abuse prevention program for urban African-American girls in early adolescence. The SEDARE captures the perceived likelihood that youth will use drugs and alcohol in specific situations. Ninety-two girls participated in the program. Girls in the intervention group had higher drug refusal efficacy as measured by the SEDARE than girls in the comparison group. Girls varied in situations they perceived they could refuse drugs and alcohol. Findings are discussed with implications for drug abuse prevention programs for urban African-American girls.

  18. Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.

    PubMed

    Koeberl, Dwight D; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G; Chen, Y-T; Bali, Deeksha S

    2011-06-01

    Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA.

  19. Enhanced Efficacy of Enzyme Replacement Therapy in Pompe Disease Through Mannose-6-Phosphate Receptor Expression in Skeletal Muscle

    PubMed Central

    Koeberl, Dwight D.; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G.; Chen, Y-T; Bali, Deeksha S.

    2011-01-01

    Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β2-agonist, enhanced CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA. PMID:21397538

  20. Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts.

    PubMed

    Cao, Shousong; Durrani, Farukh A; Toth, Karoly; Rustum, Youcef M; Seshadri, Mukund

    2011-06-01

    Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin®) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 or 20mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28days with the first dose beginning seven days prior to Irinotecan (100mg/kg, weekly × 4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical (IHC) methods were employed to study the antiangiogenic effects of Bevacizumab in vivo. Kinetics of tumor response to treatment was studied by monitoring tumor volume over a 60-day period. DCE-MRI detected a significant reduction in vascular permeability following treatment with Bevacizumab (5mg/kg) while high dose Bevacizumab (20mg/kg) induced significant microvascular damage and tumor necrosis, confirmed by immunohistochemistry (IHC). Irinotecan alone resulted in complete tumor regression (cures) in ∼40% of animals while Bevacizumab alone did not result in any cures. Treatment with Bevacizumab (5mg/kg/day×28days) in combination with Irinotecan (100mg/kg, weekly × 4) was highly effective in inhibiting FaDu tumor growth and resulted in complete tumor regression in 80% of animals. These results demonstrate that long term administration of Bevacizumab effectively modulates chemotherapeutic efficacy against HNSCC xenografts. Further investigation into the therapeutic potential of this combination strategy against HNSCC is warranted.

  1. Replication Study: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs

    PubMed Central

    Mantis, Christine; Kandela, Irawati; Aird, Fraser

    2017-01-01

    In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper “Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs“ (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result. DOI: http://dx.doi.org/10.7554/eLife.17584.001 PMID:28100395

  2. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia

    PubMed Central

    Fraietta, Joseph A.; Beckwith, Kyle A.; Patel, Prachi R.; Ruella, Marco; Zheng, Zhaohui; Barrett, David M.; Lacey, Simon F.; Melenhorst, Jan Joseph; McGettigan, Shannon E.; Cook, Danielle R.; Zhang, Changfeng; Xu, Jun; Do, Priscilla; Hulitt, Jessica; Kudchodkar, Sagar B.; Cogdill, Alexandria P.; Gill, Saar; Porter, David L.; Woyach, Jennifer A.; Long, Meixiao; Johnson, Amy J.; Maddocks, Kami; Muthusamy, Natarajan; Levine, Bruce L.; June, Carl H.; Byrd, John C.

    2016-01-01

    Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is highly promising but requires robust T-cell expansion and engraftment. A T-cell defect in chronic lymphocytic leukemia (CLL) due to disease and/or therapy impairs ex vivo expansion and response to CAR T cells. To evaluate the effect of ibrutinib treatment on the T-cell compartment in CLL as it relates to CAR T-cell generation, we examined the phenotype and function of T cells in a cohort of CLL patients during their course of treatment with ibrutinib. We found that ≥5 cycles of ibrutinib therapy improved the expansion of CD19-directed CAR T cells (CTL019), in association with decreased expression of the immunosuppressive molecule programmed cell death 1 on T cells and of CD200 on B-CLL cells. In support of these findings, we observed that 3 CLL patients who had been treated with ibrutinib for ≥1 year at the time of T-cell collection had improved ex vivo and in vivo CTL019 expansion, which correlated positively together and with clinical response. Lastly, we show that ibrutinib exposure does not impair CAR T-cell function in vitro but does improve CAR T-cell engraftment, tumor clearance, and survival in human xenograft models of resistant acute lymphocytic leukemia and CLL when administered concurrently. Our collective findings indicate that ibrutinib enhances CAR T-cell function and suggest that clinical trials with combination therapy are warranted. Our studies demonstrate that improved T-cell function may also contribute to the efficacy of ibrutinib in CLL. These trials were registered at www.clinicaltrials.gov as #NCT01747486, #NCT01105247, and #NCT01217749. PMID:26813675

  3. Efficacy of contrast-enhanced ultrasound washout rate in predicting hepatocellular carcinoma differentiation.

    PubMed

    Feng, Yan; Qin, Xia-Chuan; Luo, Yan; Li, Yong-Zhong; Zhou, Xiang

    2015-06-01

    The aim of this retrospective study was to evaluate the efficacy of contrast-enhanced ultrasound (CEUS) washout rate in predicting hepatocellular carcinoma (HCC) differentiation. Two hundred seventy-one patients underwent liver resection for HCC between April 2008 and December 2012 after being examined by CEUS using the contrast agent SonoVue with a low mechanical index (<0.1) in a routine procedure. Contrast agent washout rates obtained from video images were divided into four categories from slow to fast: WR1 = no washout in all phases (slowest); WR2 = washout after 120 s from contrast injection (late-phase washout); WR3 = washout between 41 and 120 s from contrast injection (portal venous washout); WR4 = washout before 40 s from contrast injection (fastest washout rate). HCC nodules were graded as well, moderately and poorly differentiated. Spearman rank correlation and χ(2)-tests were used to assess group relationships and differences. Receiver operating characteristic curve analysis was used to determine the diagnostic predictive value of CEUS. Among the 271 patients, 18 (6.6%) had well differentiated, 150 (55.4%) had moderately differentiated and 103 (38.0%) had poorly differentiated HCC. Statistical tests indicated that washout rate was significantly correlated with tumor differentiation (p < 0.05), and the poorly differentiated HCCs had earlier washout. At the cutoff point of WR4, CEUS based on washout rate performed poorly in distinguishing poorly differentiated from moderately and well-differentiated HCCs, with a sensitivity, specificity and accuracy (area under the curve) of 24%, 97% and 0.68, respectively. However, at the cutoff point of WR2, the sensitivity, specificity and accuracy of CEUS in differentiating well-differentiated HCC from other HCCs were significantly better: 98%, 78% and 0.96, respectively. Thus, CEUS washout rate may have a role in identifying patients with well-differentiated HCC.

  4. Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

    PubMed

    Yao, Xinpeng; Liu, Yi; Gao, Jie; Yang, Liang; Mao, Duo; Stefanitsch, Christina; Li, Yang; Zhang, Jun; Ou, Lailiang; Kong, Deling; Zhao, Qiang; Li, Zongjin

    2015-08-01

    Stem cell therapy has been proved to be an effective approach to ameliorate the heart remodeling post myocardial infarction (MI). However, poor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating MI. Here, we sought to transplant adipose derived-mesenchymal stem cells (AD-MSCs) with a hydrogel (NapFF-NO), naphthalene covalently conjugated a short peptide, FFGGG, and β-galactose caged nitric oxide (NO) donor, which can release NO molecule in response to β-galactosidase. AD-MSCs, either from transgenic mice that constitutively express GFP and firefly luciferase (Fluc), or express Fluc under the control of VEGFR2 promoter, were co-transplanted with NapFF-NO hydrogel into murine MI models. Improved cell survival and enhanced cardiac function were confirmed by bioluminescence imaging (BLI) and echocardiogram respectively. Moreover, increasing VEGFR2-luc expression was also tracked in real-time in vivo, indicating NapFF-NO hydrogel stimulated VEGF secretion of AD-MSCs. To investigate the therapeutic mechanism of NapFF-NO hydrogel, cell migration assay, paracrine action of AD-MSCs, and histology analysis were carried out. Our results revealed that condition medium from AD-MSCs cultured with NapFF-NO hydrogel could promote endothelial cell migration. Additionally, AD-MSCs showed significant improvement secretion of angiogenic factors VEGF and SDF-1α in the presence of NapFF-NO hydrogel. Finally, postmortem analysis confirmed that transplanted AD-MSCs with NapFF-NO hydrogel could ameliorate heart function by promoting angiogenesis and attenuating ventricular remodeling. In conclusion, NapFF-NO hydrogel can obviously improve therapeutic efficacy of AD-MSCs for MI by increasing cell engraftment and angiogenic paracrine action.

  5. Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model.

    PubMed

    Linard, Christine; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Benderitter, Marc

    2016-09-01

    The success of mesenchymal stem cell transplantation for proctitis depends not only on cell donors but also on host microenvironmental factors, which play a major role in conditioning mesenchymal stem cell immunosuppressive action and repair. This study sought to determine if flagellin, a TLR5 ligand, can enhance the mesenchymal stem cell treatment efficacy in radiation-induced proctitis. With the use of a colorectal model of 27 Gy irradiation in rats, we investigated and compared the effects on immune capacity and remodeling at 28 d after irradiation of the following: 1) systemic mesenchymal stem cell (5 × 10(6)) administration at d 7 after irradiation, 2) administration of flagellin at d 3 and systemic mesenchymal stem cell administration at d 7, and 3) in vitro preconditioning of mesenchymal stem cells with flagellin, 24 h before their administration on d 7. The mucosal CD8(+) T cell population was normalized after treatment with flagellin-preconditioned mesenchymal stem cells or flagellin plus mesenchymal stem cells, whereas mesenchymal stem cells alone did not alter the radiation-induced elevation of CD8(+) T cell frequency. Mesenchymal stem cell treatment returned the irradiation-elevated frequency of CD25(+) cells in the mucosa-to-control levels, whereas both flagellin-preconditioned mesenchymal stem cell and flagellin-plus-mesenchymal stem cell treatment each significantly increased not only CD25(+) cell frequency but also forkhead box p3 and IL-2Rα expression. Specifically, IL-10 was overexpressed after flagellin-preconditioned mesenchymal stem cell treatment. Analysis of collagen expression showed that the collagen type 1/collagen type 3 ratio, an indicator of wound-healing maturation, was low in the irradiated and mesenchymal stem cell-treated groups and returned to the normal level only after the flagellin-preconditioned mesenchymal stem cell treatment. This was associated with a reduction in myofibroblast accumulation. In a proctitis model, flagellin

  6. Enhancing Elementary-School Mathematics Teachers' Efficacy Beliefs: A Qualitative Action Research

    ERIC Educational Resources Information Center

    Katz, Sara; Stupel, Moshe

    2016-01-01

    Individuals and societies that can use mathematics effectively in this period of rapid changes will have a voice on increasing the opportunities and potentials which can shape their future. This has brought affective characteristics, such as self-efficacy, that affect mathematics achievement into focus of the research. Teacher efficacy refers to…

  7. Enhancing Elementary-School Mathematics Teachers' Efficacy Beliefs: A Qualitative Action Research

    ERIC Educational Resources Information Center

    Katz, Sara; Stupel, Moshe

    2016-01-01

    Individuals and societies that can use mathematics effectively in this period of rapid changes will have a voice on increasing the opportunities and potentials which can shape their future. This has brought affective characteristics, such as self-efficacy, that affect mathematics achievement into focus of the research. Teacher efficacy refers to…

  8. Five factor model personality factors moderated the effects of an intervention to enhance chronic disease management self-efficacy.

    PubMed

    Franks, Peter; Chapman, Benjamin; Duberstein, Paul; Jerant, Anthony

    2009-09-01

    Peer led interventions can enhance patient self-efficacy for managing chronic illnesses, but little is known regarding the moderators or duration of their effects. We hypothesized Homing in on Health (HIOH), a variant of the Chronic Disease Self-Management Program, would be most effective in patients high in neuroticism and low in extraversion, openness, agreeableness, and/or conscientiousness. Analysis of data from subjects (N=415) enrolled in an ongoing randomized controlled trial. Regression analyses were conducted to explore whether Five Factor Model (FFM) personality factors moderated the effects of HIOH, delivered in subjects' homes or via telephone, on disease management self-efficacy. Data were collected at 6 time points over the course of 1 year. Compared with control and telephone HIOH, home HIOH significantly increased self-efficacy, an effect peaking at 6 weeks and fully attenuating by 1 year. Moderation analyses revealed the benefit was confined to patients higher in neuroticism and/or lower in conscientiousness, agreeableness, and extraversion. A peer led intervention to enhance disease management self-efficacy had only short-term effects, and FFM personality factors moderated those effects. Measuring personality factors in chronically ill individuals may facilitate targeting of self-management interventions to those most likely to respond.

  9. Five factor model personality factors moderated the effects of an intervention to enhance chronic disease management self-efficacy

    PubMed Central

    Franks, Peter; Chapman, Benjamin; Duberstein, Paul; Jerant, Anthony

    2009-01-01

    Objectives Peer led interventions can enhance patient self-efficacy for managing chronic illnesses, but little is known regarding the moderators or duration of their effects. We hypothesized Homing in on Health (HIOH), a variant of the Chronic Disease Self-Management Program, would be most effective in patients high in neuroticism and low in extraversion, openness, agreeableness, and/or conscientiousness. Design Analysis of data from subjects (N = 415) enrolled in an ongoing randomized controlled trial Methods Regression analyses were conducted to explore whether Five Factor Model (FFM) personality factors moderated the effects of HIOH, delivered in subjects’ homes or via telephone, on disease management self-efficacy. Data were collected at 6 time points over the course of 1 year. Results Compared with control and telephone HIOH, home HIOH significantly increased self-efficacy, an effect peaking at 6 weeks and fully attenuating by 1 year. Moderation analyses revealed the benefit was confined to patients higher in neuroticism and/or lower in conscientiousness, agreeableness, and extraversion. Conclusions A peer led intervention to enhance disease management self-efficacy had only short-term effects, and FFM personality factors moderated those effects. Measuring personality factors in chronically ill individuals may facilitate targeting of self-management interventions to those most likely to respond. PMID:18808733

  10. Gold nanorod-mediated hyperthermia enhances the efficacy of HPMA copolymer - 90Y conjugates in treatment of prostate tumors

    PubMed Central

    Buckway, Brandon; Frazier, Nick; Gormley, Adam J.; Ray, Abhijit; Ghandehari, Hamidreza

    2014-01-01

    Introduction The treatment of prostate cancer using a radiotherapeutic 90Y labeled N-(2-hydroxypropyl)methacrylamide (HPMA)copolymer can be enhanced with localized tumor hyperthermia. An 111In labeled HPMA copolymer system for single photon emission computerized tomography (SPECT) was developed to observe the biodistribution changes associated with hyperthermia. Efficacy studies were conducted in prostate tumor bearing mice using the 90Y HPMA copolymer with hyperthermia. Methods HPMA copolymers containing 1, 4, 7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthesized by reversible addition-fragmentation transfer (RAFT) copolymerization and subsequently labeled with either 111In for imaging or 90Y for efficacy studies. Radiolabel stability was characterized in vitro with mouse serum. Imaging and efficacy studies were conducted in DU145 prostate tumor bearing mice. Imaging was performed using single photon emission computerized tomography (SPECT). Localized mild tumor hyperthermia was achieved by plasmonic photothermal therapy using gold nanorods. Results HPMA copolymer-DOTA conjugates demonstrated efficient labeling and stability for both radionuclides. Imaging analysis showed a marked increase of radiolabeled copolymer within the hyperthermia treated prostate tumors, with no significant accumulation in non-targeted tissues. The greatest reduction in tumor growth was observed in the hyperthermia treated tumors with 90Y HPMA copolymer conjugates. Histological analysis confirmed treatment efficacy and safety. Conclusion HPMA copolymer-DOTA conjugates radiolabeled with both the imaging and treatment radioisotopes, when combined with hyperthermia can serve as an image guided approach for efficacious treatment of prostate tumors. PMID:24461626

  11. Effects of Enhanced Caregiver Training Program on Cancer Caregiver's Self-Efficacy, Preparedness, and Psychological Well-Being

    PubMed Central

    Hendrix, Cristina C.; Bailey, Donald E.; Steinhauser, Karen E.; Olsen, Maren K.; Stechuchak, Karen M.; Lowman, Sarah G.; Schwartz, Abby J.; Riedel, Richard F.; Keefe, Francis J.; Porter, Laura S.; Tulsky, James A.

    2015-01-01

    Purpose We examined the effects of an enhanced informal caregiver training (Enhanced-CT) protocol in cancer symptom and caregiver stress management to caregivers of hospitalized cancer patients. Methods We recruited adult patients in oncology units and their informal caregivers. We utilized a two-armed, randomized controlled trial design with data collected at baseline, post-training, and at 2 and 4 weeks after hospital discharge. Primary outcomes were self-efficacy for managing patients' cancer symptoms and caregiver stress, and preparedness for caregiving. Secondary outcomes were caregiver depression, anxiety, and burden. The education comparison (EDUC) group received information about community resources. We used general linear models to test for differences in the Enhanced-CT relative to the EDUC group. Results We consented and randomized 138 dyads: Enhanced-CT = 68 and EDUC = 70. The Enhanced-CT group had a greater increase in caregiver self-efficacy for cancer symptom management and stress management, and preparation for caregiving at the post-training assessment compared to the EDUC group but not at 2 and 4-week post-discharge assessments. There were no intervention group differences in depression, anxiety, and burden. Conclusion An Enhanced-CT protocol resulted in short-term improvements in self-efficacy for managing patients' cancer symptoms and caregiver stress, and preparedness for caregiving but not in caregivers' psychological well-being. The lack of sustained effects may be related to the single-dose nature of our intervention and the changing needs of informal caregivers after hospital discharge. PMID:26062925

  12. Development of Novel Combinatorial Treatment to Prevent Chemotherapeutic Resistance and Enhance Efficacy of Riluzole in a Rodent Model of SCI

    DTIC Science & Technology

    2016-10-01

    spinal cord injury (SCI) in order to enhance the bioavailability and efficacy of riluzole, an FDA- approved neuroprotective drug . In a previously...amount of a wide range of substances, both endogenous as well as exogenous (such as drugs ) from tissues. Pgp is a significant contributor to the...process of chemotherapeutic resistance in many forms of cancer that blocks access of systemically-administered drugs into tumors, reducing their

  13. Cinobufagin enhances the protective efficacy of formalin-inactivated Salmonella typhimurium vaccine through Th1 immune response.

    PubMed

    Wu, Shuai-Cheng; Yi, Peng-Fei; Guo, Xun; Zhang, Li-Yan; Xu, Dao-Xiu; Fu, Yun-Xing; Cui, Zhen-Qiang; Shen, Hai-Qing; Wei, Xu-Bin; Fu, Ben-Dong

    2016-10-01

    Cinobufagin (CBG), one active ingredient isolated from Venenum Bufonis, has been demonstrated to have immunoregulatory effect. The aim of this study was to investigate whether CBG can enhance the protective efficacy of formalin-inactivated Salmonella typhimurium (FIST) in mice. ICR mice were immunized with FIST (10(6) CFU/mouse) alone or mixed with CBG (10, 20, and 40 μg) or alum (200 μg) on day 1 and day 15. Two weeks after the second immunization, serum and spleen were sampled for measuring FIST-specific antibody levels, cytokine levels, and splenocyte proliferation. The results showed that CBG enhanced FIST-specific IgG and IgG2a, the levels of interferon-gamma (IFNγ) and nitric oxide (NO), and the splenocyte proliferation response induced by concanavalin A, lipopolysaccharide, and FIST. In vivo protection studies showed that CBG significantly decreased the bacterial burdens in the spleen and prolonged the survival time of FIST-immunized mice challenged with live Salmonella typhimurium. In vivo IFNγ neutralization led to a significant reduction in FIST-specific IgG2a and IFNγ levels, and in the protective efficacy in CBG/FIST-immunized mice. In conclusion, CBG enhances the protective efficacy of formalin-inactivated Salmonella typhimurium vaccine by promoting the Th1 immune response.

  14. Preparation of an anhydrous reverse micelle delivery system to enhance oral bioavailability and anti-diabetic efficacy of berberine.

    PubMed

    Wang, Ting; Wang, Ning; Song, Hui; Xi, Xiaonan; Wang, JianAn; Hao, Aijun; Li, Tiefu

    2011-09-18

    To enhance oral bioavailability and anti-diabetic efficacy of berberine (BER), an anhydrous reverse micelle (ARM) delivery system was prepared through lyophilization of water-in-oil (W/O) emulsions. Using soy phosphatidylcholine as emulsifiers, BER-containing W/O emulsions were prepared and then lyophilized to form dry products which, upon addition of oil, formed clear ARMs containing amorphous BER nanoparticles. BER-loaded ARMs or free BER solutions were administered to streptozocin-induced diabetic mice. In vivo measurements demonstrated that the blood glucose levels (BGLs) of diabetic mice reduced on average to 22% of the initial values 4h after intravenous injection of BER solution at the dose of 2.5mg/kg body weight, while the average BGL reduction was 57% in the group gavaged with ARMs at the dose of 100mg/kg body weight. No significant BGL reduction was noticed in mice orally received BER solutions. Compared to BER solutions, the oral bioavailability of BER-loaded ARMs was enhanced 2.4-fold, and the maximum blood concentration of BER was enhanced 2.1-fold with a 2-h time lag leading to a prolonged efficacy. Thus, this novel ARM delivery system provides a valid method to improve oral bioavailability and anti-diabetic efficacy of BER, offering a promising product alternative to other hypoglycemic drugs for diabetes therapy.

  15. Multifunctional ZnPc-loaded mesoporous silica nanoparticles for enhancement of photodynamic therapy efficacy by endolysosomal escape.

    PubMed

    Tu, Jing; Wang, Tianxiao; Shi, Wei; Wu, Guisen; Tian, Xinhua; Wang, Yuhua; Ge, Dongtao; Ren, Lei

    2012-11-01

    The cellular uptake and localization of photosensitizer-loaded nanoparticles have significant impact on photodynamic therapy (PDT) efficacy due to short lifetime and limited action radius of singlet oxygen. Herein, we develop poly(ethylene glycol) (PEG)- and polyethylenimine (PEI)-functionalized zinc(II) phthalocyanine (ZnPc)-loaded mesoporous silica nanoparticles (MSNs), which are able to distribute in the cytosol by endolysosomal escape. In this photosensitizer-carrier system (PEG-PEI-MSNs/ZnPc), ZnPc is a PDT agent; MSNs are the nanocarrier for encapsulating ZnPc; PEI facilitates endosomal escape; and PEG enhances biocompatibility. The as-synthesized PEG-PEI-MSNs/ZnPc have a high escape efficiency from the lysosome to the cytosol due to the "proton sponge" effect of PEI. Compared with the ZnPc-loaded MSNs, the phototoxicity of the PEG-PEI-MSNs/ZnPc is greatly enhanced in vitro. By measuring the mitochondrial membrane potential, a significant loss of >80% Δψm after treatment with PEG-PEI-MSNs/ZnPc-PDT is observed. It is further demonstrated that the ultra-efficient passive tumor targeting and excellent PDT efficacy are achieved in tumor-bearing mice upon intravenous injection of PEG-PEI-MSNs/ZnPc and the followed light exposure. We present here a strategy for enhancement of PDT efficacy by endolysosomal escape and highlight the promise of using multifunctional MSNs for cancer therapy.

  16. Cannabinoid receptor CB1 mRNA is highly expressed in the rat ciliary body: implications for the antiglaucoma properties of marihuana.

    PubMed

    Porcella, A; Casellas, P; Gessa, G L; Pani, L

    1998-07-15

    We used RT-PCR to measure relative differences in cannabinoid receptor (CB) mRNAs in the rat eye, comparing CB1 or CB2 transcripts to that of the normalizing reference gene beta2 microglobulin (beta2m). Significantly higher levels of CB1 mRNA levels were found in the ciliary body (0.84+/-0.05% of beta2m) than in the iris, (0.34+/-0.04% of beta2m), retina (0.07+/-0.005% of beta2m) and choroid (0.06+/-0.005% of beta2m). CB2 mRNA was undetectable. This expression pattern supports a specific role for the CB1 receptor in controlling intraocular pressure, helping to explain the antiglaucoma property of cannabinoids.

  17. Stimulation of the cholinergic neurotransmissions enhances the efficacy of vestibular rehabilitation

    PubMed Central

    Monzani, D; Genovese, E; Marrara, A; Presutti, L; Gherpelli, C; Panzetti, P; Forghieri, M

    2010-01-01

    Summary The primary aim of this study was to investigate the efficacy of vestibular rehabilitation in a cohort of elderly labyrinthine-defective patients also affected by a moderate cognitive impairment of vascular origin. A secondary aim was to establish whether additional treatment with a cholinergic precursor (choline alphascerate) might enhance the results of the physical therapy in these patients. A retrospective clinical design was employed and data were collected from the vestibular rehabilitation treatment charts of 42 selected elderly patients who attended the tertiary referral centre of the Audiology and Vestibology of the University Hospital of Modena, Italy, in the period 1998-2008. Two groups of patients, well-matched for sex, age, and as close as possible for the vestibular examination upon admittance, were selected; Group A included 20 patients who had undergone vestibular rehabilitation training for one month and Group B included 22 patients who had attended the same physical therapy sessions as the former and had also received daily medication with 1200 mg of choline alphascerate per os. The outcome measures of the two forms of treatments were obtained from comparisons between posturographic and electronystagmographic examinations at baseline and 3 weeks after the end of treatment. Instrumental findings were completed by recording scores of the Dynamic Gait Index, the Dizziness Handicap Inventory and the Hospital Anxiety and Depression Scale before and after treatment. A statistically significant improvement in postural control (p < 0.05) and gait and balance performances (p < 0.005) was recorded in both groups; a relevant and statistically significant reduction of the asymmetry of the vestibular-ocular reflexes was also observed (p < 0.005). The self-rated dizziness handicap and psychological distress were significantly reduced (p < 0.005). Comparisons between the two groups revealed that patients who had also received medication, had achieved

  18. Efficacy and safety of penile girth enhancement by autologous fat injection for patients with thin penises.

    PubMed

    Kang, Dong Hyuk; Chung, Jae Hoon; Kim, Yong Jin; Lee, Haeng Nam; Cho, Seung Hoon; Chang, Taek Hee; Lee, Seung Wook

    2012-08-01

    This study aimed to investigate the efficacy and safety of autologous fat injection (AFI) for penile girth enhancement (PGE) in patients with thin penises. This study investigated 52 patients with a small penile circumference who underwent AFI for PGE and were followed up for more than 6 months. The patients whose proximal one third (G1) and distal one third of their penis (G2) had a mean thickness of 7.4 cm or less were selected as subjects. After fat suction using a liposuction device, fat was evenly injected into the superficial, middle, and deep layers of the Colles' fascia. Patient age and operative time were analyzed. The G1, G2, flaccid (L1), stretched length (L2), and five-item version of the International Index of Erectile Function-5 (IIEF-5) before and 6 months after the surgery were compared. Postoperative complications were surveyed. The patient mean age was 42.15 years (range, 22-56) years, and the operative time was 44.44 min (range, 37-49 min). The injected fat volume was 38.54 ml (range, 25-49 ml). Preoperatively, G1 was 7.01±0.39 cm, and G2 was 7.06±0.37 cm. Postoperatively, G1 was 9.29±0.82 cm (P<0.001), and G2 was 9.34±0.86 (P<0.001) cm 6 months after the surgery. The difference between L1 and L2 before and after the surgery was not significant. The IIEF-5 was 19.10±3.22 before the surgery and 19.90±3.05 after the surgery (P=0.001). The only complication was nodular fat observed in one case (1.92%). The use of AFI for PGE in men with thin penises was effective and safe without major complications. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

  19. DNA vaccination by electroporation and boosting with recombinant proteins enhances the efficacy of DNA vaccines for Schistosomiasis japonica.

    PubMed

    Dai, Yang; Zhu, Yinchang; Harn, Donald A; Wang, Xiaoting; Tang, Jianxia; Zhao, Song; Lu, Fei; Guan, Xiaohong

    2009-12-01

    Schistosomiasis japonica is an endemic, zoonotic disease of major public health importance in China. Control programs combining chemotherapy and snail killing have not been able to block transmission of infection in lakes and marsh regions. Vaccination is needed as a complementary approach to the ongoing control programs. In the present study, we wanted to determine if the efficacies of DNA vaccines encoding the 23-kDa tetraspanin membrane protein (SjC23), triose phosphate isomerase (SjCTPI), and sixfold-repeated genes of the complementarity determining region 3 (CDR3) in the H chain of NP30 could be enhanced by boosting via electroporation in vivo and/or with cocktail protein vaccines. Mice vaccinated with cocktail DNA vaccines showed a significant worm reduction of 32.88% (P < 0.01) and egg reduction of 36.20% (P < 0.01). Vaccine efficacy was enhanced when animals were boosted with cocktail protein vaccines; adult worm and liver egg burdens were reduced 45.35% and 48.54%, respectively. Nearly identical results were obtained in mice boosted by electroporation in vivo, with adult worm and egg burdens reduced by 45.00% and 50.88%, respectively. The addition of a protein vaccine boost to this regimen further elevated efficacy to approximately 60% for adult worm burden and greater than 60% for liver egg reduction. The levels of interleukin-2, gamma interferon, and the ratios of immunoglobulin G2a (IgG2a)/IgG1 clearly showed that cocktail DNA vaccines induced CD4(+) Th1-type responses. Boosting via either electroporation or with recombinant proteins significantly increased associated immune responses over those seen in mice vaccinated solely with DNA vaccines. Thus, schistosome DNA vaccine efficacy was significantly enhanced via boosting by electroporation in vivo and/or cocktail protein vaccines.

  20. Long-term exposure to estrogen enhances chemotherapeutic efficacy potentially through epigenetic mechanism in human breast cancer cells

    PubMed Central

    Chang, Yu-Wei

    2017-01-01

    Chemotherapy is the most common clinical option for treatment of breast cancer. However, the efficacy of chemotherapy depends on the age of breast cancer patients. Breast tissues are estrogen responsive and the levels of ovarian estrogen vary among the breast cancer patients primarily between pre- and post-menopausal age. Whether this age-dependent variation in estrogen levels influences the chemotherapeutic efficacy in breast cancer patients is not known. Therefore, the objective of this study was to evaluate the effects of natural estrogen 17 beta-estradiol (E2) on the efficacy of chemotherapeutic drugs in breast cancer cells. Estrogen responsive MCF-7 and T47D breast cancer cells were long-term exposed to 100 pg/ml estrogen, and using these cells the efficacy of chemotherapeutic drugs doxorubicin and cisplatin were determined. The result of cell viability and cell cycle analysis revealed increased sensitivities of doxorubicin and cisplatin in estrogen-exposed MCF-7 and T47D cells as compared to their respective control cells. Gene expression analysis of cell cycle, anti-apoptosis, DNA repair, and drug transporter genes further confirmed the increased efficacy of chemotherapeutic drugs in estrogen-exposed cells at molecular level. To further understand the role of epigenetic mechanism in enhanced chemotherapeutic efficacy by estrogen, cells were pre-treated with epigenetic drugs, 5-aza-2-deoxycytidine and Trichostatin A prior to doxorubicin and cisplatin treatments. The 5-aza-2 deoxycytidine pre-treatment significantly decreased the estrogen-induced efficacy of doxorubicin and cisplatin, suggesting the role of estrogen-induced hypermethylation in enhanced sensitivity of these drugs in estrogen-exposed cells. In summary, the results of this study revealed that sensitivity to chemotherapy depends on the levels of estrogen in breast cancer cells. Findings of this study will have clinical implications in selecting the chemotherapy strategies for treatment of breast

  1. Pre- and post-exposure safety and efficacy of attenuated rabies virus vaccines are enhanced by their expression of IFNγ

    SciTech Connect

    Barkhouse, Darryll A.; Faber, Milosz; Hooper, D. Craig

    2015-01-01

    Consistent with evidence of a strong correlation between interferon gamma (IFNγ) production and rabies virus (RABV) clearance from the CNS, we recently demonstrated that engineering a pathogenic RABV to express IFNγ highly attenuates the virus. Reasoning that IFNγ expression by RABV vaccines would enhance their safety and efficacy, we reverse-engineered two proven vaccine vectors, GAS and GASGAS, to express murine IFNγ. Mortality and morbidity were monitored during suckling mice infection, immunize/challenge experiments and mixed intracranial infections. We demonstrate that GASγ and GASγGAS are significantly attenuated in suckling mice compared to the GASGAS vaccine. GASγ better protects mice from lethal DRV4 RABV infection in both pre- and post-exposure experiments compared to GASGAS. Finally, GASγGAS reduces post-infection neurological sequelae, compared to control, during mixed intracranial infection with DRV4. These data show IFNγ expression by a vaccine vector can enhance its safety while increasing its efficacy as pre- and post-exposure treatment. - Highlights: • IFNγ expression improves attenuated rabies virus safety and immunogenicity. • IFNγ expression is safer and more immunogenic than doubling glycoprotein expression. • Co-infection with IFNγ-expressing RABV prevents wild-type rabies virus lethality. • Vaccine safety and efficacy is additive for IFNγ and double glycoprotein expression.

  2. Communicative social capital and collective efficacy as determinants of access to health-enhancing resources in residential communities.

    PubMed

    Matsaganis, Matthew D; Wilkin, Holley A

    2015-04-01

    This article contributes to the burgeoning literature on the social determinants of health disparities. The authors investigate how communication resources and collective efficacy, independently and in combination, shape residents' access to health enhancing resources (including healthcare services, sources of healthier food options, and public recreation spaces) in their communities. Using random digit dial telephone survey data from 833 residents of South Los Angeles communities the authors show that communicative social capital-that is, an information and problem-solving resource that accrues to residents as they become more integrated into their local communication network of neighbors, community organizations, and local media-plays a significant role in access to health resources. This relationship is complicated by individuals' health insurance and health status, as communicative social capital magnifies the sense of absence of resources for those who are in worse health and lack insurance. Communicative social capital builds collective efficacy, which is positively related to access to health-enhancing resources, but it also mediates the negative relationship between communicative social capital and access to health resources. Residents with richer stores of communicative social capital and collective efficacy report better access to health resources. The authors conclude with a discussion of implications of these findings and suggestions for future research.

  3. Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy.

    PubMed

    Han, Rui; Sun, Yuan; Kang, Chen; Sun, Huijing; Wei, Wenguang

    2017-02-01

    Combination cancer therapy has attracted considerable attention due to its enhanced antitumor efficacy and reduced toxicity granted by synergistic effects over monotherapy. The application of nanotechnology is expected to achieve coencapsulation of multiple anticancer agents with enhanced therapeutic efficacy. Herein, a unique nanomicelle based on amphiphilic dendrimer (AmD) consisting of a hydrophilic polyamidoamine dendritic shell and a hydrophobic polylactide core is developed for effectively loading and shuttling 5-fluorouracil (5-Fu) and doxorubicin (Dox). The yielded drug-encapsulated dendritic nanomicelle (5-Fu/Dox-DNM) has a modest average size of 68.6 ± 3.3 nm and shows pH-sensitive drug release manner. The parallel activity of 5-Fu and Dox show synergistic anticancer efficacy. The IC50 value of 5-Fu/Dox-DNM toward human breast cancer (MDA-MB-231) cells was 0.25 μg/mL, presenting an 11.2-fold and 6.1-fold increase in cytotoxicity compared to Dox-DNM and 5-Fu-DNM, respectively. Furthermore, 5-Fu/Dox-DNM significantly inhibits the progression of tumor growth in the MDA-MB-231 xenograft tumor mice model. In conclusion, we have demonstrated that our AmD-based combination therapeutic system has promising potential to open an avenue for coencapsulation of multiple chemotherapeutic agents to promote superior anticancer effect.

  4. Synergistic efficacy of 405 nm light and chlorinated disinfectants for the enhanced decontamination of Clostridium difficile spores.

    PubMed

    Moorhead, Sian; Maclean, Michelle; Coia, John E; MacGregor, Scott J; Anderson, John G

    2016-02-01

    The ability of Clostridium difficile to form highly resilient spores which can survive in the environment for prolonged periods causes major contamination problems. Antimicrobial 405 nm light is being developed for environmental decontamination within hospitals, however further information relating to its sporicidal efficacy is required. This study aims to establish the efficacy of 405 nm light for inactivation of C. difficile vegetative cells and spores, and to establish whether spore susceptibility can be enhanced by the combined use of 405 nm light with low concentration chlorinated disinfectants. Vegetative cells and spore suspensions were exposed to increasing doses of 405 nm light (at 70-225 mW/cm(2)) to establish sensitivity. A 99.9% reduction in vegetative cell population was demonstrated with a dose of 252 J/cm(2), however spores demonstrated higher resilience, with a 10-fold increase in required dose. Exposures were repeated with spores suspended in the hospital disinfectants sodium hypochlorite, Actichlor and Tristel at non-lethal concentrations (0.1%, 0.001% and 0.0001%, respectively). Enhanced sporicidal activity was achieved when spores were exposed to 405 nm light in the presence of the disinfectants, with a 99.9% reduction achieved following exposure to 33% less light dose than required when exposed to 405 nm light alone. In conclusion, C. difficile vegetative cells and spores can be successfully inactivated using 405 nm light, the sporicidal efficacy can be significantly enhanced when exposed in the presence of low concentration chlorinated disinfectants. Further research may lead to the potential use of 405 nm light decontamination in combination with selected hospital disinfectants to enhance C. difficile cleaning and infection control procedures. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Chronic disease self-management improved with enhanced self-efficacy.

    PubMed

    Farrell, Kathleen; Wicks, Mona N; Martin, Judy C

    2004-11-01

    This pilot study used a quasi-experimental pretest-posttest design to examine if participation in a chronic disease self-management program (CDSMP) improved self-efficacy, self-efficacy health, and self-management behaviors in an underserved, poor, rural population. The sample, recruited from two clinics in a south central state, consisted of 48 adults (59.70 +/- 11.22 years) and was 79.2% Caucasian (n = 38) and 20.8% (n = 10) African American. Trained lay leaders with chronic illnesses directed the interactive CDSMP based on Bandura's self-efficacy theory that included strategies for personal exercise program development, cognitive symptom management, problem solving, and communication skills. Program-specific paper-and-pencil instruments were completed prior to and immediately after completion of the 6-week program. Significant improvements (p <.10) in self-efficacy, self-efficacy health, and self-management behaviors occurred. Results underscore the need to evaluate intervention programs for specific populations and for a new paradigm that focuses on patient-provider partnerships that can improve health outcomes in underserved, poor, rural populations.

  6. Enhancing self-protective behavior: efficacy beliefs and peer feedback in risk communication.

    PubMed

    Verroen, Stephan; Gutteling, Jan M; De Vries, Peter W

    2013-07-01

    In times of a high-impact safety incident citizens may have a variety of sources available to help them cope with the situation. This research focuses on the interplay of efficacy information in risk communication messages and peer feedback, such as responses on social network sites (SNSs) in the context of a high-impact risk on the intention to engage in self-protective behavior. The study pitted high and low efficacy information messages against supporting and opposing peer feedback (N = 242). Results show a significant interaction effect between efficacy information in a news article and peer feedback from SNS messages on both the intention to engage in self-protective behavior and levels of involvement. Participants who received the article with more efficacy information and also received supportive peer feedback via SNS messages were more likely to express higher levels of involvement and greater intentions to engage in protective behavior. When confronted with a low efficacious news article, the effect of peer feedback on these two variables was significantly stronger. Finally, implications for theory and government risk communication are discussed. © 2012 Society for Risk Analysis.

  7. Enhancing Self-Efficacy in Elementary Science Teaching With Professional Learning Communities

    NASA Astrophysics Data System (ADS)

    Mintzes, Joel J.; Marcum, Bev; Messerschmidt-Yates, Christl; Mark, Andrew

    2013-11-01

    Emerging from Bandura's Social Learning Theory, this study of in-service elementary school teachers examined the effects of sustained Professional Learning Communities (PLCs) on self-efficacy in science teaching. Based on mixed research methods, and a non-equivalent control group experimental design, the investigation explored changes in personal self-efficacy and outcome expectancy among teachers engaged in PLCs that featured Demonstration Laboratories, Lesson Study, and annual Summer Institutes. Significant changes favoring the experimental group were found on all quantitative measures of self-efficacy. Structured clinical interviews revealed that observed changes were largely attributable to a wide range of direct (mastery) and vicarious experiences, as well as emotional reinforcement and social persuasion.

  8. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer.

    PubMed

    Zhan, Yang; Cao, Bo; Qi, Yanfeng; Liu, Shuang; Zhang, Qi; Zhou, Weidong; Xu, Duo; Lu, Hua; Sartor, Oliver; Kong, Wei; Zhang, Haitao; Dong, Yan

    2013-11-01

    The next-generation antiandrogen MDV3100 prolongs overall survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patient responses are variable, and survival benefit remains relatively small. Developing effective modality to improve MDV3100 efficacy is urgently needed. Recent evidence suggests that constitutively active androgen receptor splice variants (AR-Vs) drive resistance to MDV3100. In our study, we show that methylselenol prodrug downregulates the expression and activity of both the full-length AR (AR-FL) and AR-Vs. The downregulation is independent of androgen and could be attributable to repressed transcription of the AR gene. Cotreatment with methylselenol prodrug and MDV3100 suppresses AR signaling more dramatically than either agent alone, and synergistically inhibits the growth of CRPC cells in vitro. The combinatorial efficacy is observed in not only AR-V-expressing cells but also cells expressing predominantly AR-FL, likely owing to the ability of the two drugs to block the AR signaling cascade at distinct steps. Ectopic expression of AR-FL or AR-V7 attenuates the combinatorial efficacy, indicating that downregulating AR-FL and AR-V7 is importantly involved in mediating the combinatorial efficacy. Significantly, methylselenol prodrug also downregulates AR-FL and AR-Vs in vivo and substantially improves the antitumor efficacy of MDV3100. These findings support a potential combination therapy for improving MDV3100 efficacy, and provide a rationale for evaluating the clinical application of combining methylselenol prodrug with MDV3100 for the treatment of CRPC. © 2013 UICC.

  9. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer

    PubMed Central

    Zhan, Yang; Cao, Bo; Qi, Yanfeng; Liu, Shuang; Zhang, Qi; Zhou, Weidong; Xu, Duo; Lu, Hua; Sartor, Oliver; Kong, Wei; Zhang, Haitao; Dong, Yan

    2013-01-01

    The next-generation antiandrogen MDV3100 prolongs overall survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patient responses are variable, and survival benefit remains relatively small. Developing effective modality to improve MDV3100 efficacy is urgently needed. Recent evidence suggests that constitutively active androgen receptor splice variants (AR-Vs) drive resistance to MDV3100. In our study, we show that methylselenol prodrug downregulates the expression and activity of both the full-length AR (AR-FL) and AR-Vs. The downregulation is independent of androgen and could be attributable to repressed transcription of the AR gene. Cotreatment with methylselenol prodrug and MDV3100 suppresses AR signaling more dramatically than either agent alone, and synergistically inhibits the growth of CRPC cells in vitro. The combinatorial efficacy is observed in not only AR-V-expressing cells but also cells expressing predominantly AR-FL, likely owing to the ability of the two drugs to block the AR signaling cascade at distinct steps. Ectopic expression of AR-FL or AR-V7 attenuates the combinatorial efficacy, indicating that downregulating AR-FL and AR-V7 is importantly involved in mediating the combinatorial efficacy. Significantly, methylselenol prodrug also downregulates AR-FL and AR-Vs in vivo and substantially improves the antitumor efficacy of MDV3100. These findings support a potential combination therapy for improving MDV3100 efficacy, and provide a rationale for evaluating the clinical application of combining methylselenol prodrug with MDV3100 for the treatment of CRPC. PMID:23575870

  10. Clinical Strategies to Enhance the Efficacy of Nicotine Replacement Therapy for Smoking Cessation: A Review of the Literature

    PubMed Central

    Carpenter, Matthew J.; Jardin, Bianca F.; Burris, Jessica L.; Mathew, Amanda R.; Schnoll, Robert A.; Rigotti, Nancy A.; Cummings, K. Michael

    2013-01-01

    A number of smoking cessation pharmacotherapies have led to increases in quitting and thus to significant benefits to public health. Among existing medications, nicotine replacement therapy (NRT) has been available the longest, has the largest literature base in support, and is the only option for over-the-counter access. While the short term efficacy of NRT is well documented in clinical trials, long term abstinence rates associated with using NRT are modest, as most smokers will relapse. This literature review examines emerging clinical strategies to improve NRT efficacy. After an initial overview of NRT and its FDA-approved indications for use, we review randomized trials in which clinical delivery of NRT was manipulated and tested, in an attempt to enhance efficacy, through a) duration of use (pre-quit and extended use), b) amount of use (high dose and combination NRT), c) tailoring to specific smoker groups (genotype and phenotype), or d) use of NRT for novel purposes (relapse prevention, temporary abstinence, cessation induction). Outcomes vary within and across topic area, and we highlight areas that offer stronger promise. Combination NRT likely represents the most promising strategy moving forward; other clinical strategies offer conflicting evidence but deserve further testing (pre-quit NRT or tailored treatment), or offer potential utility but are in need of further, direct tests. Some areas, though based on a limited set of studies, do not offer great promise (high dose and extended treatment NRT). We conclude with a brief discussion of emergent NRT products (e.g., oral nicotine spray, among others), which may ultimately offer greater efficacy than current formulations. In order to further lower the prevalence of smoking, novel strategies designed to optimize NRT efficacy are needed. PMID:23572407

  11. Effect of self-efficacy enhancement program on self-care behaviors in chronic obstructive pulmonary disease

    PubMed Central

    Abedi, Heidarali; Salimi, Saleh J; Feizi, Aram; Safari, Samira

    2013-01-01

    Background: Given the importance of the chronic obstructive pulmonary disease (COPD) and role of different factors in self-care behaviors of COPD patients, this study was conducted to determine the effect of self-efficacy program on self-care behaviors of COPD patients. Materials and Methods: In this semi-experimental study, 62 COPD patients were recruited in which 31 subjects were in control group and 31 were in experimental group. Subjects were selected based on purposive sampling from Imam Hospital affiliated to the Urmia University of Medical Sciences, Iran, in 2011. Two valid and reliable questionnaires were filled after completing informed consent form. A month later, and after implementing the planned intervention, the questionnaires were completed by the subjects again. Results: The mean standard deviation of age were 64.1 (9.1) years in the control group and 65.2 (8.0) years in the experimental group. There was a statistically significant difference between self-efficacy state before and after intervention. Self-care scores in the experimental group were significantly higher after intervention (t = 25.18, P < 0.0001). Conclusions: Given the high potency of self-efficacy factors on self-care behaviors of the COPD patients, enhancement of self-efficacy in these patients can be very effective in disease control, prevention of complications, reduction of hospitalization costs, and improve their quality of life. Hence, it is suggested that in empowerment programs of these patients, special emphasis will put on the strengthening of their self-efficacy. PMID:24403947

  12. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

    PubMed Central

    Kim, Jae; John, Joel; Langford, Dianne; Walker, Ellen; Ward, Sara; Rawls, Scott M.

    2015-01-01

    The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine’s reinforcing efficacy at 100-fold lower doses than CTX. PMID:26543027

  13. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice.

    PubMed

    Kim, Jae; John, Joel; Langford, Dianne; Walker, Ellen; Ward, Sara; Rawls, Scott M

    2016-03-01

    The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine's reinforcing efficacy at 100-fold lower doses than CTX.

  14. Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder.

    PubMed

    de Kleine, Rianne A; Smits, Jasper A J; Hendriks, Gert-Jan; Becker, Eni S; van Minnen, Agnes

    2015-08-01

    Augmentation of exposure therapy with d-cycloserine (DCS) has proven efficacious across anxiety disorders, although results in PTSD have been mixed. Work in animals and anxiety-disordered patients suggest that the potentiating effects of DCS are dependent on the level of extinction learning during extinction training and exposure treatment, respectively. The aim of the current study was to replicate and extend previous work by examining the association between the degree of extinction learning and DCS efficacy in our randomized clinical trial on DCS (50 mg) versus placebo enhancement of exposure therapy in a chronic mixed-trauma PTSD sample (N=67; de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012). The decline in subjective units of distress ratings collected during and across the exposure sessions were evaluated as indices of extinction learning. First, we examined whether extinction learning during an exposure session moderated DCS effects on self-reported PTSD symptoms at the next session. Second, we examined whether averaged extinction learning over the course of treatment interacted with group assignment to predict change over time and post treatment outcome. We did not find evidence that DCS effects were moderated by the degree of extinction learning, although, extinction learning was related to outcome regardless of group assignment. In PTSD, not one extinction-learning index has been consistently linked to DCS enhanced exposure treatment outcome. More (experimental) work needs to been done to unravel the complex interplay between extinction learning and DCS enhancement, especially in PTSD patients.

  15. Enhancing Students' Learning and Self- Efficacy through Blended Learning in a Teachers' Program

    ERIC Educational Resources Information Center

    Abdelraheem, Ahmed Yousif

    2014-01-01

    Blended Learning (BL) strategies play an important role in collaboration, communication skills, motivation, attitudes, interaction with the subject and practical skills. However, their relationship with students' learning and self efficacy were not studied enough and this was the focus of this study. Therefore, the aim of the study was to…

  16. Enhancing the Academic Development of Shy Children: A Test of the Efficacy of INSIGHTS

    ERIC Educational Resources Information Center

    O'Connor, Erin E.; Cappella, Elise; McCormick, Meghan P.; McClowry, Sandee G.

    2014-01-01

    This study investigated the efficacy of the INSIGHTS into Children's Temperament intervention in supporting the academic development of shy kindergarten and first-grade children. INSIGHTS is a temperament-based intervention with teacher, parent, and classroom programs. The participants included 345 children from 22 low-income, urban elementary…

  17. Perceptual Training Methods Compared: The Relative Efficacy of Different Approaches to Enhancing Sport-Specific Anticipation

    ERIC Educational Resources Information Center

    Abernethy, Bruce; Schorer, Jorg; Jackson, Robin C.; Hagemann, Norbert

    2012-01-01

    The comparative efficacy of different perceptual training approaches for the improvement of anticipation was examined using a goalkeeping task from European handball that required the rapid prediction of shot direction. Novice participants (N = 60) were assigned equally to four different training groups and two different control groups (a placebo…

  18. Enhanced chemoprophylactic and clinical efficacy of albendazole formulated as solid dispersions in experimental cystic echinococcosis.

    PubMed

    Pensel, Patricia E; Castro, Silvina; Allemandi, Daniel; Bruni, Sergio Sánchez; Palma, Santiago D; Elissondo, María Celina

    2014-06-16

    Cystic echinococcosis is a chronic, complex, and still neglected disease. Although albendazole has demonstrated efficacy, only about one-third of patients experience complete remission or cure and 30-50% of treated patients develop some evidence of a therapeutic response. Different strategies have been developed in order to improve the albendazole water solubility and dissolution rate. The aim of the current work was to investigate the chemoprophylactic and clinical efficacy of an albendazole:poloxamer 188 solid dispersion formulation on mice infected with Echinococcus granulosus metacestodes. Albendazole formulated as solid dispersion had greater chemoprophylactic and clinical efficacy than albendazole alone. The improved in therapeutic efficacy could be a consequence of the increase in the systemic availability of albendazole sulfoxide. The work reported here demonstrates that in vivo treatment with albendazole:poloxamer 188 impairs the development of the hydatid cysts. This new pharmacotechnically based strategy could be a suitable alternative for treating cystic echinococcosis in humans. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Enhancing Entrepreneurship: The Role of Goal Orientation and Self-Efficacy

    ERIC Educational Resources Information Center

    Culbertson, Satoris S.; Smith, Michael R.; Leiva, Pedro I.

    2011-01-01

    Entrepreneurship has become increasingly important in the workplace. Research suggests motivational traits are important in pursuing entrepreneurial activities. Yet, the extent to which factors influencing entrepreneurial versus managerial goals differ remains unclear. This study assessed the influence of goal orientation and self-efficacy in…

  20. Integrating Motivational Interviewing into a Basic Counseling Skills Course to Enhance Counseling Self-Efficacy

    ERIC Educational Resources Information Center

    Iarussi, Melanie H.; Tyler, Jessica M.; Littlebear, Sarah; Hinkle, Michelle S.

    2013-01-01

    Motivational interviewing (MI), a humanistic counseling style used to help activate clients' motivation to change, was integrated into a basic counseling skills course. Nineteen graduate-level counseling students completed the Counselor Estimate of Self-Efficacy at the start and conclusion of the course. Significant differences were found between…

  1. Enhancing Self-Efficacy in Elementary Science Teaching with Professional Learning Communities

    ERIC Educational Resources Information Center

    Mintzes, Joel J.; Marcum, Bev; Messerschmidt-Yates, Christl; Mark, Andrew

    2013-01-01

    Emerging from Bandura's Social Learning Theory, this study of in-service elementary school teachers examined the effects of sustained Professional Learning Communities (PLCs) on self-efficacy in science teaching. Based on mixed research methods, and a non-equivalent control group experimental design, the investigation explored changes in…

  2. Using Trial Interviews To Enhance Student Self-Efficacy towards Pre-placement Interviews.

    ERIC Educational Resources Information Center

    Coll, Richard K.; Lay, Mark

    2001-01-01

    New Zealand cooperative education students participated in mock and preemployment employer interviews. Responses from 10 students and 10 employers showed that most students had no formal interview experience and were apprehensive about preplacement interviews. Trial interviews improved self-efficacy through exposure to employer questions and…

  3. Enhancing Self-Efficacy in Elementary Science Teaching with Professional Learning Communities

    ERIC Educational Resources Information Center

    Mintzes, Joel J.; Marcum, Bev; Messerschmidt-Yates, Christl; Mark, Andrew

    2013-01-01

    Emerging from Bandura's Social Learning Theory, this study of in-service elementary school teachers examined the effects of sustained Professional Learning Communities (PLCs) on self-efficacy in science teaching. Based on mixed research methods, and a non-equivalent control group experimental design, the investigation explored changes in…

  4. Enhancing Teacher Efficacy for Urban STEM Teachers Facing Challenges to Their Teaching

    ERIC Educational Resources Information Center

    Seals, Christopher; Mehta, Swati; Berzina-Pitcher, Inese; Graves-Wolf, Leigh

    2017-01-01

    This paper explores challenges of teaching in relation to teachers' efficacy for 49 teachers who were part of a year-long teacher development program (PD) called the UrbanSTEM program. This program took place in an urban school district that serves over 300,000 students. This research asked if there are common challenges that urban teachers face…

  5. Using an Attribution Support Tool to Enhance the Teacher Efficacy of Student Science Teachers

    ERIC Educational Resources Information Center

    de Boer, Eveline; Janssen, Fred J. J. M.; van Driel, Jan H.

    2016-01-01

    To increase the teacher efficacy of student teachers, they need positive classroom experiences: mastery experiences. These mastery experiences have to be created by the student teachers themselves. Therefore, student teachers need a tool to better understand problematic teaching experiences and help them create positive classroom experiences. Nine…

  6. Perceptual Training Methods Compared: The Relative Efficacy of Different Approaches to Enhancing Sport-Specific Anticipation

    ERIC Educational Resources Information Center

    Abernethy, Bruce; Schorer, Jorg; Jackson, Robin C.; Hagemann, Norbert

    2012-01-01

    The comparative efficacy of different perceptual training approaches for the improvement of anticipation was examined using a goalkeeping task from European handball that required the rapid prediction of shot direction. Novice participants (N = 60) were assigned equally to four different training groups and two different control groups (a placebo…

  7. The Efficacy of Corrective Feedback and Textual Enhancement in Promoting the Acquisition of Grammatical Redundancies

    ERIC Educational Resources Information Center

    Lyddon, Paul A.

    2011-01-01

    Many second language acquisition researchers (e.g., Doughty & Williams, 1998; R. Ellis, 2007; Long, 1996, 2007; Lyster, Lightbown, & Spada, 1999; Russell & Spada, 2006) have advocated the use of negative feedback to promote learner noticing of errors and the internalization of correct forms. At the same time, the true efficacy of this practice is…

  8. The Efficacy of Corrective Feedback and Textual Enhancement in Promoting the Acquisition of Grammatical Redundancies

    ERIC Educational Resources Information Center

    Lyddon, Paul A.

    2011-01-01

    Many second language acquisition researchers (e.g., Doughty & Williams, 1998; R. Ellis, 2007; Long, 1996, 2007; Lyster, Lightbown, & Spada, 1999; Russell & Spada, 2006) have advocated the use of negative feedback to promote learner noticing of errors and the internalization of correct forms. At the same time, the true efficacy of this practice is…

  9. Using an Attribution Support Tool to Enhance the Teacher Efficacy of Student Science Teachers

    ERIC Educational Resources Information Center

    de Boer, Eveline; Janssen, Fred J. J. M.; van Driel, Jan H.

    2016-01-01

    To increase the teacher efficacy of student teachers, they need positive classroom experiences: mastery experiences. These mastery experiences have to be created by the student teachers themselves. Therefore, student teachers need a tool to better understand problematic teaching experiences and help them create positive classroom experiences. Nine…

  10. Powerpoint's Power in the Classroom: Enhancing Students' Self-Efficacy and Attitudes

    ERIC Educational Resources Information Center

    Susskind, J.E.

    2005-01-01

    The current study examined the effects of non-interactive computer assisted instruction on students' performance, self-efficacy, motivation, and attitudes. Half the lectures presented to two Introduction to Psychology college classes were taught in a traditional lecture format and half were accompanied by PowerPoint multimedia. Lecture order was…

  11. How Setting Goals Enhances Learners' Self-Efficacy Beliefs in Listening Comprehension

    ERIC Educational Resources Information Center

    Ballesteros Muñoz, Liliana; Tutistar Jojoa, Silvana

    2014-01-01

    This article outlines a study that explores the relationship between SMART goal setting (Specific, Measurable, Attainable, Relevant, and Time-based) and learning English in Colombia concerning a foreign language learners' self-efficacy beliefs in listening. The participants were seventh and ninth grade students of two schools in Bogotá, Colombia.…

  12. Reflective Dialogue: A Path to Enhanced Teacher Efficacy and Classroom Practice

    ERIC Educational Resources Information Center

    Isai, Shelley

    2010-01-01

    Literature abounds on professional development. However, teacher change is not so much the result of professional development, but rather successful implementation of strategies learned into the classroom: a mastery experience. Mastery experience, after all, is the most influential predicator of teacher efficacy, which is equated to student…

  13. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model

    PubMed Central

    Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R.; Zhang, Leying; Vonderfecht, Steven L.; Alizadeh, Darya; Berlin, Jacob M.; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG. PMID:26829221

  14. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.

    PubMed

    Ouyang, Mao; White, Ethan E; Ren, Hui; Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R; Zhang, Leying; Vonderfecht, Steven L; Alizadeh, Darya; Berlin, Jacob M; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.

  15. Immune activation efficacy of indolicidin is enhanced upon conjugation with carbon nanotubes and gold nanoparticles.

    PubMed

    Sur, Abhinav; Pradhan, Biswaranjan; Banerjee, Arka; Aich, Palok

    2015-01-01

    Antibiotic resistance is concern of today's world. Search for alternative molecules, for treatment and immune stimulation, remains at the forefront. One such group of biomolecules with promise, along the line of immune stimulation or therapy, is host defense peptide (HDP). These molecules, however, are required at a higher dose to be effective which leads to high cost. To alleviate such problems, an aid can be used to achieve similar efficacy but at a smaller effective dose of the immune stimulant. We hypothesised that by conjugating HDPs with carbon nanotubes and/or gold nanoparticles, it would be possible to stimulate a protective immune response in host system at a lower dosage of HDP. In this report, we characterized, using biophysical methodologies, conjugation of Indolicidin, as a representative of HDP. We further established efficacy of peptide-nanomaterial conjugates in activating innate immunity and protecting against pathogen infection in vitro at a significantly small dose.

  16. Enhancing role breadth self-efficacy: the roles of job enrichment and other organizational interventions.

    PubMed

    Parker, S K

    1998-12-01

    Role breadth self-efficacy (RBSE) refers to employees' perceived capability of carrying out a broader and more proactive set of work tasks that extend beyond prescribed technical requirements. A newly developed scale of RBSE was internally consistent and distinct from the related concepts of proactive personality and self-esteem. In an initial cross-sectional study (N = 580), work design variables (job enrichment, job enlargement, and membership of improvement groups) were the key organizational predictors of RBSE. These investigations were repeated in a second cross-sectional study (N = 622) and extended by examining change over time (N = 459). The longitudinal analysis showed that increased job enrichment and increased quality of communication predicted the development of greater self-efficacy.

  17. Immunosuppressive Myeloid Cells' Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy.

    PubMed

    Kamran, Neha; Kadiyala, Padma; Saxena, Meghna; Candolfi, Marianela; Li, Youping; Moreno-Ayala, Mariela A; Raja, Nicholas; Shah, Diana; Lowenstein, Pedro R; Castro, Maria G

    2017-01-04

    Survival of glioma (GBM) patients treated with the current standard of care remains dismal. Immunotherapeutic approaches that harness the cytotoxic and memory potential of the host immune system have shown great benefit in other cancers. GBMs have developed multiple strategies, including the accumulation of myeloid-derived suppressor cells (MDSCs) to induce immunosuppression. It is therefore imperative to develop multipronged approaches when aiming to generate a robust anti-tumor immune response. Herein, we tested whether combining MDSC depletion or checkpoint blockade would augment the efficacy of immune-stimulatory herpes simplex type-I thymidine kinase (TK) plus Fms-like tyrosine kinase ligand (Flt3L)-mediated immune stimulatory gene therapy. Our results show that MDSCs constitute >40% of the tumor-infiltrating immune cells. These cells express IL-4Rα, inducible nitric oxide synthase (iNOS), arginase, programmed death ligand 1 (PDL1), and CD80, molecules that are critically involved in antigen-specific T cell suppression. Depletion of MDSCs strongly enhanced the TK/Flt3L gene therapy-induced tumor-specific CD8 T cell response, which lead to increased median survival and percentage of long-term survivors. Also, combining PDL1 or CTLA-4 immune checkpoint blockade greatly improved the efficacy of TK/Flt3L gene therapy. Our results, therefore, indicate that blocking MDSC-mediated immunosuppression holds great promise for increasing the efficacy of gene therapy-mediated immunotherapies for GBM.

  18. Association with Amino Acids Does Not Enhance Efficacy of Polymerized Liposomes As a System for Lung Gene Delivery

    PubMed Central

    Bandeira, Elga; Lopes-Pacheco, Miquéias; Chiaramoni, Nadia; Ferreira, Débora; Fernandez-Ruocco, Maria J.; Prieto, Maria J.; Maron-Gutierrez, Tatiana; Perrotta, Ramiro M.; de Castro-Faria-Neto, Hugo C.; Rocco, Patricia R. M.; Alonso, Silvia del Valle; Morales, Marcelo M.

    2016-01-01

    Development of improved drug and gene delivery systems directly into the lungs is highly desirable given the important burden of respiratory diseases. We aimed to evaluate the safety and efficacy of liposomes composed of photopolymerized lipids [1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine] associated with amino acids as vectors for gene delivery into the lungs of healthy animals. Lipopolymer vesicles, in particular, are more stable than other types of liposomes. In this study, lipopolymers were associated with l-arginine, l-tryptophan, or l-cysteine. We hypothesized that the addition of these amino acids would enhance the efficacy of gene delivery to the lungs by the lipopolymers. l-Arginine showed the highest association efficiency due to its positive charge and better surface interactions. None of the formulations caused inflammation or altered lung mechanics, suggesting that these lipopolymers can be safely administered as aerosols. All formulations were able to induce eGFP mRNA expression in lung tissue, but the addition of amino acids reduced delivery efficacy when compared with the simple lipopolymer particle. These results indicate that this system could be further explored for gene or drug delivery targeting lung diseases. PMID:27199766

  19. Sulforaphane Potentiates the Efficacy of 17-Allylamino 17-Demethoxygeldanamycin Against Pancreatic Cancer Through Enhanced Abrogation of Hsp90 Chaperone Function

    PubMed Central

    Li, Yanyan; Zhang, Tao; Schwartz, Steven J.; Sun, Duxin

    2013-01-01

    Heat shock protein 90 (Hsp90), an essential molecular chaperone that regulates the stability of a wide range of oncogenic proteins, is a promising target for cancer therapeutics. We investigated the combination efficacy and potential mechanisms of sulforaphane, a dietary component from broccoli and broccoli sprouts, and 17-allylamino 17-demethoxygeldanamycin (17-AAG), an Hsp90 inhibitor, in pancreatic cancer. MTS assay demonstrated that sulforaphane sensitized pancreatic cancer cells to 17-AAG in vitro. Caspase-3 was activated to 6.4-fold in response to simultaneous treatment with sulforaphane and 17-AAG, whereas 17-AAG alone induced caspase-3 activity to 2-fold compared to control. ATP binding assay and coimmunoprecipitation revealed that sulforaphane disrupted Hsp90-p50Cdc37 interaction, whereas 17-AAG inhibited ATP binding to Hsp90. Concomitant use of sulforaphane and 17-AAG synergistically downregulated Hsp90 client proteins in Mia Paca-2 cells. Co-administration of sulforaphane and 17-AAG in pancreatic cancer xenograft model led to more than 70% inhibition of the tumor growth, whereas 17-AAG alone only suppressed the tumor growth by 50%. Our data suggest that sulforaphane potentiates the efficacy of 17-AAG against pancreatic cancer through enhanced abrogation of Hsp90 function. These findings provide a rationale for further evaluation of broccoli/broccoli sprout preparations combined with 17-AAG for better efficacy and lower dose-limiting toxicity in pancreatic cancer. PMID:21875325

  20. Induction of resident memory T cells enhances the efficacy of cancer vaccine

    PubMed Central

    Nizard, Mevyn; Roussel, Hélène; Diniz, Mariana O.; Karaki, Soumaya; Tran, Thi; Voron, Thibault; Dransart, Estelle; Sandoval, Federico; Riquet, Marc; Rance, Bastien; Marcheteau, Elie; Fabre, Elizabeth; Mandavit, Marion; Terme, Magali; Blanc, Charlotte; Escudie, Jean-Baptiste; Gibault, Laure; Barthes, Françoise Le Pimpec; Granier, Clemence; Ferreira, Luis C. S.; Badoual, Cecile; Johannes, Ludger; Tartour, Eric

    2017-01-01

    Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them. PMID:28537262

  1. Induction of resident memory T cells enhances the efficacy of cancer vaccine.

    PubMed

    Nizard, Mevyn; Roussel, Hélène; Diniz, Mariana O; Karaki, Soumaya; Tran, Thi; Voron, Thibault; Dransart, Estelle; Sandoval, Federico; Riquet, Marc; Rance, Bastien; Marcheteau, Elie; Fabre, Elizabeth; Mandavit, Marion; Terme, Magali; Blanc, Charlotte; Escudie, Jean-Baptiste; Gibault, Laure; Barthes, Françoise Le Pimpec; Granier, Clemence; Ferreira, Luis C S; Badoual, Cecile; Johannes, Ludger; Tartour, Eric

    2017-05-24

    Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them.

  2. Enhancing Predicted Efficacy of Tumor Treating Fields Therapy of Glioblastoma Using Targeted Surgical Craniectomy: A Computer Modeling Study

    PubMed Central

    Korshoej, Anders Rosendal; Saturnino, Guilherme Bicalho; Rasmussen, Line Kirkegaard; von Oettingen, Gorm; Sørensen, Jens Christian Hedemann; Thielscher, Axel

    2016-01-01

    Objective The present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer. Methods We used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios. Results For the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60–70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30–50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50–70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect. Conclusions Our results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in

  3. Cystic echinococcosis therapy: Albendazole-loaded lipid nanocapsules enhance the oral bioavailability and efficacy in experimentally infected mice.

    PubMed

    Pensel, Patricia E; Ullio Gamboa, Gabriela; Fabbri, Julia; Ceballos, Laura; Sanchez Bruni, Sergio; Alvarez, Luis I; Allemandi, Daniel; Benoit, Jean Pierre; Palma, Santiago D; Elissondo, María C

    2015-12-01

    Therapeutic failures attributed to medical management of cystic echinococcosis (CE) with albendazole (ABZ) have been primarily linked to the poor drug absorption rate resulting in low drug level in plasma and hydatid cysts. Lipid nanocapsules (LNCs) represent nanocarriers designed to encapsulate lipophilic drugs, such as ABZ. The goals of the current work were: (i) to characterize the plasma and cyst drug exposure after the administration of ABZ as ABZ-LNCs or ABZ suspension (ABZ-SUSP) in mice infected with Echinococcus granulosus, and ii) to compare the clinical efficacies of both ABZ formulations. Enhanced ABZ sulphoxide (ABZ-SO) concentration profiles were obtained in plasma and cysts from ABZ-LNC treated animals. ABZSO exposure (AUC0-LOQ) was significantly higher in plasma and cyst after the ABZ-LNC treatments, both orally and subcutaneously, compared to that observed after oral administration of ABZ-SUSP. Additionally, ABZSO concentrations measured in cysts from ABZ-LNC treated mice were 1.7-fold higher than those detected in plasma. This enhanced drug availability correlated with an increased efficacy against secondary CE in mice observed for the ABZ-LNCs, while ABZ-SUSP did not reach differences with the untreated control group. This new pharmacotechnically-based strategy could be a potential alternative to improve the treatment of human CE. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer.

    PubMed

    Asangani, Irfan A; Wilder-Romans, Kari; Dommeti, Vijaya L; Krishnamurthy, Pranathi M; Apel, Ingrid J; Escara-Wilke, June; Plymate, Stephen R; Navone, Nora M; Wang, Shaomeng; Feng, Felix Y; Chinnaiyan, Arul M

    2016-04-01

    Next-generation antiandrogen therapies, such as enzalutamide and abiraterone, have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines, which acquired potential resistance mechanisms, including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor. BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of bromodomain and extraterminal (BET) inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide, and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling preclinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC. ©2016 American Association for Cancer Research.

  5. An Education Intervention to Enhance Staff Self-Efficacy to Provide Dementia Care in an Acute Care Hospital in Canada

    PubMed Central

    Gillies, Leslie; Coker, Esther; Pizzacalla, Anne; Montemuro, Maureen; Suva, Grace; McLelland, Victoria

    2016-01-01

    Education is needed for enhanced capacity of acute hospitals to provide dementia care. A nonrandomized controlled, repeated-measures design was used to evaluate a dementia education program delivered to an intervention group (IG, n = 468), compared to a wait-listed group (n = 277), representing separate sites of a multisite hospital. Participants completed self-efficacy for dementia and satisfaction measures and provided written descriptions of dementia care collected at baseline, postintervention (IG only), and at 8-week follow-up. Oral narratives were gathered from IG participants 8 weeks postintervention. The IG demonstrated significant improvement in self-efficacy scores from baseline to immediately postintervention (P < .001), sustained at 8 weeks. There were no changes from baseline to 8 weeks postintervention evident in the wait-listed group (P = .21). Intervention group participants described positive impacts including implementation of person-centered care approaches. Implementation of dementia care education programs throughout hospital settings is promising for the enhancement of dementia care. PMID:27659392

  6. Enhanced clinical outcome with manual massage following cryolipolysis treatment: a 4-month study of safety and efficacy.

    PubMed

    Boey, Gerald E; Wasilenchuk, Jennifer L

    2014-01-01

    Cryolipolysis procedures have been shown to safely and effectively reduce the thickness of fat in a treated region. This study was conducted to determine whether the addition of post-treatment manual massage would improve efficacy while maintaining the safety profile of the original cryolipolysis treatment protocol. The study population consisted of an efficacy group (n = 10) and a safety group (n = 7). Study subjects were treated on each side of the lower abdomen with a Cooling Intensity Factor of 42 (-72.9 mW/cm(2) ) for 60 minutes. One side of the abdomen was massaged post-treatment and the other side served as the control. Immediately post-treatment, the massage side was treated for 1 minute using a vigorous kneading motion followed by 1 minute of circular massage using the pads of the fingers. For the efficacy group, photos and ultrasound measurements were taken at baseline, 2 months, and 4 months post-treatment. For the safety group, histological analysis was completed at 0, 3, 8, 14, 30, 60, and 120 days post-treatment to examine the effects of massage on subcutaneous tissue over time. Post-treatment manual massage resulted in a consistent and discernible increase in efficacy over the non-massaged side. At 2 months post-treatment, mean fat layer reduction was 68% greater in the massage side than in the non-massage side as measured by ultrasound. By 4 months, mean fat layer reduction was 44% greater in the massage side. Histological results showed no evidence of necrosis or fibrosis resulting from the massage. Post-treatment manual massage is a safe and effective technique to enhance the clinical outcome from a cryolipolysis procedure. © 2013 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

  7. Investigation of the Efficacy of Transdermal Penetration Enhancers Through the Use of Human Skin and a Skin Mimic Artificial Membrane.

    PubMed

    Balázs, Boglárka; Vizserálek, Gábor; Berkó, Szilvia; Budai-Szűcs, Mária; Kelemen, András; Sinkó, Bálint; Takács-Novák, Krisztina; Szabó-Révész, Piroska; Csányi, Erzsébet

    2016-03-01

    The aim of this study was to investigate the behavior of promising penetration enhancers through the use of 2 different skin test systems. Hydrogel-based transdermal formulations were developed with ibuprofen as a nonsteroidal anti-inflammatory drug. Transcutol and sucrose esters were used as biocompatible penetration enhancers. The permeability measurements were performed with ex vivo Franz diffusion cell methods and a newly developed Skin Parallel Artificial Membrane Permeability Assays (PAMPA) model. Franz diffusion measurement is commonly used as a research tool in studies of diffusion through synthetic membranes in vitro or penetration through ex vivo human skin, whereas Skin PAMPA involves recently published artificial membrane-based technology for the fast prediction of skin penetration. It is a 96-well plate-based model with optimized artificial membrane structure containing free fatty acid, cholesterol, and synthetic ceramide analog compounds to mimic the stratum corneum barrier function. Transdermal preparations containing 2.64% of different sucrose esters and/or Transcutol and a constant (5%) of ibuprofen were investigated to determine the effects of these penetration enhancers. The study demonstrated the good correlation of the permeability data obtained through use of human skin membrane and the in vitro Skin PAMPA system. The Skin PAMPA artificial membrane serves as quick and relatively deep tool in the early stages of transdermal delivery systems, through which the enhancing efficacy of excipients can be screened so as to facilitate the choice of effective penetration components.

  8. Convection-enhanced delivery of polyethylene glycol-coated liposomal doxorubicin: characterization and efficacy in rat intracranial glioma models.

    PubMed

    Kikuchi, Toshio; Saito, Ryuta; Sugiyama, Shin-ichirou; Yamashita, Yoji; Kumabe, Toshihiro; Krauze, Michal; Bankiewicz, Krystof; Tominaga, Teiji

    2008-11-01

    The characteristics of polyethylene glycol-coated liposomal doxorubicin (PLD), the only liposomal drug now clinically available for intravenous injection, were investigated after convection-enhanced delivery (CED) into the rat brain parenchyma. The distribution, tissue retention, and toxicity profile were evaluated after CED into the rat brain parenchyma. The antitumor efficacy was also determined in rodent intracranial U-251MG and U-87MG glioma models. Convection-enhanced delivery of PLD achieved wider distributions and delayed onset of toxicity in the brain parenchyma compared with CED of free doxorubicin infusion. Fluorescence generated from doxorubicin infused as PLD was detected until at least 30 days after infusion. Local toxicity was not observed when a 10% dilution of the commercially available PLD solution was used (0.2 mg/ml doxorubicin), but was significant at higher concentrations. Results after 10% PLD was delivered locally with CED demonstrated significant survival prolongation in both intracranial U-251MG and U-87MG xenograft models. Convection-enhanced delivery of PLD achieved extensive tissue distribution and sustained drug release. Convection-enhanced delivery of PLD is a promising chemotherapy for the treatment of malignant gliomas.

  9. Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy.

    PubMed

    Highfill, Steven L; Cui, Yongzhi; Giles, Amber J; Smith, Jillian P; Zhang, Hua; Morse, Elizabeth; Kaplan, Rosandra N; Mackall, Crystal L

    2014-05-21

    Suppression of the host's immune system plays a major role in cancer progression. Tumor signaling of programmed death 1 (PD1) on T cells and expansion of myeloid-derived suppressor cells (MDSCs) are major mechanisms of tumor immune escape. We sought to target these pathways in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood. Murine RMS showed high surface expression of PD-L1, and anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 had limited benefit. RMS induced robust expansion of CXCR2(+)CD11b(+)Ly6G(hi) MDSCs, and CXCR2 deficiency prevented CD11b(+)Ly6G(hi) MDSC trafficking to the tumor. When tumor trafficking of MDSCs was inhibited by CXCR2 deficiency, or after anti-CXCR2 monoclonal antibody therapy, delayed anti-PD1 treatment induced significant antitumor effects. Thus, CXCR2(+)CD11b(+)Ly6G(hi) MDSCs mediate local immunosuppression, which limits the efficacy of checkpoint blockade in murine RMS. Human pediatric sarcomas also produce CXCR2 ligands, including CXCL8. Patients with metastatic pediatric sarcomas display elevated serum CXCR2 ligands, and elevated CXCL8 is associated with diminished survival in this population. We conclude that accumulation of MDSCs in the tumor bed limits the efficacy of checkpoint blockade in cancer. We also identify CXCR2 as a novel target for modulating tumor immune escape and present evidence that CXCR2(+)CD11b(+)Ly6G(hi) MDSCs are an important suppressive myeloid subset in pediatric sarcomas. These findings present a translatable strategy to improve the efficacy of checkpoint blockade by preventing trafficking of MDSCs to the tumor site.

  10. Antigen-Sparing and Enhanced Efficacy of Multivalent Vaccines Adjuvanted with Immunopotentiators in Chickens

    PubMed Central

    Wu, Peipei; Lu, Jihu; Feng, Lei; Wu, Hongzhuan; Zhang, Xuehua; Mei, Mei; Hou, Jibo; Liu, Xiufan; Tang, Yinghua

    2017-01-01

    We previously described that immunopotentiators, CVCVA5, increased the efficacy of H5 and H9 subtype avian influenza vaccines in chickens, ducks, and geese. In this study, we further investigated the effects of the CVCVA5 for improving the efficacy of other univalent or multivalent inactivated vaccines. The immune response administrated with half-dose of monovalent vaccine plus CVCVA5 were higher than those of one dose of monovalent vaccine without immunopotentiators as measured by levels of antibodies from serum, tears and bronchoalveolar lavage fluids, and cytokines of IFNγ and IL-4 from serum. Vaccines included the univalent vaccine of Newcastle Disease virus (ND), Egg Drop Syndrome virus (EDS), Infectious Bronchitis virus (IB), and Infectious Bursal Disease virus (IBD). The CVCVA5 also improved the immune response of both ND and IBD vaccines with less dosage. The sterile protective immunity was monitored with one- or a half-dose of adjuvanted ND vaccine or one dose of adjuvanted IBD vaccine, respectively. The improved immune efficacy was observed in a half-dose of adjuvanted bivalent vaccines compared to one dose of vaccines without CVCVA5 as measured by the antibody levels, including bivalent vaccine of ND-H9, ND-IB, and ND-IBD. The CVCVA5 also boosted the immune efficacy of the tetravalent vaccine (ND-IB-EDS-H9). A half-dose of adjuvanted commercial vaccine or 75% antigen-sparing adjuvanted vaccine elicited similar antibody levels to those of one dose non-adjuvanted commercial vaccines. The CVCVA5 improved the effect of a booster vaccination as measured by the antibody levels against H5 or H9 virus antigens, in which chickens primed with the adjuvanted ND-IB vaccines given a booster with H5–H9 bivalent vaccines without CVCVA5 using 5-day intervals. The inflammatory response may contribute to these additional effects by increasing the levels of IFNγ and IL-4 after the injection of the adjuvanted ND-IB vaccines. Results indicated that the CVCVA5 improved

  11. Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy.

    PubMed

    Spencer, Drew A; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Polster, Sean P; Murphy, Jason P; Lesniak, Maciej S

    2015-01-01

    Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.

  12. Simultaneous delivery of cytotoxic and biologic therapeutics using nanophotoactivatable liposomes enhances treatment efficacy in a mouse model of pancreatic cancer.

    PubMed

    Tangutoori, Shifalika; Spring, Bryan Q; Mai, Zhiming; Palanisami, Akilan; Mensah, Lawrence B; Hasan, Tayyaba

    2016-01-01

    A lack of intracellular delivery systems has limited the use of biologics such as monoclonal antibodies (mAb) that abrogate molecular signaling pathways activated to promote escape from cancer treatment. We hypothesized that intracellular co-delivery of the photocytotoxic chromophore benzoporphyrin derivative monoacid A (BPD) and the anti-VEGF mAb bevacizumab in a nanophotoactivatable liposome (nanoPAL) might enhance the efficacy of photodynamic therapy (PDT) combined with suppression of VEGF-mediated signaling pathways. As a proof-of-concept we found that nanoPAL-PDT induced enhanced extra- and intracellular bevacizumab delivery and enhanced acute cytotoxicity in vitro. In an in vivo subcutaneous mouse model of pancreatic ductal adenocarcinoma, nanoPAL-PDT achieved significantly enhanced tumor reduction. We attribute this to the optimal incorporation of insoluble BPD into the lipid bilayer, enhancing photocytotoxicity, and the simultaneous spatiotemporal delivery of bevacizumab, ensuring efficient neutralization of the rapid but transient burst of VEGF following PDT. From the Clinical Editor: Most patients with pancreatic ductal adenocarcinoma (PDAC) by the time present the disease it is very advanced, which unavoidably translates to poor survival. For these patients, use of traditional chemotherapy often becomes ineffective due to tumor resistance to drugs. Photodynamic therapy (PDT) can be an effective modality against chemo-resistant cancers. In this article, the authors investigated the co-delivery of a photocytotoxic agent and anti-VEGF mAb using liposomes. This combination was shown to results in enhanced tumor killing. This method should be applicable to other combination of treatments.

  13. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis

    PubMed Central

    Tricco, Andrea C.; Soobiah, Charlene; Berliner, Shirra; Ho, Joanne M.; Ng, Carmen H.; Ashoor, Huda M.; Chen, Maggie H.; Hemmelgarn, Brenda; Straus, Sharon E.

    Background: Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment. Methods: Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool. Results: We screened 15 554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini–Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] −0.22 to 0.50; Alzheimer’s Disease Assessment Scale — cognition subscale: 3 RCTs, standardized MD −0.07, 95% CI−0.16 to 0.01]) or function (Alzheimer’s Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI −0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo. Interpretation: Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment. PMID:24043661

  14. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model

    PubMed Central

    Rincón, Esther; Cejalvo, Teresa; Kanojia, Deepak; Alfranca, Arantzazu; Rodríguez-Milla, Miguel Ángel; Hoyos, Raul Andrés Gil; Han, Yu; Zhang, Lingjiao; Alemany, Ramón; Lesniak, Maciej S.; García-Castro, Javier

    2017-01-01

    Oncolytic virotherapy represents a promising alternative for cancer treatment; however, viral delivery to the tumor represents a major challenge. Mesenchymal stem cells (MSCs) chemotax to tumors, and can serve as a viral delivery tool. Previously, we demonstrated antitumor therapeutic efficacy for mesenchymal stem cells (MSCs) infected with the oncolytic human adenovirus ICOVIR5 (Celyvir) for treatment of neuroblastoma patients. Given the lack of suitable immunocompetent preclinical models, the mechanism underlying Celyvir antitumor activity remains unknown. In this study, we used the syngeneic murine CMT64 cell line as a human adenovirus-semi-permissive tumor model and demonstrate the homing capacity of mouse Celyvir (mCelyvir) to CMT64 tumors. We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t. ICOVIR5 alone. Interestingly, the superior therapeutic effect of the combined therapy was associated with a higher tumor infiltration of CD8+ and CD4+ T cells. Our findings suggest that the use of MSCs as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, not only by driving the adenovirus to tumors, but also through their potential to recruit T cells. PMID:28525366

  15. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model.

    PubMed

    Rincón, Esther; Cejalvo, Teresa; Kanojia, Deepak; Alfranca, Arantzazu; Rodríguez-Milla, Miguel Ángel; Gil Hoyos, Raul Andrés; Han, Yu; Zhang, Lingjiao; Alemany, Ramón; Lesniak, Maciej S; García-Castro, Javier

    2017-07-11

    Oncolytic virotherapy represents a promising alternative for cancer treatment; however, viral delivery to the tumor represents a major challenge. Mesenchymal stem cells (MSCs) chemotax to tumors, and can serve as a viral delivery tool. Previously, we demonstrated antitumor therapeutic efficacy for mesenchymal stem cells (MSCs) infected with the oncolytic human adenovirus ICOVIR5 (Celyvir) for treatment of neuroblastoma patients. Given the lack of suitable immunocompetent preclinical models, the mechanism underlying Celyvir antitumor activity remains unknown. In this study, we used the syngeneic murine CMT64 cell line as a human adenovirus-semi-permissive tumor model and demonstrate the homing capacity of mouse Celyvir (mCelyvir) to CMT64 tumors. We found that the combined treatment of mCelyvir and intratumoral injections (i.t.) of ICOVIR5 was more effective than treatment with i.t. ICOVIR5 alone. Interestingly, the superior therapeutic effect of the combined therapy was associated with a higher tumor infiltration of CD8+ and CD4+ T cells. Our findings suggest that the use of MSCs as carriers of oncolytic adenovirus can improve the clinical efficacy of anti-cancer virotherapy, not only by driving the adenovirus to tumors, but also through their potential to recruit T cells.

  16. Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

    PubMed Central

    Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

    2009-01-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

  17. Development of intravenous lipid emulsion of α-asarone with significantly improved safety and enhanced efficacy.

    PubMed

    Ma, Wei-Cong; Zhang, Qing; Li, Hui; Larregieu, Caroline A; Zhang, Na; Chu, Ting; Jin, Hui; Mao, Sheng-Jun

    2013-06-25

    Severe adverse events have been frequently associated with taking the commercially available formulation of α-asarone injection (α-asarone-I). Hence, we sought to develop an intravenous lipid emulsion of α-asarone (α-asarone-LE), where we hypothesized that these adverse events could be prevented. Using a central composite design-response surface methodology, we developed and optimized an emulsion formulation of α-asarone-LE that composed of 10.0% (w/v) soybean oil, 0.4% (w/v) α-asarone, 1.2% (w/v) soybean lecithin, 0.3% (w/v) F68, and 2.2% (w/v) glycerol. The mean particle size of α-asarone-LE was 226±11 nm, the ζ-potential was -25.6±1.2 mV, the encapsulation efficiency was 99.2±0.1% and the drug loading efficiency was 3.45%. Stability, safety, and efficacy studies of α-asarone-LE were systematically investigated and compared to those of α-asarone-I. The α-asarone-LE not only showed a desired stability, but also exhibited excellent safety and improved efficacy in vivo, indicating its great potential for clinical application in the future. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. The Glutaminase-1 Inhibitor 968 Enhances Dihydroartemisinin-Mediated Antitumor Efficacy in Hepatocellular Carcinoma Cells

    PubMed Central

    Zheng, Meihong; Zhang, Yonghui; Chen, Aiping; Wu, Junhua; Wei, Jiwu

    2016-01-01

    Reprogrammed metabolism and redox homeostasis are potential targets of cancer therapy. Our previous study demonstrated that the kidney form of glutaminase (GLS1) is highly expressed in hepatocellular carcinoma (HCC) cells and can be used as a target for effective anticancer therapy. Dihydroartemisinin (DHA) increases intracellular reactive oxygen species (ROS) levels leading to cytotoxicity in cancer cells. However, the heterogeneity of cancer cells often leads to differing responses to oxidative lesions. For instance, cancer cells with high ratio of GSH/GSSG, a critical ROS scavenger, are resistant to ROS-induced cytotoxicity. We postulate that a combinatorial strategy firstly disrupting redox homeostasis followed by DHA might yield a profound antitumor efficacy. In this study, when HCC cells were treated with a GLS1 inhibitor 968, the ROS elimination capacity was significantly reduced in HCC cells, which rendered HCC cells but not normal endothelial cells more sensitive to DHA-mediated cytotoxicity. We further confirmed that this synergistic antitumor efficacy was mediated by excessive ROS generation in HCC cells. NAC, a ROS inhibitor, partly rescued the combinatorial cytotoxic effect of 968 and DHA. Given that GLS1 is a potential antitumor target and DHA has been safely used in clinic, our findings provide new insight into liver cancer therapy targeting glutamine metabolism combined with the ROS generator DHA, which can be readily translated into cancer clinical trials. PMID:27835669

  19. Enzyme augmentation therapy enhances the therapeutic efficacy of bone marrow transplantation in mucopolysaccharidosis type II mice.

    PubMed

    Akiyama, Kazumasa; Shimada, Yohta; Higuchi, Takashi; Ohtsu, Makoto; Nakauchi, Hiromitsu; Kobayashi, Hiroshi; Fukuda, Takahiro; Ida, Hiroyuki; Eto, Yoshikatsu; Crawford, Brett E; Brown, Jillian R; Ohashi, Toya

    2014-02-01

    Before the availability of an enzyme replacement therapy (ERT) for mucopolysaccharidosis type II (MPS II), patients were treated by bone marrow transplantation (BMT). However, the effectiveness of BMT for MPS II was equivocal, particularly at addressing the CNS manifestations. To study this further, we subjected a murine model of MPS II to BMT and evaluated the effect at correcting the biochemical and pathological aberrations in the viscera and CNS. Our results indicated that BMT reduced the accumulation of glycosaminoglycans (GAGs) in a variety of visceral organs, but not in the CNS. With the availability of an approved ERT for MPS II, we investigated and compared the relative merits of the two strategies either as a mono or combination therapy. We showed that the combination of BMT and ERT was additive at reducing tissue levels of GAGs in the heart, kidney and lung. Moreover, ERT conferred greater efficacy if the immunological response against the infused recombinant enzyme was low. Finally, we showed that pathologic GAGs might potentially represent a sensitive biomarker to monitor the therapeutic efficacy of therapies for MPS II. © 2013.

  20. Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer.

    PubMed

    Li, Jie; Wang, Ruixin; Kong, Yifan; Broman, Meaghan M; Carlock, Colin; Chen, Long; Li, Zhiguo; Farah, Elia; Ratliff, Timothy L; Liu, Xiaoqi

    2017-03-01

    Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with olaparib results in an override of the G1-S checkpoint, leading to high expression of Plk1, which attenuates olaparib's overall efficacy. In BRCA1 wild-type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi. Mol Cancer Ther; 16(3); 469-79. ©2017 AACR. ©2017 American Association for Cancer Research.

  1. Liposomal co-delivery of curcumin and albumin/paclitaxel nanoparticle for enhanced synergistic antitumor efficacy.

    PubMed

    Ruttala, Hima Bindu; Ko, Young Tag

    2015-04-01

    Paclitaxel (PTX) and curcumin (CUR) are potent chemotherapeutic agents used in the treatment of cancer. In the present study, hybrid polymer-lipid nanoparticles co-loaded with PTX and CUR were developed to investigate the therapeutic potential of a combination drug regimen. For this purpose, PTX-loaded albumin nanoparticles (APN) were prepared and encapsulated in PEGylated hybrid liposomes containing CUR (CL-APN) via a thin-film hydration technique. CL-APN was nanosized with a uniform spherical morphology. PTX and CUR release was sustained and occurred in a sequential manner, wherein CUR was expected to downregulate the nuclear factor NF-κB and Akt pathways and increase the therapeutic efficacy of PTX. The ratiometric combination of PTX and CUR was significantly more cytotoxic than the individual drugs. Importantly, dual-drug-loaded nanocarriers exhibited a superior cytotoxic effect than a cocktail combination at a lower dose. CL-APN induced significantly higher early and late apoptosis, induced a stronger G2/M arrest, and significantly increased the subG1 cell population. By combining CUR, an effective NF-κB inhibitor, with PTX, a powerful anticancer drug, in a polymer-lipid hybrid nanoparticle system, we could improve the therapeutic efficacy in cancer treatments. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against various malignancies. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Gene therapy for brain cancer: combination therapies provide enhanced efficacy and safety.

    PubMed

    Candolfi, Marianela; Kroeger, Kurt M; Muhammad, A K M G; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N; Lowenstein, Pedro R; Castro, Maria G

    2009-10-01

    Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM.

  3. Vancomycin-Rifampin Combination Therapy Has Enhanced Efficacy against an Experimental Staphylococcus aureus Prosthetic Joint Infection

    PubMed Central

    Niska, Jared A.; Shahbazian, Jonathan H.; Ramos, Romela Irene; Francis, Kevin P.; Bernthal, Nicholas M.

    2013-01-01

    Treatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in which Staphylococcus aureus was inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention. In vivo bioluminescence imaging, ex vivo CFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuable in vivo preclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects. PMID:23917317

  4. Co-delivery of docetaxel and palmitoyl ascorbate by liposome for enhanced synergistic antitumor efficacy

    PubMed Central

    Li, Junxiu; Guo, Chaorui; Feng, Fan; Fan, Ali; Dai, Yu; Li, Ning; Zhao, Di; Chen, Xijing; Lu, Yang

    2016-01-01

    Palmitoyl ascorbate (PA) as an antioxidant has the potential for the treatment of cancer. In the present study, a nanocarrier system was developed for co-delivery of docetaxel (DOC) with palmitoyl ascorbate and the therapeutic efficacy of a combination drug regimen was investigated. For this purpose, different ratios of docetaxel and palmitoyl ascorbate were co-encapsulated in a liposome and they all showed high encapsulation efficiency. The average diameters of the liposomes ranged from 140 to 170 nm. Negative zeta potential values were observed for all systems, ranged from −40 mV to −56 mV. Studies on drug release and cellular uptake of the co-delivery system demonstrated that both drugs were effectively taken up by the cells and released slowly. Moreover, the liposome loading drugs with DOC/PA concentration ratio of 1:200 showed the highest anti-tumor activity to three different types of tumor cells. The higher in vivo therapeutic efficacy with lower systemic toxicity of the DOC-PA200-LPs was also verified by the H22 tumor bearing mice model. Our results showed that such co-loaded delivery systems could serve as a promising therapeutic approach to improve clinical outcomes against hepatic carcinoma. PMID:27934917

  5. Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy

    PubMed Central

    Filip, Gabriela Adriana; Olteanu, Diana; Cenariu, Mihai; Tabaran, Flaviu; Ion, Rodica Mariana; Gligor, Lucian; Baldea, Ioana

    2017-01-01

    Background Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine—Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. Methods Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. Results GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)—related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. Conclusions Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. General significance Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy. PMID:28278159

  6. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer

    PubMed Central

    Wu, Sheng-Kai; Chiang, Chi-Feng; Hsu, Yu-Hone; Lin, Tzu-Hung; Liou, Houng-Chi; Fu, Wen-Mei; Lin, Win-Li

    2014-01-01

    The blood–brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers. PMID:25278753

  7. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer.

    PubMed

    Wu, Sheng-Kai; Chiang, Chi-Feng; Hsu, Yu-Hone; Lin, Tzu-Hung; Liou, Houng-Chi; Fu, Wen-Mei; Lin, Win-Li

    2014-01-01

    The blood-brain/tumor barrier inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time focused ultrasound (FUS) hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10-minute transcranial FUS hyperthermia on day 6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD + hyperthermia groups was measured using an IVIS spectrum system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD + hyperthermia compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

  8. Targeting Polo-Like Kinase 1 Enhances Radiation Efficacy for Head-and-Neck Squamous Cell Carcinoma

    SciTech Connect

    Gerster, Kate; Shi Wei; Ng, Benjamin; Yue Shijun; Ito, Emma; Waldron, John; Gilbert, Ralph; Liu Feifei

    2010-05-01

    Purpose: To investigate the efficacy of targeting polo-like kinase 1 (Plk1) combined with ionizing radiotherapy (RT) for head-and-neck squamous cell carcinoma (HNSCC). Methods and Materials: Polo-like kinase 1 messenger ribonucleic acid (mRNA) was targeted by small interfering RNA (siRNA) transfection into the FaDu HNSCC cell line; reduction was confirmed using quantitative real-time polymerase chain reaction. The cellular effects were assessed using [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium], clonogenic, flow cytometric, and caspase assays. In vivo efficacy of siPlk1 was evaluated using mouse xenograft models. Results: Small interfering Plk1 significantly decreased Plk1 mRNA expression, while also increasing cyclin B1 and p21(Waf1/CIP1) mRNA levels after 24 h. This depletion resulted in a time-dependent increase in FaDu cytotoxicity, which was enhanced by the addition of RT. Flow cytometric and caspase assays demonstrated progressive apoptosis, DNA double-strand breaks (gamma-H2AX), G2/M arrest, and activation of caspases 3 and 7. Implantation of siPlk1-treated FaDu cells in severe combined immunodeficient mice delayed tumor formation, and systemic administration of siPlk1 inhibited tumor growth enhanced by RT. Conclusions: These data demonstrate the suitability of Plk1 as a potential therapeutic target for HNSCC, because Plk1 depletion resulted in significant cytotoxicity in vitro and abrogated tumor-forming potential in vivo. The effects of Plk1 depletion were enhanced with the addition of RT, indicating that Plk1 represents an important potential radiation sensitizer for HNSCC.

  9. From Burdens to Benefits: The Societal Impact of PDL-Enriched, Efficacy-Enhanced Educators

    ERIC Educational Resources Information Center

    Shaha, Steven H.; Glassett, Kelly F.; Rosenlund, David; Copas, Aimee; Huddleston, T. Lisa

    2016-01-01

    Societies continue to absorb increased burdens in cost for helping citizens unable to achieve at optimal levels. Building on past research, we project educational benefits to offset current societal burdens through enhanced educator capabilities. Studies reviewed show participation in a high-impact professional development and learning solution…

  10. Efficacy of Two Mathematics Interventions for Enhancing Fluency with Elementary Students

    ERIC Educational Resources Information Center

    Mong, Michael D.; Mong, Kristi W.

    2010-01-01

    An alternating treatments design was used to evaluate two curriculum-based mathematics interventions designed to enhance fluency with three elementary school students. Results indicate that both the Math to Mastery (MTM) intervention and the Cover, Copy, Compare (CCC) intervention were effective at increasing mathematics fluency, as measured by…

  11. Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation

    PubMed Central

    Moore, Caroline M.; Loizidou, Marilena; MacRobert, Alexander J.; Woodhams, Josephine H.

    2016-01-01

    Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI‐based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy. PMID:25758607

  12. Enhancing the efficacy of cancer vaccines in urologic oncology: new directions.

    PubMed

    Kusmartsev, Sergei; Vieweg, Johannes

    2009-10-01

    Immunotherapeutic interventions have long been utilized in urologic oncology for the treatment of metastatic renal cell or superficial transitional cell carcinoma. Most recently, the first active specific immunotherapeutic approach, a cancer vaccine, has passed the final phase of human testing and its approval by the FDA is pending. However, evidence suggests that the full protective and therapeutic potential of cancer vaccines has not yet been achieved. Through multiple mechanisms, tumors promote conditions in the tumor-bearing host that mitigate or even eliminate the vaccine-induced antitumor response. Restoration of the impaired immune function is, therefore, imperative for achieving optimum vaccine efficacy. Targeted pharmacological interventions are capable of overcoming tumor-mediated immunosuppression, and thereby enable cancer vaccination to reach its full therapeutic potential.

  13. Enhancing the efficacy of cytotoxic agents for cancer therapy using photochemical internalisation.

    PubMed

    Martinez de Pinillos Bayona, Alejandra; Moore, Caroline M; Loizidou, Marilena; MacRobert, Alexander J; Woodhams, Josephine H

    2016-03-01

    Photochemical internalisation (PCI) is a technique for improving cellular delivery of certain bioactive agents which are prone to sequestration within endolysosomes. There is a wide range of agents suitable for PCI-based delivery including toxins, oligonucleotides, genes and immunoconjugates which demonstrates the versatility of this technique. The basic mechanism of PCI involves triggering release of the agent from endolysosomes within the target cells using a photosensitiser which is selectively retained with the endolysosomal membranes. Excitation of the photosensitiser by visible light leads to disruption of the membranes via photooxidative damage thereby releasing the agent into the cytosol. This treatment enables the drugs to reach their intended subcellular target more efficiently and improves their efficacy. In this review we summarise the applications of this technique with the main emphasis placed on cancer chemotherapy.

  14. Enhanced efficacy and sensory properties of an anti-dandruff shampoo containing zinc pyrithione and climbazole.

    PubMed

    Turner, G A; Matheson, J R; Li, G-Z; Fei, X-Q; Zhu, D; Baines, F L

    2013-02-01

    Dandruff is a common complaint and is suffered by as much as half of the population at some time post puberty. The condition is characterized by the presence of flakes on the scalp and in the hair, and is often accompanied by itch. The most common treatment for dandruff is the use of shampoo formulations that contain fungistatic agents such as zinc pyrithione (ZPT) and octopirox. Whilst most antidandruff shampoos are effective in resolving the symptoms of dandruff these shampoos can often result in hair condition that is less than acceptable to consumers which can lead to a tendency for them to revert to use of a non-antidandruff shampoo. This can result in a rapid return of dandruff symptoms. The aim of this investigation was to study the impact of using a combination of antidandruff actives and silicones on the resolution of dandruff and to deliver superior sensory properties to the hair. We have demonstrated that shampoo containing the dual active system of ZPT/Climbazole deposits both active agents onto a model skin surface (VitroSkin) and reduces Malassezia furfur regrowth in vitro. Clinical evaluation of the dual active shampoo demonstrated superior efficacy and retained superiority during a regression phase where all subjects reverted to using a non-antidandruff shampoo. We have also demonstrated that it is possible to deposit silicone materials from antidandruff shampoo uniformly over both virgin and damaged hair fibres that results in smoother hair fibres (as evidenced by reduced dry friction). This combination of antidandruff agents and conditioning silicones delivered from a shampoo provides subjects with superior antidandruff efficacy and desired end sensory benefits ensuring compliance and longer term dandruff removal.

  15. Enhanced photodynamic efficacy towards melanoma cells by encapsulation of Pc4 in silica nanoparticles

    SciTech Connect

    Zhao Baozhong; Yin Junjie; Bilski, Piotr J.; Chignell, Colin F.; Roberts, Joan E.; He Yuying

    2009-12-01

    Nanoparticles have been explored recently as an efficient means of delivering photosensitizers for cancer diagnosis and photodynamic therapy (PDT). Silicon phthalocyanine 4 (Pc4) is currently being clinically tested as a photosensitizer for PDT. Unfortunately, Pc4 aggregates in aqueous solutions, which dramatically reduces its PDT efficacy and therefore limits its clinical application. We have encapsulated Pc4 using silica nanoparticles (Pc4SNP), which not only improved the aqueous solubility, stability, and delivery of the photodynamic drug but also increased its photodynamic efficacy compared to free Pc4 molecules. Pc4SNP generated photo-induced singlet oxygen more efficiently than free Pc4 as measured by chemical probe and EPR trapping techniques. Transmission electron microscopy and dynamic light scattering measurements showed that the size of the particles is in the range of 25-30 nm. Cell viability measurements demonstrated that Pc4SNP was more phototoxic to A375 or B16-F10 melanoma cells than free Pc4. Pc4SNP photodamaged melanoma cells primarily through apoptosis. Irradiation of A375 cells in the presence of Pc4SNP resulted in a significant increase in intracellular protein-derived peroxides, suggesting a Type II (singlet oxygen) mechanism for phototoxicity. More Pc4SNP than free Pc4 was localized in the mitochondria and lysosomes. Our results show that these stable, monodispersed silica nanoparticles may be an effective new formulation for Pc4 in its preclinical and clinical studies. We expect that modifying the surface of silicon nanoparticles encapsulating the photosensitizers with antibodies specific to melanoma cells will lead to even better early diagnosis and targeted treatment of melanoma in the future.

  16. Antiangiogenic Arming of an Oncolytic Vaccinia Virus Enhances Antitumor Efficacy in Renal Cell Cancer Models▿ †

    PubMed Central

    Guse, Kilian; Sloniecka, Marta; Diaconu, Iulia; Ottolino-Perry, Kathryn; Tang, Nan; Ng, Calvin; Le Boeuf, Fabrice; Bell, John C.; McCart, J. Andrea; Ristimäki, Ari; Pesonen, Sari; Cerullo, Vincenzo; Hemminki, Akseli

    2010-01-01

    Oncolytic vaccinia viruses have shown compelling results in preclinical cancer models and promising preliminary safety and antitumor activity in early clinical trials. However, to facilitate systemic application it would be useful to improve tumor targeting and antitumor efficacy further. Here we report the generation of vvdd-VEGFR-1-Ig, a targeted and armed oncolytic vaccinia virus. Tumor targeting was achieved by deletion of genes for thymidine kinase and vaccinia virus growth factor, which are necessary for replication in normal but not in cancer cells. Given the high vascularization typical of kidney cancers, we armed the virus with the soluble vascular endothelial growth factor (VEGF) receptor 1 protein for an antiangiogenic effect. Systemic application of high doses of vvdd-VEGFR-1-Ig resulted in cytokine induction in an immunocompromised mouse model. Upon histopathological analysis, splenic extramedullary hematopoiesis was seen in all virus-injected mice and was more pronounced in the vvdd-VEGFR-1-Ig group. Analysis of the innate immune response after intravenous virus injection revealed high transient and dose-dependent cytokine elevations. When medium and low doses were used for intratumoral or intravenous injection, vvdd-VEGFR-1-Ig exhibited a stronger antitumor effect than the unarmed control. Furthermore, expression of VEGFR-1-Ig was confirmed, and a concurrent antiangiogenic effect was seen. In an immunocompetent model, systemic vvdd-VEGFR-1-Ig exhibited superior antitumor efficacy compared to the unarmed control virus. In conclusion, the targeted and armed vvdd-VEGFR-1-Ig has promising anticancer activity in renal cell cancer models. Extramedullary hematopoiesis may be a sensitive indicator of vaccinia virus effects in mice. PMID:19906926

  17. Enhanced photodynamic efficacy towards melanoma cells by encapsulation of Pc4 in silica nanoparticles.

    PubMed

    Zhao, Baozhong; Yin, Jun-Jie; Bilski, Piotr J; Chignell, Colin F; Roberts, Joan E; He, Yu-Ying

    2009-12-01

    Nanoparticles have been explored recently as an efficient means of delivering photosensitizers for cancer diagnosis and photodynamic therapy (PDT). Silicon phthalocyanine 4 (Pc4) is currently being clinically tested as a photosensitizer for PDT. Unfortunately, Pc4 aggregates in aqueous solutions, which dramatically reduces its PDT efficacy and therefore limits its clinical application. We have encapsulated Pc4 using silica nanoparticles (Pc4SNP), which not only improved the aqueous solubility, stability, and delivery of the photodynamic drug but also increased its photodynamic efficacy compared to free Pc4 molecules. Pc4SNP generated photo-induced singlet oxygen more efficiently than free Pc4 as measured by chemical probe and EPR trapping techniques. Transmission electron microscopy and dynamic light scattering measurements showed that the size of the particles is in the range of 25-30 nm. Cell viability measurements demonstrated that Pc4SNP was more phototoxic to A375 or B16-F10 melanoma cells than free Pc4. Pc4SNP photodamaged melanoma cells primarily through apoptosis. Irradiation of A375 cells in the presence of Pc4SNP resulted in a significant increase in intracellular protein-derived peroxides, suggesting a Type II (singlet oxygen) mechanism for phototoxicity. More Pc4SNP than free Pc4 was localized in the mitochondria and lysosomes. Our results show that these stable, monodispersed silica nanoparticles may be an effective new formulation for Pc4 in its preclinical and clinical studies. We expect that modifying the surface of silicon nanoparticles encapsulating the photosensitizers with antibodies specific to melanoma cells will lead to even better early diagnosis and targeted treatment of melanoma in the future.

  18. Enhanced Photodynamic Efficacy towards Melanoma Cells by Encapsulation of Pc4 in Silica Nanoparticles

    PubMed Central

    Zhao, Baozhong; Yin, Jun-Jie; Bilski, Piotr J.; Chignell, Colin F.; Roberts, Joan E.; He, Yu-Ying

    2009-01-01

    Nanoparticles have been explored recently as an efficient means of delivering photosensitizers for cancer diagnosis and photodynamic therapy (PDT). Silicon phthalocyanine 4 (Pc4) is currently being clinically tested as a photosensitizer for PDT. Unfortunately, Pc4 aggregates in aqueous solutions, which dramatically reduces its PDT efficacy and therefore limits its clinical application. We have encapsulated Pc4 using silica nanoparticles (Pc4SNP), which not only improved the aqueous solubility, stability, and delivery of the photodynamic drug but also increased its photodynamic efficacy compared to free Pc4 molecules. Pc4SNP generated photo-induced singlet oxygen more efficiently than free Pc4 as measured by chemical probe and EPR trapping techniques. Transmission electron microscopy and dynamic light scattering measurements showed that the size of the particles is in the range of 25-30 nm. Cell viability measurements demonstrated that Pc4SNP was more phototoxic to A375 or B16-F10 melanoma cells than free Pc4. Pc4SNP photodamaged melanoma cells primarily through apoptosis. Irradiation of A375 cells in the presence of Pc4SNP resulted in a significant increase in intracellular protein-derived peroxides, suggesting a Type II (singlet oxygen) mechanism for phototoxicity. More Pc4SNP than free Pc4 was localized in the mitochondria and lysosomes. Our results show that these stable, monodispersed silica nanoparticles may be an effective new formulation for Pc4 in its preclinical and clinical studies. We expect that modifying the surface of silicon nanoparticles encapsulating the photosensitizers with antibodies specific to melanoma cells will lead to even better early diagnosis and targeted treatment of melanoma in the future. PMID:19695274

  19. A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

    PubMed

    Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

    2017-05-01

    Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

  20. Inhibition of endothelin-1 and KCL-induced increase of [CA2+]i by antiglaucoma drugs in cultured A7r5 vascular smooth-muscle cells.

    PubMed

    Wu, Kwou-Yeung; Wang, Hwei-Zu; Hong, Show-Jen

    2004-06-01

    Over contraction of vascular smooth muscle may result in ischemia to ocular neuronal cells and deteriorate the glaucoma. The purpose of this study was to investigate the inhibitory effects of various commercial antiglaucoma drugs including brimonidine, dipivefrin, betaxolol, timolol, levobunolol, carteolol, brinzolamide, dorzolamide, unoprostone, latanoprost, pilocarpine, and preservative benzalkonium chloride on endothelin-1(ET-1) and KCl-induced increase of intracellular free Ca2+ ([Ca2+]i) in cultured rat A7r5 vascular smooth muscle cells. These drugs were diluted from original concentrations to 1/100, 1/1000, and 1/10000. [Ca2+]i mobility was analyzed by spectrofluorometry after loading with fura-2-AM. Betaxolol, timolol, levobunolol, and carteolol were found to inhibit KCl-induced release of [Ca2+]i in a dose-dependent manner. High concentrations of betaxolol, timolol, levobunolol, carteolol, and unoprostone also inhibited ET-1-induced increase of [Ca2+]i in A7r5 cells. However, ET-1- and KCl-induced increase of [Ca2+]i was not diminished by other drugs including brimonidine, dipivefrin, brinzolamide, dorzolamide, latanoprost, pilocarpine, and benzalkonium chloride. These results indicate that high concentrations of unoprostone and beta-adrenergic blocking agents including betaxolol, timolol, levobunolol, and carteolol may inhibit ET-1-induced increase of [Ca2+]i. The mechanism may be mediated by inhibition of extracellular calcium influx via blocking of L-type voltage-dependent Ca2+ channel in A7r5 cells.

  1. Cordycepin enhances Epstein-Barr virus lytic infection and Epstein-Barr virus-positive tumor treatment efficacy by doxorubicin.

    PubMed

    Du, Yinping; Yu, Jieshi; Du, Li; Tang, Jun; Feng, Wen-Hai

    2016-07-01

    The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors.

  2. A novel micelle-forming material used for preparing a theranostic vehicle exhibiting enhanced in vivo therapeutic efficacy.

    PubMed

    Chen, Hsiao-Ping; Chen, Ming-Hong; Tung, Fu-I; Liu, Tse-Ying

    2015-05-14

    A new micelle-forming material, folic acid-conjugated carboxymethyl lauryl chitosan (FA-CLC), and superparamagnetic iron oxide (SPIO) nanoparticles were used for preparing an imaging-guided drug vehicle (the FA-CLC/SPIO hybrid micelle) that demonstrates targeted delivery, imaging, and controlled release of hydrophobic agents. We found that the ratio of viable normal cells to tumor cells was increased prominently after delivery of camptothecin (CPT)-loaded FA-CLC/SPIO micelles and therapeutic sonication. In addition, a magnetic field could enhance the tumor-targeting effect of FA-CLC/SPIO micelles. Therefore, after sequential administration of magnetic attraction to CPT-loaded FA-CLC/SPIO micelles, and therapeutic sonication, the in vivo therapeutic efficacy of CPT was markedly enhanced. However, a nonfocused magnetic field could enhance the undesirable accumulation of iron-containing vehicles in the liver if the tumor (i.e., magnetic attraction site) is near the liver. We propose that magnetic attraction must be carefully applied, far from the liver.

  3. Enhancing meaningful learning and self-efficacy through collaboration between dental hygienist and physiotherapist students - a scholarship project.

    PubMed

    Johannsen, A; Bolander-Laksov, K; Bjurshammar, N; Nordgren, B; Fridén, C; Hagströmer, M

    2012-11-01

    Within the field of Dental Hygiene (DH) and Physiotherapy (PT), students are taught to use an evidence-based approach. Educators need to consider the nature of evidence-based practice from the perspective of content knowledge and learning strategies. Such effort to seek best available evidence and to apply a systematic and scholarly approach to teaching and learning is called scholarship of teaching and learning. To evaluate the application of the scholarship model including an evidence-based approach to enhance meaningful learning and self-efficacy among DH and PT students. Based on the research on student learning, three central theories were identified (constructivism, meaningful learning and self-efficacy). These were applied in our context to support learner engagement and the application of prior knowledge in a new situation. The DH students performed an oral health examination on the PT students, and the PT students performed an individual health test on the DH students; both groups used motivational interviewing. Documentation of student's learning experience was carried out through seminars and questionnaires. The students were overall satisfied with the learning experience. Most appreciated are that it reflected a 'real' professional situation and that it also reinforced important learning from their seminars. The scholarship model made the teachers aware of the importance of evidence-based teaching. Furthermore, the indicators for meaningful learning and increased self-efficacy were high, and the students became more engaged by practising in a real situation, more aware of other health professions and reflected about tacit knowledge. © 2012 John Wiley & Sons A/S.

  4. Cold storage enhances the efficacy and margin of security in postharvest irradiation treatments against fruit flies (Diptera: Tephritidae).

    PubMed

    Follett, Peter A; Snook, Kirsten

    2013-10-01

    Cold storage is used to preserve fruit quality after harvest during transportation in marketing channels. Low temperature can be a stressor for insects that reduces survivorship, and cold storage may contribute to the efficacy of postharvest quarantine treatments such as irradiation against quarantine insect pests. The combined effect of irradiation and cold storage was examined in a radiation-tolerant fruit fly, Bactrocera cucurbitae Coquillet (melon fly), and a radiation-intolerant fruit fly, Ceratitis capitata (Wiedemann) (Mediterranean fruit fly) (Diptera: Tephritidae). Third instars on diet or in papaya were treated with a sublethal radiation dose of 30 Gy and stored at 4 or 11 degrees C for 3-13 d and held for adult emergence. For both fruit fly species, survival of third instars to the adult stage generally decreased with increasing cold storage duration at 4 or 11 degrees C in diet or papaya. Survivorship differences were highly significant for the effects of substrate (diet > papaya), temperature (11 > 4 degrees C),and irradiation (0 > 30 Gy). Few Mediterranean fruit flies survived in any cold storage treatment after receiving a radiation dose of 30 Gy. No melon fly larvae survived to the adult stage after irradiation and 11 d cold storage at 4 or 11 degrees C in papayas. Cold storage enhances the efficacy and widens the margin of security in postharvest irradiation treatments. Potentially irradiation and cold storage can be used in combination to reduce the irradiation exposure requirements of quarantine treatments.

  5. PEGylated polypeptide lipid nanocapsules to enhance the anticancer efficacy of erlotinib in non-small cell lung cancer.

    PubMed

    Kim, Jeonghwan; Ramasamy, Thiruganesh; Choi, Ju Yeon; Kim, Ssang Tae; Youn, Yu Seok; Choi, Han-Gon; Yong, Chul Soon; Kim, Jong Oh

    2017-02-01

    In this study, a core-shell type polypeptide-based lipid nanocapsule was developed to enhance anticancer efficacy of erlotinib in non-small cell lung cancers. Mean particle size of PEGylated polypeptide-lipid nanocapsules (PLN) for erlotinib (ERL) delivery was ∼200nm with an effective surface charge of -20mV. Protective PEGylated polypeptide layer acted as a molecular fence and effectively controlled the diffusion of erlotinib from the lipid nanocapsule core, whereas pH-responsiveness of poly(L-aspartic acid) accelerated the release of erlotinib in acidic conditions. Blank lipid nanocapsules showed excellent biocompatibility. ERL-loaded PLN (ERL-PLN) showed dose-dependent cytotoxicity in NCI-H358 and HCC-827 lung cancer cells. ERL-PLN treatment resulted in a superior tumor regression profile in a xenograft tumor model, compared to free ERL and control, suggesting high therapeutic efficacy. ERL-PLN-treated mice showed 5- and 2-fold smaller tumor volume compared to control and free ERL groups, respectively. Based on these results, PLN provide a promising drug delivery approach for lung cancer therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Physical activity enhances long-term quality of life in older adults: efficacy, esteem, and affective influences.

    PubMed

    Elavsky, Steriani; McAuley, Edward; Motl, Robert W; Konopack, James F; Marquez, David X; Hu, Liang; Jerome, Gerald J; Diener, Ed

    2005-10-01

    Physical activity has been effective in enhancing quality of life (QOL) of older adults over relatively short periods of time. However, little is known about the long-term effects of physical activity and even less about the possible mediators of this relationship. We examined the mediating effects of psychological variables on the relationship between physical activity and global QOL (satisfaction with life) in older adults over a 4-year period. Participants (N = 174, M age = 66.7 years) completed a battery of psychosocial measures at 1 and 5 years following enrollment in a 6-month randomized controlled exercise trial. Panel analysis conducted within a covariance modeling framework indicated that physical activity was related to self-efficacy, physical self-esteem, and positive affect at 1 year, and in turn, greater levels of self-efficacy and positive affect were associated with higher levels of QOL. Analyses indicated that changes in physical activity over the 4-year period were related to increases in physical self-esteem and positive affect, but only positive affect directly influenced improvements in QOL. The findings lend support to the position that physical activity effects on QOL are in part mediated by intermediate psychological outcomes and that physical activity can have long-term effects on well-being.

  7. Dual actions of albumin packaging and tumor targeting enhance the antitumor efficacy and reduce the cardiotoxicity of doxorubicin in vivo

    PubMed Central

    Zheng, Ke; Li, Rui; Zhou, Xiaolei; Hu, Ping; Zhang, Yaxin; Huang, Yunmei; Chen, Zhuo; Huang, Mingdong

    2015-01-01

    Doxorubicin (DOX) is an effective chemotherapy drug used to treat different types of cancers. However, DOX has severe side effects, especially life-threatening cardiotoxicity. We herein report a new approach to reduce the toxicity of DOX by embedding DOX inside human serum albumin (HSA). HSA is further fused by a molecular biology technique with a tumor-targeting agent, amino-terminal fragment of urokinase (ATF). ATF binds with a high affinity to urokinase receptor, which is a cell-surface receptor overexpressed in many types of tumors. The as-prepared macromolecule complex (ATF–HSA:DOX) was not as cytotoxic as free DOX to cells in vitro, and was mainly localized in cell cytosol in contrast to DOX that was localized in cell nuclei. However, in tumor-bearing mice, ATF–HSA:DOX was demonstrated to have an enhanced tumor-targeting and antitumor efficacy compared with free DOX. More importantly, histopathological examinations of the hearts from the mice treated with ATF–HSA:DOX showed a significantly reduced cardiotoxicity compared with hearts from mice treated with free DOX. These results demonstrate the feasibility of this approach in reducing the cardiotoxicity of DOX while strengthening its antitumor efficacy. Such a tumor-targeted albumin packaging strategy can also be applied to other antitumor drugs. PMID:26346331

  8. Immobilized silver nanoparticles enhance contact killing and show highest efficacy: elucidation of the mechanism of bactericidal action of silver.

    PubMed

    Agnihotri, Shekhar; Mukherji, Soumyo; Mukherji, Suparna

    2013-08-21

    Antimicrobial materials with immobilized/entrapped silver nanoparticles (AgNPs) are of considerable interest. There is significant debate on the mode of bactericidal action of AgNPs, and both contact killing and/or ion mediated killing have been proposed. In this study, AgNPs were immobilized on an amine-functionalized silica surface and their bactericidal activity was studied concurrently with the silver release profile over time. This was compared with similar studies performed using colloidal AgNPs and AgCl surfaces that released Ag ions. We conclude that contact killing is the predominant bactericidal mechanism and surface immobilized nanoparticles show greater efficacy than colloidal AgNPs, as well as a higher concentration of silver ions in solution. In addition, the AgNP immobilized substrate was used multiple times with good efficacy, indicating this immobilization protocol is effective for retaining AgNPs while maintaining their disinfection potential. The antibacterial surface was found to be extremely stable in aqueous medium and no significant leaching (∼1.15% of total silver deposited) of the AgNPs was observed. Thus, immobilization of AgNPs on a surface may promote reuse, reduce environmental risks associated with leaching of AgNPs and enhance cost effectiveness.

  9. Vitamin E-rich Nanoemulsion Enhances the Antitumor Efficacy of Low-Dose Paclitaxel by Driving Th1 Immune Response.

    PubMed

    Ye, Jun; Dong, Wujun; Yang, Yanfang; Hao, Huazhen; Liao, Hengfeng; Wang, Bangyuan; Han, Xue; Jin, Yiqun; Xia, Xuejun; Liu, Yuling

    2017-06-01

    To overcome the drawbacks of high dose regimen and improve the outcomes of chemotherapy at a low dose, an immunotherapeutic nanoemulsion based combination of chemotherapeutic agent (paclitaxel) with immunomodulatory agent (vitamin E) was developed and evaluated for their antitumor effect against breast cancer. A total of five nanoemulsions loaded with various content of vitamin E were prepared and characterized. The immunoregulatory effects of vitamin E along with the overall antitumor efficacy of vitamin E-rich nanoemulsion with a low dose of paclitaxel were investigated through in vitro and in vivo experiments. Vitamin E-rich nanoemulsion exhibited relatively narrow size distribution, high entrapment efficiency and controlled in vitro release profile. In RAW264.7 cells, vitamin E-rich nanoemulsion significantly enhanced the secretion of Th1 cytokines and down-regulated the secretion of Th2 cytokine. In a co-culture system, vitamin E-rich nanoemulsion induced a high apoptosis rate in MDA-MB-231 cells as compared with vitamin E-low nanoemulsion. Furthermore, vitamin E-rich nanoemulsion exhibited superior in vivo antitumor efficacy in comparison with Taxol and vitamin E-low nanoemulsion at a paclitaxel dose of 4 mg/kg. Vitamin E-rich nanoemulsion has great potential for the treatment of breast cancers with a low dose of paclitaxel via driving Th1 immune response.

  10. Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation.

    PubMed

    Fischer, K; Ohori, S; Meral, F C; Uehara, M; Giannini, S; Ichimura, T; Smith, R N; Jolesz, F A; Guleria, I; Zhang, Y; White, P J; McDannold, N J; Hoffmeister, K; Givertz, M M; Abdi, R

    2016-12-23

    One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

  11. Emotion regulation skills training enhances the efficacy of inpatient cognitive behavioral therapy for major depressive disorder: a randomized controlled trial.

    PubMed

    Berking, Matthias; Ebert, David; Cuijpers, Pim; Hofmann, Stefan G

    2013-01-01

    Deficits in emotion regulation skills are possible factors maintaining major depressive disorder (MDD). Therefore, the aim of the study was to test whether integrating a systematic emotion regulation training (ERT) enhances the efficacy of routine inpatient cognitive behavioral therapy (CBT) for MDD. In a prospective randomized controlled trial, 432 inpatients meeting criteria for MDD were assigned to receive either routine CBT or CBT enriched with an intense emotion regulation skills training (CBT-ERT). Participants in the CBT-ERT condition demonstrated a significantly greater reduction in depression (response rates - CBT: 75.5%, CBT-ERT: 84.9%; remission rates - CBT: 51.1%, CBT-ERT: 65.1%). Moreover, CBT-ERT participants demonstrated a significantly greater reduction of negative affect, as well as a greater increase of well-being and emotion regulation skills particularly relevant for mental health. Integrating strategies that target emotion regulation skills improves the efficacy of CBT for MDD. Copyright © 2013 S. Karger AG, Basel.

  12. A bacterial protein enhances the release and efficacy of liposomal cancer drugs.

    PubMed

    Cheong, Ian; Huang, Xin; Bettegowda, Chetan; Diaz, Luis A; Kinzler, Kenneth W; Zhou, Shibin; Vogelstein, Bert

    2006-11-24

    Clostridium novyi-NT is an anaerobic bacterium that can infect hypoxic regions within experimental tumors. Because C. novyi-NT lyses red blood cells, we hypothesized that its membrane-disrupting properties could be exploited to enhance the release of liposome-encapsulated drugs within tumors. Here, we show that treatment of mice bearing large, established tumors with C. novyi-NT plus a single dose of liposomal doxorubicin often led to eradication of the tumors. The bacterial factor responsible for the enhanced drug release was identified as a previously unrecognized protein termed liposomase. This protein could potentially be incorporated into diverse experimental approaches for the specific delivery of chemotherapeutic agents to tumors.

  13. Plasmid containing CpG motifs enhances the efficacy of porcine reproductive and respiratory syndrome live attenuated vaccine.

    PubMed

    Guo, Xiaoyu; Zhang, Quan; Hou, Shaohua; Zhai, Guoqin; Zhu, Hongfei; Sánchez-Vizcaíno, J M

    2011-12-15

    Porcine reproductive and respiratory syndrome (PRRS) is now among the most important swine diseases that affect the Chinese swine industry. Both killed and live attenuated vaccines are currently used against the disease, but neither of them could provide full protection after vaccination. In the present study, the adjuvanticity of a plasmid containing CpG motifs (pUC18-CpG) was introduced to enhance the efficacy of a commercial PRRS live attenuated vaccine. After vaccination, PRRSV-specific antibodies, PRRSV-specific cytokines, and clinical parameters were studied and compared between different vaccinated groups. During a following challenge study, co-administration of pUC18-CpG with the vaccine could confer higher protection rate. Our results have shown that co-administration of pUC18-CpG with the vaccine could elicit more potent adaptive immune response and provide better protection. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Long-lasting efficacy of the cognitive enhancer cytotoxic necrotizing factor 1.

    PubMed

    Borrelli, Sonia; Musilli, Marco; Martino, Assunta; Diana, Giovanni

    2013-01-01

    Rho GTPases are key regulators of the activity-dependent changes of neural circuits. Besides being involved in nervous system development and repair, this neural structural plasticity is believed to constitute the cellular basis of learning and memory. Here we report that concurrent modulation of cerebral Rho GTPases, including Rac, Rho and Cdc42 subfamilies, by Cytotoxic Necrotizing Factor 1 (CNF1, 10 fmol/kg intracerebroventricularly) improves object recognition in both C57BL/6J and CD1 mice. The improvement is long lasting, as it is still observed 90 days post treatment. At this time, the treatment is associated with enhancement of neurotransmission and long-term potentiation. The effects depend on changes in Rho GTPase status, since the recombinant molecule CNF1 C866S, in which the enzymatic activity was abolished through substitution of serine to cysteine at position 866, is ineffective. The study confirms the role of Rho GTPases in learning and suggests that a single administration of CNF1 is effective for a long time after administration. In general, the long-lasting cognition enhancing effect of CNF1 might be beneficial for the treatment of CNS disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

  15. Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy.

    PubMed

    Dhupkar, Pooja; Gordon, Nancy

    2017-01-01

    Interleukin-2 (IL-2) is a very well-known cytokine that has been studied for the past 35 years. It plays a major role in the growth and proliferation of many immune cells such NK and T cells. It is an important immunotherapy cytokine for the treatment of various diseases including cancer. Systemic delivery of IL-2 has shown clinical benefit in renal cell carcinoma and melanoma patients. However, its use has been limited by the numerous toxicities encountered with the systemic delivery. Intravenous IL-2 causes the well-known "capillary leak syndrome," or the leakage of fluid from the circulatory system to the interstitial space resulting in hypotension (low blood pressure), edema, and dyspnea that can lead to circulatory shock and eventually cardiopulmonary collapse and multiple organ failure. Due to the toxicities associated with systemic IL-2, an aerosolized delivery approach has been developed, which enables localized delivery and a higher local immune cell activation. Since proteins are absorbed via pulmonary lymphatics, after aerosol deposition in the lung, aerosol delivery provides a means to more specifically target IL-2 to the local immune system in the lungs with less systemic effects. Its benefits have extended to diseases other than cancer. Delivery of IL-2 via aerosol or as nebulized IL-2 liposomes has been previously shown to have less toxicity and higher efficacy against sarcoma lung metastases. Dogs with cancer provided a highly relevant means to determine biodistribution of aerosolized IL-2 and IL-2 liposomes. However, efficacy of single-agent IL-2 is limited. As in general, for most immune-therapies, its effect is more beneficial in the face of minimal residual disease. To overcome this limitation, combination therapies using aerosol IL-2 with adoptive transfer of T cells or NK cells have emerged.Using a human osteosarcoma (OS) mouse model, we have demonstrated the efficacy of single-agent aerosol IL-2 and combination therapy aerosol IL-2 and NK

  16. Development of an enhanced anticaries efficacy dual component dentifrice containing sodium fluoride and dicalcium phosphate dihydrate.

    PubMed

    Sullivan, R J; Masters, J; Cantore, R; Roberson, A; Petrou, I; Stranick, M; Goldman, H; Guggenheim, B; Gaffar, A

    2001-05-01

    A dual-chamber dentifrice, which contains sodium fluoride (NaF) in one component and dicalcium phosphate dihydrate (dical) in the other, has been developed. The dentifrice is packaged in a dual-chamber tube and is formulated to deliver 1100 ppm F. A series of studies consisting of in vitro fluoride uptake, in vivo calcium labeling, intraoral remineralization-demineralization, and animal caries studies were performed to support the improved anticaries efficacy of this product in comparison to a sodium fluoride/silica dentifrice (NaF/silica). An in vitro fluoride uptake study comparing 1100 ppm F NaF/dical dentifrice to 1100 ppm F NaF/silica showed that NaF/dical delivered significantly more fluoride than NaF/silica, 3.72 +/- 0.36 micrograms/cm2 versus 2.41 +/- 0.10 micrograms/cm2. A 6-day in vivo brushing study with a 44Ca labeled NaF/dical dentifrice showed that calcium from dical penetrated demineralized enamel and was present in plaque up to 18 hrs since the last brushing. An intra-oral remineralization-demineralization study was performed to evaluate NaF/dical's ability to promote remineralization in comparison to three silica-based dentifrices containing 0, 250, and 1100 ppm F as NaF. The percent mineral changes after treatment were +20.44 +/- 17.14 for NaF/dical, +9.27 +/- 19.53 for 1100 ppm NaF/silica, -1.43 +/- 20.57 for 250 ppm NaF/silica, and -12.36 +/- 32.76 for 0 ppm F/silica. A statistical analysis showed that the dual-chamber NaF/dical dentifrice was significantly more effective than the 1100 ppm NaF/silica dentifrice at promoting remineralization. A rat caries study was performed to evaluate NaF/dical ability to prevent caries in comparison to 1100 ppm F NaF/silica, 250 ppm F NaF/silica, silica, and dical dentifrices. The mean smooth surface caries scores were 1.6 +/- 2.8 for NaF/dical, 5.5 +/- 6.2 for 1100 ppm F NaF/silica, 10.6 +/- 6.2 for 250 ppm F NaF/silica, 13.7 +/- 4.7 for 0 ppm F/silica, and 9.5 +/- 7.8 0 ppm F/dical. A statistical analysis

  17. Nkx2.5 enhances the efficacy of mesenchymal stem cells transplantation in treatment heart failure in rats.

    PubMed

    Deng, Bo; Wang, Jin Xin; Hu, Xing Xing; Duan, Peng; Wang, Lin; Li, Yang; Zhu, Qing Lei

    2017-08-01

    The aim of this study is to determine whether Nkx2.5 transfection of transplanted bone marrow mesenchymal stem cells (MSCs) improves the efficacy of treatment of adriamycin-induced heart failure in a rat model. Nkx2.5 was transfected in MSCs by lentiviral vector transduction. The expressions of Nkx2.5 and cardiac specific genes in MSCs and Nkx2.5 transfected mesenchymal stem cells (MSCs-Nkx2.5) were analyzed with quantitative real-time PCR and Western blot in vitro. Heart failure models of rats were induced by adriamycin and were then randomly divided into 3 groups: injected saline, MSCs or MSCs-Nkx2.5 via the femoral vein respectively. Four weeks after injection, the cardiac function, expressions of cardiac specific gene, fibrosis formation and collagen volume fraction in the myocardium as well as the expressions of GATA4 and MEF2 in rats were analyzed with echocardiography, immunohistochemistry, Masson staining, quantitative real-time PCR and Western blot, respectively. Nkx2.5 enhanced cardiac specific gene expressions including α-MHC, TNI, CKMB, connexin-43 in MSCs-Nkx2.5 in vitro. Both MSCs and MSCs-Nkx2.5 improved cardiac function, promoted the differentiation of transplanted MSCs into cardiomyocyte-like cells, decreased fibrosis formation and collagen volume fraction in the myocardium, as well as increased the expressions of GATA4 and MEF2 in adriamycin-induced rat heart failure models. Moreover, the effect was much more remarkable in MSCs-Nkx2.5 than in MSCs group. This study has found that Nkx2.5 enhances the efficacy of MSCs transplantation in treatment adriamycin-induced heart failure in rats. Nkx2.5 transfected to transplanted MSCs provides a potential effective approach to heart failure. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Novel nitric oxide generating compound glycidyl nitrate enhances the therapeutic efficacy of chemotherapy and radiotherapy

    SciTech Connect

    Ning, Shoucheng; Bednarski, Mark; Oronsky, Bryan; Scicinski, Jan; Knox, Susan J.

    2014-05-09

    Highlights: • Glycidyl nitrate (GLYN) is a NO generating small molecule and has ability to release NO on bioactivation in tumor cells. • GLYN-induced intracellular NO generation was attenuated by NO scavengers. • GLYN increases tumor blood flow in tumor-bearing animal model. • GLYN significantly increased the anti-tumor efficacy of cisplatin and radiation therapy in mice. • GLYN is well tolerated with no obvious systemic toxicities at its effective therapeutic doses in preclinical animal studies. - Abstract: Selective release of nitric oxide (NO) in tumors could improve the tumor blood flow and drug delivery for chemotherapeutic agents and radiotherapy, thereby increasing the therapeutic index. Glycidyl nitrate (GLYN) is a NO generating small molecule, and has ability to release NO on bioactivation in SCC VII tumor cells. GLYN-induced intracellular NO generation was significantly attenuated by NO scavenger carboxy-PTIO (cPTIO) and NAC. GLYN significantly increases tumor blood flow, but has no effect on the blood flow of normal tissues in tumor-bearing mice. When used with cisplatin, GLYN significantly increased the tumor growth inhibition effect of cisplatin. GLYN also had a modest radiosensitizing effect in vitro and in vivo. GLYN was well tolerated and there were no acute toxicities found at its effective therapeutic doses in preclinical studies. These results suggest that GLYN is a promising new drug for use with chemotherapy and radiotherapy, and provide a compelling rationale for future studies of GLYN and related compounds.

  19. Enhanced efficacy (intrinsic activity) of cyclic opioid peptide analogs at the. mu. -receptor

    SciTech Connect

    Schiller, P.W.; Lemieux, C.; Nguyen, T.M.D.; Maziak, L.A.

    1986-05-01

    Side-chain to end group cyclized enkephalin analogs (e.g. H-Tyr-cyclo(-D-Lys-Gly-Phe-Leu-) and cyclic opioid peptide analogs obtained through covalent linkage of two side-chains (e.g. H-Tyr-D-Cys-Gly-Phe-Cys-NH/sub 2/ or H-Tyr-D-Lys-Gly-Phe-Glu-NH/sub 3/) were tested in the ..mu..-receptor-representative guinea pig ileum (GPI) bioassay and in a binding assay based on displacement of the ..mu..-ligand (/sup 3/H)DAGO from rat brain membranes. The cyclic analogs were 5 to 70 times more potent in the GPI assay than in the binding assay, whereas linear analogs showed equal potency in the two assays. These results suggest that the efficacy (intrinsic activity) of cyclic opioid peptide analogs at the ..mu..-receptor is increased as a consequence of the conformation constraint imposed through ring closure. This effect was most pronounced in analogs containing a long hydrophobic sidechain as part of the ring structure in the 2-position of the peptide sequence. Further experimental evidence ruled out the possibilities that these potency discrepancies may be due to differences in enzymatic degradation, dissimilar exposure of the receptors in their lipid environment or interaction with different receptor types in the two assay systems. It can be hypothesized that the semi-rigid cyclic analogs may induce a more productive conformational change in the receptor protein than the linear peptides.

  20. Enhancing Photodynamyc Therapy Efficacy by Combination Therapy: Dated, Current and Oncoming Strategies

    PubMed Central

    Postiglione, Ilaria; Chiaviello, Angela; Palumbo, Giuseppe

    2011-01-01

    Combination therapy is a common practice in many medical disciplines. It is defined as the use of more than one drug to treat the same disease. Sometimes this expression describes the simultaneous use of therapeutic approaches that target different cellular/molecular pathways, increasing the chances of killing the diseased cell. This short review is concerned with therapeutic combinations in which PDT (Photodynamyc Therapy) is the core therapeutic partner. Besides the description of the principal methods used to assess the efficacy attained by combinations in respect to monotherapy, this review describes experimental results in which PDT was combined with conventional drugs in different experimental conditions. This inventory is far from exhaustive, as the number of photosensitizers used in combination with different drugs is very large. Reports cited in this work have been selected because considered representative. The combinations we have reviewed include the association of PDT with anti-oxidants, chemotherapeutics, drugs targeting topoisomerases I and II, antimetabolites and others. Some paragraphs are dedicated to PDT and immuno-modulation, others to associations of PDT with angiogenesis inhibitors, receptor inhibitors, radiotherapy and more. Finally, a look is dedicated to combinations involving the use of natural compounds and, as new entries, drugs that act as proteasome inhibitors. PMID:24212824

  1. Berberine nanosuspension enhances hypoglycemic efficacy on streptozotocin induced diabetic C57BL/6 mice.

    PubMed

    Wang, Zhiping; Wu, Junbiao; Zhou, Qun; Wang, Yifei; Chen, Tongsheng

    2015-01-01

    Berberine (Ber), an isoquinoline derivative alkaloid and active ingredient of Coptis, has been demonstrated to possess antidiabetic activities. However its low oral bioavailability restricts its clinical application. In this report, Ber nanosuspension (Ber-NS) composed of Ber and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by high pressure homogenization technique. Antidiabetic effects of Ber-NS relative to efficacy of bulk Ber were evaluated in streptozotocin (STZ) induced diabetic C57BL/6 mice. The particle size and zeta potential of Ber-NS were 73.1 ± 3.7 nm and 6.99 ± 0.17 mV, respectively. Ber-NS (50 mg/kg) treatment via oral gavage for 8 weeks resulted in a superior hypoglycemic and total cholesterol (TC) and body weight reduction effects compared to an equivalent dose of bulk Ber and metformin (Met, 300 mg/kg). These data indicate that a low dosage Ber-NS decreases blood glucose and improves lipid metabolism in type 2 diabetic C57BL/6 mice. These results suggest that the delivery of Ber as a nanosuspension is a promising approach for treating type 2 diabetes.

  2. Iron oxide nanoparticle-mediated hyperthermia stimulates dispersal in bacterial biofilms and enhances antibiotic efficacy

    PubMed Central

    Nguyen, Thuy-Khanh; Duong, Hien T. T.; Selvanayagam, Ramona; Boyer, Cyrille; Barraud, Nicolas

    2015-01-01

    The dispersal phase that completes the biofilm lifecycle is of particular interest for its potential to remove recalcitrant, antimicrobial tolerant biofilm infections. Here we found that temperature is a cue for biofilm dispersal and a rise by 5 °C or more can induce the detachment of Pseudomonas aeruginosa biofilms. Temperature upshifts were found to decrease biofilm biomass and increase the number of viable freely suspended cells. The dispersal response appeared to involve the secondary messenger cyclic di-GMP, which is central to a genetic network governing motile to sessile transitions in bacteria. Furthermore, we used poly((oligo(ethylene glycol) methyl ether acrylate)-block-poly(monoacryloxy ethyl phosphate)-stabilized iron oxide nanoparticles (POEGA-b-PMAEP@IONPs) to induce local hyperthermia in established biofilms upon exposure to a magnetic field. POEGA-b-PMAEP@IONPs were non-toxic to bacteria and when heated induced the detachment of biofilm cells. Finally, combined treatments of POEGA-b-PMAEP@IONPs and the antibiotic gentamicin reduced by 2-log the number of colony-forming units in both biofilm and planktonic phases after 20 min, which represent a 3.2- and 4.1-fold increase in the efficacy against planktonic and biofilm cells, respectively, compared to gentamicin alone. The use of iron oxide nanoparticles to disperse biofilms may find broad applications across a range of clinical and industrial settings. PMID:26681339

  3. A Radio Frequency Electric Current Enhances Antibiotic Efficacy against Bacterial Biofilms

    PubMed Central

    Caubet, R.; Pedarros-Caubet, F.; Chu, M.; Freye, E.; de Belém Rodrigues, M.; Moreau, J. M.; Ellison, W. J.

    2004-01-01

    Bacterial biofilms are notably resistant to antibiotic prophylaxis. The concentration of antibiotic necessary to significantly reduce the number of bacteria in the biofilm matrix can be several hundred times the MIC for the same bacteria in a planktonic phase. It has been observed that the addition of a weak continuous direct electric current to the liquid surrounding the biofilm can dramatically increase the efficacy of the antibiotic. This phenomenon, known as the bioelectric effect, has only been partially elucidated, and it is not certain that the electrical parameters are optimal. We confirm here the bioelectric effect for Escherichia coli biofilms treated with gentamicin and with oxytetracycline, and we report a new bioelectric effect with a radio frequency alternating electric current (10 MHz) instead of the usual direct current. None of the proposed explanations (transport of ions within the biofilm, production of additional biocides by electrolysis, etc.) of the direct current bioelectric effect are applicable to the radio frequency bioelectric effect. We suggest that this new phenomenon may be due to a specific action of the radio frequency electromagnetic field upon the polar parts of the molecules forming the biofilm matrix. PMID:15561841

  4. Targeting Notch enhances the efficacy of ERK inhibitors in BRAF-V600E melanoma

    PubMed Central

    Krepler, Clemens; Xiao, Min; Samanta, Minu; Vultur, Adina; Chen, Hsin-Yi; Brafford, Patricia; Reyes-Uribe, Patricia I.; Halloran, Molly; Chen, Thomas; He, Xu; Hristova, Denitsa; Liu, Qin; Samatar, Ahmed A.; Davies, Michael A.; Nathanson, Katherine L.; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard; Villanueva, Jessie

    2016-01-01

    The discovery of activating BRAF mutations in approximately 50% of melanomas has led to the development of MAPK pathway inhibitors, which have transformed melanoma therapy. However, not all BRAF-V600E melanomas respond to MAPK inhibition. Therefore, it is important to understand why tumors with the same oncogenic driver have variable responses to MAPK inhibitors. Here, we show that concurrent loss of PTEN and activation of the Notch pathway is associated with poor response to the ERK inhibitor SCH772984, and that co-inhibition of Notch and ERK decreased viability in BRAF-V600E melanomas. Additionally, patients with low PTEN and Notch activation had significantly shorter progression free survival when treated with BRAF inhibitors. Our studies provide a rationale to further develop combination strategies with Notch antagonists to maximize the efficacy of MAPK inhibition in melanoma. Our findings should prompt the evaluation of combinations co-targeting MAPK/ERK and Notch as a strategy to improve current therapies and warrant further evaluation of co-occurrence of aberrant PTEN and Notch activation as predictive markers of response to therapy. PMID:27655717

  5. Efficacy of Carcass Electrical Stimulation in Meat Quality Enhancement: A Review

    PubMed Central

    Adeyemi, Kazeem Dauda; Sazili, Awis Qurni

    2014-01-01

    The use of electrical stimulation (ES) as a management tool to improve meat quality and efficiency of meat processing is reviewed. The basis of the efficacy of ES is its ability to fast track postmortem glycolysis, which in turn stimulates myriad histological, physical, biochemical, biophysical and physiological changes in the postmortem muscle. Electrical stimulation hastens the onset and resolution of rigor mortis thereby reducing processing time and labor and plays a vital role in improving meat tenderness and other meat quality traits. However, ES may have negative impacts on some meat quality traits such as color stability and water holding capacity in some animals. Electrical stimulation is not an end in itself. In order to achieve the desired benefits from its application, the technique must be properly used in conjunction with various intricate antemortem, perimortem and postmortem management practices. Despite extensive research on ES, the fundamental mechanisms and the appropriate commercial applications remained obscured. In addition, muscles differ in their response to ES. Thus, elementary knowledge of the various alterations with respect to muscle type is needed in order to optimize the effectiveness of ES in the improvement of meat quality. PMID:25049973

  6. Facile preparation of paclitaxel loaded silk fibroin nanoparticles for enhanced antitumor efficacy by locoregional drug delivery.

    PubMed

    Wu, Puyuan; Liu, Qin; Li, Rutian; Wang, Jing; Zhen, Xu; Yue, Guofeng; Wang, Huiyu; Cui, Fangbo; Wu, Fenglei; Yang, Mi; Qian, Xiaoping; Yu, Lixia; Jiang, Xiqun; Liu, Baorui

    2013-12-11

    Non-toxic, safe materials and preparation methods are among the most important factors when designing nanoparticles (NPs) for future clinical application. Here we report a novel and facile method encapsulating anticancer drug paclitaxel (PTX) into silk fibroin (SF), a biocompatible and biodegradable natural polymer, without adding any toxic organic solvents, surfactants or other toxic agents. The paclitaxel loaded silk fibroin nanoparticles (PTX-SF-NPs) with a diameter of 130 nm were formed in an aqueous solution at room temperature by self-assembling of SF protein, which demonstrated mainly silk I conformation in the NPs. In cellular uptake experiments, coumarin-6 loaded SF NPs were taken up efficiently by two human gastric cancer cell lines BGC-823 and SGC-7901. In vitro cytotoxicity studies demonstrated that PTX kept its pharmacological activity when incorporating into PTX-SF-NPs, while SF showed no cytotoxicity to cells. The in vivo antitumor effects of PTX-SF-NPs were evaluated on gastric cancer nude mice exnograft model. We found that locoregional delivery of PTX-SF-NPs demonstrated superior antitumor efficacy by delaying tumor growth and reducing tumor weights compared with systemic administration. Furthermore, the organs of mice in NP treated groups didn't show obvious toxicity, indicating the in vivo safety of SF NPs. These results suggest that SF NPs are promising drug delivery carriers, and locoregional delivery of SF NPs could be a potential future clinical cancer treatment regimen.

  7. Harnessing structure-activity relationship to engineer a cisplatin nanoparticle for enhanced antitumor efficacy.

    PubMed

    Paraskar, Abhimanyu S; Soni, Shivani; Chin, Kenneth T; Chaudhuri, Padmaparna; Muto, Katherine W; Berkowitz, Julia; Handlogten, Michael W; Alves, Nathan J; Bilgicer, Basar; Dinulescu, Daniela M; Mashelkar, Raghunath A; Sengupta, Shiladitya

    2010-07-13

    Cisplatin is a first line chemotherapy for most types of cancer. However, its use is dose-limited due to severe nephrotoxicity. Here we report the rational engineering of a novel nanoplatinate inspired by the mechanisms underlying cisplatin bioactivation. We engineered a novel polymer, glucosamine-functionalized polyisobutylene-maleic acid, where platinum (Pt) can be complexed to the monomeric units using a monocarboxylato and an O --> Pt coordinate bond. We show that at a unique platinum to polymer ratio, this complex self-assembles into a nanoparticle, which releases cisplatin in a pH-dependent manner. The nanoparticles are rapidly internalized into the endolysosomal compartment of cancer cells, and exhibit an IC50 (4.25 +/- 0.16 microM) comparable to that of free cisplatin (3.87 +/- 0.37 microM), and superior to carboplatin (14.75 +/- 0.38 microM). The nanoparticles exhibited significantly improved antitumor efficacy in terms of tumor growth delay in breast and lung cancers and tumor regression in a K-ras(LSL/+)/Pten(fl/fl) ovarian cancer model. Furthermore, the nanoparticle treatment resulted in reduced systemic and nephrotoxicity, validated by decreased biodistribution of platinum to the kidney as quantified using inductively coupled plasma spectroscopy. Given the universal need for a better platinate, we anticipate this coupling of nanotechnology and structure-activity relationship to rationally reengineer cisplatin could have a major impact globally in the clinical treatment of cancer.

  8. Efficacy of magnifying endoscopy with flexible spectral imaging color enhancement in the diagnosis of colorectal tumors.

    PubMed

    Yoshida, Naohisa; Naito, Yuji; Kugai, Munehiro; Inoue, Ken; Uchiyama, Kazuhiko; Takagi, Tomohisa; Ishikawa, Takeshi; Handa, Osamu; Konishi, Hideyuki; Wakabayashi, Naoki; Kokura, Satoshi; Yagi, Nobuaki; Morimoto, Yasutaka; Yanagisawa, Akio; Yoshikawa, Toshikazu

    2011-01-01

    Magnifying endoscopy with flexible spectral imaging color enhancement (FICE) is an image-enhanced endoscopy that captures the surface and vascular patterns of colorectal tumors. We evaluated and compared FICE magnification to narrow-band imaging (NBI) magnification. Flexible spectral imaging color enhancement or NBI magnification was performed to the visualize surface and vascular patterns of colorectal tumors, classified into 4 types: Type A, Type B, Type C1/C2, and Type C3, as previously reported. A total of 235 colorectal tumors were examined. The correlations between classifications found by FICE or NBI magnification and histopathological diagnoses were examined. Image evaluation was validated by assessing inter-observer and intra-observer agreements on examinations. Twenty-eight hyperplastic polyps (HPs), 115 tubular adenomas (TAs), 72 mucosal and slightly invaded submucosal cancers (M-sSM), and 20 massively invaded submucosal cancers (mSM) were diagnosed. By FICE magnification, HP and TA were observed in 93.3 and 6.7% of Type A (15 lesions), respectively. TA, M-sSM, and HP were observed in 82.6, 15.4, and 2.0% of Type B (52 lesions),respectively. M-sSM, TA, and mSM were observed in 50.0,46.0, and 4.0% of Type C1/2 (50 lesions), respectively.mSMs were observed in all 7 Type C3 lesions. In diagnosing mSM in Type C3, the sensitivity and specificity of FICE magnification were 77.7 and 100%, respectively, compared to those of NBI, at 63.6 and 99.0%, respectively. Imaging evaluation was validated accurately by intra- and intraobserver measurements showing consistent results. The classification of colorectal tumors by FICE magnification correlated well with the histopathological diagnoses, similar to findings for NBI magnification. FICE magnification can be evaluated accurately with the same diagnostic classifications as those used for NBI magnification.

  9. Enhanced antifungal efficacy of tebuconazole using gated pH-driven mesoporous nanoparticles

    PubMed Central

    Mas, Núria; Galiana, Irene; Hurtado, Silvia; Mondragón, Laura; Bernardos, Andrea; Sancenón, Félix; Marcos, María D; Amorós, Pedro; Abril-Utrillas, Nuria; Martínez-Máñez, Ramón; Murguía, José Ramón

    2014-01-01

    pH-sensitive gated mesoporous silica nanoparticles have been synthesized. Increased extracellular pH and internalization into living yeast cells triggered molecular gate aperture and cargo release. Proper performance of the system was demonstrated with nanodevices loaded with fluorescein or with the antifungal agent tebuconazole. Interestingly, nanodevices loaded with tebuconazole significantly enhanced tebuconazole cytotoxicity. As alterations of acidic external pH are a key parameter in the onset of fungal vaginitis, this nanodevice could improve the treatment for vaginal mycoses. PMID:24920897

  10. Supercritical processed starch nanosponge as a carrier for enhancement of dissolution and pharmacological efficacy of fenofibrate.

    PubMed

    Jadhav, Nitin V; Vavia, Pradeep R

    2017-06-01

    In current study, supercritical processed starch nanosponge (SSNS) used as a carrier for poorly water soluble drug (fenofibrate) to enhance its in-vitro and in-vivo performance. SSNS was prepared by using sol- gel method and effective supercritical drying technique. Fenofibrate was loaded into the SSNS by using solvent immersion method with selected and optimized organic solvent. BET surface area of SSNS was evaluated by nitrogen adsorption/desorption analysis. SSNS and drug loaded SSNS were characterized by DSC, XRPD, FTIR, SEM, Contact angle study and evaluated for in-vitro, in-vivo studies. The results revealed that the formed SSNS material has high surface area (180m2/gm) with pore size (40 nm to 200nm). The DSC and XRPD study revealed the amorphization of drug within a SSNS. SEM study showed the continuous porous structure with differ nanosized pores of SSNS. Contact angle study showed improvement in aqueous wetting property of drug within a SSNS. In-vitro drug release study showed remarkable dissolution enhancement of SSNS formulation as compared to plain drug. In vivo pharmacodynamic study (hyperlipidaemia model) showed SNSS based formulation significantly improved the bioavailability of drug. Thus SSNS carrier system has good potential to be explored as a delivery system for poorly water soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. A bioengineered niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy

    PubMed Central

    Quarta, Marco; Brett, Jamie O.; DiMarco, Rebecca; De Morree, Antoine; Boutet, Stephane C.; Chacon, Robert; Gibbons, Michael C.; Garcia, Victor A.; Su, James; Shrager, Joseph B.; Heilshorn, Sarah; Rando, Thomas A.

    2016-01-01

    A promising therapeutic strategy for diverse genetic disorders involves transplantation of autologous stem cells that have been genetically corrected ex vivo. A major challenge in such approaches is a loss of stem cell potency during stem cell culture. Here we describe a system for maintaining muscle stem cells (MuSCs) in vitro in a potent, quiescent state. Using a machine learning method, we identified a molecular signature of quiescence and used it to screen for factors that could maintain mouse MuSC quiescence, thus defining a quiescence medium (QM). We also designed artificial muscle fibers (AMFs) that mimic the native myofiber of the MuSC niche. Mouse MuSCs maintained in QM on AMFs showed enhanced potential for engraftment, tissue regeneration and self-renewal after transplantation in mice. An artificial niche adapted to human MuSCs showed similarly prolonged quiescence in vitro and enhanced potency in vivo. Our approach for maintaining quiescence may be applicable to stem cells from a range of other tissues. PMID:27240197

  12. Gef gene therapy enhances the therapeutic efficacy of cytotoxics in colon cancer cells.

    PubMed

    Ortiz, Raúl; Prados, Jose; Melguizo, Consolación; Rama, Ana R; Alvarez, Pablo J; Rodríguez-Serrano, Fernando; Caba, Octavio; Boulaiz, Houria; Aranega, Antonia

    2012-10-01

    The potential use of gene therapy to improve the response of patients with advanced cancer is being intensively analyzed. We evaluated the cytotoxic impact of the gef gene, a suicide gene, which has a demonstrated antiproliferative activity in tumor cells, in colon carcinoma cells in order to improve the antitumour effect of chemotherapeutic drugs used as first line treatment in the management of advanced colon cancer. We found that the gef gene induced a marked decrease in cell viability (50% in 24h) in T-84 cells through cell death by apoptosis. Interestingly, when gef gene expression was combined with drugs of choice in the clinical treatment of colon cancer (5-fluorouracil, oxaliplatin and irinotecan), a strong synergistic effect was observed with approximately a 15-20% enhancement of the antiproliferative effect. Our data demonstrate, for the first time, that gef gene expression induces significant growth arrest in colon cancer cells and that it is able to enhance the effect of some cytotoxic drugs compared with a single therapeutic approach. These results indicate the potential therapeutic value of the gef gene in colon cancer combination therapy. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  13. Immunotherapeutic target expression on breast tumors can be amplified by hormone receptor antagonism: a novel strategy for enhancing efficacy of targeted immunotherapy.

    PubMed

    Jaini, Ritika; Loya, Matthew G; Eng, Charis

    2017-05-16

    Immunotherapy has historically been successful in highly antigenic tumors but has shown limited therapeutic efficacy in non-antigenic tumors such as breast cancers. Our previous studies in autoimmunity have demonstrated that increased antigen load within a tissue enhances immune reactivity against it. We therefore hypothesized that enhancing expression of target proteins on breast tumors can increase efficacy of targeted immunotherapy. We hypothesized that antagonism of the estrogen receptor (ER) can increase expression of targets that are hormonally regulated and facilitate enhanced tumor recognition by targeted immunotherapy. We used a lactation protein α-Lactalbumin, a known immunotherapeutic target on breast tumors, as our model target antigen. Enhancement of target protein expression in human and murine breast tumors was tested in vitro and in vivo by ER antagonism using clinically established ER modulators, Tamoxifen and Fulvestrant. We show that antagonism of the ER can induce a 2-3 fold increase in expression of target proteins on tumors leaving the normal breast tissue unaffected. Tumor progression studies in 4T1 tumor-bearing mice show that efficacy of adoptively transferred cell based targeted immunotherapy was enhanced by target antigen amplification resulting in significantly higher tumor inhibition. However, in spite of increased target expression, anti-tumor efficacy of direct immunization was not enhanced probably due to other limiting factors involved in the immune priming process. Our study provides a novel combinatorial clinical strategy for enhancing efficacy of immunotherapy not only on breast tumors but potentially also for other hormonally driven tumors such as those of the prostate, testis and ovary.

  14. Does low-level laser therapy enhance the efficacy of intravenous regional anesthesia?

    PubMed Central

    Nesioonpour, Sholeh; Akhondzadeh, Reza; Mokmeli, Soheila; Moosavi, Shahnam; Mackie, Mandana; Naderan, Morteza

    2014-01-01

    BACKGROUND: The use of intravenous regional anesthesia (IVRA) is limited by pain resulting from the application of tourniquets and postoperative pain. OBJECTIVE: To assess the efficacy of low-level laser therapy added to IVRA for improving pain related to surgical fixation of distal radius fractures. METHODS: The present double-blinded, placebo-controlled, randomized clinical trial involved 48 patients who were undergoing surgical fixation of distal radius fractures. Participants were randomly assigned to either an intervention group (n=24), who received 808 nm laser irradiation as 4 J/point for 20 s over ipsilateral three nerve roots in the cervical region corresponding to C5–C8 vertebrae, and 808 nm laser irradiation as 0.1 J/cm2 for 5 min in a tangential scanning mode over the affected extremity; or a control group (n=24), who underwent the same protocol and timing of laser probe application with the laser switched off. Both groups received the same IVRA protocol using 2% lidocaine. RESULTS: The mean visual analogue scale scores were significantly lower in the laser-assisted group than in the lidocaine-only group on all measurements during and after operation (P<0.05). The mean time to the first need for fentanyl administration during the operation was longer in the laser group (P=0.04). The total amount of fentanyl administered to patients was significantly lower in the laser-assisted group (P=0.003). The laser group needed significantly less pethidine for pain relief (P=0.001) and at a later time (P=0.002) compared with the lidocaine-only group. There was no difference between the groups in terms of mean arterial pressure and heart rate. CONCLUSION: The addition of gallium-aluminum-arsenide laser irradiation to intravenous regional anesthesia is safe, and reduces pain during and after the operation. PMID:24945286

  15. Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade.

    PubMed

    Han, Sang-oh; Li, Songtao; Brooks, Elizabeth D; Masat, Elisa; Leborgne, Christian; Banugaria, Suhrad; Bird, Andrew; Mingozzi, Federico; Waldmann, Herman; Koeberl, Dwight

    2015-01-01

    Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease.

  16. Enhanced Efficacy from Gene Therapy in Pompe Disease Using Coreceptor Blockade

    PubMed Central

    Han, Sang-oh; Li, Songtao; Brooks, Elizabeth D.; Masat, Elisa; Leborgne, Christian; Banugaria, Suhrad; Bird, Andrew; Mingozzi, Federico; Waldmann, Herman

    2015-01-01

    Abstract Enzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid α-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease. PMID:25382056

  17. Use of biotin targeted methotrexate–human serum albumin conjugated nanoparticles to enhance methotrexate antitumor efficacy

    PubMed Central

    Taheri, Azade; Dinarvand, Rassoul; Nouri, Faranak Salman; Khorramizadeh, Mohammad Reza; Borougeni, Atefeh Taheri; Mansoori, Pooria; Atyabi, Fatemeh

    2011-01-01

    Biotin molecules could be used as suitable targeting moieties in targeted drug delivery systems against tumors. To develop a biotin targeted drug delivery system, we employed human serum albumin (HSA) as a carrier. Methotrexate (MTX) molecules were conjugated to HSA. MTX-HSA nanoparticles (MTX-HSA NPs) were prepared from these conjugates by cross-linking the HSA molecules. Biotin molecules were then conjugated on the surface of MTX-HSA NPs. The anticancer efficacy of biotin targeted MTX-HSA NPs was evaluated in mice bearing 4T1 breast carcinoma. A single dose of biotin targeted MTX-HSA NPs showed stronger in vivo antitumor activity than non-targeted MTX-HSA NPs and free MTX. By 7 days after treatment, average tumor volume in the biotin targeted MTX-HSA NPs-treated group decreased to 17.6% of the initial tumor volume when the number of attached biotin molecules on MTX-HSA-NPs was the highest. Average tumor volume in non-targeted MTX-HSA NPs-treated mice grew rapidly and reached 250.7% of the initial tumor volume. Biotin targeted MTX-HSA NPs increased the survival of tumor-bearing mice to 47.5 ± 0.71 days and increased their life span up to 216.7%. Mice treated with biotin targeted MTX-HSA NPs showed slight body weight loss (8%) 21 days after treatment, whereas non-targeted MTX-HSA NPs treatment at the same dose caused a body weight loss of 27.05% ± 3.1%. PMID:21931482

  18. Photoactivation of curcumin and sodium hypochlorite to enhance antibiofilm efficacy in root canal dentin.

    PubMed

    Neelakantan, Prasanna; Cheng, Cheng Qing; Ravichandran, Vinoddhine; Mao, Teresa; Sriraman, Priyanka; Sridharan, Swetha; Subbarao, Chandana; Sharma, Subash; Kishen, Anil

    2015-03-01

    To test the effect of ultrasonic or light activated curcumin and sodium hypochlorite against Enterococcus faecalis biofilms in vitro. E. faecalis biofilms were grown within root canals (n=175) and divided into 7 groups (n=25). Group 1, sterile saline; group 2, 3% sodium hypochlorite; group 3, 3% sodium hypochlorite activated with ultrasonic files (30s cycles for 4min); group 4, 3% sodium hypochlorite irradiated with blue light (1200mw/cm(2) for 4min); group 5, curcumin (2.5mg/mL); group 6, curcumin (2.5mg/mL) activated with ultrasonic files (30s cycles for 4min); group 7, curcumin (2.5mg/mL) irradiated with blue light. The biofilms' ultrastructure was examined using scanning electron microscopy. Bacterial viability was assessed by confocal microscopy. Data were analyzed by one-way ANOVA and Student-Newman-Keuls test (P=0.05). The quantitative analysis of the colony-forming units was carried out from dentinal shaving and analyzed by One-way ANOVA and Tukey multiple comparison test (P=0.05). All treatment groups showed a significantly higher percentage of dead bacteria than the saline control (P<0.05). The percentage of dead bacteria was significantly higher when light activated curcumin was used (P<0.05). At both depths (200 and 400 microns), light activated curcumin showed no growth of bacteria. Light activation produced significantly higher antibacterial efficacy than ultrasonic agitation, with light activated curcumin producing the maximum elimination of biofilm bacteria within the root canal lumen and dentinal tubules. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Enhanced efficacy of an AAV vector encoding chimeric, highly secreted acid alpha-glucosidase in glycogen storage disease type II.

    PubMed

    Sun, Baodong; Zhang, Haoyue; Benjamin, Daniel K; Brown, Talmage; Bird, Andrew; Young, Sarah P; McVie-Wylie, Alison; Chen, Y-T; Koeberl, Dwight D

    2006-12-01

    Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid alpha-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1 x 10(10) vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3 x 10(10) vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.

  20. Deoxycholic acid-modified chitooligosaccharide/mPEG-PDLLA mixed micelles loaded with paclitaxel for enhanced antitumor efficacy.

    PubMed

    Jiang, Chengjun; Wang, Hangxiang; Zhang, Xiaomin; Sun, Zhibin; Wang, Feng; Cheng, Jun; Xie, Haiyang; Yu, Bo; Zhou, Lin

    2014-11-20

    Poly(ethylene glycol) (PEG) as a block in polymeric micelles can prolong circulation life and reduce systemic clearance but decrease the cellular uptake. To overcome this limitation, a mixed micelle composed of deoxycholic acid-modified chitooligosaccharide (COS-DOCA) and methoxy poly(ethylene glycol)-polylactide copolymer (mPEG-PDLLA) was designed to load paclitaxel (PTX). The PTX-loaded mixed micelles was prepared by nanoprecipitation method with high drug-loading efficiency of 8.03% and encapsulation efficiency of 97.09% as well as small size (∼40 nm) and narrow size distribution. COS-DOCA/mPEG-PDLLA mixed micelles exhibited the sustained release property. Due to the positive charge and bioadhesive property of COS-DOCA, the cellular uptake of PTX in mixed micelles was higher in cancer cells but lower in macrophage cells compared to the mPEG-PDLLA micelles. The systemic toxicity of PTX in mixed micelles was much lower than Taxol using zebrafish as a toxicological model. Furthermore, the PTX-loaded COS-DOCA/mPEG-PDLLA mixed micelles can prolong the blood circulation time of PTX and enhance the antitumor efficacy in A549 lung xenograft model. Our findings indicate that COS-DOCA/mPEG-PDLLA mixed micelles could be a potential vehicle for enhanced delivery of anticancer drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells.

    PubMed

    Rupp, Levi J; Schumann, Kathrin; Roybal, Kole T; Gate, Rachel E; Ye, Chun J; Lim, Wendell A; Marson, Alexander

    2017-04-07

    Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize programmed cell death protein 1 [PD-1]) have both opened new avenues for cancer treatment, but the clinical potential of combined disruption of inhibitory checkpoints and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous xenograft model. To overcome this suppressed anti-tumor response, we developed a protocol for combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing and lentiviral transduction to generate PD-1 deficient anti-CD19 CAR T cells. Pdcd1 (PD-1) disruption augmented CAR T cell mediated killing of tumor cells in vitro and enhanced clearance of PD-L1+ tumor xenografts in vivo. This study demonstrates improved therapeutic efficacy of Cas9-edited CAR T cells and highlights the potential of precision genome engineering to enhance next-generation cell therapies.

  2. Enhanced antitumor efficacy by cyclic RGDyK-conjugated and paclitaxel-loaded pH-responsive polymeric micelles.

    PubMed

    Gao, Yajie; Zhou, Yanxia; Zhao, Lei; Zhang, Chao; Li, Yushu; Li, Jinwen; Li, Xinru; Liu, Yan

    2015-09-01

    Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH-sensitive copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin αvβ3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK-conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin αvβ3-rich prostate cancers.

  3. A Dual TLR Agonist Adjuvant Enhances the Immunogenicity and Protective Efficacy of the Tuberculosis Vaccine Antigen ID93

    PubMed Central

    Orr, Mark T.; Beebe, Elyse A.; Hudson, Thomas E.; Moon, James J.; Fox, Christopher B.; Reed, Steven G.; Coler, Rhea N.

    2014-01-01

    With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4+ T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG. PMID:24404140

  4. A dual TLR agonist adjuvant enhances the immunogenicity and protective efficacy of the tuberculosis vaccine antigen ID93.

    PubMed

    Orr, Mark T; Beebe, Elyse A; Hudson, Thomas E; Moon, James J; Fox, Christopher B; Reed, Steven G; Coler, Rhea N

    2014-01-01

    With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+) T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.

  5. Synergistic efficacy of salicylic acid with a penetration enhancer on human skin monitored by OCT and diffuse reflectance spectroscopy.

    PubMed

    Zhao, Qingliang; Dai, Cuixia; Fan, Shanhui; Lv, Jing; Nie, Liming

    2016-10-10

    Salicylic acid (SA) has been frequently used as a facial chemical peeling agent (FCPA) in various cosmetics for facial rejuvenation and dermatological treatments in the clinic. However, there is a tradeoff between therapeutic effectiveness and possible adverse effects caused by this agent for cosmetologists. To optimize the cosmetic efficacy with minimal concentration, we proposed a chemical permeation enhancer (CPE) azone to synergistically work with SA on human skin in vivo. The optical properties of human skin after being treated with SA alone and SA combined with azone (SA@azone) were successively investigated by diffuse reflectance spectroscopy (DRS) and optical coherence tomography (OCT). Our results revealed that as the SA concentration increased, the light reflectance decreased and the absorption increased. We also found that SA@azone exhibited a synergistic effect on enhancing light penetration and OCT imaging depth. We demonstrated that the combination of DRS and OCT techniques could be used as a noninvasive, rapid and accurate measurement method to monitor the subtle changes of skin tissue after treatment with FCPA and CPE. The approach will greatly benefit the development of clinical cosmetic surgery, dermatosis diagnosis and therapeutic effect inspection in related biomedical studies.

  6. iRGD tumor-penetrating peptide-modified oncolytic adenovirus shows enhanced tumor transduction, intratumoral dissemination and antitumor efficacy.

    PubMed

    Puig-Saus, C; Rojas, L A; Laborda, E; Figueras, A; Alba, R; Fillat, C; Alemany, R

    2014-08-01

    Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or tumor cells, exposure by proteolysis of a C-terminal motif that binds to neuropilin-1 (NRP-1) and cell internalization. We have genetically inserted the iRGD peptide in the fiber C terminus of ICOVIR15K, an oncolytic tumor-retargeted adenovirus to increase its tumor penetration. In vitro, NRP-1 interaction improved binding and internalization of the virus in different cancer cells overexpressing integrins and NRP-1. However, such NRP-1-mediated internalization did not affect transduction or cytotoxicity. In vivo, iRGD did not change the normal organ transduction pattern, with liver and spleen as main targeted organs. In tumors, however, iRGD enhanced transduction and early adenovirus dissemination through the tumor mass leading to an improved antitumor efficacy.

  7. Synergistic efficacy of salicylic acid with a penetration enhancer on human skin monitored by OCT and diffuse reflectance spectroscopy

    NASA Astrophysics Data System (ADS)

    Zhao, Qingliang; Dai, Cuixia; Fan, Shanhui; Lv, Jing; Nie, Liming

    2016-10-01

    Salicylic acid (SA) has been frequently used as a facial chemical peeling agent (FCPA) in various cosmetics for facial rejuvenation and dermatological treatments in the clinic. However, there is a tradeoff between therapeutic effectiveness and possible adverse effects caused by this agent for cosmetologists. To optimize the cosmetic efficacy with minimal concentration, we proposed a chemical permeation enhancer (CPE) azone to synergistically work with SA on human skin in vivo. The optical properties of human skin after being treated with SA alone and SA combined with azone (SA@azone) were successively investigated by diffuse reflectance spectroscopy (DRS) and optical coherence tomography (OCT). Our results revealed that as the SA concentration increased, the light reflectance decreased and the absorption increased. We also found that SA@azone exhibited a synergistic effect on enhancing light penetration and OCT imaging depth. We demonstrated that the combination of DRS and OCT techniques could be used as a noninvasive, rapid and accurate measurement method to monitor the subtle changes of skin tissue after treatment with FCPA and CPE. The approach will greatly benefit the development of clinical cosmetic surgery, dermatosis diagnosis and therapeutic effect inspection in related biomedical studies.

  8. Synergistic efficacy of salicylic acid with a penetration enhancer on human skin monitored by OCT and diffuse reflectance spectroscopy

    PubMed Central

    Zhao, Qingliang; Dai, Cuixia; Fan, Shanhui; Lv, Jing; Nie, Liming

    2016-01-01

    Salicylic acid (SA) has been frequently used as a facial chemical peeling agent (FCPA) in various cosmetics for facial rejuvenation and dermatological treatments in the clinic. However, there is a tradeoff between therapeutic effectiveness and possible adverse effects caused by this agent for cosmetologists. To optimize the cosmetic efficacy with minimal concentration, we proposed a chemical permeation enhancer (CPE) azone to synergistically work with SA on human skin in vivo. The optical properties of human skin after being treated with SA alone and SA combined with azone (SA@azone) were successively investigated by diffuse reflectance spectroscopy (DRS) and optical coherence tomography (OCT). Our results revealed that as the SA concentration increased, the light reflectance decreased and the absorption increased. We also found that SA@azone exhibited a synergistic effect on enhancing light penetration and OCT imaging depth. We demonstrated that the combination of DRS and OCT techniques could be used as a noninvasive, rapid and accurate measurement method to monitor the subtle changes of skin tissue after treatment with FCPA and CPE. The approach will greatly benefit the development of clinical cosmetic surgery, dermatosis diagnosis and therapeutic effect inspection in related biomedical studies. PMID:27721398

  9. Enhancing the efficacy of heart surgery by optimizing patients' preoperative expectations: study protocol of a randomized controlled trial.

    PubMed

    Laferton, Johannes A C; Shedden Mora, Meike; Auer, Charlotte J; Moosdorf, Rainer; Rief, Winfried

    2013-01-01

    In coronary heart disease (CHD) and heart surgery, there is sound evidence for the relationship between patients' expectations and treatment outcome, especially for outcome variables such as disability and quality of life. In addition, patients' expectations have been shown to be modifiable through psychological interventions. Therefore, targeting patients' expectations might offer a promising opportunity to enhance heart surgery outcome. However, few studies have tried to actively change patients' expectations before surgery. The purpose of this clinical trial is to optimize patients' outcome expectations before undergoing coronary artery bypass graft surgery (CABG) through a brief psychoeducational program. The present article describes the study protocol and reports preliminary data on feasibility. Using a randomized controlled design, 180 patients who are scheduled to undergo elective CABG are randomly assigned to either (1) standard medical care (SMC) alone, (2) to an additional expectation manipulation intervention during the 2 weeks before surgery, and (3) to an additional attention-control group ("supportive therapy"). The main goal is to test (a) whether expectation manipulation intervention can optimize patients' expectations and (b) whether optimized expectations lead to enhanced surgery efficacy. The primary outcome variable is illness-related disability 6 months after surgery, whereas secondary outcome variables will be quality of life, return to work, physical activity, and medical outcome variables. First, feasibility data of 36 patients show that the patients appreciated the additional psychological intervention before CABG. Satisfaction of those who received psychological interventions was very high. Copyright © 2013 Mosby, Inc. All rights reserved.

  10. Tetracycline-regulated intratumoral expression of interleukin-3 enhances the efficacy of radiation therapy for murine prostate cancer.

    PubMed

    Tsai, C-H; Hong, J-H; Hsieh, K-F; Hsiao, H-W; Chuang, W-L; Lee, C-C; McBride, W H; Chiang, C-S

    2006-12-01

    The aim of this study was to investigate means of increasing the efficiency with which cancer cell death following local radiation therapy (RT) is translated into the generation of tumor immunity since, if this were to be achieved, it would be expected to enhance the rates of disease-free recurrence and survival. Our investigations centered around the use of interleukin-3 (IL-3), expressed intratumorally using an inducible adenoviral vector, to alter the immunogenicity of established murine TRAMP-C1 prostate cancer receiving a course of fractionated local RT (7 Gy per fraction per day for 5 days). Because high systemic levels of IL-3 can be associated with toxicity, a tetracycline-regulated gene delivery system was employed. The results show that while intratumoral IL-3 expression or RT alone caused a modest delay in TRAMP-C1 tumor growth, the combination was synergistic with 50% of mice being cured and developing a long-term, tumor-specific state of immunity. Immunological analyses performed on splenic lymphocytes demonstrated that, compared to RT or IL-3 alone, combined treatment significantly increased the number of tumor-specific IFN-gamma-secreting and cytotoxic T cells. The study demonstrates that tetracycline-regulated IL-3 gene expression within tumors can enhance the immune response to prostate cancer and this can augment the efficacy of a course of RT without additional side effects.

  11. Vitamin E containing polymer micelles for reducing normal cell cytotoxicity and enhancing chemotherapy efficacy.

    PubMed

    Lee, Kuan-Yi; Chiang, Yi-Ting; Hsu, Ning-Yu; Yang, Chieh-Yu; Lo, Chun-Liang; Ku, Chen-An

    2015-09-01

    An α-tocopheryl succinate (α-TOS) containing diblock copolymer micellar system was used to deliver doxorubicin (Dox), an anticancer drug, for HCT116 colon cancer therapy. The α-TOS containing diblock copolymers were synthesized by conjugation of α-TOS molecules and a mPEG-b-PHEMA hydrophilic diblock copolymer by ester bonds. The Dox-loaded polymeric micelles were then obtained by solvent exchange process. In acidic surroundings such as endosomes or secondary lysosomes, the structures of the Dox-loaded polymeric micelles deformed and released the drug loads. Additionally, Dox-loaded polymeric micelles enhanced the cytotoxicity of Dox and α-TOS to cancer cells in vitro. Dox-loaded polymeric micelles also showed an exceptional tumor inhibiting effect in vivo. This study indicates that the α-TOS containing polymeric micelle system can be used as a drug carrier for cancer therapy.

  12. Enhancement of chemotherapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b.

    PubMed

    Sandhu, Rupninder; Rivenbark, Ashley G; Coleman, William B

    2012-01-01

    A subset of primary breast cancers and breast cancer cell lines express a hypermethylation defect (characterized by DNMT hyperactivity and DNMT3b overexpression) which contributes to chemotherapy resistance and provides a target for development of new treatment strategies. The objective of the current study was to determine if targeting the epigenome enhances the sensitivity of breast cancer cells to cytotoxic chemotherapy. Hypermethylator breast cancer cell lines (MDA-MB-453, BT549, and Hs578T) were treated with 250 or 500 nM 5-aza-2'-deoxycytidine (5-aza) and/or were subjected to RNAi-mediated DNMT3b knockdown (KD), and then tested for sensitivity to doxorubicin hydrochloride (DOX), paclitaxel (PAX), and 5-fluorouracil (5-FU). In MDA-MB-453 cells, DNMT3b KD reduces the IC(50) for DOX from 0.086 to 0.048 μM (44% reduction), for PAX from 0.497 to 0.376 nM (24%), and for 5-FU from 0.817 to 0.145 mM (82%). Treatment with 250 nM 5-aza for 7 days did not increase the efficacy of DOX, PAX, or 5-FU, but 7-day treatment with 500 nM 5-aza sensitized cells, reducing the IC(50) for DOX to 0.035 μM (60%), PAX to 0.311 nM (37%), and 5-FU to 0.065 mM (92%). 5-aza treatment of DNMT3b KD cells reduced the IC(50) for DOX to 0.036 μM (59%), for PAX to 0.313 nM (37%) and for 5-FU to 0.067 (92%). Similar trends of enhancement of cell kill were seen in BT549 (13-60%) and Hs578T (29-70%) cells after RNAi-mediated DNMT3b KD and/or treatment with 5-aza. The effectiveness of DOX, PAX, and 5-FU is enhanced through targeted and/or pharmacological inhibition of DNMT3b, strongly suggesting that combined epigenetic and cytotoxic treatment will improve the efficacy of breast cancer chemotherapy.

  13. Efficacy enhancement of trisodium phosphate against spoilage and pathogenic bacteria in model biofilms and on adipose tissue.

    PubMed

    Korber, D R; Greer, G G; Wolfaardt, G M; Kohlman, S

    2002-04-01

    A two-step approach for enhancing the efficacy of trisodium phosphate (TSP) was evaluated using meat spoilage and pathogenic bacteria in flow cell biofilms and adipose tissue model systems. The process was based on the plasmolysis of attached bacteria (biofilms) with a hyperosmotic solution (1.5 M NaCl) and the subsequent deplasmolysis of cells with a low-osmotic-strength solution containing different concentrations of TSP (0.1, 0.25, 0.5, 0.625, and 1.0 % [wt/vol]). Escherichia coli, Salmonella Enteritidis, Pseudomonas sp., Listeria monocytogenes, and Brochothrix thermosphacta strains were cultivated for 24 h as pure culture biofilms in glass flow cells with complex media and were then treated with either 0.1, 0.25, 0.5, 0.625, and 1.0% TSP, or the same TSP concentrations delivered in conjunction with plasmolysis-deplasmolysis (PDP). Confocal scanning laser microscopy, a commercial fluorescent viability probe, and image analysis were then used to quantify the relative abundances of living and dead cells remaining after the different treatment regimes. With the exception of L. monocytogenes (which was resistant to TSP concentrations of up to 5%), the PDP process increased the sensitivity of the test strains to TSP. However, when similar experiments were conducted with pork adipose tissue, it became evident that higher TSP concentrations were necessary to produce significant decreases in the number of viable cells and that the PDP process generally failed to enhance TSP efficacy. An exception was L. monocytogenes, which exhibited an increase in sensitivity to TSP when inoculated tissue was pretreated with 1.5 M NaCl. It is thought that factors contributing to the failure of the PDP process to enhance the activity of TSP in meat systems involves the mode of TSP antimicrobial activity, alkaline pH stress, and the chemically complex, buffered nature of meats. It remains to be determined whether the PDP process is suitable for use with other food grade antimicrobial

  14. A new herbal combination, Etana, for enhancing erectile function: an efficacy and safety study in animals.

    PubMed

    Qinna, N; Taha, H; Matalka, K Z; Badwan, A A

    2009-01-01

    We present herein a new herbal combination called Etana that is composed of five herbal extracts including Panax quinquelotius (Ginseng), Eurycoma longifolia (Tongkat Ali), Epimedium grandiflorum (Horny goat weed), Centella asiatica (Gotu Kola) and flower pollen extracts. Most of the above-mentioned extracts have a long historical and traditional use for erectile dysfunction (ED). On the basis of the mechanism of action of each of the above, a combination is introduced to overcome several physiological or induced factors of ED. This study was conducted to show an enhancement of erectile function in male rats. The animals were observed for 3 h after each administration for penile erection, genital grooming and copulation mounting, and the penile erection index (PEI) was calculated. The maximum response was observed at the concentration of 7.5 mg kg(-1) of Etana. At a 7.5 mg kg(-1) single dose, the percentage of responding rats was 53+/-7 with a PEI of 337+/-72 compared with 17+/-6 with a PEI of 30+/-10 for control animals. This PEI was significantly (P<0.001) higher than each single component and than the sum of any two herbal components of Etana. When compared with sildenafil citrate, Etana induced more pronounced PEI than 0.36 mg kg(-1), but similar to 0.71 mg kg(-1) of sildenafil. Furthermore, full acute and sub-acute toxicity studies showed no toxic effects of Etana. In conclusion, this study describes a new and safe combination of herbal components that enhance erectile function in male rats. Clinical studies are warranted for evaluating Etana's significance in ED.

  15. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    SciTech Connect

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-06-02

    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  16. Vitamin D enhances the efficacy of photodynamic therapy in a murine model of breast cancer

    PubMed Central

    Rollakanti, Kishore R; Anand, Sanjay; Maytin, Edward V

    2015-01-01

    Cutaneous metastasis occurs more frequently in breast cancer than in any other malignancy in women, causing significant morbidity. Photodynamic therapy (PDT), which combines a porphyrin-based photosensitizer and activation by light, can be employed for breast cancer (especially cutaneous metastases) but tumor control after PDT has not surpassed traditional treatments methods such as surgery, radiation, and chemotherapy up to now. Here, we report that breast cancer nodules in mice can be effectively treated by preconditioning the tumors with 1α, 25-dihydroxyvitamin D3 (calcitriol; Vit D) prior to administering 5-aminolevulinate (ALA)-based PDT. Breast carcinoma tumors (MDA-MB-231 cells implanted subcutaneously in nude mice) received systemic Vit D (1 μg/kg) for 3 days prior to receiving ALA. The addition of Vit D increased intratumoral accumulation of protoporphyrin IX (PpIX) by 3.3 ± 0.5-fold, relative to mice receiving ALA alone. Bioluminescence imaging in vivo and immunohistochemical staining confirmed that tumor-specific cell death after ALA-PDT was markedly enhanced (36.8 ± 7.4-fold increase in TUNEL-positive nuclei; radiance decreased to 14% of control) in Vit D pretreated tumors as compared to vehicle-pretreated tumors. Vit D stimulated proliferation (10.7 ± 2.8-fold) and differentiation (9.62 ± 1.7-fold) in tumor cells, underlying an augmented cellular sensitivity to ALA-PDT. The observed enhancement of tumor responses to ALA-PDT after low, nontoxic doses of Vit D supports a new combination approach that deserves consideration in the clinical setting, and offers potential for improved remission of cutaneous breast cancer metastases. PMID:25712788

  17. Enhanced therapeutic efficacy of an adenovirus-PEI-bile-acid complex in tumors with low coxsackie and adenovirus receptor expression.

    PubMed

    Lee, Cho-Hee; Kasala, Dayananda; Na, Youjin; Lee, Min Sang; Kim, Sung Wan; Jeong, Ji Hoon; Yun, Chae-Ok

    2014-07-01

    Adenovirus (Ad) is a potential vehicle for cancer gene therapy. However, cells that express low levels of the coxsackie and adenovirus receptor (CAR) demonstrate poor Ad infection efficiency. We developed a bile acid-conjugated poly(ethyleneimine) (DA3)-coated Ad complex (Ad/DA3) to enhance Ad transduction efficiency. The size distribution and zeta potential of Ad/DA3 increased to 324 ± 3.08 nm and 10.13 ± 0.21 mV, respectively, compared with those of naked Ad (108 ± 2.26 nm and -17.7 ± 1.5 mV). The transduction efficiency of Ad/DA3 increased in a DA3 polymer concentration-dependent manner. Enhanced gene transfer by Ad/DA3 was more evident in CAR-moderate and CAR-negative cancer cells. Competition assays with a CAR-specific antibody revealed that internalization of Ad/DA3 was not mediated primarily by CAR but involved clathrin-, caveolae-, and macropinocytosis-mediated endocytosis. Cancer cell death was significantly increased when oncolytic Ad and DA3 were complexed (RdB-KOX/DA3) compared to that of naked oncolytic Ad and was inversely proportional to CAR levels. Importantly, RdB-KOX/DA3 significantly enhanced apoptosis, reduced angiogenesis, reduced proliferation, and increased active viral replication in human tumor xenografts compared to that of naked Ad. These results demonstrate that a hybrid vector system can increase the efficacy of oncolytic Ad virotherapy, particularly in CAR-limited tumors.

  18. Efficacy of Flaxseed Flour as Bind Enhancing Agent on the Quality of Extended Restructured Mutton Chops

    PubMed Central

    Sharma, Heena; Sharma, Brahma Deo; Mendiratta, S. K.; Talukder, Suman; Ramasamy, Giriprasad

    2014-01-01

    Consumers have become very conscious about their nutrition and well being due to changes in their socio-economic lifestyle and rapid urbanization. Therefore, development of technology for production of low cost and functional meat products is urgently required. One such approach is innovative restructuring technology in which binding of meat pieces still remains the main challenge and extension of product is generally associated with poor binding and texture. Thus, the present study was envisaged as an attempt to solve this problem by the incorporation of flaxseed flour (FF) as bind enhancing agent. The FF was used at three different levels viz., 0.5%, 1%, and 1.5% to replace lean meat in pre-standardized restructured mutton chops formulation. The products were subjected to analysis for physico-chemical, sensory and textural properties. Cooking yield, moisture percentage and fat percentage increased with increase in the level of incorporation of FF, however, protein percent and pH decreased with increase in the level of incorporation. Shear force value of product incorporated with 1.5% FF was significantly higher (p<0.01) than control and product containing 0.5% FF level. Among the sensory attributes, product with 1% flaxseed flour showed significantly higher values (p<0.05) for general appearance, binding, texture and overall acceptability. Hardness showed significant increasing (p<0.01) values with increasing levels of incorporation of flaxseed flour, however all other parameters of texture profile analysis showed a decreasing trend. On the basis of sensory scores and physico-chemical properties, the optimum incorporation level of FF was adjudged as 1%. Products incorporated with optimum level of flaxseed flour (1%) were also assessed for water activity and microbiological quality during the storage period of 15 days. It was found that the extended restructured product could be safely stored under refrigeration (4°C±1°C) in low density polyethylene (LDPE

  19. Efficacy of flaxseed flour as bind enhancing agent on the quality of extended restructured mutton chops.

    PubMed

    Sharma, Heena; Sharma, Brahma Deo; Mendiratta, S K; Talukder, Suman; Ramasamy, Giriprasad

    2014-02-01

    Consumers have become very conscious about their nutrition and well being due to changes in their socio-economic lifestyle and rapid urbanization. Therefore, development of technology for production of low cost and functional meat products is urgently required. One such approach is innovative restructuring technology in which binding of meat pieces still remains the main challenge and extension of product is generally associated with poor binding and texture. Thus, the present study was envisaged as an attempt to solve this problem by the incorporation of flaxseed flour (FF) as bind enhancing agent. The FF was used at three different levels viz., 0.5%, 1%, and 1.5% to replace lean meat in pre-standardized restructured mutton chops formulation. The products were subjected to analysis for physico-chemical, sensory and textural properties. Cooking yield, moisture percentage and fat percentage increased with increase in the level of incorporation of FF, however, protein percent and pH decreased with increase in the level of incorporation. Shear force value of product incorporated with 1.5% FF was significantly higher (p<0.01) than control and product containing 0.5% FF level. Among the sensory attributes, product with 1% flaxseed flour showed significantly higher values (p<0.05) for general appearance, binding, texture and overall acceptability. Hardness showed significant increasing (p<0.01) values with increasing levels of incorporation of flaxseed flour, however all other parameters of texture profile analysis showed a decreasing trend. On the basis of sensory scores and physico-chemical properties, the optimum incorporation level of FF was adjudged as 1%. Products incorporated with optimum level of flaxseed flour (1%) were also assessed for water activity and microbiological quality during the storage period of 15 days. It was found that the extended restructured product could be safely stored under refrigeration (4°C±1°C) in low density polyethylene (LDPE

  20. Immobilized silver nanoparticles enhance contact killing and show highest efficacy: elucidation of the mechanism of bactericidal action of silver

    NASA Astrophysics Data System (ADS)

    Agnihotri, Shekhar; Mukherji, Soumyo; Mukherji, Suparna

    2013-07-01

    Antimicrobial materials with immobilized/entrapped silver nanoparticles (AgNPs) are of considerable interest. There is significant debate on the mode of bactericidal action of AgNPs, and both contact killing and/or ion mediated killing have been proposed. In this study, AgNPs were immobilized on an amine-functionalized silica surface and their bactericidal activity was studied concurrently with the silver release profile over time. This was compared with similar studies performed using colloidal AgNPs and AgCl surfaces that released Ag ions. We conclude that contact killing is the predominant bactericidal mechanism and surface immobilized nanoparticles show greater efficacy than colloidal AgNPs, as well as a higher concentration of silver ions in solution. In addition, the AgNP immobilized substrate was used multiple times with good efficacy, indicating this immobilization protocol is effective for retaining AgNPs while maintaining their disinfection potential. The antibacterial surface was found to be extremely stable in aqueous medium and no significant leaching (~1.15% of total silver deposited) of the AgNPs was observed. Thus, immobilization of AgNPs on a surface may promote reuse, reduce environmental risks associated with leaching of AgNPs and enhance cost effectiveness.Antimicrobial materials with immobilized/entrapped silver nanoparticles (AgNPs) are of considerable interest. There is significant debate on the mode of bactericidal action of AgNPs, and both contact killing and/or ion mediated killing have been proposed. In this study, AgNPs were immobilized on an amine-functionalized silica surface and their bactericidal activity was studied concurrently with the silver release profile over time. This was compared with similar studies performed using colloidal AgNPs and AgCl surfaces that released Ag ions. We conclude that contact killing is the predominant bactericidal mechanism and surface immobilized nanoparticles show greater efficacy than colloidal Ag

  1. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells

    PubMed Central

    Wang, Liang; Chan, Judy Y.; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P.; Shan, Luchen; Lee, Simon M.

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity. PMID:27559313

  2. Heparin-functionalized Pluronic nanoparticles to enhance the antitumor efficacy of sorafenib in gastric cancers.

    PubMed

    Yang, Ying-Chi; Cai, Jun; Yin, Jie; Zhang, Jun; Wang, Kang-Li; Zhang, Zhong-Tao

    2016-01-20

    In this study, chitosan/heparin immobilized delivery system was developed for the delivery of sorafenib in gastric cancers. The SRF NP was nanosized with spherical outfit and present in the amorphous form. The SRF NP exhibited a sustained release of drug at pH 7.4 conditions and enhanced drug released at pH 5.5 conditions. Flow cytometer analysis showed that cellular uptake of NP increased two-fold after 4h of incubation compared to 1h incubation. The SRF NP showed superior anticancer effect compared to that of free SRF in BGC-823 cancer cells. SRF NP induced a remarkable apoptosis of cancer cells consistent with the cytotoxicity assay. Approximately, ∼ 50% of cell fractions were observed in early apoptosis phase with ∼ 15% of cells in the late apoptosis stage. Consistently, SRF NP exhibited a strong band for caspase-3 and P-53 than compared to free SRF in MGC-823 cancer cells. Importantly, SRF NP showed superior anticancer effect in xenograft tumor model making it a promising delivery vehicle in the treatment of gastric cancers.

  3. Combining Immune Checkpoint Inhibitors and Kinase-Inhibiting Supramolecular Therapeutics for Enhanced Anticancer Efficacy.

    PubMed

    Kulkarni, Ashish; Natarajan, Siva Kumar; Chandrasekar, Vineethkrishna; Pandey, Prithvi Raj; Sengupta, Shiladitya

    2016-09-29

    A major limitation of immune checkpoint inhibitors is that only a small subset of patients achieve durable clinical responses. This necessitates the development of combinatorial regimens with immunotherapy. However, some combinations, such as MEK- or PI3K-inhibitors with a PD1-PDL1 checkpoint inhibitor, are pharmacologically challenging to implement. We rationalized that such combinations can be enabled using nanoscale supramolecular targeted therapeutics, which spatially home into tumors and exert temporally sustained inhibition of the target. Here we describe two case studies where nanoscale MEK- and PI3K-targeting supramolecular therapeutics were engineered using a quantum mechanical all-atomistic simulation-based approach. The combinations of nanoscale MEK- and PI3K-targeting supramolecular therapeutics with checkpoint PDL1 and PD1 inhibitors exert enhanced antitumor outcome in melanoma and breast cancers in vivo, respectively. Additionally, the temporal sequence of administration impacts the outcome. The combination of supramolecular therapeutics and immunotherapy could emerge as a paradigm shift in the treatment of cancer.

  4. Enhanced preclinical efficacy of tamoxifen developed as alginate-cysteine/disulfide bond reduced albumin nanoparticles.

    PubMed

    Martínez, A; Muñiz, E; Iglesias, I; Teijón, J M; Blanco, M D

    2012-10-15

    Tamoxifen (TMX) is the most common clinical choice for the treatment of advanced or metastatic estrogen-dependent breast cancer. However, research on new challenging therapies is necessary due to its undesirable side effects and the limitation of the treatment only to the oral route. In this study, the antitumor activity of TMX-loaded nanoparticles based on different mixtures of alginate-cysteine and disulfide bond reduced bovine serum albumin was tested in vivo in MCF-7 nude mice xenograft model. These systems showed an enhancement of the TMX antitumor activity, since lower tumor evolutions and lower tumor growth rates were observed in mice treated with them. Moreover, histological and immunohistochemical studies revealed that treatments with TMX-loaded nanoparticles showed the most regressive and less proliferative tumor tissues. TMX biodistribution studies determined that TMX-loaded nanoparticles caused more accumulation of the drug into the tumor site with undetectable levels of TMX in plasma, reducing the possibility of delivering TMX to other not-targeted organs and, consequently, developing possible side effects. Thus, these TMX nanoparticulate systems are expected to provide a novel approach to the treatment of breast cancer in the future. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Inhibiting NANOG Enhances Efficacy of BH3 Mimetics | Center for Cancer Research

    Cancer.gov

    BCL-2 family proteins regulate cell fate. Some members promote cell survival while others induce programmed cell death. A third group, the BH3-only members, modulates the activities of the rest of the family. Some cancers, including those of the colon and rectum, express elevated levels of pro-survival BCL-2 members, which may protect cancer cells from chemotherapy. BH3 mimetics are novel therapies that target and inhibit these pro-survival family members. Two in particular, ABT-737 and ABT-199, have activity against multiple cancer types, though neither targets the protein MCL-1, which is related to the BCL-2 family and causes resistance to the BH3 mimetics. Recent studies have revealed that the embryonic regulator NANOG and the related gene NANOGP8 can indirectly regulate MCL-1 via the kinase AKT. Abid Mattoo, Ph.D., J. Milburn Jessup, M.D., and colleagues of CCR’s Laboratory of Experimental Carcinogenesis, hypothesized that combining NANOG or NANOGP8 inhibition with a BH3 mimetic would enhance the latter’s anticancer activity.

  6. Enhanced tolerance and antitumor efficacy by docetaxel-loaded albumin nanoparticles.

    PubMed

    Tang, Xiaolei; Wang, Guijun; Shi, Runjie; Jiang, Ke; Meng, Lingtong; Ren, Hao; Wu, Jinhui; Hu, Yiqiao

    2016-10-01

    Docetaxel is one of the most active chemotherapeutic agents for cancer treatment. The traditional docetaxel injection (TAXOTERE®) is currently formulated in the surfactant polysorbate 80, which has been associated with severe adverse reactions. To avoid the use of polysorbate 80 as well as to reduce the systemic toxicity of docetaxel, in this study, docetaxel-loaded albumin nanoparticles were fabricated by a novel simple self-assembly method. The resulting nanoparticles showed a mean diameter size of 150 nm. After being encapsulated into nanoparticles, docetaxel displayed similar cytotoxicity to traditional injection. Since polysorbate 80 was not involved in nanoparticles, the hemolysis was completely eliminated. The maximal tolerance dose of nanoparticles was also increased, which allowed a higher dose to be safely intravenously injected and produced ideal antitumor effects. The 150 nm diameter also allowed the nanoparticles to accumulate in tumor tissue via the enhanced permeability and retention effect. The passive targeting ability further caused the higher antitumor effects of nanoparticles than that of traditional injection at the same dose (7.5 mg/kg). Therefore, docetaxel-loaded albumin nanoparticles fabricated by our strategy showed higher promise in their safety and effectiveness than the traditional docetaxel injection.

  7. A Novel Agent Enhances the Chemotherapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Wang, Liang; Chan, Judy Y; Zhou, Xinhua; Cui, Guozhen; Yan, Zhixiang; Wang, Li; Yan, Ru; Di, Lijun; Wang, Yuqiang; Hoi, Maggie P; Shan, Luchen; Lee, Simon M

    2016-01-01

    We have previously demonstrated that DT-010, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), displays anti-tumor effects in breast cancer cells both in vitro and in vivo. In the present study, we investigated whether DT-010 enhances the chemotherapeutic effect of doxorubicin (Dox) in MCF-7 breast cancer cells and exerts concurrent cardioprotective benefit at the same time. Our findings showed that DT-010 was more potent than TMP, DSS, or their combination in potentiating Dox-induced toxicity in MCF-7 cells. Co-treatment with DT-010 and Dox increased apoptosis in MCF-7 cells relative to Dox alone. Further study indicated that glycolytic capacity, glycolytic reserve and lactate level of MCF-7 cells were significantly inhibited after DT-010 treatment. DT-010 also increased the expression of the pro-survival protein GRP78, which was inhibited by co-treatment with Dox. Both endoplasmic reticulum stress inhibitor 4-PBA and knockdown of the expression of GRP78 protein potentiated DT-010-mediated apoptosis in MCF-7 cells. Moreover, DT-010 inhibited Dox-induced cardiotoxicity in H9c2 myoblasts. In conclusion, DT-010 and Dox confer synergistic anti-tumor effect in MCF-7 breast cancer cells through downregulation of the glycolytic pathway and inhibition of the expression of GRP78. Meanwhile, DT-010 also protects against Dox-induced cardiotoxicity.

  8. Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow

    PubMed Central

    Okamoto, Ayaka; Asai, Tomohiro; Ryu, Sho; Ando, Hidenori; Maeda, Noriyuki; Dewa, Takehisa; Oku, Naoto

    2016-01-01

    Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused on blood flow in tumors treated with miR499, since some angiogenic vessels are known to lack blood flow. Tetraethylenepentamine-based polycation liposomes (TEPA-PCL) were prepared and modified with Ala-Pro-Arg-Pro-Gly peptide (APRPG) for targeted delivery of miR-499 (APRPG-miR-499) to angiogenic vessels and tumor cells. The tumor blood flow was significantly improved, so-called normalized, after systemic administration of APRPG-miR-499 to Colon 26 NL-17 carcinoma–bearing mice. In addition, the accumulation of doxorubicin (DOX) in the tumors was increased by pre-treatment with APRPG-miR-499. Moreover, the combination therapy of APRPG-miR-499 and DOX resulted in significant suppression of the tumors. Taken together, our present data indicate that miR-499 delivered with APRPG-modified-TEPA-PCL normalized tumor vessels, resulting in enhancement of intratumoral accumulation of DOX. Our findings suggest that APRPG-miR-499 may be a therapeutic, or a combination therapeutic, candidate for cancer treatment. PMID:26797645

  9. Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow.

    PubMed

    Okamoto, Ayaka; Asai, Tomohiro; Ryu, Sho; Ando, Hidenori; Maeda, Noriyuki; Dewa, Takehisa; Oku, Naoto

    2016-01-19

    Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused on blood flow in tumors treated with miR499, since some angiogenic vessels are known to lack blood flow. Tetraethylenepentamine-based polycation liposomes (TEPA-PCL) were prepared and modified with Ala-Pro-Arg-Pro-Gly peptide (APRPG) for targeted delivery of miR-499 (APRPG-miR-499) to angiogenic vessels and tumor cells. The tumor blood flow was significantly improved, so-called normalized, after systemic administration of APRPG-miR-499 to Colon 26 NL-17 carcinoma-bearing mice. In addition, the accumulation of doxorubicin (DOX) in the tumors was increased by pre-treatment with APRPG-miR-499. Moreover, the combination therapy of APRPG-miR-499 and DOX resulted in significant suppression of the tumors. Taken together, our present data indicate that miR-499 delivered with APRPG-modified-TEPA-PCL normalized tumor vessels, resulting in enhancement of intratumoral accumulation of DOX. Our findings suggest that APRPG-miR-499 may be a therapeutic, or a combination therapeutic, candidate for cancer treatment.

  10. Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma.

    PubMed

    Liu, Yang; Cai, Pengcheng; Wang, Ning; Zhang, Qianwen; Chen, Fenghua; Shi, Liang; Zhang, Yang; Wang, Lin; Hu, Lihua

    2017-03-04

    Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice. We discovered that trametinib remarkably promoted apoptosis and inhibited cell proliferation while inhibition of MEK improved the expression of Tim-3 and caused the decrease of CD8(+) T cells; to the contrary, anti-Tim-3 mAb enhanced antitumor immunity by stimulating CD8(+) T cells, thus the combined therapy produced potent antitumor effect cooperatively. Taken together, our study provides compelling evidence for combining trametinib and anti-Tim-3 mAb as a potential valuable regimen in treating melanoma.

  11. Selenium enhances the efficacy of Radachlorin mediated-photodynamic therapy in cervical cancer model

    NASA Astrophysics Data System (ADS)

    Bae, Dong Han; Wen, Lan Ying; Bae, Su Mi; Kang, Uk; Kim, Keun Hee; Jheon, Sang Hoon; Lee, Jeong Sang; Ahn, Woong Shick

    2009-06-01

    Selenium, an essential trace element possessing anti-carcinogenic properties, can induce apoptosis in cancer cells. Our goal was to investigate the enhanced anti-tumor effects of photodynamic therapy (PDT) plus selenium in TC-1 tumor cells implanted into mice. The MTT assay and tumor growth inhibition study were evaluated at various time intervals after the PDT plus a various dose of selenium. Following Radachlorin injections after 3 hr, the mice were then administrated selenium (2ug/kg b.w.) and then, tumors were treated with external light treatment (300 J/cm2). The selenium was administered daily for 20 days. PDT or selenium was found to be more compared to control groups. Moreover, the PDT combined with selenium demonstrated a significant suppression of tumor growth in vitro and in vivo. The tumor growth by the PDT combined with selenium was significantly reduced. These data suggest that selenium plus PDT can induce a significant tumor suppression response compared with PDT alone. Also, it can be an effective approach to induce anti-cancer therapy strategy.

  12. Enhancing the Efficacy of Drug-loaded Nanocarriers against Brain Tumors by Targeted Radiation Therapy

    PubMed Central

    Baumann, Brian C.; Kao, Gary D.; Mahmud, Abdullah; Harada, Takamasa; Swift, Joe; Chapman, Christina; Xu, Xiangsheng; Discher, Dennis E.; Dorsey, Jay F.

    2013-01-01

    Glioblastoma multiforme (GBM) is a common, usually lethal disease with a median survival of only ~15 months. It has proven resistant in clinical trials to chemotherapeutic agents such as paclitaxel that are highly effective in vitro, presumably because of impaired drug delivery across the tumor's blood-brain barrier (BBB). In an effort to increase paclitaxel delivery across the tumor BBB, we linked the drug to a novel filomicelle nanocarrier made with biodegradable poly(ethylene-glycol)-block-poly(ε-caprolactone-r-D,L-lactide) and used precisely collimated radiation therapy (RT) to disrupt the tumor BBB's permeability in an orthotopic mouse model of GBM. Using a non-invasive bioluminescent imaging technique to assess tumor burden and response to therapy in our model, we demonstrated that the drug-loaded nanocarrier (DLN) alone was ineffective against stereotactically implanted intracranial tumors yet was highly effective against GBM cells in culture and in tumors implanted into the flanks of mice. When targeted cranial RT was used to modulate the tumor BBB, the paclitaxel-loaded nanocarriers became effective against the intracranial tumors. Focused cranial RT improved DLN delivery into the intracranial tumors, significantly improving therapeutic outcomes. Tumor growth was delayed or halted, and survival was extended by >50% (p<0.05) compared to the results obtained with either RT or the DLN alone. Combinations of RT and chemotherapeutic agents linked to nanocarriers would appear to be an area for future investigations that could enhance outcomes in the treatment of human GBM. PMID:23296073

  13. MicroRNAs Used in Combination with Anti-Cancer Treatments Can Enhance Therapy Efficacy

    PubMed Central

    Mognato, Maddalena; Celotti, Lucia

    2015-01-01

    MicroRNAs (miRNAs), a recently discovered class of small non-coding RNAs, constitute a promising approach to anti-cancer treatments when they are used in combination with other agents. MiRNAs are evolutionarily conserved non-coding RNAs that negatively regulate gene expression by binding to the complementary sequence in the 3’-untranslated region (UTR) of target genes. MiRNAs typically suppress gene expression by direct association with target transcripts, thus decreasing the expression levels of target proteins. The delivery to cells of synthetic miRNAs that mimic endogenous miRNA targeting genes involved in the DNA-Damage Response (DDR) can perturb the process, making cells more sensitive to chemotherapy or radiotherapy. This review examines how cells respond to combined therapy and it provides insights into the role of miRNAs in targeting the DDR repair pathway when they are used in combination with chemical compounds or ionizing radiation to enhance cellular sensitivity to treatments. PMID:26156420

  14. Enhancement of the protective efficacy of a ROP18 vaccine against chronic toxoplasmosis by nasal route.

    PubMed

    Rashid, Imran; Moiré, Nathalie; Héraut, Bruno; Dimier-Poisson, Isabelle; Mévélec, Marie-Noëlle

    2017-02-01

    Infection with the parasite Toxoplasma gondii causes serious public health problems and is of great economic importance worldwide. No vaccine is currently available, so the design of efficient vaccine strategies is still a topical question. In this study, we evaluated the immunoprophylactic potential of a T. gondii virulence factor, the rhoptry kinase ROP18, in a mouse model of chronic toxoplasmosis: first using a recombinant protein produced in Schneider insect cells adjuvanted with poly I:C emulsified in Montanide SV71 by a parenteral route or adjuvanted with cholera toxin by the nasal route and second using a DNA plasmid encoding ROP18 adjuvanted with GM-CSF ± IL-12 DNA. If both intranasal and subcutaneous recombinant ROP18 immunizations induced predominantly anti-ROP18 IgG1 antibodies and generated a mixed systemic Th1-/Th2-type cellular immune response characterized by the production of IFN-γ, IL-2, Il-10 and IL-5, only intranasal vaccination induced a mucosal (IgA) humoral response in intestinal washes associated with a significant brain cyst reduction (50 %) after oral challenge with T. gondii cysts. DNA immunization induced antibodies and redirected the cellular immune response toward a Th1-type response (production of IFN-γ and IL-2) but did not confer protection. These results suggest that ROP18 could be a component of a subunit vaccine against toxoplasmosis and that strategies designed to enhance mucosal protective immune responses could lead to more encouraging results.

  15. Hormonal enhancement of insecticide efficacy in Tribolium castaneum: oxidative stress and metabolic aspects.

    PubMed

    Plavšin, Ivana; Stašková, Tereza; Šerý, Michal; Smýkal, Vlastimil; Hackenberger, Branimir K; Kodrík, Dalibor

    2015-04-01

    Insect anti-stress responses, including those induced by insecticides, are controlled by adipokinetic hormones (AKHs). We examined the physiological consequences of Pyrap-AKH application on Tribolium castaneum adults (AKH-normal and AKH-deficient prepared by the RNAi technique) treated by two insecticides, pirimiphos-methyl and deltamethrin. Co-application of pirimiphos-methyl and/or deltamethrin with AKH significantly increased beetle mortality compared with application of the insecticides alone. This co-treatment was accompanied by substantial stimulation of general metabolism, as monitored by carbon dioxide production. Further, the insecticide treatment alone affected some basic markers of oxidative stress: it lowered total antioxidative capacity as well as the activity of superoxide dismutase in the beetle body; in addition, it enhanced the activity of catalase and glutathione-S-transferase. However, these discrepancies in oxidative stress markers were eliminated/reduced by co-application with Pyrap-AKH. We suggest that the elevation of metabolism, which is probably accompanied with faster turnover of toxins, might be responsible for the higher mortality that results after AKH and insecticide co-application. Changes in oxidative stress markers are probably not included in the mechanisms responsible for increased mortality.

  16. Time Course of Conjunctival Hyperemia Induced by a Rho-kinase Inhibitor Anti-glaucoma Eye Drop: Ripasudil 0.4.

    PubMed

    Terao, Etsuko; Nakakura, Shunsuke; Fujisawa, Yasuko; Fujio, Yuki; Matsuya, Kanae; Kobayashi, Yui; Tabuchi, Hitoshi; Yoneda, Tsuyoshi; Fukushima, Atsuki; Kiuchi, Yoshiaki

    2017-05-01

    We investigated the detailed time course of conjunctival hyperemia induced by ripasudil 0.4%, a novel Rho-kinase inhibitor anti-glaucoma eye drop, in healthy subjects. We recruited 51 healthy subjects and administered ripasudil 0.4% in their right eye. We evaluated conjunctival hyperemia using slit lamp photography and measured the intraocular pressure (IOP) using the Icare PRO Rebound Tonometer at baseline and after 5, 15, 30, 60, 90, and 120 min. The conjunctival hyperemia score was graded by three independent observers on a scale of 0 (none) to 3 (severe). Additionally, we analyzed the "percent coverage" of conjunctival hyperemia by using an automated hyperemia analysis software program; this program provides the pixel coverage of the conjunctival vessels in the region of interest. Dunnett and Steel multiple comparison tests were used, as appropriate, for the subsequent analyses. The conjunctival hyperemia score and percent coverage increased rapidly after the instillation of ripasudil 0.4%, peaking at 15 min (score: 1.83 ± 0.29 [mean ± SD]) and 5 min (11.6% ± 4.7%), respectively, and then gradually decreasing until 120 min (0.45 ± 0.22 and 4.7% ± 1.8%, respectively), when they reached a level that was not significantly different from the baseline values. The IOP decreased significantly compared to the baseline at 30, 60, and 90 min, based on the Dunnett test. Conjunctival hyperemia induced by ripasudil 0.4% peaks rapidly to moderate severity, but subsides relatively quickly.

  17. Agreement between diurnal variations of intraocular pressure by Tono-Pen and Goldmann applanation tonometer in patients on topical anti-glaucoma medication.

    PubMed

    Gupta, Shikha; Sinha, Gautam; Sharma, Reetika; Nayak, Bhagabat; Patil, Bharat; Kashyap, Bibhuti; Shameer, Abdul; Dada, Tanuj

    2016-02-01

    To estimate agreement in diurnal variations of intraocular pressure (IOP) by Tono-Pen (TP) and Goldmann applanation tonometer (GAT) in glaucoma patients on topical anti-glaucoma medication(s). IOP was measured at every 3 h from 7 a.m. to 10 a.m. in 50 eyes of glaucoma patients on topical medication(s). Diurnal fluctuation of IOP by each method was calculated as maximum-minimum IOP in a day. Central corneal thickness (CCT) was measured by ultrasonic pachymeter. There was good correlation between TP and GAT at all times during a day, minimum, and maximum IOPs during a day (Correlation coefficient, 0.706 at 7 a.m., 0.624 at 10 a.m., 0.682 at 1 p.m., 0.814 at 4 p.m., 0.652 at 7 p.m., 0.572 at 10 p.m., 0.668 minimum IOP, 0.689 maximum IOP). Mean IOPs by TP were always higher than GAT at all times during a day. Bland-Altman plots suggested a close relationship between the two sets of readings, and that this relationship was consistent at different times in a day, in maximum IOPs, minimum IOPs and also in fluctuation of IOPs. Linear regression analysis between the differences of diurnal fluctuation (diurnal fluctuation by GAT-diurnal fluctuation by TP) and CCT showed strong association (R 2 = 0.857, p < 0.001). The mean change in difference of diurnal fluctuation (GAT-TP) for a 10-micron increase in CCT was 0.69 mmHg. TP can be considered a reliable alternative to GAT in glaucoma patients for knowing the diurnal control of IOP; however these two methods should not be used interchangeably. Difference of diurnal fluctuation between two methods is dependent on CCT.

  18. Technology-enhanced maintenance of treatment gains in eating disorders: efficacy of an intervention delivered via text messaging.

    PubMed

    Bauer, Stephanie; Okon, Eberhard; Meermann, Rolf; Kordy, Hans

    2012-08-01

    Given the lack of maintenance interventions for eating disorders, a program delivered via the short message service (SMS) and text messaging was developed to support patients after their discharge from inpatient treatment. The efficacy of the intervention was studied in a randomized controlled trial. Additionally, its impact on the utilization of outpatient treatment during follow-up was investigated. One hundred sixty-five female patients with bulimia nervosa or a related eating disorder not otherwise specified were randomly assigned to a control group (treatment as usual; TAU) or an intervention group (SMS-based maintenance intervention; SMS). After hospital discharge, participants in the intervention group submitted a weekly symptom report via text message for 16 weeks and received tailored feedback. Primary outcome was the rate of partial remission 8 months after discharge from inpatient treatment. The difference in remission rates reached significance in the intent-to-treat analyses (SMS = 51.2%; TAU = 36.1%), χ²(1) = 3.81, p = .05, and approached significance in the completer analysis (SMS = 59.2%; TAU = 43.5%), χ²(1) = 3.44, p = .06. There were no differences in the utilization of outpatient treatment. Remission rates between the intervention and control groups were not significantly different among patients who used outpatient treatment (63.2% vs. 55.6%), χ²(1) = 0.44, p = .51. A significant difference was found in those who did not utilize such treatment (54.5% vs. 30.3%), χ²(1) = 3.97, p = .046. The aftercare intervention was efficacious in enhancing treatment outcome after discharge from inpatient treatment. © 2012 American Psychological Association

  19. Aucklandia lappa DC. extract enhances gefitinib efficacy in gefitinib-resistance secondary epidermal growth factor receptor mutations.

    PubMed

    Huang, Guan; Tong, Yanli; He, Qidi; Wang, Jie; Chen, Zuanguang

    2017-07-12

    Aucklandia lappa DC. is a widely used medicinal plant in China, India and Pakistan for a long time. Previously, a number of different pharmacological experiments in vitro and in vivo have convincingly demonstrated the abilities of it to exhibit anticancer activities. Reynoutria japonica Houtt. has also been widely used as traditional Chinese medicinal plant. Previous studies have demonstrated that it is bioactive to exhibit anticancer activities. This study aims to investigate whether the extracts of Aucklandia lappa DC. and Reynoutria japonica Houtt. are capable of treating drug-resistant non-small cell lung cancer (NSCLC), providing support for novel usage beyond traditional uses. Extracts combined with gefitinib have been tested taking the vulval development of transgenic C. elegans (jgIs25) as an effective and simple in vivo model system, evaluating their efficacy against acquired NSCLC. Synchronous larval 1 (L1) larvae were treated with extracts plus gefitinib and cultured to obtain mainly L4 larvae. The multivulva (Muv) phenotype was recorded at the adult stage. Our data showed that Aucklandia lappa DC. extract could significantly enhance the efficacy of gefitinib, suppressing the Muv phenotype of jgIs25. Meanwhile, it could also down-regulate the mRNA and protein expression of EGFR in jgIs25. Collectively, our results verified that the capability of Aucklandia lappa DC. to inhibit Muv phenotype may be based on the EGFR signaling pathway inhibition. We demonstrated that the co-administration of Aucklandia lappa DC. with gefitinib may provide an effective strategy for the therapy of EGFR inhibitor resistant NSCLCs. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  20. Potential Use of Cyclodextrin Complexes for Enhanced Stability, Anti-inflammatory Efficacy, and Ocular Bioavailability of Loteprednol Etabonate.

    PubMed

    Soliman, Osama Abd El-Aazeem; Mohamed, Elham Abdel Monem; El-Dahan, Marwa Salah; Khatera, Nabil Abdullah Ali

    2017-05-01

    Loteprednol etabonate (LE) is a soft corticosteroid that maintains therapeutic activity with much reduced adverse effects. Yet, its ocular bioavailability is hindered by its poor aqueous solubility. Early attempts of LE complexation with cyclodextrins (CDs) did not involve the study of the effects of various complexation methods on the characteristics of the complexes formed. Formulation of complexes into different delivery systems as well in vitro and in vivo assessments has not been accomplished in the earlier studies. In this study, complexation of LE with each of hydroxypropyl-β-cyclodextrin (HP-β-CD) and β-cyclodextrin (β-CD) by kneading, freeze drying, and co-precipitation was attempted. These complexes were incorporated into gels, drops, and ocuserts using hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), and sodium alginate (ALG). These formulae were examined with respect to drug content, pH, viscosity, in vitro release, and stability for 6 months. Kinetic analysis of release data was done. Selected formulations were assessed for their efficacy in the treatment of ocular allergic conjunctivitis and their ocular bioavailability in rabbits' eyes. All formulations exhibited accepted drug content, pH, and viscosity. The drug release was increased by complexation particularly with HP-β-CD in the order of ocuserts ≥ drops > gels, being the highest for HPMC preparations that also exhibited the greatest stability and anti-inflammatory activity especially in case of LE-HP-β-CD complexes. Ocuserts of co-precipitated LE-HP-β-CD using HPMC (5% w/w) and Carbopol 934P (0.1% w/w) provided a significantly enhanced stability (p < 0.05), ocular anti-inflammatory efficacy (p < 0.05), and ocular bioavailability (p < 0.0001), to be represented as a potential ocular delivery system of LE.

  1. Targeting Heparan Sulfate Proteoglycans and their Modifying Enzymes to Enhance Anticancer Chemotherapy Efficacy and Overcome Drug Resistance.

    PubMed

    Lanzi, Cinzia; Zaffaroni, Nadia; Cassinelli, Giuliana

    2017-01-01

    Targeting heparan sulfate proteoglycans (HSPGs) and enzymes involved in heparan sulfate (HS) chain editing is emerging as a new anticancer strategy. The involvement of HSPGs in tumor cell signaling, inflammation, angiogenesis and metastasis indicates that agents able to inhibit aberrant HSPG functions can potentially act as multitarget drugs affecting both tumor cell growth and the supportive boost provided by the microenvironment. Moreover, accumulating evidence supports that an altered expression or function of HSPGs, or of the complex enzyme system regulating their activities, can also depress the tumor response to anticancer treatments in several tumor types. Thereby, targeting HSPGs or HSPG modifying enzymes appears an appealing approach to enhance chemotherapy efficacy. A great deal of effort from academia and industry has led to the development of agents mimicking HS, and/or inhibiting HSPG modifying enzymes. Inhibitors of Sulf-2, an endosulfatase that edits the HS sulfation pattern, and inhibitors of heparanase, the endoglycosidase that produces functional HS fragments, appear particularly promising. In fact, a Sulf-2 inhibitor (OKN-007), and two heparanase inhibitors/HS mimics (roneparstat, PG545) are currently under early clinical investigation. In this review, we summarized preclinical studies in experimental tumor models of the main chemical classes of Sulf-2 and heparanase inhibitors. We described examples of different mechanisms through which heparanase and HSPGs, often in cooperation, may impact tumor sensitivity to various antitumor agents. Finally, we reported a few preclinical studies showing increased antitumor efficacy obtained with the use of candidate clinical HS mimics in combination regimens. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  2. Teacher Self-Efficacy Enhancement and School Location: Implication for Students' Achievement in Economics in Senior Secondary School in Ibadan, Oyo State, Nigeria

    ERIC Educational Resources Information Center

    Durowoju, Esther O.; Onuka, Adams O. U.

    2015-01-01

    The paper investigated the effect of teacher self-efficacy enhancement and school location on students' achievement in Economics in Senior Secondary School in Ibadan Metropolis of Oyo State, Nigeria. Three hypotheses were tested at 0.05 level of significance. Multi-stage sampling technique was adopted in the study. Four Local Government Areas (two…

  3. Administration of Oral Itraconazole Capsule with Whole Milk Shows Enhanced Efficacy As Supported by Scanning Electron Microscopy in a Child with Tinea Capitis Due to Microsporum canis.

    PubMed

    Chen, Shuang; Ran, Yuping; Dai, Yalin; Lama, Jebina; Hu, Wenying; Zhang, Chaoliang

    2015-01-01

    Although diagnosis and treatment of tinea capitis in children are not difficult, treatment failures are still somewhat common. We report a case of pediatric tinea capitis cured using oral itraconazole administered with whole milk, after prior treatment failure when oral itraconazole was administered with water. This apparent enhanced efficacy in one individual was demonstrated using scanning electron microscopy. © 2015 Wiley Periodicals, Inc.

  4. Programme Recruitment and Evaluation: The Effect of an Employability Enhancement Programme on the General Self-Efficacy Levels of Unemployed Graduates

    ERIC Educational Resources Information Center

    Hazenberg, R.; Seddon, F.; Denny, S.

    2015-01-01

    This paper reports research that engaged in the evaluation of an intervention programme designed to enhance the employability of a group of unemployed graduates. The evaluation adopted a quasi-experimental intervention research method employing a general self-efficacy scale, which had been validated in prior research. Results revealed that…

  5. Enhancing Cardiac Rehabilitation With Stress Management Training: A Randomized, Clinical Efficacy Trial.

    PubMed

    Blumenthal, James A; Sherwood, Andrew; Smith, Patrick J; Watkins, Lana; Mabe, Stephanie; Kraus, William E; Ingle, Krista; Miller, Paula; Hinderliter, Alan

    2016-04-05

    Cardiac rehabilitation (CR) is the standard of care for patients with coronary heart disease. Despite considerable epidemiological evidence that high stress is associated with worse health outcomes, stress management training (SMT) is not included routinely as a component of CR. One hundred fifty-one outpatients with coronary heart disease who were 36 to 84 years of age were randomized to 12 weeks of comprehensive CR or comprehensive CR combined with SMT (CR+SMT), with assessments of stress and coronary heart disease biomarkers obtained before and after treatment. A matched sample of CR-eligible patients who did not receive CR made up the no-CR comparison group. All participants were followed up for up to 5.3 years (median, 3.2 years) for clinical events. Patients randomized to CR+SMT exhibited greater reductions in composite stress levels compared with those randomized to CR alone (P=0.022), an effect that was driven primarily by improvements in anxiety, distress, and perceived stress. Both CR groups achieved significant, and comparable, improvements in coronary heart disease biomarkers. Participants in the CR+SMT group exhibited lower rates of clinical events compared with those in the CR-alone group (18% versus 33%; hazard ratio=0.49; 95% confidence interval, 0.25-0.95; P=0.035), and both CR groups had lower event rates compared with the no-CR group (47%; hazard ratio=0.44; 95% confidence interval, 0.27-0.71; P<0.001). CR enhanced by SMT produced significant reductions in stress and greater improvements in medical outcomes compared with standard CR. Our findings indicate that SMT may provide incremental benefit when combined with comprehensive CR and suggest that SMT should be incorporated routinely into CR. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00981253. © 2016 American Heart Association, Inc.

  6. Enhancing Cardiac Rehabilitation With Stress Management Training: A Randomized Clinical Efficacy Trial

    PubMed Central

    Blumenthal, James A.; Sherwood, Andrew; Smith, Patrick J.; Watkins, Lana; Mabe, Stephanie; Kraus, William E.; Ingle, Krista; Miller, Paula; Hinderliter, Alan

    2016-01-01

    Background Cardiac rehabilitation (CR) is the standard of care for patients with coronary heart disease (CHD). Despite considerable epidemiologic evidence that high stress is associated with worse health outcomes, stress management training (SMT) is not included routinely as a component of CR. Methods and Results 151 outpatients with CHD aged 36 to 84 years were randomized to 12-weeks of comprehensive CR or comprehensive CR combined with SMT (CR+SMT), with assessments of stress and CHD biomarkers obtained before and after treatment. A matched sample of CR-eligible patients who did not receive CR comprised a No-CR comparison group. All participants were followed for up to 5.3 years (median = 3.2 years) for clinical events. Patients randomized to CR+SMT exhibited greater reductions in composite stress levels compared with those randomized to CR alone (P = 0.022), an effect that was driven primarily by improvements in anxiety, distress, and perceived stress. Both CR groups achieved significant, and comparable, improvements in CHD biomarkers. Participants in the CR+SMT group exhibited lower rates of clinical events compared with CR alone (18% vs. 33%, HR = 0.49 [0.25, 0.95], P = 0.035) and both CR groups had lower event rates compared to the No-CR group (47%, HR = 0.44 [0.27, 0.71], P < .001). Conclusions CR enhanced by SMT produced significant reductions in stress and greater improvements in medical outcomes compared with standard CR. Our findings indicate that SMT may provide incremental benefit when combined with comprehensive CR and suggest that SMT should be incorporated routinely into CR. Clinical Trial Registration Information www.Clinicaltrials.gov. Identifier: NCT00981253. PMID:27045127

  7. Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: Therapeutic efficacy evaluation.

    PubMed

    Huo, Zhi-Jun; Wang, Shi-Jiang; Wang, Zhi-Qi; Zuo, Wen-Shu; Liu, Ping; Pang, Bo; Liu, Kai

    2015-10-01

    The present study was performed to investigate the therapeutic performance of polymer-lipid hybrid nanoparticles towards the delivery of lapatinib (LPT) in breast cancers. We have successfully developed the lapatinib-loaded polymer-lipid hybrid nanosystem and showed its therapeutic potential in in vitro and in vivo models of breast cancer. The nanoformulations consisted of a polymeric core (poly[lactide-co-glycolide]-D-a-tocopheryl polyethylene glycol 1000 succinate [PLGA-TPGS]), which was then enveloped by a PEGylated lipid layer (DSPE-PEG) (PLPT) to maintain the structural integrity. The PLPT formulation controlled the drug release in pH 7.4 conditions and accelerated the release at pH 5.5 conditions. The PLPT showed a remarkable cellular internalization and efficiently killed the MCF-7 cancer cells in a time- and concentration-dependent manner. Moreover, LPT-loaded nanoparticles effectively induced apoptosis of cancer cells than compared to free LPT. Pharmacokinetic data suggested that nanoparticles could significantly enhance the blood circulation time of LPT by reducing the uptake by a reticuloendothelial system (RES). The prolonged blood circulation of PLPT could allow the preferential accumulation of drug in the tumor tissues. Importantly, PLPT significantly reduced the tumor burden of cancerous mice and effectively controlled the tumor cell proliferation. TUNEL assay further showed a greater apoptosis of tumor tissues in the PLPT treated mice group. Our results suggest that the use of a hybrid system may allow a decrease in the dosage regimen without the loss of therapeutic effect. Overall, lapatinib-loaded hybrid nanoparticles hold great potential for achieving an optimal therapeutic effect in breast cancer treatment. The present anticancer drug delivery system could be potentially applied for the treatment of other cancers.

  8. Novel monoclonal antibody against beta 1 integrin enhances cisplatin efficacy in human lung adenocarcinoma cells.

    PubMed

    Kim, Min-Young; Cho, Woon-Dong; Hong, Kwon Pyo; Choi, Da Bin; Hong, Jeong Won; Kim, Soseul; Moon, Yoo Ri; Son, Seung-Myoung; Lee, Ok-Jun; Lee, Ho-Chang; Song, Hyung Geun

    2016-05-01

    The use of anti-beta 1 integrin monoclonal antibody in lung cancer treatment has proven beneficial. Here, we developed a novel monoclonal antibody (mAb), called P5, by immunizing mice with human peripheral blood mononuclear cells (PBMC). Its anti-tumor effect is now being tested, in a clinical phase III trial, in combinatorial treatments with various chemical drugs. To confirm that P5 indeed binds to beta 1 integrin, cell lysates were immunoprecipitated with commercial anti-beta 1 integrin mAb (TS2/16) and immunoblotted against P5 to reveal a 140 kDa molecular weight band, as expected. Immunoprecipitation with P5 followed by LC/MS protein sequence analysis further verified P5 antigen to be beta 1 integrin. Cisplatin treatment upregulated cell surface expression of beta 1 integrin in A549 cells, while causing inhibition of cell growth. When cells were co-treated with different concentrations of P5 mAb, the cisplatin-mediated inhibitory effect was enhanced in a dose-dependent manner. Our findings show that a combinatorial treatment of P5 mAb and cisplatin in A549 cells resulted in a 30% increase in apoptosis, compared to baseline, and significantly more when compared to either the cisplatin or P5 alone group. The entire peptide sequences in CDR from variable region of Ig heavy and light chain gene for P5 mAb are also disclosed. Together, these results provide evidence of the beneficial effect of P5 mAb in combinatorial treatment of human lung adenocarcinoma.

  9. Enhanced efficacy and reduced side effects of diazepam by kava combination.

    PubMed

    Tawfiq, Rasha A; Nassar, Noha N; El-Eraky, Wafaa I; El-Denshary, Ezzeldein S

    2014-09-01

    The long term use of antiepileptic drugs possesses many unwanted effects; thus, new safe combinations are urgently mandated. Hence, the present study aimed to investigate the anticonvulsant effect of kava alone or in combination with a synthetic anticonvulsant drug, diazepam (DZ). To this end, female Wistar rats were divided into two subsets, each comprising 6 groups as follows: group (i) received 1% Tween 80 p.o. and served as control, while groups (ii) and (iii) received kava at two dose levels (100 and 200 mg/kg, p.o.). The remaining three groups received (iv) DZ alone (10 mg/kg p.o.) or kava in combination with DZ (v) (5 mg/kg, p.o.) or (vi) (10 mg/kg, p.o.). Results of the present study revealed that kava increased the maximal electroshock seizure threshold (MEST) and enhanced the anticonvulsant effect of diazepam following both acute and chronic treatment. Moreover, neither kava nor its combination with DZ impaired motor co-ordination either acutely or chronically. Furthermore, kava ameliorated both the reduction in locomotor activity as well as changes in liver function tests induced by chronic administration of DZ. Moreover, no elevation was shown in the creatinine concentration vs. control group following chronic administration of kava or DZ either alone or in combination with kava. In conclusion, the present study suggests the possibility of combining a low dose DZ with kava to reduce harmful effects and might be recommended for clinical use in patients chronically treated with this synthetic anticonvulsant drug.

  10. Enhanced stability and antibacterial efficacy of a traditional Chinese medicine-mediated silver nanoparticle delivery system

    PubMed Central

    Sun, Wenjie; Qu, Ding; Ma, Yihua; Chen, Yan; Liu, Congyan; Zhou, Jing

    2014-01-01

    Silver nanoparticles (AgNPs) are widely used as antibacterial products in various fields. Recent studies have suggested that AgNPs need an appropriate stabilizer to improve their stability. Some antibacterial traditional Chinese medicines (TCMs) contain various reductive components, which can not only stabilize AgNPs but also enhance their antimicrobial activity. In this study, we developed a series of novel AgNPs using a TCM extract as a stabilizer, reducing agent, and antimicrobial agent (TCM-AgNPs). A storage stability investigation of the TCM-AgNPs suggested a significant improvement when compared with bare AgNPs. Further, conjugation of TCMs onto the AgNP surface resulted in stronger antimicrobial potency on antibacterial evaluation using Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus with minimum inhibitory concentration 50% (MIC50) ratios (and minimum bactericidal concentration 90% [MBC90] ratios) of AgNPs to respective TCM-AgNPs as assessment indices. Among these, P. cuspidatum Sieb. et-conjugated AgNPs (P.C.-AgNPs) had the advantage of a combination of TCMs and AgNPs and was studied in detail with regard to its synthesis and characterization. The extraction time, reaction temperature, and concentrations of AgNO3 and Polygonum cuspidatum Sieb. et extract were critical factors in the preparation of P.C.-AgNPs. Further, the results of X-ray diffraction and Fourier transform infrared spectroscopy indicated successful preparation of P.C.-AgNPs. In representative studies, P.C.-AgNPs showed a well-defined spherical shape, a homogeneous small particle size (36.78 nm), a narrow polydispersity index (0.105), and a highly negative zeta potential (−23.6 mV) on transmission electron microscopy and dynamic light scattering. These results indicate that TCM-AgNPs have a potential role as antibacterial agents in the clinic setting. PMID:25473286

  11. Enhanced stability and antibacterial efficacy of a traditional Chinese medicine-mediated silver nanoparticle delivery system.

    PubMed

    Sun, Wenjie; Qu, Ding; Ma, Yihua; Chen, Yan; Liu, Congyan; Zhou, Jing

    2014-01-01

    Silver nanoparticles (AgNPs) are widely used as antibacterial products in various fields. Recent studies have suggested that AgNPs need an appropriate stabilizer to improve their stability. Some antibacterial traditional Chinese medicines (TCMs) contain various reductive components, which can not only stabilize AgNPs but also enhance their antimicrobial activity. In this study, we developed a series of novel AgNPs using a TCM extract as a stabilizer, reducing agent, and antimicrobial agent (TCM-AgNPs). A storage stability investigation of the TCM-AgNPs suggested a significant improvement when compared with bare AgNPs. Further, conjugation of TCMs onto the AgNP surface resulted in stronger antimicrobial potency on antibacterial evaluation using Pseudomonas aeruginosa, Staphylococcus epidermidis, and Staphylococcus aureus with minimum inhibitory concentration 50% (MIC50) ratios (and minimum bactericidal concentration 90% [MBC90] ratios) of AgNPs to respective TCM-AgNPs as assessment indices. Among these, P. cuspidatum Sieb. et-conjugated AgNPs (P.C.-AgNPs) had the advantage of a combination of TCMs and AgNPs and was studied in detail with regard to its synthesis and characterization. The extraction time, reaction temperature, and concentrations of AgNO3 and Polygonum cuspidatum Sieb. et extract were critical factors in the preparation of P.C.-AgNPs. Further, the results of X-ray diffraction and Fourier transform infrared spectroscopy indicated successful preparation of P.C.-AgNPs. In representative studies, P.C.-AgNPs showed a well-defined spherical shape, a homogeneous small particle size (36.78 nm), a narrow polydispersity index (0.105), and a highly negative zeta potential (-23.6 mV) on transmission electron microscopy and dynamic light scattering. These results indicate that TCM-AgNPs have a potential role as antibacterial agents in the clinic setting.

  12. Novel nanosystem to enhance the antitumor activity of lapatinib in breast cancer treatment: Therapeutic efficacy evaluation

    PubMed Central

    Huo, Zhi-Jun; Wang, Shi-Jiang; Wang, Zhi-Qi; Zuo, Wen-Shu; Liu, Ping; Pang, Bo; Liu, Kai

    2015-01-01

    The present study was performed to investigate the therapeutic performance of polymer-lipid hybrid nanoparticles towards the delivery of lapatinib (LPT) in breast cancers. We have successfully developed the lapatinib-loaded polymer-lipid hybrid nanosystem and showed its therapeutic potential in in vitro and in vivo models of breast cancer. The nanoformulations consisted of a polymeric core (poly[lactide-co-glycolide]-D-a-tocopheryl polyethylene glycol 1000 succinate [PLGA–TPGS]), which was then enveloped by a PEGylated lipid layer (DSPE-PEG) (PLPT) to maintain the structural integrity. The PLPT formulation controlled the drug release in pH 7.4 conditions and accelerated the release at pH 5.5 conditions. The PLPT showed a remarkable cellular internalization and efficiently killed the MCF-7 cancer cells in a time- and concentration-dependent manner. Moreover, LPT-loaded nanoparticles effectively induced apoptosis of cancer cells than compared to free LPT. Pharmacokinetic data suggested that nanoparticles could significantly enhance the blood circulation time of LPT by reducing the uptake by a reticuloendothelial system (RES). The prolonged blood circulation of PLPT could allow the preferential accumulation of drug in the tumor tissues. Importantly, PLPT significantly reduced the tumor burden of cancerous mice and effectively controlled the tumor cell proliferation. TUNEL assay further showed a greater apoptosis of tumor tissues in the PLPT treated mice group. Our results suggest that the use of a hybrid system may allow a decrease in the dosage regimen without the loss of therapeutic effect. Overall, lapatinib-loaded hybrid nanoparticles hold great potential for achieving an optimal therapeutic effect in breast cancer treatment. The present anticancer drug delivery system could be potentially applied for the treatment of other cancers. PMID:26177628

  13. The vascular disrupting agent ZD6126 shows increased antitumor efficacy and enhanced radiation response in large, advanced tumors

    SciTech Connect

    Siemann, Dietmar W. . E-mail: siemadw@ufl.edu; Rojiani, Amyn M.

    2005-07-01

    Purpose: ZD6126 is a vascular-targeting agent that induces selective effects on the morphology of proliferating and immature endothelial cells by disrupting the tubulin cytoskeleton. The efficacy of ZD6126 was investigated in large vs. small tumors in a variety of animal models. Methods and Materials: Three rodent tumor models (KHT, SCCVII, RIF-1) and three human tumor xenografts (Caki-1, KSY-1, SKBR3) were used. Mice bearing leg tumors ranging in size from 0.1-2.0 g were injected intraperitoneally with a single 150 mg/kg dose of ZD6126. The response was assessed by morphologic and morphometric means as well as an in vivo to in vitro clonogenic cell survival assay. To examine the impact of tumor size on the extent of enhancement of radiation efficacy by ZD6126, KHT sarcomas of three different sizes were irradiated locally with a range of radiation doses, and cell survival was determined. Results: All rodent tumors and human tumor xenografts evaluated showed a strong correlation between increasing tumor size and treatment effect as determined by clonogenic cell survival. Detailed evaluation of KHT sarcomas treated with ZD6126 showed a reduction in patent tumor blood vessels that was {approx}20% in small (<0.3 g) vs. >90% in large (>1.0 g) tumors. Histologic assessment revealed that the extent of tumor necrosis after ZD6126 treatment, although minimal in small KHT sarcomas, became more extensive with increasing tumor size. Clonogenic cell survival after ZD6126 exposure showed a decrease in tumor surviving fraction from approximately 3 x 10{sup -1} to 1 x 10{sup -4} with increasing tumor size. When combined with radiotherapy, ZD6126 treatment resulted in little enhancement of the antitumor effect of radiation in small (<0.3 g) tumors but marked increases in cell kill in tumors larger than 1.0 g. Conclusions: Because bulky neoplastic disease is typically the most difficult to manage, the present findings provide further support for the continued development of vascular

  14. Comparative Bacteriological Efficacy of Pharmacokinetically Enhanced Amoxicillin-Clavulanate against Streptococcus pneumoniae with Elevated Amoxicillin MICs and Haemophilus influenzae

    PubMed Central

    Berry, Valerie; Hoover, Jennifer; Singley, Christine; Woodnutt, Gary

    2005-01-01

    A new pharmacokinetically enhanced formulation of amoxicillin-clavulanate (2,000 mg of amoxicillin/125 mg of clavulanate twice a day; ratio 16:1) has been designed, with sustained-release technology, to allow coverage of bacterial strains with amoxicillin-clavulanic acid MICs of at least 4/2 μg/ml. The bacteriological efficacy of amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was compared in a rat model of respiratory tract infection versus four other amoxicillin-clavulanate formulations: 8:1 three times a day (1,000/125 mg), 7:1 three times a day (875/125 mg), 7:1 twice a day (875/125 mg), and 4:1 three times a day (500/125 mg); levofloxacin (500 mg once a day); and azithromycin (1,000 mg on day 1 followed thereafter by 500 mg once a day). Bacterial strains included Streptococcus pneumoniae, with amoxicillin-clavulanic acid MICs of 2/1 (one strain), 4/2, or 8/4 μg/ml (three strains each), and Haemophilus influenzae, one β-lactamase-positive strain and one β-lactamase-negative, ampicillin-resistant strain. Animals were infected by intrabronchial instillation. Antibacterial treatment commenced 24 h postinfection, with doses delivered by computer-controlled intravenous infusion to approximate the concentrations achieved in human plasma following oral administration. Plasma concentrations in the rat corresponded closely with target human concentrations for all antimicrobials tested. Amoxicillin-clavulanate, 2,000/125 mg twice a day, ratio 16:1, was effective against all S. pneumoniae strains tested, including those with amoxicillin-clavulanic acid MICs of up to 8/4 μg/ml and against β-lactamase-producing and β-lactamase-negative ampicillin-resistant H. influenzae. These results demonstrate the bacteriological efficacy of pharmacokinetically enhanced amoxicillin-clavulanate 2,000/125 mg twice a day (ratio 16:1) against S. pneumoniae with amoxicillin-clavulanic acid MICs of at least 4/2 μg/ml and support clavulanate 125 mg twice a day as

  15. Combining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy

    SciTech Connect

    Chen Bin; Pogue, Brian W. . E-mail: pogue@dartmouth.edu; Hoopes, P. Jack; Hasan, Tayyaba

    2005-03-15

    treatments. Histologic studies confirmed that this combined treatment led to damage to both tumor vasculature and tumor cells. Importantly, the combined PDT treatment did not increase normal tissue damage and tissue recovered well at 60 days after treatment. Conclusions: Our results suggest that targeting both tumor vascular and cellular compartments by combining a long-interval PDT with a short-interval PDT can be an effective and safe way to enhance PDT damage to tumor tissue.

  16. Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment efficacy in ovarian cancer

    PubMed Central

    Kim, Joo-Eun; Park, Young-Joon

    2017-01-01

    cancers characterized by CD44 overexpression, enhanced active tumor targeting, and low toxicity. PMID:28176896

  17. Paclitaxel-loaded hyaluronan solid nanoemulsions for enhanced treatment efficacy in ovarian cancer.

    PubMed

    Kim, Joo-Eun; Park, Young-Joon

    2017-01-01

    cancers characterized by CD44 overexpression, enhanced active tumor targeting, and low toxicity.

  18. Enhanced efficacy of photodynamic therapy after fractional resurfacing: fractional photodynamic rejuvenation.

    PubMed

    Ruiz-Rodriguez, Ricardo; López, Laura; Candelas, Daniel; Zelickson, Brian

    2007-08-01

    study shows a potential for enhanced clinical results when using combined fractional resurfacing and ALA-PDT compared to fractional resurfacing alone.

  19. The effects of a computer skill training programme adopting social comparison and self-efficacy enhancement strategies on self-concept and skill outcome in trainees with physical disabilities.

    PubMed

    Tam, S F

    2000-10-15

    The aim of this controlled, quasi-experimental study was to evaluate the effects of both self-efficacy enhancement and social comparison training strategy on computer skills learning and self-concept outcome of trainees with physical disabilities. The self-efficacy enhancement group comprised 16 trainees, the tutorial training group comprised 15 trainees, and there were 25 subjects in the control group. Both the self-efficacy enhancement group and the tutorial training group received a 15 week computer skills training course, including generic Chinese computer operation, Chinese word processing and Chinese desktop publishing skills. The self-efficacy enhancement group received training with tutorial instructions that incorporated self-efficacy enhancement strategies and experienced self-enhancing social comparisons. The tutorial training group received behavioural learning-based tutorials only, and the control group did not receive any training. The following measurements were employed to evaluate the outcomes: the Self-Concept Questionnaire for the Physically Disabled Hong Kong Chinese (SCQPD), the computer self-efficacy rating scale and the computer performance rating scale. The self-efficacy enhancement group showed significantly better computer skills learning outcome, total self-concept, and social self-concept than the tutorial training group. The self-efficacy enhancement group did not show significant changes in their computer self-efficacy: however, the tutorial training group showed a significant lowering of their computer self-efficacy. The training strategy that incorporated self-efficacy enhancement and positive social comparison experiences maintained the computer self-efficacy of trainees with physical disabilities. This strategy was more effective in improving the learning outcome (p = 0.01) and self-concept (p = 0.05) of the trainees than the conventional tutorial-based training strategy.

  20. Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis

    PubMed Central

    Liao, Wenbin; Pham, Victor; Liu, Linan; Riazifar, Milad; Pone, Egest J; Zhang, Shirley Xian; Ma, Fengxia; Lu, Mengrou; Walsh, Craig M.; Zhao, Weian

    2015-01-01

    Systemic administration of mesenchymal stem cells (MSCs) affords the potential to ameliorate the symptoms of Multiple Sclerosis (MS) in both preclinical and clinical studies. However, the efficacy of MSC-based therapy for MS likely depends on the number of cells that home to inflamed tissues and on the controlled production of paracrine and immunomodulatory factors. Previously, we reported that engineered MSCs expressing P-selectin glycoprotein ligand-1 (PSGL-1) and Sialyl-Lewisx (SLeX) via mRNA transfection facilitated the targeted delivery of anti-inflammatory cytokine interleukin-10 (IL-10) to inflamed ear. Here, we evaluated whether targeted delivery of MSCs with triple PSGL1/SLeX/IL-10 engineering improves therapeutic outcomes in mouse experimental autoimmune encephalomyelitis (EAE), a murine model for human MS. We found PSGL-1/SLeX mRNA transfection significantly enhanced MSC homing to the inflamed spinal cord. This is consistent with results from in vitro flow chamber assays in which PSGL-1/SleX mRNA transfection significantly increased the percentage of rolling and adherent cells on activated brain microvascular endothelial cells, which mimic the inflamed endothelium of blood brain/spinal cord barrier in EAE. In addition, IL-10-transfected MSCs show significant inhibitory activity on the proliferation of CD4+ T lymphocytes from EAE mice. In vivo treatment with MSCs engineered with PSGL-1/SLeX/IL-10 in EAE mice exhibited a superior therapeutic function over native (unmodified) MSCs, evidenced by significantly improved myelination and decreased lymphocytes infiltration into the white matter of the spinal cord. Our strategy of targeted delivery of performance-enhanced MSCs could potentially be utilized to increase the effectiveness of MSC-based therapy for MS and other central nervous system (CNS) disorders. PMID:26584349

  1. TXA709, an FtsZ-Targeting Benzamide Prodrug with Improved Pharmacokinetics and Enhanced In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Kaul, Malvika; Mark, Lilly; Zhang, Yongzheng; Parhi, Ajit K.; Lyu, Yi Lisa; Pawlak, Joan; Saravolatz, Stephanie; Saravolatz, Louis D.; Weinstein, Melvin P.; LaVoie, Edmond J.

    2015-01-01

    The clinical development of FtsZ-targeting benzamide compounds like PC190723 has been limited by poor drug-like and pharmacokinetic properties. Development of prodrugs of PC190723 (e.g., TXY541) resulted in enhanced pharmaceutical properties, which, in turn, led to improved intravenous efficacy as well as the first demonstration of oral efficacy in vivo against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Despite being efficacious in vivo, TXY541 still suffered from suboptimal pharmacokinetics and the requirement of high efficacious doses. We describe here the design of a new prodrug (TXA709) in which the Cl group on the pyridyl ring has been replaced with a CF3 functionality that is resistant to metabolic attack. As a result of this enhanced metabolic stability, the product of the TXA709 prodrug (TXA707) is associated with improved pharmacokinetic properties (a 6.5-fold-longer half-life and a 3-fold-greater oral bioavailability) and superior in vivo antistaphylococcal efficacy relative to PC190723. We validate FtsZ as the antibacterial target of TXA707 and demonstrate that the compound retains potent bactericidal activity against S. aureus strains resistant to the current standard-of-care drugs vancomycin, daptomycin, and linezolid. These collective properties, coupled with minimal observed toxicity to mammalian cells, establish the prodrug TXA709 as an antistaphylococcal agent worthy of clinical development. PMID:26033735

  2. Sequential co-delivery of miR-21 inhibitor followed by burst release doxorubicin using NIR-responsive hollow gold nanoparticle to enhance anticancer efficacy.

    PubMed

    Ren, Yu; Wang, Ruirui; Gao, Lizhang; Li, Ke; Zhou, Xuan; Guo, Hua; Liu, Chaoyong; Han, Donglin; Tian, Jianguo; Ye, Qing; Hu, Ye Tony; Sun, Duxin; Yuan, Xubo; Zhang, Ning

    2016-04-28

    Previous literature and our study showed the delivery sequence of microRNA inhibitor and chemotherapeutic compounds achieve distinct therapeutic anticancer efficacy. Yet, it is challenging to use nanoparticle to achieve sequential drug delivery. In the current study, we designed sequential co-delivery system using a near-infrared-radiation (NIR) responsive hollow gold nanoparticle (HGNPs) to achieve sequential release of microRNA inhibitor (miR-21i)/doxirubicin(Dox) in order to achieve synergistic efficacy. PAMAM modified HGNPs was used to encapsulate miR-21i and Dox. Upon entering tumor cells, miRNA-21i was released first to sensitize the cancer cells, the subsequent burst release of Dox was achieved by NIR triggered collapse of HGNPs. This sequential delivery of miRNA-21i and Dox produced a synergistic apoptotic response, thereby enhancing anticancer efficacy by 8-fold and increasing anti-cancer stem cell activity by 50-fold. The sequential delivery of miR-21i and Dox using HGNPs under NIR after intravenous administration showed high tumor accumulation and significantly improved efficacy, which was 4-fold compared to free Dox group. These data suggested that the sequential co-delivery of miR-21i followed by burst release Dox using NIR-responsive HGNPs sensitized cancer cells to chemotherapeutic compound, which provided a novel concept for co-delivery miRNA inhibitors and chemotherapeutic compounds to enhance their efficacy.

  3. A Galleria mellonella infection model reveals double and triple antibiotic combination therapies with enhanced efficacy versus a multidrug-resistant strain of Pseudomonas aeruginosa.

    PubMed

    Krezdorn, Jessica; Adams, Sophie; Coote, Peter J

    2014-07-01

    The aim of this study was to compare the inhibitory effect of antibiotic combinations in vitro with efficacy in Galleria mellonella larvae in vivo to identify efficacious combinations that target Pseudomonas aeruginosa. P. aeruginosa NCTC 13437, a multidrug-resistant strain resistant to β-lactams and aminoglycosides, was used. Susceptibility to cefotaxime, piperacillin, meropenem, amikacin, levofloxacin and colistin alone, or in dual or triple combinations, was measured in vitro via a 24 h time-kill assay. In vitro results were then compared with the efficacy of the same dual or triple antibiotic combinations versus G. mellonella larvae infected with P. aeruginosa. G. mellonella haemolymph burden of P. aeruginosa was determined over 96 h post-infection and treatment with the most potent combination therapies. Many dual and triple combinations of antibiotics displayed synergistic inhibition of multidrug-resistant P. aeruginosa in vitro. There was little correlation between combinations that were synergistic in vitro and those that showed enhanced efficacy in vivo versus infected G. mellonella larvae. The most potent dual and triple combinations in vivo were cefotaxime plus piperacillin, and meropenem plus piperacillin and amikacin, respectively. Fewer combinations were found to offer enhanced therapeutic benefit in vivo compared with in vitro. The therapeutic benefit arising from treatment with antibiotic combinations in vivo correlated with reduced larval burden of P. aeruginosa. This study has identified antibiotic combinations that merit further investigation for their clinical potential and has demonstrated the utility of using G. mellonella to screen for novel antibiotic treatments that demonstrate efficacy in vivo.

  4. Therapeutic efficacy of a herpes simplex virus with radiation or temozolomide for intracranial glioblastoma after convection-enhanced delivery.

    PubMed

    Hadjipanayis, Costas G; Fellows-Mayle, Wendy; Deluca, Neal A

    2008-11-01

    The herpes simplex virus-1 (HSV-1)-infected cell protein 0 (ICP0) is an E3 ubiquitin ligase implicated in cell cycle arrest and DNA repair inhibition. Convection-enhanced delivery (CED) of either the replication-defective, ICP0-producing HSV-1 mutant, d106, or the recombinant d109, devoid of all viral genome expression, was performed to determine the in vivo efficacy of ICP0 in combination with ionizing radiation (IR) or systemic temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). Intracranial U87-MG xenografts were established in athymic nude mice. Animal survival was determined after mice underwent intracranial CED of either the replication-defective d106 or d109 viruses, or Hanks' balanced salt solution (HBSS), before a single session of whole-brain irradiation or TMZ treatment. Median survival for animals that underwent treatment with HBSS alone, d109 alone, d106 alone, HBSS + IR, HBSS + TMZ, d109 + IR, d106 + IR, and d106 + TMZ was 28, 35, 41, 39, 44, 39, 68 (P < 0.01), and 66 days (P < 0.01), respectively. Intracerebral d106 CED resulted in a significant increase in athymic nude mouse survival when combined with IR or TMZ. d106 CED allows for distribution of HSV-1 in human GBM xenografts and persistent viral infection.

  5. CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma

    PubMed Central

    Zhou, Jin; Wu, Zhong; Wong, Gabrielle; Pectasides, Eirini; Nagaraja, Ankur; Stachler, Matthew; Zhang, Haikuo; Chen, Ting; Zhang, Haisheng; Liu, Jie Bin; Xu, Xinsen; Sicinska, Ewa; Sanchez-Vega, Francisco; Rustgi, Anil K.; Diehl, J. Alan; Wong, Kwok-Kin; Bass, Adam J.

    2017-01-01

    Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial–mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade. We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy. Furthermore, genomic profiling shows that cell cycle regulators are altered in the majority of EGFR-amplified tumours and a combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of resistance in vitro and in vivo. These data suggest that upfront combination strategies targeting EGFR amplification, guided by adaptive pathway reactivation or by co-occurring genomic alterations, should be tested clinically. PMID:28059068

  6. Gracilaria lemaneiformis polysaccharide as integrin-targeting surface decorator of selenium nanoparticles to achieve enhanced anticancer efficacy.

    PubMed

    Jiang, Wenting; Fu, Yuanting; Yang, Fang; Yang, Yufeng; Liu, Ting; Zheng, Wenjie; Zeng, Lilan; Chen, Tianfeng

    2014-08-27

    The poor permeability of glioma parenchyma represents a major limit for antiglioblastoma drug delivery. Gracilaria lemaneiformis polysaccharide (GLP), which has a high binding affinity to αvβ3 integrin overexpressed in glioma cells, was employed in the present study to functionalize selenium nanoparticles (SeNPs) to achieve antiglioblastoma efficacy. GLP-SeNPs showed satisfactory size distribution, high stability, and selectivity between cancer and normal cells. In U87 glioma cell membrane, which has a high integrin expression level, GLP-SeNPs exhibited significantly higher cellular uptake than unmodified SeNPs. As expected, U87 cells exhibited a greater uptake of GLP-SeNPs than C6 cells with low integrin expression level. Furthermore, the internalization of GLP-SeNPs was inhibited by cyclo-(Arg-Gly-Asp-Phe-Lys) peptides, suggesting that cellular uptake into U87 cells and C6 cells occurred via αvβ3 integrin-mediated endocytosis. For U87 cells, the cytotoxicity of SeNPs decorated by GLP was enhanced significantly because of the induction of various apoptosis signaling pathways. Internalized GLP-SeNPs triggered intracellular reactive oxygen species downregulation. Therefore, p53, MAPKs, and AKT pathways were activated to advance cell apoptosis. These findings suggest that surface decoration of nanomaterials with GLP could be an efficient strategy for design and preparation of glioblastoma targeting nanodrugs.

  7. Enhanced efficacy of sequential administration of Albendazole for the clearance of Wuchereria bancrofti infection: Double blind RCT.

    PubMed

    De Britto, R L; Vanamail, P; Sankari, T; Vijayalakshmi, G; Das, L K; Pani, S P

    2015-06-01

    Till today, there is no effective treatment protocol for the complete clearance of Wuchereria bancrofti (W.b) infection that causes secondary lymphoedema. In a double blind randomized control trial (RCT), 146 asymptomatic W. b infected individuals were randomly assigned to one of the four regimens for 12 days, DEC 300 mg + Doxycycline 100 mg coadministration or DEC 300 mg + Albendazole 400 mg co-administration or DEC 300 mg + Albendazole 400 mg sequential administration or control regimen DEC 300 mg and were followed up at 13, 26 and 52 weeks post-treatment for the clearance of infection. At intake, there was no significant variation in mf counts (F(3,137)=0.044; P=0.988) and antigen levels (F(3,137)=1.433; P=0.236) between the regimens. Primary outcome analysis showed that DEC + Albendazole sequential administration has an enhanced efficacy over DEC + Albendazole co-administration (80.6 Vs 64.7%), and this regimen is significantly different when compared to DEC + doxycycline co-administration and control (P<0.05), in clearing microfilaria in 13 weeks. Secondary outcome analysis showed that, all the trial regimens were comparable to control regimen in clearing antigen (F(3, 109)=0.405; P=0.750). Therefore, DEC + Albendazole sequential administration appears to be a better option for rapid clearance of W. b microfilariae in 13 weeks time. (Clinical trials.gov identifier - NCT02005653).

  8. Mixed poly(vinyl pyrrolidone)-based drug-loaded nanomicelles shows enhanced efficacy against pancreatic cancer cell lines.

    PubMed

    Veeren, Anisha; Bhaw-Luximon, Archana; Mukhopadhyay, Debabrata; Jhurry, Dhanjay

    2017-03-18

    We report in this paper on the enhanced efficacy of a physical mixture of two single anti-cancer loaded nanomicelles against PANC-1 and BxPC-3. Poly(vinyl pyrrolidone-b-polycaprolactone) (PVP-b-PCL) and poly(vinyl pyrrolidone-b-poly(dioxanone-co-methyl dioxanone)) (PVP-b-P(DX-co-MeDX)) were synthesized and successfully loaded with various anti-cancer drugs - gemcitabine (GEM), doxorubicin.HCl (DOX.HCl), doxorubicin.NH2 (DOX), 5-fluorouracil (5-FU) and paclitaxel (PTX). Spherical micelles of size 160-477 nm were obtained as characterized by DLS while sizes determined by TEM were in the range 140-250 nm. The hydrophobic drugs had a higher loading percentage efficiency compared to hydrophilic drugs in the trend PTX>DOX>5-FU>GEM>DOX.HCl whereas the drug release pattern followed the reverse trend in accordance with decreased polymer-drug interaction as quantified by the binding constant and micellar drug location. Cellular uptake studies showed that nanomicelles are taken up by pancreatic cancer cells into the cytoplasm and nucleus. The free nanomicelles were confirmed to be non-cytotoxic. A physical mixture of GEM loaded micelles and DOX.HCl loaded micelles of comparable size showed significantly higher cytotoxicity than either the free drug mixture or the individual single drug loaded micelles as confirmed by their IC50 values.

  9. Does computerized working memory training with game elements enhance motivation and training efficacy in children with ADHD?

    PubMed

    Prins, Pier J M; Dovis, Sebastiaan; Ponsioen, Albert; ten Brink, Esther; van der Oord, Saskia

    2011-03-01

    This study examined the benefits of adding game elements to standard computerized working memory (WM) training. Specifically, it examined whether game elements would enhance motivation and training performance of children with ADHD, and whether it would improve training efficacy. A total of 51 children with ADHD aged between 7 and 12 years were randomly assigned to WM training in a gaming format or to regular WM training that was not in a gaming format. Both groups completed three weekly sessions of WM training. Children using the game version of the WM training showed greater motivation (i.e., more time training), better training performance (i.e., more sequences reproduced and fewer errors), and better WM (i.e., higher scores on a WM task) at post-training than children using the regular WM training. Results are discussed in terms of executive functions and reinforcement models of ADHD. It is concluded that WM training with game elements significantly improves the motivation, training performance, and working memory of children with ADHD. The findings of this study are encouraging and may have wide-reaching practical implications in terms of the role of game elements in the design and implementation of new intervention efforts for children with ADHD.

  10. Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: a new paradigm for effective cancer therapy.

    PubMed

    Dong, Lan-Feng; Jameson, Victoria J A; Tilly, David; Prochazka, Lubomir; Rohlena, Jakub; Valis, Karel; Truksa, Jaroslav; Zobalova, Renata; Mahdavian, Elahe; Kluckova, Katarina; Stantic, Marina; Stursa, Jan; Freeman, Ruth; Witting, Paul K; Norberg, Erik; Goodwin, Jacob; Salvatore, Brian A; Novotna, Jana; Turanek, Jaroslav; Ledvina, Miroslav; Hozak, Pavel; Zhivotovsky, Boris; Coster, Mark J; Ralph, Stephen J; Smith, Robin A J; Neuzil, Jiri

    2011-06-01

    Mitochondria are emerging as intriguing targets for anti-cancer agents. We tested here a novel approach, whereby the mitochondrially targeted delivery of anti-cancer drugs is enhanced by the addition of a triphenylphosphonium group (TPP(+)). A mitochondrially targeted analog of vitamin E succinate (MitoVES), modified by tagging the parental compound with TPP(+), induced considerably more robust apoptosis in cancer cells with a 1-2 log gain in anti-cancer activity compared to the unmodified counterpart, while maintaining selectivity for malignant cells. This is because MitoVES associates with mitochondria and causes fast generation of reactive oxygen species that then trigger mitochondria-dependent apoptosis, involving transcriptional modulation of the Bcl-2 family proteins. MitoVES proved superior in suppression of experimental tumors compared to the untargeted analog. We propose that mitochondrially targeted delivery of anti-cancer agents offers a new paradigm for increasing the efficacy of compounds with anti-cancer activity. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Enhancing adolescent self-efficacy and collective efficacy through public engagement around HIV/AIDS competence: a multilevel, cluster randomized-controlled trial.

    PubMed

    Carlson, Mary; Brennan, Robert T; Earls, Felton

    2012-09-01

    The potential capacity of children to confront the HIV/AIDS pandemic is rarely considered. Interventions to address the impact of the pandemic on children and adolescents commonly target only their vulnerabilities. We evaluated the Young Citizens Program, an adolescent-centered health promotion curriculum designed to increase self- and collective efficacy through public education and community mobilization across a municipality in the Kilimanjaro Region of Tanzania. The theoretical framework for the program integrates aspects of human capability, communicative action, social ecology and social cognition. The design consists of a cluster randomized-controlled trial (CRCT). Fifteen pairs of matched geopolitically defined neighborhoods of roughly 2000-4000 residents were randomly allocated to treatment and control arms. Within each neighborhood cluster, 24 randomly selected adolescents, ages 9-14, deliberated on topics of social ecology, citizenship, community health and HIV/AIDS competence. Building on their acquired understanding and confidence, they dramatized the scientific basis and social context of HIV infection, testing and treatment in their communities over a 28-week period. The curriculum comprised 5 modules: Group Formation, Understanding our Community, Health and our Community, Making Assessments and Taking Action in our Community and Inter-Acting in our Community. Adolescent participants and adult residents representative of their neighborhoods were surveyed before and after the intervention; data were analyzed using multilevel modeling. In treatment neighborhoods, adolescents increased their deliberative and communicative efficacy and adults showed higher collective efficacy for children. Following the CRCT assessments, the control group received the same curriculum. In the Kilimanjaro Region, the Young Citizens Program is becoming recognized as a structural, health promotion approach through which adolescent self-efficacy and child collective efficacy

  12. Self-Efficacy for Coping with Cancer Enhances the Effect of Reiki Treatments During the Pre-Surgery Phase of Breast Cancer Patients.

    PubMed

    Chirico, Andrea; D'Aiuto, Giuseppe; Penon, Antonella; Mallia, Luca; DE Laurentiis, Michelino; Lucidi, Fabio; Botti, Gerardo; Giordano, Antonio

    2017-07-01

    Self-efficacy for coping with cancer plays a critical role in influencing psychological cancer-related outcomes, some studies suggested its role in enhancing or reducing the effects of psychological interventions in cancer patients. Reiki has recently been included among the efficacious complementary therapeutic intervention for cancer patients. The present study evaluated the role of self-efficacy for coping with cancer as buffer of the Reiki treatment effects on cancer-related symptoms in a randomized controlled trial (intervention versus control group) of breast cancer patients (N=110) during the pre-surgery phase. Results showed that self-efficacy for coping with cancer can influence the effect of a Reiki treatment. Higher efficacious patients showed a more powerful effect of the Reiki intervention on both anxiety and mood than the low efficacious patients. From a practical perspective, the study provides insightful results for healthcare professionals. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Pre-service teachers' knowledge of phonemic awareness: relationship to perceived knowledge, self-efficacy beliefs, and exposure to a multimedia-enhanced lecture.

    PubMed

    Martinussen, Rhonda; Ferrari, Julia; Aitken, Madison; Willows, Dale

    2015-10-01

    This study examined the relations among perceived and actual knowledge of phonemic awareness (PA), exposure to PA instruction during practicum, and self-efficacy for teaching PA in a sample of 54 teacher candidates (TCs) enrolled in a 1-year Bachelor of Education program in a Canadian university. It also assessed the effects of a brief multimedia-enhanced lecture on TCs' actual knowledge of PA and efficacy ratings. Prior to the lecture, teacher candidates' scores on the PA assessment were relatively low with a mean percentage correct of 56.3%. Actual knowledge was not significantly correlated with perceived knowledge or self-efficacy ratings. Perceived knowledge was significantly and positively correlated with efficacy ratings and students' rating of their exposure to PA instruction during their practicum experience. A path analysis revealed that the relationship between exposure to PA instruction and self-efficacy beliefs was mediated by perceived knowledge controlling for actual knowledge and general prior experience working with young children. Analyses also revealed that TCs made significant gains in self-efficacy as well as actual knowledge when re-assessed after the lecture with a mean post-lecture score of 71.4%. Written feedback from the TCs indicated that the digital video clips included in the lecture provided clarity regarding the type of instructional practices that teachers could use to support phonemic awareness development in children. Implications for practice and future research on teacher preparation are discussed.

  14. Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

    SciTech Connect

    Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei; Uesato, Shin-ichi; Watanabe, Kazushi; Tanimura, Susumu; Koji, Takehiko; Kohno, Michiaki

    2013-04-19

    Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

  15. Efficacy of Enhanced External Counterpulsation in Patients With Chronic Refractory Angina on Canadian Cardiovascular Society (CCS) Angina Class

    PubMed Central

    Zhang, Chunmei; Liu, Xiangjuan; Wang, Xiaomeng; Wang, Qi; Zhang, Yun; Ge, Zhiming

    2015-01-01

    Abstract A growing number of patients with chronic artery disease suffer from angina, despite the optimal medical management (ie, β-blockers, calcium channel blockers, and long-acting nitrates) and revascularization. Currently, enhanced external counterpulsation (EECP) therapy has been verified as a noninvasive, safe therapy for refractory angina. The study was designed to evaluate the efficacy of EECP in patients with chronic refractory angina according to Canadian Cardiovascular Society (CCS) angina class. We identified systematic literature through MEDLINE, EMBASE, the Cochrane Clinical Trials Register Database, and the ClinicalTrials. gov Website from 1990 to 2015. Studies were considered eligible if they were prospective and reported data on CCS class before and after EECP treatment. Meta-analysis was performed to assess the efficacy of EECP therapy by at least 1 CCS angina class improvement, and proportion along with the 95% confidence interval (CI) was calculated. Statistical heterogeneity was calculated by I2 statistic and the Q statistic. Sensitivity analysis was addressed to test the influence of trials on the overall pooled results. Subgroup analysis was applied to explore potential reasons for heterogeneity. Eighteen studies were enrolled in our meta-analysis. Pooled analysis showed 85% of patients underwent EECP had a reduction by at least one CCS class (95%CI 0.81–0.88, I2 = 58.5%, P < 0.001). The proportion of patients enrolled at primarily different studies with chronic heart failure (CHF) improved by at least 1 CCS class was about 84% after EECP (95%CI 0.81–0.88, I2 = 32.7%, P = 0.1668). After 3 large studies were excluded, the pooled proportion was 82% (95%CI 0.79–0.86, I2 = 18%, P = 0.2528). Funnel plot indicated that some asymmetry while the Begg and Egger bias statistic showed no publication bias (P = 0.1495 and 0.2859, respectively). Our study confirmed that EECP provided an effective treatment for patients

  16. Efficacy of Repeat Review with Flexible Spectral Imaging Color Enhancement in Patients with no Findings by Capsule Endoscopy

    PubMed Central

    Minami-Kobayashi, Yuka; Yamada, Atsuo; Watabe, Hirotsugu; Suzuki, Hirobumi; Hirata, Yoshihiro; Yamaji, Yutaka; Yoshida, Haruhiko; Koike, Kazuhiko

    2016-01-01

    Background/Aim: The efficacy of flexible spectral imaging color enhancement (FICE) ch. 1 (F1) for the detection of ulcerative lesions and angioectasias in the small intestine with capsule endoscopy (CE) has been reported. In the present study, we evaluated whether F1 could detect incremental findings in patients with no findings in a standard review mode. Patients and Methods: In total, 52 patients (age: 60.1 ± 15.3 years; 30 males) with obscure gastrointestinal bleeding (OGIB) who underwent CE and in whom no lesion was detected in the small intestine in the standard mode (first review) were enrolled. Two experienced endoscopists independently reviewed CE videos again by F1 (second review). The following findings were defined to be significant: Ulcers, erosions, aphthas, angioectasias, tumors, and bleeding. Incremental findings at the second review were checked at F1 and in standard mode by the two reviewers (third review). Finally, the findings were confirmed by the agreement of the two reviewers at the third review. Results: F1 detected five significant lesions in three patients with overt OGIB; three erosions, one aphtha, and one angioectasia. For nonsignificant lesions, F1 detected 12 red mucosas and 16 red spots. Moreover, 29 patients with 71 findings were considered false positives. Conclusion: F1 detected incremental significant findings in a small percentage of patients with no findings in the standard review mode. In addition, F1 showed many false-positive findings. The incremental effect of a repeated review by F1 in patients with no findings in the first review is limited. PMID:27748326

  17. Neuropilin-1-targeted gold nanoparticles enhance therapeutic efficacy of platinum(IV) drug for prostate cancer treatment.

    PubMed

    Kumar, Anil; Huo, Shuaidong; Zhang, Xu; Liu, Juan; Tan, Aaron; Li, Shengliang; Jin, Shubin; Xue, Xiangdong; Zhao, YuanYuan; Ji, Tianjiao; Han, Lu; Liu, Hong; Zhang, XiaoNing; Zhang, Jinchao; Zou, Guozhang; Wang, Tianyou; Tang, Suoqin; Liang, Xing-Jie

    2014-05-27

    Platinum-based anticancer drugs such as cisplatin, oxaliplatin, and carboplatin are some of the most potent chemotherapeutic agents but have limited applications due to severe dose-limiting side effects and a tendency for cancer cells to rapidly develop resistance. The therapeutic index can be improved through use of nanocarrier systems to target cancer cells efficiently. We developed a unique strategy to deliver a platinum(IV) drug to prostate cancer cells by constructing glutathione-stabilized (Au@GSH) gold nanoparticles. Glutathione (GSH) has well-known antioxidant properties, which lead to cancer regression. Here, we exploit the advantages of both the antioxidant properties and high surface-area-to-volume ratio of Au@GSH NPs to demonstrate their potential for delivery of a platinum(IV) drug by targeting the neuropilin-1 receptor (Nrp-1). A lethal dose of a platinum(IV) drug functionalized with the Nrp-1-targeting peptide (CRGDK) was delivered specifically to prostate cancer cells in vitro. Targeted peptide ensures specific binding to the Nrp-1 receptor, leading to enhanced cellular uptake level and cell toxicity. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when functionalized with the targeting peptide and drug. The uptake of drug-loaded nanocarriers is dependent on the interaction with Nrp-1 in cell lines expressing high (PC-3) and low (DU-145) levels of Nrp-1, as confirmed through inductively coupled plasma mass spectrometry and confocal microscopy. The nanocarriers have effective anticancer activity, through upregulation of nuclear factor kappa-B (NF-κB) protein (p50 and p65) expression and activation of NF-κB-DNA-binding activity. Our preliminary investigations with platinum(IV)-functionalized gold nanoparticles along with a targeting peptide hold significant promise for future cancer treatment.

  18. Curcumin-loaded redox response of self-assembled micelles for enhanced antitumor and anti-inflammation efficacy

    PubMed Central

    Zhao, Shuang; Ma, Litao; Cao, Chengwen; Yu, Qianqian; Chen, Lanmei; Liu, Jie

    2017-01-01

    At present, it has become evident that inflammation plays a critical role in tumor growth; meanwhile, chemotherapeutic agents using nanocarriers have been suggested as a promising strategy in cancer treatment. In this study, novel redox-responsive micelles were prepared from monomethoxy-poly(ethylene glycol)-chitosan-S-S-hexadecyl (C16-SS-CS-mPEG). These micelles were able to carry and deliver drugs into tumor cells. To serve as a control, monomethoxy-poly(ethylene glycol)-chitosan-C-C-hexadecyl (C16-CC-CS-mPEG) was developed in a similar fashion to that used to yield C16-CC-CS-mPEG without a redox-responsive disulfide bond. The cellular uptake mechanisms of both micelles were determined. The efficient intracellular drug release from micelles in MCF-7 cells was further confirmed. Results indicated that curcumin (Cur) could rapidly form C16-SS-CS-mPEG@ Cur micelles when exposed to reducing agents and efficaciously enhance intracellular accumulation. The cytotoxicity assay demonstrated that C16-SS-CS-mPEG@Cur exhibited satisfactory cytotoxicity against MCF-7 cells. Anti-inflammation assay results indicated that C16-SS-CS-mPEG@Cur treatment significantly downregulated tumor necrosis factor (TNF-α) expression and showed good anti-inflammatory effects in tumor microenvironment. Most importantly, antitumor effects in vivo showed satisfactory therapeutic effects with C16-SS-CS-mPEG@Cur. Hence, C16-SS-CS-mPEG@Cur micelles can be useful in tumor therapy. PMID:28408820

  19. Honokiol Enhances Paclitaxel Efficacy in Multi-Drug Resistant Human Cancer Model through the Induction of Apoptosis

    PubMed Central

    Wang, Xu; Beitler, Jonathan J.; Wang, Hong; Lee, Michael J.; Huang, Wen; Koenig, Lydia; Nannapaneni, Sreenivas; Amin, A. R. M. Ruhul; Bonner, Michael; Shin, Hyung Ju C.; Chen, Zhuo Georgia; Arbiser, Jack L.; Shin, Dong M.

    2014-01-01

    Resistance to chemotherapy remains a major obstacle in cancer therapy. This study aimed to evaluate the molecular mechanism and efficacy of honokiol in inducing apoptosis and enhancing paclitaxel chemotherapy in pre-clinical multi-drug resistant (MDR) cancer models, including lineage-derived human MDR (KB-8-5, KB-C1, KB-V1) and their parental drug sensitive KB-3-1 cancer cell lines. In vitro analyses demonstrated that honokiol effectively inhibited proliferation in KB-3-1 cells and the MDR derivatives (IC50 ranging 3.35±0.13 µg/ml to 2.77±0.22 µg/ml), despite their significant differences in response to paclitaxel (IC50 ranging 1.66±0.09 ng/ml to 6560.9±439.52 ng/ml). Honokiol induced mitochondria-dependent and death receptor-mediated apoptosis in MDR KB cells, which was associated with inhibition of EGFR-STAT3 signaling and downregulation of STAT3 target genes. Combined treatment with honokiol and paclitaxel synergistically augmented cytotoxicity in MDR KB cells, compared with treatment with either agent alone in vitro. Importantly, the combined treatment significantly inhibited in vivo growth of KB-8-5 tumors in a subcutaneous model. Tumor tissues from the combination group displayed a significant inhibition of Ki-67 expression and an increase in TUNEL-positive cells compared with the control group. These results suggest that targeting multidrug resistance using honokiol in combination with chemotherapy drugs may provide novel therapeutic opportunities. PMID:24586249

  20. Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis.

    PubMed

    Wang, Xu; Beitler, Jonathan J; Wang, Hong; Lee, Michael J; Huang, Wen; Koenig, Lydia; Nannapaneni, Sreenivas; Amin, A R M Ruhul; Bonner, Michael; Shin, Hyung Ju C; Chen, Zhuo Georgia; Arbiser, Jack L; Shin, Dong M

    2014-01-01

    Resistance to chemotherapy remains a major obstacle in cancer therapy. This study aimed to evaluate the molecular mechanism and efficacy of honokiol in inducing apoptosis and enhancing paclitaxel chemotherapy in pre-clinical multi-drug resistant (MDR) cancer models, including lineage-derived human MDR (KB-8-5, KB-C1, KB-V1) and their parental drug sensitive KB-3-1 cancer cell lines. In vitro analyses demonstrated that honokiol effectively inhibited proliferation in KB-3-1 cells and the MDR derivatives (IC50 ranging 3.35 ± 0.13 µg/ml to 2.77 ± 0.22 µg/ml), despite their significant differences in response to paclitaxel (IC50 ranging 1.66 ± 0.09 ng/ml to 6560.9 ± 439.52 ng/ml). Honokiol induced mitochondria-dependent and death receptor-mediated apoptosis in MDR KB cells, which was associated with inhibition of EGFR-STAT3 signaling and downregulation of STAT3 target genes. Combined treatment with honokiol and paclitaxel synergistically augmented cytotoxicity in MDR KB cells, compared with treatment with either agent alone in vitro. Importantly, the combined treatment significantly inhibited in vivo growth of KB-8-5 tumors in a subcutaneous model. Tumor tissues from the combination group displayed a significant inhibition of Ki-67 expression and an increase in TUNEL-positive cells compared with the control group. These results suggest that targeting multidrug resistance using honokiol in combination with chemotherapy drugs may provide novel therapeutic opportunities.

  1. Enhanced efficacy of anti-miR-191 delivery through stearylamine liposome formulation for the treatment of breast cancer cells.

    PubMed

    Sharma, Shivani; Rajendran, Vinoth; Kulshreshtha, Ritu; Ghosh, Prahlad C

    2017-09-15

    MicroRNAs are gaining rapid attention as promising targets for cancer treatment; however, efficient delivery of therapeutic miRNA or anti-miRNA into cancer cells remains a major challenge. Our previous work identified miR-191 as an oncogenic miRNA overexpressed in breast cancer that assists in progression of malignant transformation. Thus, inhibition of miR-191 using antisense miR-191 (anti-miR-191) has immense therapeutic potential. Here, we have developed a stearylamine (SA) based cationic liposome for delivery of miR-191 inhibitor (anti-miR-191), and studied its efficacy in breast cancer cells (MCF-7 and ZR-75-1) in culture. SA liposomes alone inhibited cancer cell growth with lesser IC50s (50% inhibitory concentration) values as compared to normal mouse fibroblast cells (L929). The efficient delivery of anti-miR-191 in SA liposome complex was found to be highly effective in killing the cancer cells than a comparable dose of SA free anti-miR-191 liposome complex. The formulation also showed negligible cytotoxicity in human erythrocytes. Combined treatment of SA liposome with anti-miR-191 markedly enhanced apoptotic cell death and suppressed the migration of cancer cells in vitro. Notably, anti-miR-191 loaded SA liposome complex increased chemosensitivity of breast cancer cells to currently used anti-cancer drugs (doxorubicin or cisplatin) in free form. Our work demonstrates that anti-miR-191 loaded in SA liposome complex has promising clinical application for breast cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Delivery of acetylthevetin B, an antitumor cardiac glycoside, using polymeric micelles for enhanced therapeutic efficacy against lung cancer cells

    PubMed Central

    Zhu, Jing-jing; Zhang, Xin-xin; Miao, Yun-qiu; He, Shu-fang; Tian, Dan-mei; Yao, Xin-sheng; Tang, Jin-shan; Gan, Yong

    2017-01-01

    Acetylthevetin B (ATB), a cardiac glycoside from the seed of Thevetia peruviana (Pers) K Schum (yellow oleander), exhibits not only antitumor activity but also potential cardiac toxicity. In the present study, we attempted to enhance its antitumor action and decrease its adverse effects via chitosan-Pluronic P123 (CP) micelle encapsulation. Two ATB-loaded CP micelles (ATB-CP1, ATB-CP2) were prepared using an emulsion/solvent evaporation technique. They were spherical in shape with a particle size of 40–50 nm, showed a neutral zeta potential, and had acceptable encapsulation efficiency (>90%). Compared to the free ATB (IC50=2.94 μmol/L), ATB-loaded CP micelles exerted much stronger cytotoxicity against human lung cancer A549 cells with lower IC50 values (0.76 and 1.44 μmol/L for ATB-CP1 and ATB-CP2, respectively). After administration of a single dose in mice, the accumulation of ATB-loaded CP1 micelles in the tumor and lungs, respectively, was 15.31-fold and 9.49-fold as high as that of free ATB. A549 xenograft tumor mice treated with ATB-loaded CP1 micelles for 21 d showed the smallest tumor volume (one-fourth of that in the control group) and the highest inhibition rate (85.6%) among all the treatment groups. After 21-d treatment, no significant pathological changes were observed in hearts and other main tissues. In summary, ATB may serve as a promising antitumor chemotherapeutic agent for lung cancer, and its antitumor efficacy was significantly improved by CP micelles, with lower adverse effects. PMID:27917871

  3. Enhancement of plaque removal efficacy by tooth brushing with baking soda dentifrices: results of five clinical studies.

    PubMed

    Putt, Mark S; Milleman, Kimberly R; Ghassemi, Annahita; Vorwerk, Linda M; Hooper, William J; Soparkar, Pramod M; Winston, Anthony E; Proskin, Howard M

    2008-01-01

    An earlier clinical study demonstrated that brushing with a commercial Arm & Hammer dentifrice containing baking soda physically removed significantly more plaque than brushing with either of two commercial dentifrices which did not contain baking soda. However, little has been done to confirm these results and to compare baking soda-containing dentifrices with more recently commercialized non-baking soda dentifrice formulations. The objective of this study was to compare commercial dentifrices containing 20% to 65% baking soda and commercial dentifrices without baking soda in enhancing plaque removal efficacy of tooth brushing. Five randomized, controlled, blinded, crossover clinical studies were performed among healthy adult volunteers who provided informed consent. After approximately 24 hours without oral hygiene, subjects with sufficient plaque were enrolled in the study phase. Plaque was scored before and after supervised brushing for one minute using the Turesky, et al. modification of the Quigley-Hein Plaque Index at six sites per tooth according to Soparkar's modification as described by Lobene, et al. In each study, wash-out periods with a regular dentifrice not evaluated in the study separated each product treatment. In all studies, every dentifrice exhibited a significant (p < 0.0001) reduction in 24-hour plaque scores. Between-group comparisons of whole mouth plaque scores in all five studies demonstrated that brushing with baking soda dentifrices resulted in statistically greater (p < 0.01) reductions in whole mouth mean plaque scores than brushing with dentifrices that did not contain baking soda. Results on other tooth surfaces, such as facial, lingual, proximal, and gingival surfaces also demonstrated statistically greater (p < 0.05) reductions in mean plaque scores for the baking soda-containing dentifrices as compared to the baking soda-free dentifrices. In three of the studies comparing different levels of baking soda, brushing with dentifrices

  4. Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy.

    PubMed

    Zhang, Chengyuan; Pan, Dayi; Li, Jin; Hu, Jiani; Bains, Ashika; Guys, Nicholas; Zhu, Hongyan; Li, Xiaohui; Luo, Kui; Gong, Qiyong; Guc, Zhongwei

    2017-03-01

    Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycylphenylalanylleucylglycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17 ± 38.27%) and a 2-fold higher value of tumor growth inhibition (~90%) than GEM∙HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110 nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and

  5. Coating doxorubicin-loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmaniain hamsters by inducing Th1-type immune responses

    PubMed Central

    Kansal, S; Tandon, R; Verma, A; Misra, P; Choudhary, A K; Verma, R; Verma, P R P; Dube, A; Mishra, P R

    2014-01-01

    Background and Purpose The aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). Experimental Approach NE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. Key Results Size and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (−)32.6 ± 2.1 mV, 342 ± 4.1 nm and (−)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. Conclusions and Implications Our results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system. PMID:24837879

  6. Enhancing Writing Self-Efficacy Beliefs of Students with Learning Disabilities Improves Their Writing Processes and Products

    ERIC Educational Resources Information Center

    de Caso, Ana Maria; Garcia, Jesus Nicasio; Diez, Carmen; Robledo, Patricia; Alvarez, Maria Lourdes

    2010-01-01

    Introduction: The use of self efficacy has been suggested as an effective classroom intervention procedure. The present research examined the use of self-efficacy training on the writing of Spanish elementary student with learning disabilities. Objectives: We present a research study focused on the improvement of the writing product and the…

  7. Enhancing Writing Self-Efficacy Beliefs of Students with Learning Disabilities Improves Their Writing Processes and Products

    ERIC Educational Resources Information Center

    de Caso, Ana Maria; Garcia, Jesus Nicasio; Diez, Carmen; Robledo, Patricia; Alvarez, Maria Lourdes

    2010-01-01

    Introduction: The use of self efficacy has been suggested as an effective classroom intervention procedure. The present research examined the use of self-efficacy training on the writing of Spanish elementary student with learning disabilities. Objectives: We present a research study focused on the improvement of the writing product and the…

  8. General and Specific Self-Efficacy in the Context of a Training Intervention to Enhance Performance Expectancy

    ERIC Educational Resources Information Center

    Schwoerer, Catherine E.; May, Douglas R.; Hollensbe, Elaine C.; Mencl, Jennifer

    2005-01-01

    A pretest-posttest field study investigated self-efficacy, both general and specific, in an intensive training experience to prepare new recruits for their work assignments. Specific issues addressed include (1) the effects of the training experience on general self-efficacy (GSE), work-specific selfefficacy (SSE), and performance expectancy; (2)…

  9. Explaining Perceptions of Principal Leadership Behaviors that Enhance Middle School Teacher Self-Efficacy: A Mixed Methods Study

    ERIC Educational Resources Information Center

    Charf, Michelle R.

    2009-01-01

    Teachers are primarily responsible for the educational achievement of all students. Past research has shown that Teacher Self-Efficacy plays a large role in academic success of students. This study investigates various levels of teacher efficacy and the individual perceptions of teacher in regards to principal leadership behaviors, specifically,…

  10. Effectiveness of a patient education intervention in enhancing the self-efficacy of hospitalized patients to recognize and report acute deteriorating conditions.

    PubMed

    See, Min Ting Alicia; Chan, Wai-Chi Sally; Huggan, Paul John; Tay, Yee Kian; Liaw, Sok Ying

    2014-10-01

    To develop and pilot test the effectiveness of a patient education intervention in enhancing the self-efficacy of hospitalized patients to recognize and report symptoms of acute deteriorating conditions. Using cluster randomization, acute care general wards were randomized to the experimental and control groups. 34 patients in the experimental group received a 30-minute patient education intervention on Alert Worsening conditions And Report Early (AWARE) while 33 patients in the control group received the routine care only. Levels of self-efficacy to recognize and report symptoms were measured before and after the intervention. The level of self-efficacy reported by the experimental group was significantly higher than the control group (p<0.0001). The AWARE intervention was effective in enhancing the self-efficacy of hospitalized patients to recognize and report acute deteriorating conditions. Patient engagement through patient education could be included in the rapid response system which aims to reduce hospital mortality and cardiac arrest rates in the general wards. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Adherence to Continuous Positive Airway Pressure in Existing Users: Self-Efficacy Enhances the Association between Continuous Positive Airway Pressure and Adherence

    PubMed Central

    Dzierzewski, Joseph M.; Wallace, Douglas M.; Wohlgemuth, William K.

    2016-01-01

    positive airway pressure in existing users: self-efficacy enhances the association between continuous positive airway pressure and adherence. J Clin Sleep Med 2016;12(2):169–176. PMID:26350607

  12. Enhancement of Protective Efficacy through Adenoviral Vectored Vaccine Priming and Protein Boosting Strategy Encoding Triosephosphate Isomerase (SjTPI) against Schistosoma japonicum in Mice

    PubMed Central

    Dai, Yang; Wang, Xiaoting; Tang, Jianxia; Zhao, Song; Xing, Yuntian; Dai, Jianrong; Jin, Xiaolin; Zhu, Yinchang

    2015-01-01

    Background Schistosomiasis japonica is a zoonotic parasitic disease; developing transmission blocking veterinary vaccines are urgently needed for the prevention and control of schistosomiasis in China. Heterologous prime-boost strategy, a novel vaccination approach, is more effective in enhancing vaccine efficacy against multiple pathogens. In the present study, we established a novel heterologous prime-boost vaccination strategy, the rAdV-SjTPI.opt intramuscular priming and rSjTPI subcutaneous boosting strategy, and evaluated its protective efficacy against Schistosoma japonicum in mice. Methodology/Principal Findings Adenoviral vectored vaccine (rAdV-SjTPI.opt) and recombinant protein vaccine (rSjTPI) were prepared and used in different combinations as vaccines in a mouse model. The specific immune responses and protective efficacies were evaluated. Furthermore, the longevity of protective efficacy was also determined. Results showed that the rAdV-SjTPI.opt priming-rSjTPI boosting strategy elicited higher levels of specific IgG responses and broad-spectrum specific cellular immune responses. The protective efficacy could reach up to nearly 70% and 50% of protection could be observed at 10 weeks after the last immunization in mice. Conclusions/Significance The rAdV-SjTPI.opt intramuscular priming-rSjTPI subcutaneous boosting vaccination strategy is a novel, highly efficient, and stable approach to developing vaccines against Schistosoma japonicum infections in China. PMID:25793406

  13. Diagnostic efficacy of contrast-enhanced sonography by combined qualitative and quantitative analysis in breast lesions: a comparative study with magnetic resonance imaging.

    PubMed

    Wang, Lin; Du, Jing; Li, Feng-Hua; Fang, Hua; Hua, Jia; Wan, Cai-Feng

    2013-10-01

    The purpose of this study was to evaluate the diagnostic efficacy of contrast-enhanced sonography for differentiation of breast lesions by combined qualitative and quantitative analyses in comparison to magnetic resonance imaging (MRI). Fifty-six patients with American College of Radiology Breast Imaging Reporting and Data System category 3 to 5 breast lesions on conventional sonography were evaluated by contrast-enhanced sonography and MRI. A comparative analysis of diagnostic results between contrast-enhanced sonography and MRI was conducted in light of the pathologic findings. Pathologic analysis showed 26 benign and 30 malignant lesions. The predominant enhancement patterns of the benign lesions on contrast-enhanced sonography were homogeneous, centrifugal, and isoenhancement or hypoenhancement, whereas the patterns of the malignant lesions were mainly heterogeneous, centripetal, and hyperenhancement. The detection rates for perfusion defects and peripheral radial vessels in the malignant group were much higher than those in the benign group (P < .05). As to quantitative analysis, statistically significant differences were found in peak and time-to-peak values between the groups (P < .05). With pathologic findings as the reference standard, the sensitivity, specificity, and accuracy of contrast-enhanced sonography and MRI were 90.0%, 92.3%, 91.1% and 96.7%, 88.5%, and 92.9%, respectively. The two methods had a concordant rate of 87.5% (49 of 56), and the concordance test gave a value of κ = 0.75, indicating that there was high concordance in breast lesion assessment between the two diagnostic modalities. Contrast-enhanced sonography provided typical enhancement patterns and valuable quantitative parameters, which showed good agreement with MRI in diagnostic efficacy and may potentially improve characterization of breast lesions.

  14. Tumor-penetration and antitumor efficacy of cetuximab are enhanced by co-administered iRGD in a murine model of human NSCLC

    PubMed Central

    Zhang, Yang; Yang, Jie; Ding, Manhua; Li, Liantao; Lu, Zheng; Zhang, Qing; Zheng, Junnian

    2016-01-01

    Lung cancer is the leading cause of cancer-associated mortality, worldwide. For this reason, novel therapies are required for the treatment of this devastating disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), which is overexpressed in a variety of solid tumors, including non-small cell lung cancer (NSCLC). The therapeutic efficacy of cetuximab for NSCLC is limited to use as a monotherapy or in combination with chemotherapy. The objective of the present study was to develop a novel strategy to enhance the therapeutic efficacy of cetuximab for NSCLC by a co-administration with the tumor-penetrating internalizing RGD peptide (iRGD). Human NSCLC subcutaneous xenograft models established with the A549 cell line in nude mice were treated with 30 mg/kg cetuximab, 4 mg/kg iRGD, cetuximab plus iRGD or phosphate-buffered saline. The tumor-penetration, in vivo therapeutic efficacy and involved mechanism were evaluated. The present study showed that the A549 xenograft model is sensitive to the co-administration of cetuximab and iRGD. Treatment with cetuximab plus iRGD resulted in a significant increase in the tumor-penetration of cetuximab and tumor reduction compared with cetuximab monotherapy. In conclusion, iRGD enhances the effects of co-administered cetuximab in an NSCLC model. The combined application of cetuximab and iRGD may be a novel strategy to enhance the clinical therapeutic efficacy of cetuximab for the treatment of NSCLC. PMID:27899989

  15. Enhancement of the efficacy of cancer chemotherapy by the pineal hormone melatonin and its relation with the psychospiritual status of cancer patients

    PubMed Central

    Messina, Giuseppina; Lissoni, Paolo; Marchiori, Paolo; Bartolacelli, Erio; Brivio, Fernando; Magotti, Luciano

    2010-01-01

    BACKGROUND: The anti-oxidant and immunomodulating natural agents may enhance the efficacy of cancer chemotherapy. One of the most important agents is the pineal hormone melatonin (MLT) which may exert both anti-oxidant and antiproliferative immunostimulating anticancer effects. This study was performed to evaluate the efficacy of a biochemotherapeutic regimen in metastatic cancer patients, and its therapeutic activity in relation to the psychospiritual status of patients. METHODS: The study included 50 metastatic non-small cell lung cancer (NSCLC) patients and a control group of 100 patients. Chemotherapy consisted of cisplatin plus gemcitabine. MLT was given orally at 20 mg/day in the evening. Patients were subdivided into 5 psychic profiles, as follows: spiritual faith, rationale faith, anxiety, apathy, and accusation behavior. RESULTS: Tumor response rate was significantly higher in patients treated by chemotherapy plus MLT than in those treated by chemotherapy alone (21/50 vs. 24/100, p < 0.001). However, the percentage of objective tumor regressions obtained in patients with spiritual faith was significantly higher than that found in the overall other patients concomitantly treated by chemotherapy plus MLT (6/8 vs. 15/42, p < 0.01). CONCLUSIONS: In conclusion, the efficacy of chemotherapy may be enhanced by the pineal hormone MLT, by representing a new promising biochemotherapeutic combination; also despite its objective ability to enhance chemotherapy efficacy, the activity of MLT is depending at least in part on the psychospiritual status of cancer patients, and it is maximal in the presence of a real spiritual faith. PMID:21526086

  16. Safety and Efficacy of Gadobutrol for Contrast-enhanced Magnetic Resonance Imaging of the Central Nervous System: Results from a Multicenter, Double-blind, Randomized, Comparator Study

    PubMed Central

    Gutierrez, Juan E; Rosenberg, Martin; Seemann, Jörg; Breuer, Josy; Haverstock, Daniel; Agris, Jacob; Balzer, Thomas; Anzalone, Nicoletta

    2015-01-01

    PURPOSE Contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) with gadolinium-based contrast agents (GBCAs) is standard of care for CNS imaging and diagnosis because of the visualization of lesions that cause blood–brain barrier breakdown. Gadobutrol is a macrocyclic GBCA with high concentration and high relaxivity. The objective of this study was to compare the safety and efficacy of gadobutrol 1.0 M vs unenhanced imaging and vs the approved macrocyclic agent gadoteridol 0.5 M at a dose of 0.1 mmol/kg bodyweight. MATERIALS AND METHODS Prospective, multicenter, double-blind, crossover trial in patients who underwent unenhanced MRI followed by enhanced imaging with gadobutrol or gadoteridol. Three blinded readers assessed the magnetic resonance images. The primary efficacy variables included number of lesions detected, degree of lesion contrast-enhancement, lesion border delineation, and lesion internal morphology. RESULTS Of the 402 treated patients, 390 patients received study drugs. Lesion contrast-enhancement, lesion border delineation, and lesion internal morphology were superior for combined unenhanced/gadobutrol-enhanced imaging vs unenhanced imaging (P < 0.0001 for all). Compared with gadoteridol, gadobutrol was non-inferior for all primary variables and superior for lesion contrast-enhancement, as well as sensitivity and accuracy for detection of malignant disease. The percentage of patients with at least one drug-related adverse event was similar for gadobutrol (10.0%) and gadoteridol (9.7%). CONCLUSION Gadobutrol is an effective and well-tolerated macrocyclic contrast agent for MRI of the CNS. Gadobutrol demonstrates greater contrast-enhancement and improved sensitivity and accuracy for detection of malignant disease than gadoteridol, likely because of its higher relaxivity. PMID:25922578

  17. CTLA4-CD28 chimera gene modification of T cells enhances the therapeutic efficacy of donor lymphocyte infusion for hematological malignancy.

    PubMed

    Park, Hyung Bae; Lee, Ji Eun; Oh, Yu Mi; Lee, Sang Jin; Eom, Hyeon-Seok; Choi, Kyungho

    2017-07-28

    Donor lymphocyte infusion (DLI) followed by hematopoietic stem cell transplantation has served as an effective prevention/treatment modality against the relapse of some hematologic tumors, such as chronic myeloid leukemia (CML). However, the therapeutic efficacies of DLI for other types of leukemia, including acute lymphocytic leukemia (ALL), have been limited thus far. Therefore, we examined whether increasing the reactivity of donor T cells by gene modification could enhance the therapeutic efficacy of DLI in a murine model of ALL. When a CTLA4-CD28 chimera gene (CTC28) in which the intracellular signaling domain of CTLA4 was replaced with the CD28 signaling domain was introduced into CD4 and CD8 T cells in DLI, the graft-versus-tumor (GVT) effect was significantly increased. This effect was correlated with an increased expansion of donor CD8 T cells in vivo, and the depletion of CD8 T cells abolished this effect. The CD8 T cell expansion and the enhanced GVT effect were dependent on the transduction of both CD4 and CD8 T cells with CTC28, which emphasizes the role of dual modification in this therapeutic effect. The CTC28-transduced T cells that expanded in vivo also exhibited enhanced functionality. Although the potentiation of the GVT effect mediated by the CTC28 gene modification of T cells was accompanied by an increase of graft-versus-host disease (GVHD), the GVHD was not lethal and was mitigated by treatment with IL-10 gene-modified third-party mesenchymal stem cells. Thus, the combined genetic modification of CD4 and CD8 donor T cells with CTC28 could be a promising strategy for enhancing the therapeutic efficacy of DLI.

  18. Enhanced efficacy of cidofovir combined with vaccinia immune globulin in treating progressive cutaneous vaccinia virus infections in immunosuppressed hairless mice.

    PubMed

    Smee, Donald F; Dagley, Ashley; Downs, Brittney; Hagloch, Joseph; Tarbet, E Bart

    2015-01-01

    The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment.

  19. Enhanced Efficacy of Cidofovir Combined with Vaccinia Immune Globulin in Treating Progressive Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice

    PubMed Central

    Dagley, Ashley; Downs, Brittney; Hagloch, Joseph; Tarbet, E. Bart

    2014-01-01

    The treatment of progressive vaccinia in individuals has involved antiviral drugs, such as cidofovir (CDV), brincidofovir, and/or tecovirimat, combined with vaccinia immune globulin (VIG). VIG is costly, and its supply is limited, so sparing the use of VIG during treatment is an important objective. VIG sparing was modeled in immunosuppressed mice by maximizing the treatment benefits of CDV combined with VIG to determine the effective treatments that delayed the time to death, reduced cutaneous lesion severity, and/or decreased tissue viral titers. SKH-1 hairless mice immunosuppressed with cyclophosphamide and hairless SCID mice (SHO strain) were infected cutaneously with vaccinia virus. Monotherapy, dual combinations (CDV plus VIG), or triple therapy (topical CDV, parenteral CDV, and VIG) were initiated 2 days postinfection and were given every 3 to 4 days through day 11. The efficacy assessment included survival rate, cutaneous lesion severity, and viral titers. Delays in the time to death and the reduction in lesion severity occurred in the following order of efficacy: triple therapy had greater efficacy than double combinations (CDV plus VIG or topical plus parenteral CDV), which had greater efficacy than VIG alone. Parenteral administration of CDV or VIG was necessary to suppress virus titers in internal organs (liver, lung, and spleen). The skin viral titers were significantly reduced by triple therapy only. The greatest efficacy was achieved by triple therapy. In humans, this regimen should translate to a faster cure rate, thus sparing the amount of VIG used for treatment. PMID:25385098

  20. A proactive classroom management model to enhance self-efficacy levels in teachers of adolescents who display disruptive behaviors.

    PubMed

    Pace, Rolanda T; Boykins, Anita D; Davis, Sheila P

    2014-02-01

    The aims of this project were to determine teachers' self-efficacy levels at baseline and after participating in a proactive classroom management model intervention. Teachers (N = 26) were recruited from a rural middle school in a south central state. Data required for analysis were drawn from the Teachers' Sense of Efficacy Scale (long form). A statistically significant difference (t[25] = 7.68, p < 0.001) was noted in teachers' self-efficacy levels from pre- to post-intervention. Findings support the need for proactive classroom management training for teachers as well as the need for psychiatric and mental health nurse consultants within the school system. Teacher classroom management strategies should also include appropriate response to individual student's needs, effective communication, and insight regarding the behaviors of students from diverse backgrounds. Copyright 2014, SLACK Incorporated.

  1. When does transformational leadership enhance employee proactive behavior? The role of autonomy and role breadth self-efficacy.

    PubMed

    Den Hartog, Deanne N; Belschak, Frank D

    2012-01-01

    Two multisource studies address the interactive effects of personal and contextual variables on employees' proactive behavior. In line with previous work, we find positive main effects of transformational leadership, role breadth self-efficacy, and job autonomy on employee proactive behavior (personal initiative in Study 1 and prosocial proactive behavior in Study 2). As expected, a 3-way interaction qualifies these main effects: In situations of high autonomy, transformational leadership relates positively to proactive behavior for individuals high (but not low) on self-efficacy. Vice versa, in situations low on job autonomy, transformational leadership relates positively to proactive behavior for individuals low (but not high) on self-efficacy. This pattern is found both for self-ratings and peer-ratings of employees' proactive behavior in Study 1 and for supervisor ratings of such behavior in Study 2.

  2. Therapeutic efficacy of 177Lu-CHX-A″-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

    PubMed Central

    Kelly, Marcus P; Lee, Sze Ting; Lee, F-T; Smyth, Fiona E; Davis, Ian D.; Brechbiel, Martin W; Scott, Andrew M

    2008-01-01

    Background This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo. Methods The in vitro cytotoxicity of 177Lu labeled hu3S193 on Ley positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo. Results 177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 ± 3.9 %ID/g observed at 120 hr post injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350μCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy. Conclusions 177Lu-hu3S193 RIT is effective as a single agent in the treatment of Ley positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies. PMID:18942092

  3. An Open-Label, Multicenter, Evaluator-Blinded Study to Assess the Efficacy and Safety of a New Hyaluronic Acid-Based Gel Product for Lip Enhancement.

    PubMed

    Samuelson, Ulf; Fagrell, Dan; Wetter, Anne; Kuusk, Sandra; Hamilton, Lynn; Haglund, Pyra

    2015-09-01

    A stabilized hyaluronic acid (HA)-based lidocaine-containing gel of nonanimal origin has been developed for lip enhancement. To evaluate the efficacy, safety, and injection procedure of the HA gel in subjects seeking lip enhancement. Thirty subjects were treated in the upper and lower lips. Retreatment was offered at 3 months. Efficacy was assessed over 9 months using the Global Aesthetic Improvement Scale (GAIS), the Medicis Lip Fullness Scale, and a subject questionnaire. Safety was assessed by a 14-day subject diary and recording of adverse events (AEs) during the whole study. Over 9 months after treatment, 86% to 97% of subjects and independent evaluators assessed both lips as improved. At all study visits, 72% to 93% of the subjects were satisfied with their lips and ≥96% reported that their lips had a natural look. Most AEs were mild-to-moderate local injection site reactions. Lip enhancement with this HA-based gel generated high subject satisfaction and natural-looking lips. The effect lasted for up to 9 months according to the GAIS ratings by subjects and independent evaluators. The product was well tolerated; most AEs were mild-to-moderate local injection site reactions.

  4. Phospho-sulindac (OXT-328) Inhibits the Growth of Human Lung Cancer Xenografts in Mice: Enhanced Efficacy and Mitochondria Targeting by Its Formulation in Solid Lipid Nanoparticles

    PubMed Central

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Rigas, Basil; Constantinides, Panayiotis P.

    2013-01-01

    Purpose To evaluate the antitumor efficacy of solid lipid nanoparticle–encapsulated phospho-sulindac (SLN-PS) in human lung cancer. Methods PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. Results SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (~14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Conclusions Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation. PMID:22723123

  5. Enhanced drug-loading and therapeutic efficacy of hydrotropic oligomer-conjugated glycol chitosan nanoparticles for tumor-targeted paclitaxel delivery.

    PubMed

    Koo, Heebeom; Min, Kyung Hyun; Lee, Sang Cheon; Park, Jae Hyung; Park, Kinam; Jeong, Seo Young; Choi, Kuiwon; Kwon, Ick Chan; Kim, Kwangmeyung

    2013-12-28

    Enhanced drug-loading and therapeutic efficacies are highly essential properties for nanoparticles as tumor-targeting drug carriers. Herein, we developed the glycol chitosan nanoparticles with hydrotropic oligomers (HO-CNPs) as a new tumor targeting drug delivery system. For enhancing drug-loading efficiency of paclitaxel in drug carriers, hydrotropic 2-(4-(vinylbenzyloxy)-N,N-diethylnicotinamide) (VBODENA-COOH) oligomers, that were used for enhancing the aqueous solubility of paclitaxel, were directly conjugated to glycol chitosan polymers. The amphiphilic conjugates readily formed nanoparticle structure (average size=302 ± 22 nm) in aqueous condition. Water-insoluble paclitaxel (PTX) was readily encapsulated into HO-CNPs with a high drug-loading amount up to 24.2 wt.% (2.4 fold higher than other polymeric nanoparticles) by a simple dialysis method. The PTX encapsulated HO-CNPs (PTX-HO-CNPs; average size=343 ± 12 nm) were very stable in aqueous media up to 50 days. Also, PTX-HO-CNPs presented rapid cellular uptake and lower cytotoxicity in cell culture system, compared to Cremophor EL/ethanol formulation of PTX. In tumor-bearing mice, the extravasation and accumulation of PTX-HO-CNPs in tumor tissue were precisely observed by intravital fluorescence imaging techniques. Furthermore, PTX-HO-CNPs showed the higher therapeutic efficacy, compared to Abraxane®, a commercialized PTX-formulation. These overall results demonstrate its potential as a new nano-sized PTX carrier for cancer treatment. © 2013.

  6. Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles.

    PubMed

    Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo; Huang, Liqun; Sun, Yu; Xie, Gang; Vrankova, Kveta; Constantinides, Panayiotis P; Rigas, Basil

    2012-11-01

    To evaluate the antitumor efficacy of solid lipid nanoparticle-encapsulated phospho-sulindac (SLN-PS) in human lung cancer. PS was incorporated into SLNs using the emulsion evaporation technique. We determined the antitumor activity of SLN-PS in cultured lung cancer cells. The performance of SLN-PS was further evaluated by pharmacokinetic studies in mice and in a model of human lung cancer xenografts in nude mice. SLN-PS was >4-fold more potent than PS in inhibiting the growth of A549 and H510 cells in vitro. SLN-PS enhanced cellular uptake and facilitated PS accumulation in mitochondria, leading to oxidative stress and apoptosis via the mitochondrial-apoptosis pathway. SLN-PS was highly effective in suppressing the growth of A549 xenografts (78% inhibition compared to control, p < 0.01); while PS had no significant effect. Formulation of PS in SLNs resulted in improved pharmacokinetics in mice and an enhanced (≈ 14-fold) accumulation of PS and its metabolites in A549 xenografts. Finally, SLN-PS enhanced urinary F2-isoprostane uniquely in mice bearing A549 xenografts compared to untreated controls, suggesting that SLN-PS specifically induced oxidative stress in tumors. Our results show that SLN-PS is efficacious in suppressing the growth of lung cancer and merits further evaluation.

  7. Efficacy of an Integrated School Curriculum Pedometer Intervention to Enhance Physical Activity and to Reduce Weight Status in Children

    ERIC Educational Resources Information Center

    Duncan, Michael; Birch, Samantha; Woodfield, Lorayne

    2012-01-01

    The purpose of this study was to examine the efficacy of an integrated school curriculum pedometer intervention on children's physical activity and weight status. Following ethics approval and informed consent, 59 children (22 boys, 27 girls, aged 10-11) from a primary school in central England completed a four-week integrated physical activity…

  8. Enhancing Pre-Service Physics Teachers' Perceived Self-Efficacy of Argumentation-Based Pedagogy through Modelling and Mastery Experiences

    ERIC Educational Resources Information Center

    Ogan-Bekiroglu, Feral; Aydeniz, Mehmet

    2013-01-01

    This study explored the impact of explicit instruction on argumentation-based pedagogy, coupled with modelling and hands-on learning activities on pre-service physics teachers' perceived self-efficacy to teach science through argumentation. Participants consisted of 24 pre-service physics teachers attending an established teacher education program…

  9. An Examination of the Efficacy of Insights in Enhancing the Academic and Behavioral Development of Children in Early Grades

    ERIC Educational Resources Information Center

    O'Connor, Erin E.; Cappella, Elise; McCormick, Meghan P.; McClowry, Sandee G.

    2014-01-01

    The primary aim of this group randomized trial was to test the efficacy of INSIGHTS Into Children's Temperament (INSIGHTS) in increasing the academic achievement and sustained attention and reducing the disruptive behavior problems of low-income kindergarten and 1st grade children. Twenty-two urban elementary schools serving low-income families…

  10. Technology-Enhanced Maintenance of Treatment Gains in Eating Disorders: Efficacy of an Intervention Delivered via Text Messaging

    ERIC Educational Resources Information Center

    Bauer, Stephanie; Okon, Eberhard; Meermann, Rolf; Kordy, Hans

    2012-01-01

    Objective: Given the lack of maintenance interventions for eating disorders, a program delivered via the short message service (SMS) and text messaging was developed to support patients after their discharge from inpatient treatment. Method: The efficacy of the intervention was studied in a randomized controlled trial. Additionally, its impact on…

  11. Assessing and Enhancing Pre-Service Science Teachers' Self-Efficacy to Teach Science through Argumentation: Challenges and Possible Solutions

    ERIC Educational Resources Information Center

    Aydeniz, Mehmet; Ozdilek, Zehra

    2016-01-01

    The purpose of this study was to explore the impact of an intervention on pre-service science teachers' self-efficacy to teach science through argumentation and explore the challenges they experienced while implementing argumentation. Forty pre-service science teachers in their final semester of schooling participated in an intervention that…

  12. An Examination of the Efficacy of Insights in Enhancing the Academic and Behavioral Development of Children in Early Grades

    ERIC Educational Resources Information Center

    O'Connor, Erin E.; Cappella, Elise; McCormick, Meghan P.; McClowry, Sandee G.

    2014-01-01

    The primary aim of this group randomized trial was to test the efficacy of INSIGHTS Into Children's Temperament (INSIGHTS) in increasing the academic achievement and sustained attention and reducing the disruptive behavior problems of low-income kindergarten and 1st grade children. Twenty-two urban elementary schools serving low-income families…

  13. Technology-Enhanced Maintenance of Treatment Gains in Eating Disorders: Efficacy of an Intervention Delivered via Text Messaging

    ERIC Educational Resources Information Center

    Bauer, Stephanie; Okon, Eberhard; Meermann, Rolf; Kordy, Hans

    2012-01-01

    Objective: Given the lack of maintenance interventions for eating disorders, a program delivered via the short message service (SMS) and text messaging was developed to support patients after their discharge from inpatient treatment. Method: The efficacy of the intervention was studied in a randomized controlled trial. Additionally, its impact on…

  14. Efficacy of an Integrated School Curriculum Pedometer Intervention to Enhance Physical Activity and to Reduce Weight Status in Children

    ERIC Educational Resources Information Center

    Duncan, Michael; Birch, Samantha; Woodfield, Lorayne

    2012-01-01

    The purpose of this study was to examine the efficacy of an integrated school curriculum pedometer intervention on children's physical activity and weight status. Following ethics approval and informed consent, 59 children (22 boys, 27 girls, aged 10-11) from a primary school in central England completed a four-week integrated physical activity…

  15. Limits of PowerPoint's Power: Enhancing Students' Self-Efficacy and Attitudes but Not Their Behavior

    ERIC Educational Resources Information Center

    Susskind, Joshua E.

    2008-01-01

    The effects of accompanying lectures with computer-mediated PowerPoint presentations or PowerPoint generated overheads on students' self-efficacy, attitudes, course performance, and class-related behaviors were examined. Two Introduction to Developmental Psychology sections were initially taught with lectures accompanied by either overheads or…

  16. Limits of PowerPoint's Power: Enhancing Students' Self-Efficacy and Attitudes but Not Their Behavior

    ERIC Educational Resources Information Center

    Susskind, Joshua E.

    2008-01-01

    The effects of accompanying lectures with computer-mediated PowerPoint presentations or PowerPoint generated overheads on students' self-efficacy, attitudes, course performance, and class-related behaviors were examined. Two Introduction to Developmental Psychology sections were initially taught with lectures accompanied by either overheads or…

  17. A Small-Scale Randomized Efficacy Trial of Carescapes: Enhancing Children's Social Development in Child Care Homes

    ERIC Educational Resources Information Center

    Rusby, Julie C.; Smolkowski, Keith; Marquez, Brion; Taylor, Ted K.

    2008-01-01

    The quality of the child care environment and caregiver practices can potentially have significant, lasting impact on children's social development. This study involves the development and a small-scale efficacy trial of the Carescapes program, a video-based training program that focuses on promoting positive social development in young children…

  18. Assessing and Enhancing Pre-Service Science Teachers' Self-Efficacy to Teach Science through Argumentation: Challenges and Possible Solutions

    ERIC Educational Resources Information Center

    Aydeniz, Mehmet; Ozdilek, Zehra

    2016-01-01

    The purpose of this study was to explore the impact of an intervention on pre-service science teachers' self-efficacy to teach science through argumentation and explore the challenges they experienced while implementing argumentation. Forty pre-service science teachers in their final semester of schooling participated in an intervention that…

  19. Enhancing Pre-Service Physics Teachers' Perceived Self-Efficacy of Argumentation-Based Pedagogy through Modelling and Mastery Experiences

    ERIC Educational Resources Information Center

    Ogan-Bekiroglu, Feral; Aydeniz, Mehmet

    2013-01-01

    This study explored the impact of explicit instruction on argumentation-based pedagogy, coupled with modelling and hands-on learning activities on pre-service physics teachers' perceived self-efficacy to teach science through argumentation. Participants consisted of 24 pre-service physics teachers attending an established teacher education program…

  20. GET.ON Mood Enhancer: efficacy of Internet-based guided self-help compared to psychoeducation for depression: an investigator-blinded randomised controlled trial.

    PubMed

    Ebert, David Daniel; Lehr, Dirk; Baumeister, Harald; Boß, Leif; Riper, Heleen; Cuijpers, Pim; Reins, Jo Annika; Buntrock, Claudia; Berking, Matthias

    2014-01-30

    Major depressive disorder (MDD) imposes a considerable disease burden on individuals and societies. A large number of randomised controlled trials (RCTs) have shown the efficacy of Internet-based guided self-help interventions in reducing symptoms of depression. However, study quality varies considerably. The aim of this study is to evaluate the efficacy of a new Internet-based guided self-help intervention (GET.ON Mood Enhancer) compared to online-based psychoeducation in an investigator-blinded RCT. A RCT will be conducted to compare the efficacy of GET.ON Mood Enhancer with an active control condition receiving online psychoeducation on depression (OPD). Both treatment groups will have full access to treatment as usual. Adults with MDD (n=128) will be recruited and randomised to one of the two conditions. Primary outcome will be observer-rated depressive symptoms (HRSD-24) by independent assessors blind to treatment conditions. Secondary outcomes include changes in self-reported depressive symptom severity, anxiety and quality of life. Additionally, potential negative effects of the treatments will systematically be evaluated on several dimensions (for example, symptom deteriorations, attitudes toward seeking psychological help, relationships and stigmatisation). Assessments will take place at baseline, 6 and 12 weeks after randomisation. This study evaluates a new Internet-based guided self-help intervention for depression using an active control condition (psychoeducation-control) and an independent, blinded outcome evaluation. This study will further enhance the evidence for Internet-based guided self-help interventions for MDD. German Clinical Trial Registration (DRKS): DRKS00005025.

  1. U6 promoter-enhanced GlnUAG suppressor tRNA has higher suppression efficacy and can be stably expressed in 293 cells.

    PubMed

    Koukuntla, Ramesh; Ramsey, William J; Young, Won-Bin; Link, Charles J

    2013-02-01

    Almost one-third of all human genetic diseases are the result of nonsense mutations that can result in truncated proteins. Nonsense suppressor tRNAs (NSTs) were proposed as valuable tools for gene therapy of genetic diseases caused by premature termination codons (PTCs). Although various strategies have been adapted aiming to increase NST expression and efficacy, low suppression efficacies of NSTs and toxicity associated with stable expression of suppressor tRNAs have hampered the development of NST-mediated gene therapy. We have employed the U6 promoter to enhance Gln-Amber suppressor tRNA (GlnUAG) expression and to increase PTC suppression in mammalian cells. In an attempt to study the toxic effects of NSTs, a stable 293 cell line constitutively expressing a U6 promoter-enhanced GlnUAG tRNA was established. To examine whether any proteomic changes occurred in cells that constitutively express suppressor tRNA, whole cell proteins from cells with and without any suppressor tRNA expression were analyzed. The data obtained suggest that U6 promoter-enhanced GlnUAG tRNAs have higher suppression efficacies than multimers of the same suppressor tRNA without a U6 promoter. Proteomic analysis of cells constitutively expressing the GlnUAG suppressor tRNA indicates that stable expression of NSTs may not lead to significant read through of normal cellular proteins. Because most tRNAs have cell-specific differential expression, this technique will enable the expression of different kinds of suppressor tRNAs in various cell types at high, functionally relevant levels. The techniques developed in the present study may contribute to the further development of suppressor tRNA-mediated gene therapy. Copyright © 2013 John Wiley & Sons, Ltd.

  2. Safety, Tolerance, and Enhanced Efficacy of a Bioavailable Formulation of Curcumin With Fenugreek Dietary Fiber on Occupational Stress: A Randomized, Double-Blind, Placebo-Controlled Pilot Study.

    PubMed

    Pandaran Sudheeran, Subash; Jacob, Della; Natinga Mulakal, Johannah; Gopinathan Nair, Gopakumar; Maliakel, Abhilash; Maliakel, Balu; Kuttan, Ramadasan; Im, Krishnakumar

    2016-06-01

    Drug delivery systems capable of delivering free (unconjugated) curcuminoids is of great therapeutic significance, since the absorption of bioactive and permeable form plays a key factor in mediating the efficacy of a substance which undergoes rapid biotransformation. Considering the recent understanding on the relatively high bioactivities and blood-brain-barrier permeability of free curcuminoids over their conjugated metabolites, the present human study investigated the safety, antioxidant efficacy, and bioavailability of CurQfen (curcumagalactomannoside [CGM]), a food-grade formulation of natural curcumin with fenugreek dietary fiber that has shown to possess improved blood-brain-barrier permeability and tissue distribution in rats. In this randomized double-blinded and placebo-controlled trial, 60 subjects experiencing occupational stress-related anxiety and fatigue were randomized to receive CGM, standard curcumin, and placebo for 30 days (500 mg twice daily). The study demonstrated the safety, tolerance, and enhanced efficacy of CGM in comparison with unformulated standard curcumin. A significant improvement in the quality of life (P < 0.05) with considerable reduction in stress (P < 0.001), anxiety (P < 0.001), and fatigue (P < 0.001) was observed among CGM-treated subjects as compared with the standard curcumin group, when monitored by SF-36, Perceived Stress Scale with 14 items, and Beck Anxiety Inventory scores. Improvement in the quality of life was further correlated with the significant enhancement in endogenous antioxidant markers (P < 0.01) and reduction in lipid peroxidation (P < 0.001). Further comparison of the free curcuminoids bioavailability after a single-dose (500 mg once per day) and repeated-dose (500 mg twice daily for 30 days) oral administration revealed enhanced absorption and improved pharmacokinetics of CGM upon both single- (30.7-fold) and repeated-dose (39.1-fold) administrations.

  3. Nebivolol potentiates the efficacy of PDE5 inhibitors to relax corpus cavernosum and penile arteries from diabetic patients by enhancing the NO/cGMP pathway.

    PubMed

    Martínez-Salamanca, Juan I; La Fuente, José M; Cardoso, José; Fernández, Argentina; Cuevas, Pedro; Wright, Harold M; Angulo, Javier

    2014-05-01

    The efficacy of oral pharmacotherapy for erectile dysfunction (ED) (i.e., type 5 phosphodiesterase[PDE5] inhibitors) is significantly reduced in diabetic patients. Nebivolol is a selective β1-blocker used for treatinghy pertension that has been shown to increase the efficacy of sildenafil to reverse ED in diabetic rats. To evaluate the effects of nebivolol on the efficacy of the PDE5 inhibitors, sildenafil, tadalafil, and vardenafil to relax human corpus cavernosum (HCC) and vasodilate human penile resistance arteries (HPRA) from diabetic patients with ED (DMED). The influence of nebivolol on the capacity of these three PDE5 inhibitors to stimulate cyclic guanosine monophosphate (cGMP) production in HCC was also evaluated. HCC and HPRA were obtained from organ donors without ED (NEND; n = 18) or patients with diabetes undergoing penile prosthesis implantation (DMED; n = 19). Relaxations of HCC strips and HPRA to sildenafil,tadalafil, and vardenafil were evaluated in organ chambers and wire myographs. cGMP content in HCC was determined by ether extraction and quantification by ELISA. Effects of nebivolol on PDE5 inhibitor-induced relaxation of HCC, vasodilation ofHPRA and cGMP accumulation in HCC. Treatment with nebivolol (1 μM) significantly potentiated sildenafil-, tadalafil- and vardenafil-induced relaxations of HCC and vasodilations of HPRA from both NEND and DMED. Enhancement of relaxant capacity by nebivolol resulted in reversion of the impairment of PDE5 inhibition-induced responses in DMED and it was accompanied by enhancing the ability of PDE5 inhibitors to increase cGMP in HCC restoring reduced cGMP levelsin HCC from DMED. Nebivolol potentiated the capacity of PDE5 inhibitors to relax vascular structures of erectile tissue from diabetic patients by enhancing the nitric oxide (NO)/cGMP pathway in these tissues. These effects suggest a potential therapeutic utility of nebivolol as an adjunct to PDE5 inhibitors for the treatment of ED associated with

  4. Disruption of a putative intersubunit electrostatic bond enhances agonist efficacy at the human α1 glycine receptor.

    PubMed

    Welsh, Brian T; Todorovic, Jelena; Kirson, Dean; Allen, Hunter M; Bayly, Michelle D; Mihic, S John

    2017-02-15

    Partial agonists have lower efficacies than compounds considered 'full agonists', eliciting submaximal responses even at saturating concentrations. Taurine is a partial agonist at the glycine receptor (GlyR), a member of the cys-loop ligand-gated ion channel superfamily. The molecular mechanisms responsible for agonism are not fully understood but evidence suggests that efficacy at these receptors is determined by conformational changes that occur early in the process of receptor activation. We previously identified a residue located near the human α1 glycine binding site (aspartate-97; D97) that, when mutated to arginine (D97R), results in GlyR channels opening spontaneously with a high open probability, mimicking the effects of saturating glycine concentrations on wildtype GlyR. This D97 residue is hypothesized to form an electrostatic interaction with arginine-119 on an adjacent subunit, stabilizing the channel in a shut state. Here we demonstrate that the disruption of this putative bond increases the efficacy of partial agonists including taurine, as well as two other β-amino acid partial agonists, β-aminobutyric acid (β-ABA) and β-aminoisobutyric acid (β-AIBA). Even the subtle charge-conserving mutation of D97 to glutamate (D97E) markedly affects partial agonist efficacy. Mutation to the neutral alanine residue in the D97A mutant mimics the effects seen with D97R, indicating that charge repulsion does not significantly affect these findings. Our findings suggest that the determination of efficacy following ligand binding to the glycine receptor may involve the disruption of an intersubunit electrostatic interaction occurring near the agonist binding site.

  5. A Randomized Trial of Comparing the Efficacy of Two Neurofeedback Protocols for Treatment of Clinical and Cognitive Symptoms of ADHD: Theta Suppression/Beta Enhancement and Theta Suppression/Alpha Enhancement

    PubMed Central

    Mohagheghi, Arash; Moghaddasi Bonab, Nafiseh; Chalabianloo, Gholamreza; Noorazar, Seyed Gholamreza; Tabatabaei, Seyed Mahmoud; Farhang, Sara

    2017-01-01

    Introduction. Neurofeedback (NF) is an adjuvant or alternative therapy for children with Attention Deficit Hyperactivity Disorder (ADHD). This study intended to compare the efficacy of two different NF protocols on clinical and cognitive symptoms of ADHD. Materials and Methods. In this clinical trial, sixty children with ADHD aged 7 to 10 years old were randomly grouped to receive two different NF treatments (theta suppression/beta enhancement protocol and theta suppression/alpha enhancement protocol). Clinical and cognitive assessments were conducted prior to and following the treatment and also after an eight-week follow-up. Results. Both protocols alleviated the symptoms of ADHD in general (p < 0.001), hyperactivity (p < 0.001), inattention (p < 0.001), and omission errors (p < 0.001); however, they did not affect the oppositional and impulsive scales nor commission errors. These effects were maintained after an eight-week intervention-free period. The only significant difference between the two NF protocols was that high-frequency alpha enhancement protocol performed better in suppressing omission errors (p < 0.001). Conclusion. The two NF protocols with theta suppression/beta enhancement and theta suppression/alpha enhancement have considerable and comparable effect on clinical symptoms of ADHD. Alpha enhancement protocol was more effective in suppressing omission errors. PMID:28321406

  6. Colistin enhances therapeutic efficacy of